**Extrapulmonary Tuberculosis**

**Chapter 7**

Provisional chapter

**Breast and Cervix Uteri: Rare Locations for**

Breast and Cervix Uteri: Rare Locations for

*Mycobacterium Tuberculosis* **Infections and**

Tuberculosis

Manuela Cristina Russu, Şerban Nastasia,

Manuela Cristina Russu, Şerban Nastasia,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75044

Ruxandra Viorica Stănculescu

Mycobacterium

Daniela Degeratu and

Abstract

1. Introduction

Daniela Degeratu and Ruxandra Viorica Stănculescu

**Complications-Cases Report and Literature Review**

DOI: 10.5772/intechopen.75044

Breast and cervix uteri are rare locations for Mycobacterium tuberculosis (MbT) infection and MbT association to cervical cancer is more rare in European countries. This chapter analyses two cases of rare locations of tuberculosis (TB) in young Romanian women. The first patient presented a chronic primary TB breast abscess, non-pregnancy related with periods of apparent healing and repeated areolar fistula formation. In the second case, the unexpected discovery of secondary TB endocervical granulomatous inflammation with caseous necrosis on a radical hysterectomy specimen, performed after chemoradiotherapy for squamous nonkeratinizing cell carcinoma is presented. Worldwide incidence, risk factors, hypothetic mechanisms of primary/secondary breast and cervix uteri MbT infection, the association to highrisk HPV, microbiological diagnosis difficulties, the differentials to pyogenic abscesses, other chronic granulomas and breast cancer treatment issues are presented in the reviewed literature, focusing on the peculiarities of these rare locations and complications. It is recalled an old concept of "therapeutic antitubercular" test when all other assessments steps are usefulness.

Keywords: tuberculosis, breast abscess, cervical caseous granuloma, carcinoma

Tuberculosis (TB) is an old disease, known since 5000BC, and contemporary professional and scientific communities are challenged by the WHO's "Global Tuberculosis Report 2017" showing 6.3 million new cases of TB in 2016, with about 16% expected to die due to TB by 2020.

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Complications-Cases Report and Literature Review

Infections and

#### **Breast and Cervix Uteri: Rare Locations for** *Mycobacterium Tuberculosis* **Infections and Complications-Cases Report and Literature Review** Breast and Cervix Uteri: Rare Locations for Mycobacterium Tuberculosis Infections and Complications-Cases Report and Literature Review

DOI: 10.5772/intechopen.75044

Manuela Cristina Russu, Şerban Nastasia, Daniela Degeratu and Ruxandra Viorica Stănculescu Manuela Cristina Russu, Şerban Nastasia, Daniela Degeratu and Ruxandra Viorica Stănculescu

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75044

#### Abstract

Breast and cervix uteri are rare locations for Mycobacterium tuberculosis (MbT) infection and MbT association to cervical cancer is more rare in European countries. This chapter analyses two cases of rare locations of tuberculosis (TB) in young Romanian women. The first patient presented a chronic primary TB breast abscess, non-pregnancy related with periods of apparent healing and repeated areolar fistula formation. In the second case, the unexpected discovery of secondary TB endocervical granulomatous inflammation with caseous necrosis on a radical hysterectomy specimen, performed after chemoradiotherapy for squamous nonkeratinizing cell carcinoma is presented. Worldwide incidence, risk factors, hypothetic mechanisms of primary/secondary breast and cervix uteri MbT infection, the association to highrisk HPV, microbiological diagnosis difficulties, the differentials to pyogenic abscesses, other chronic granulomas and breast cancer treatment issues are presented in the reviewed literature, focusing on the peculiarities of these rare locations and complications. It is recalled an old concept of "therapeutic antitubercular" test when all other assessments steps are usefulness.

Keywords: tuberculosis, breast abscess, cervical caseous granuloma, carcinoma

#### 1. Introduction

Tuberculosis (TB) is an old disease, known since 5000BC, and contemporary professional and scientific communities are challenged by the WHO's "Global Tuberculosis Report 2017" showing 6.3 million new cases of TB in 2016, with about 16% expected to die due to TB by 2020.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

These data may be connected to the lack of an effective vaccine, and of sensitive and rapid diagnostic tests, to the appearance of multidrug resistant strains of Mycobacterium tuberculosis (MbT) [1, 2]. Low income, immunosuppressive disorders, worldwide travels and immigration are associated to TB globalization [3]. Breast and uterine cervix are rare locations for MbT even in TB endemic countries [1]. This chapter analyses two cases of rare locations of TB in young women from Romania, a middle-income country. The first case is a chronic, non-pregnancyrelated primary breast abscess, with areolar fistula formation between periods of apparent healing. The second case is an association of secondary endocervical tuberculosis to a squamous cervical carcinoma in a young woman with a previous lung tuberculosis, without activation during/after specific cervical cancer therapy. In Europe, there are few papers in the form of case reports on breast or cervix uteri tuberculosis. Breast and cervix uteri tuberculosis are uncommon diseases with non-specific clinical, imagistic and or cytological/histological findings. Misdiagnosis or the diagnosis after many negative assessments for these rare TB locations are common, because biopsy specimens are paucibacillary, and other investigations such as microscopy and culture are frequently negative, as it is the PCR for MbT. MbT can simulate cervical carcinoma in premenopause and postmenopause [4, 5] due to abnormal vaginal bleeding at clinical presentation.

The cytological examination after Giemsa stain from the fistula's purulent discharge shows a rich cellular smear, with many polymorphs background, lymphohistiocytic aggregates and Langhans type multinuclear giant cells, fibrin debris and rare epithelial cells, which conducted

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135

It is decided and incision-excision of the inflammatory mammary gland tissue was performed, with large drainage of the remaining cavity, samples collection for pathology/microbiology

In January 2015, a new fistula occurred on the opposite on the opposite area of the right nipple, with discharge of purulent material, without fever or other general symptoms, as she never

The cultures for aerobic/anaerobic germs and yeasts are sterile, the pathological examination discovers rare epithelial cells of squamous type, lymphocytes, plasma cells, histiocytes, multinuclear giant cells of Langhans type and a multitude of blood vessels. The Ziehl Neelsen stain for acid-fast bacilli and PCR for MbT from sample collected at excision biopsy are

In March 2015, a 6 months antitubercular treatment (ATT) with three drugs was recommended: isoniazid, rifampicin and ethambutol with intensive therapy for the first 3 months is administered. The follow up from May 2015 (after 2 months of intensive therapy) shows remission of the fistulas, heal of the skin, the persistency of the nipple retraction and a

The second case: A 29 years merchandise by occupation, smoker of five cigarettes per day, non-alcoholic, married since 10 years is presenting for repeated postcoital abnormal vaginal bleeding and blood-stained discharge since 6 months. History: physiology: the menarche:

Figure 1. Photograph of the scar from slowly-healing post-incision/excision-drainage wound of the right breast, and the

to the conclusion of a chronic breast inflammatory granuloma.

presented at each previous medical consultations (Figure 1).

The chest X-ray examination is normal and the PPD skin test is 10 mm.

2 kg weight gain. The patient had a total 9 months ATT (Figure 3).

new fistula on the opposite part of the right areola and purulent discharge.

The final diagnosis is primary non-gestational breast tuberculosis abscess.

and no other unwanted events as shock or toxemia.

negative (Figure 2(A, B)).

We intent to review and refresh the theories/hypothesis on the epidemiology, pathophysiology, diagnosis and therapeutic issues on these rare MbT locations and complications. In countries like Romania, where TB is non-endemic and the diagnosis for extra pulmonary tuberculosis is a surprise, the golden standard of microbiological evidence of MbT is rare, even with the new molecular techniques. It is reconsidered the "old concept of the therapeutic test" with antitubercular drugs, which was proved to be active in pulmonary tuberculosis.

#### 2. Cases presentation

First case: A 31 years old Caucasian woman, higher studies and salaried, married, nuligesta, on combined oral contraceptives, no family or personal history of tuberculosis or known exposure to a person with tuberculosis, no mammary surgery, is presenting in December 2014 with nipple retraction and inversion, skin redness and thickening, over a breast inflammatory tumor of 2 x 1 cm size, in the internal upper quadrant of the right breast, freely mobile and a fistula at areola level, with no axillary or cervical lymphadenopathy, and normal left breast. The systemic examination is non-contributory, and no associated constitutional symptoms, as fever, no weight and appetite loss are registered.

The patient had three previous similar episodes, since 2007, with a fistula of the right breast abscess, sterile cultures for aerobic/anaerobic germs, and yeasts in the nipple purulent discharge.

Routine hematological and biochemical investigations, and serum prolactin levels are normal, HIV test is negative. Breast sonography reveals skin thickening, nipple retraction and dilated terminal ducts and ill-defined thick-walled cystic mass of 2.9 cm diameter.

The cytological examination after Giemsa stain from the fistula's purulent discharge shows a rich cellular smear, with many polymorphs background, lymphohistiocytic aggregates and Langhans type multinuclear giant cells, fibrin debris and rare epithelial cells, which conducted to the conclusion of a chronic breast inflammatory granuloma.

It is decided and incision-excision of the inflammatory mammary gland tissue was performed, with large drainage of the remaining cavity, samples collection for pathology/microbiology and no other unwanted events as shock or toxemia.

In January 2015, a new fistula occurred on the opposite on the opposite area of the right nipple, with discharge of purulent material, without fever or other general symptoms, as she never presented at each previous medical consultations (Figure 1).

The cultures for aerobic/anaerobic germs and yeasts are sterile, the pathological examination discovers rare epithelial cells of squamous type, lymphocytes, plasma cells, histiocytes, multinuclear giant cells of Langhans type and a multitude of blood vessels. The Ziehl Neelsen stain for acid-fast bacilli and PCR for MbT from sample collected at excision biopsy are negative (Figure 2(A, B)).

The chest X-ray examination is normal and the PPD skin test is 10 mm.

These data may be connected to the lack of an effective vaccine, and of sensitive and rapid diagnostic tests, to the appearance of multidrug resistant strains of Mycobacterium tuberculosis (MbT) [1, 2]. Low income, immunosuppressive disorders, worldwide travels and immigration are associated to TB globalization [3]. Breast and uterine cervix are rare locations for MbT even in TB endemic countries [1]. This chapter analyses two cases of rare locations of TB in young women from Romania, a middle-income country. The first case is a chronic, non-pregnancyrelated primary breast abscess, with areolar fistula formation between periods of apparent healing. The second case is an association of secondary endocervical tuberculosis to a squamous cervical carcinoma in a young woman with a previous lung tuberculosis, without activation during/after specific cervical cancer therapy. In Europe, there are few papers in the form of case reports on breast or cervix uteri tuberculosis. Breast and cervix uteri tuberculosis are uncommon diseases with non-specific clinical, imagistic and or cytological/histological findings. Misdiagnosis or the diagnosis after many negative assessments for these rare TB locations are common, because biopsy specimens are paucibacillary, and other investigations such as microscopy and culture are frequently negative, as it is the PCR for MbT. MbT can simulate cervical carcinoma in premenopause and postmenopause [4, 5] due to abnormal

We intent to review and refresh the theories/hypothesis on the epidemiology, pathophysiology, diagnosis and therapeutic issues on these rare MbT locations and complications. In countries like Romania, where TB is non-endemic and the diagnosis for extra pulmonary tuberculosis is a surprise, the golden standard of microbiological evidence of MbT is rare, even with the new molecular techniques. It is reconsidered the "old concept of the therapeutic test" with

First case: A 31 years old Caucasian woman, higher studies and salaried, married, nuligesta, on combined oral contraceptives, no family or personal history of tuberculosis or known exposure to a person with tuberculosis, no mammary surgery, is presenting in December 2014 with nipple retraction and inversion, skin redness and thickening, over a breast inflammatory tumor of 2 x 1 cm size, in the internal upper quadrant of the right breast, freely mobile and a fistula at areola level, with no axillary or cervical lymphadenopathy, and normal left breast. The systemic examination is non-contributory, and no associated constitutional symptoms, as

The patient had three previous similar episodes, since 2007, with a fistula of the right breast abscess, sterile cultures for aerobic/anaerobic germs, and yeasts in the nipple purulent dis-

Routine hematological and biochemical investigations, and serum prolactin levels are normal, HIV test is negative. Breast sonography reveals skin thickening, nipple retraction and dilated

terminal ducts and ill-defined thick-walled cystic mass of 2.9 cm diameter.

antitubercular drugs, which was proved to be active in pulmonary tuberculosis.

vaginal bleeding at clinical presentation.

fever, no weight and appetite loss are registered.

2. Cases presentation

charge.

134 Tuberculosis

In March 2015, a 6 months antitubercular treatment (ATT) with three drugs was recommended: isoniazid, rifampicin and ethambutol with intensive therapy for the first 3 months is administered. The follow up from May 2015 (after 2 months of intensive therapy) shows remission of the fistulas, heal of the skin, the persistency of the nipple retraction and a 2 kg weight gain. The patient had a total 9 months ATT (Figure 3).

The final diagnosis is primary non-gestational breast tuberculosis abscess.

The second case: A 29 years merchandise by occupation, smoker of five cigarettes per day, non-alcoholic, married since 10 years is presenting for repeated postcoital abnormal vaginal bleeding and blood-stained discharge since 6 months. History: physiology: the menarche:

Figure 1. Photograph of the scar from slowly-healing post-incision/excision-drainage wound of the right breast, and the new fistula on the opposite part of the right areola and purulent discharge.

Per-rectal examination: smooth rectal mucosa, and freely mobile, no induration or nodularity

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Pap smear: epithelioid-like cell clusters with atypia. Colposcopic examination increased vascularity on the posterior cervical ridge, acetowhite on the anterior cervical ridge, with negative iodine stain with precise contour around the previously described cauliflower-like tumor.

Provisional diagnosis of carcinoma cervix stage I B was kept, and after preliminary investigations, patient was posted for multiple cervical biopsies—the tumor and from other four cardi-

The histopathological diagnosis came out to be squamous non-keratinizing cell carcinoma (Figure 4), and the specific tests for viral infection had revealed the presence of genotype 33 HPV. Hematological test: low degree anemia (Hb: 11.0 mg/dL, Ht; 34%), leukocytosis and

Chest radiography showed fibrous and fibro-nodular sequelae of pulmonary tuberculosis.

lymphnodes shows their reactive aspect, lipo-dystrophy and micro-calcifications.

After 4 weeks of radiotherapy (tele-radiation and 2 cures of brachytherapy) plus chemotherapy (cisplatin), the patient is proposed for surgery, which is accepted and it is done a Wertheim's radical hysterectomy with bilateral pelvic node dissection. The post-surgery pathological examination showed a cervix with large areas of ulceration, polymorph inflammatory infiltrate and multinuclear giant cells of foreign body type, micro-calcifications and small islands of squamous non-keratinizing cancer cells. The endocervix presents a granulomatous inflammation with caseous necrosis and Langhans multinuclear giant cells. The vaginal part and the lateral part of the cervix have no neoplastic invasion. The endometrium is atrophic, the ovaries have albicans bodies, the tubes have hypoplastic mucosa,and the examination of 10

PCR for MbT was performed on archived tissue (formalin-fixed paraffin embedded uterine tissue) following detection of cervical TB by pathology, was positive in the cervix. The patient

Figure 4. Two confluent epithelioid caseous granulomas with Langhans-type gint multinuclear cells and lymphocytic inflammatory infiltrate at the periphery, HE stain, 10 x. Collection of Degeratu Daniela, "Dr I. Cantacuzino" Laboratory of

of both parametrials.

nal points in the vicinity.

Biochemical and coagulation tests: normal.

thrombocytosis.

Pathology.

Figure 2. Pathological images (A. Hematoxylin & Eosin, 40X; B. Hematoxylin & Eosin, 20X): Inflammatory granulomatous lesions: Rich chronic inflammatory infiltrate, with many histiocytes (with epithelioid aspect) and frequent multinuclear giant cells Langhans-type. Collection of Degeratu Daniela, "Dr I. Cantacuzino" Laboratory of Pathology.

Figure 3. Photograph of the right breast after two months of intense active antitubercular treatment. Patient in recumbent position with healed wound, without sinuses of the areola, and inverted nipple.

14 years; 2 full-term spontaneous deliveries; 1 abortion; pathology: pulmonary tuberculosis (treated and considered healed in 2002); no surgical illness. LMP: August 20, 2008, immunological pregnancy and HIV tests: negative. General physical examination was essentially normal; abdominal examination revealed no mass, no ascites, no hepatosplenomegaly and no other abnormality.

Vaginal speculum examination: an irregular, cauliflower-like tumor of 4 cm in the largest size on the anterior cervical ridge, spontaneously bleeding, and on touch; normal vaginal walls and bilateral fornices.

Vaginal bimanual examination: anteverted uterus of normal shape, and volume, firm, mobile and no adnexal mass.

Per-rectal examination: smooth rectal mucosa, and freely mobile, no induration or nodularity of both parametrials.

Pap smear: epithelioid-like cell clusters with atypia. Colposcopic examination increased vascularity on the posterior cervical ridge, acetowhite on the anterior cervical ridge, with negative iodine stain with precise contour around the previously described cauliflower-like tumor.

Provisional diagnosis of carcinoma cervix stage I B was kept, and after preliminary investigations, patient was posted for multiple cervical biopsies—the tumor and from other four cardinal points in the vicinity.

The histopathological diagnosis came out to be squamous non-keratinizing cell carcinoma (Figure 4), and the specific tests for viral infection had revealed the presence of genotype 33 HPV.

Hematological test: low degree anemia (Hb: 11.0 mg/dL, Ht; 34%), leukocytosis and thrombocytosis.

Biochemical and coagulation tests: normal.

14 years; 2 full-term spontaneous deliveries; 1 abortion; pathology: pulmonary tuberculosis (treated and considered healed in 2002); no surgical illness. LMP: August 20, 2008, immunological pregnancy and HIV tests: negative. General physical examination was essentially normal; abdominal examination revealed no mass, no ascites, no hepatosplenomegaly and no

Figure 3. Photograph of the right breast after two months of intense active antitubercular treatment. Patient in recumbent

position with healed wound, without sinuses of the areola, and inverted nipple.

Figure 2. Pathological images (A. Hematoxylin & Eosin, 40X; B. Hematoxylin & Eosin, 20X): Inflammatory granulomatous lesions: Rich chronic inflammatory infiltrate, with many histiocytes (with epithelioid aspect) and frequent multinuclear giant cells Langhans-type. Collection of Degeratu Daniela, "Dr I. Cantacuzino" Laboratory of Pathology.

Vaginal speculum examination: an irregular, cauliflower-like tumor of 4 cm in the largest size on the anterior cervical ridge, spontaneously bleeding, and on touch; normal vaginal walls and

Vaginal bimanual examination: anteverted uterus of normal shape, and volume, firm, mobile

other abnormality.

136 Tuberculosis

bilateral fornices.

and no adnexal mass.

Chest radiography showed fibrous and fibro-nodular sequelae of pulmonary tuberculosis.

After 4 weeks of radiotherapy (tele-radiation and 2 cures of brachytherapy) plus chemotherapy (cisplatin), the patient is proposed for surgery, which is accepted and it is done a Wertheim's radical hysterectomy with bilateral pelvic node dissection. The post-surgery pathological examination showed a cervix with large areas of ulceration, polymorph inflammatory infiltrate and multinuclear giant cells of foreign body type, micro-calcifications and small islands of squamous non-keratinizing cancer cells. The endocervix presents a granulomatous inflammation with caseous necrosis and Langhans multinuclear giant cells. The vaginal part and the lateral part of the cervix have no neoplastic invasion. The endometrium is atrophic, the ovaries have albicans bodies, the tubes have hypoplastic mucosa,and the examination of 10 lymphnodes shows their reactive aspect, lipo-dystrophy and micro-calcifications.

PCR for MbT was performed on archived tissue (formalin-fixed paraffin embedded uterine tissue) following detection of cervical TB by pathology, was positive in the cervix. The patient

Figure 4. Two confluent epithelioid caseous granulomas with Langhans-type gint multinuclear cells and lymphocytic inflammatory infiltrate at the periphery, HE stain, 10 x. Collection of Degeratu Daniela, "Dr I. Cantacuzino" Laboratory of Pathology.

has a normal evolution post-radio, chemotherapy and post-surgery, without any reactivation of the pulmonary tuberculosis.

21–30 years, predominantly, a case being reported during pregnancy [14], and rarely in prepubescent [15] and elderly postmenopausal women [16], the last category being more affected in the early twentieth century, and in the last years it is discovered in women and men [17, 18]. None of the recognized risk factors (multiparity, lactation, trauma, past history of suppurative mastitis, breast surgery/breast reconstruction [19, 20], silicon breast introduction or AIDS [21]

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In developing countries like India, TB is a major socioeconomic burden, afflicting 14 million people mostly in the reproductive age group (15–45 years). Regarding the genital tract, fallopian tubes are involved in almost all the cases of pelvic tuberculosis, endometrium in 50– 60% and ovaries in 20–30% [22]. Cervical tuberculosis accounts for 0.1–0.65% of all cases of the

The breast was considered an organ that offers resistance to the survival and multiplication of the tubercle bacillus [24], like other organs such as spleen, skeletal muscle or cervix uteri, and this property is one of the reasons for the uncommon diagnosis of breast TB, and in countries like India it is supposed that the breast TB is confused to carcinoma [25], or to a pyogenic breast abscess [26], or to other diseases [27], tubercular mastitis being a "great masquerader" [28]. In contrast to this quality, when breast is infected with MbT, it was proved that BRCA 1/2 network is suppressed during infection suggesting that breast cell proliferation suppression is

Breast TB is described to be primary or isolated, and secondary. The primary breast TB is appreciated when the breast infection is the only manifestation of the disease, no demonstrable tuberculous focus exists elsewhere in the body [30], and the infection is through abrasions or through the openings of the ducts in the nipple. Primary breast TB is rare in comparison to secondary to lung or extrapulmonary, and the authors consider that the Romanian case is among primary breast tuberculosis. The secondary type is appreciated when a pre-existing lesion is located elsewhere in the body. Secondary MbT can spread by three routes such as hematogenous, lymphatic or directly from the primary location such as lung, pleura, ribs, mediastinum and articular lesions. It is supposed that the patient had acquired the MbT during a plain long distance travel, some previous years ago, when she claimed the first episode of breast inflammation; extensive travels seem to be responsible for tuberculosis globalization, statement common to others' physicians [3], which is an explanation for a primary men's breast tuberculosis, as it the case of a 44 years old Lithuanian man living in UK [18]. In countries where TB is endemic, young lactating women are more prone to develop breast tuberculosis, being described an incidence that can vary in the limits of 7–33% [31–33]. All

was present in the Romanian reported case.

disease and 5–24% of genital tract [23].

4.1. Pathophysiology of breast tuberculosis

a feature of Koch bacilli survival [29].

4. Pathophysiology

3.2. Epidemiology of cervix uteri tuberculosis

#### 3. Epidemiology: risk factors

#### 3.1. Epidemiology of breast tuberculosis

Breast TB was first described in a very young woman by Sir Astley Cooper in 1829 as "scrofulous swelling of the bosom", and the location of MbT in the cervix uteri was first described 2 years later by Renaud (1831). Extrapulmonary TB was reported in nearly 18% of cases in USA [6], and TB location in the breasts is extremely rare in Western populations from 0.025 to 0.1% of all surgically treated breast diseases. In the last 20 years, the Southern European countries such as Greece, Turkey, Italy and Spain reported rare such cases, and 0.64–3.59% of all mammary treatable conditions are in developing countries from Asia [7], where the overall incidence of histological confirmed breast TB is 0.4% per year [8]. In India, the incidence of breast TB is five times less common than carcinoma of the breast [8]. There are described fluctuations in the incidence of generally breast TB, with the highest incidence in Southern Turkey in 2007 [10], and in the last 8 years (Table 1) the reported cases with primary breast TB have an increasing incidence all over the world, as it is the Romanian case, which had the first episode in 2007. Mammary involvement is nearly equal in frequency in the right and left (40.0 vs. 44.0%) [10], bilateral disease is rare [11, 12], as it is the infra-mammary location of tuberculosis [13]. Breast tuberculosis is affecting women in the reproductive age,


It, Italy; Gr, Greece; T, Turkey; Ch, China; R, Romania; Mo, Morocco; In, India; Tw, Taiwan; Ir, Iran; Br, Brasil; Mx, Mexico; Co, Columbia; US, United States of America.

Table 1. Annual worldwide published cases with primary breast tuberculosis (last 16 years medical literature - Google scholar, Medline, web of science).

21–30 years, predominantly, a case being reported during pregnancy [14], and rarely in prepubescent [15] and elderly postmenopausal women [16], the last category being more affected in the early twentieth century, and in the last years it is discovered in women and men [17, 18]. None of the recognized risk factors (multiparity, lactation, trauma, past history of suppurative mastitis, breast surgery/breast reconstruction [19, 20], silicon breast introduction or AIDS [21] was present in the Romanian reported case.

#### 3.2. Epidemiology of cervix uteri tuberculosis

In developing countries like India, TB is a major socioeconomic burden, afflicting 14 million people mostly in the reproductive age group (15–45 years). Regarding the genital tract, fallopian tubes are involved in almost all the cases of pelvic tuberculosis, endometrium in 50– 60% and ovaries in 20–30% [22]. Cervical tuberculosis accounts for 0.1–0.65% of all cases of the disease and 5–24% of genital tract [23].

#### 4. Pathophysiology

has a normal evolution post-radio, chemotherapy and post-surgery, without any reactivation

Breast TB was first described in a very young woman by Sir Astley Cooper in 1829 as "scrofulous swelling of the bosom", and the location of MbT in the cervix uteri was first described 2 years later by Renaud (1831). Extrapulmonary TB was reported in nearly 18% of cases in USA [6], and TB location in the breasts is extremely rare in Western populations from 0.025 to 0.1% of all surgically treated breast diseases. In the last 20 years, the Southern European countries such as Greece, Turkey, Italy and Spain reported rare such cases, and 0.64–3.59% of all mammary treatable conditions are in developing countries from Asia [7], where the overall incidence of histological confirmed breast TB is 0.4% per year [8]. In India, the incidence of breast TB is five times less common than carcinoma of the breast [8]. There are described fluctuations in the incidence of generally breast TB, with the highest incidence in Southern Turkey in 2007 [10], and in the last 8 years (Table 1) the reported cases with primary breast TB have an increasing incidence all over the world, as it is the Romanian case, which had the first episode in 2007. Mammary involvement is nearly equal in frequency in the right and left (40.0 vs. 44.0%) [10], bilateral disease is rare [11, 12], as it is the infra-mammary location of tuberculosis [13]. Breast tuberculosis is affecting women in the reproductive age,

00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16

0 3 T

> 0 2 In Tw

Br

0 00 0 01

2 In

Co

Mo

Mx

0 00 1

8 In

3 Ir In R

0 0

US

0 000

0 001

000

8 Ir In 0

of the pulmonary tuberculosis.

138 Tuberculosis

3. Epidemiology: risk factors

3.1. Epidemiology of breast tuberculosis

Continent Number of cases since the year 2000 (00)

001

1 Mo

1 In

Br

Mo

Gr

0 1 T

0 0 0 35

North America 0 0 0 0 0 0 0 0 0 0 0 0 1

Br

0 01

1 T

In

1 Ch

0 0000 000 01

0 1 In

00 01

It, Italy; Gr, Greece; T, Turkey; Ch, China; R, Romania; Mo, Morocco; In, India; Tw, Taiwan; Ir, Iran; Br, Brasil; Mx, Mexico;

Table 1. Annual worldwide published cases with primary breast tuberculosis (last 16 years medical literature - Google

0 0 0 0 0 0 38 0 0 0 0 0 0 0 0 0 0

Europe 1

Asia 8

Australia New Zeeland

Africa 0 1

It

In

Co, Columbia; US, United States of America.

South America 0 0 3

scholar, Medline, web of science).

#### 4.1. Pathophysiology of breast tuberculosis

The breast was considered an organ that offers resistance to the survival and multiplication of the tubercle bacillus [24], like other organs such as spleen, skeletal muscle or cervix uteri, and this property is one of the reasons for the uncommon diagnosis of breast TB, and in countries like India it is supposed that the breast TB is confused to carcinoma [25], or to a pyogenic breast abscess [26], or to other diseases [27], tubercular mastitis being a "great masquerader" [28]. In contrast to this quality, when breast is infected with MbT, it was proved that BRCA 1/2 network is suppressed during infection suggesting that breast cell proliferation suppression is a feature of Koch bacilli survival [29].

Breast TB is described to be primary or isolated, and secondary. The primary breast TB is appreciated when the breast infection is the only manifestation of the disease, no demonstrable tuberculous focus exists elsewhere in the body [30], and the infection is through abrasions or through the openings of the ducts in the nipple. Primary breast TB is rare in comparison to secondary to lung or extrapulmonary, and the authors consider that the Romanian case is among primary breast tuberculosis. The secondary type is appreciated when a pre-existing lesion is located elsewhere in the body. Secondary MbT can spread by three routes such as hematogenous, lymphatic or directly from the primary location such as lung, pleura, ribs, mediastinum and articular lesions. It is supposed that the patient had acquired the MbT during a plain long distance travel, some previous years ago, when she claimed the first episode of breast inflammation; extensive travels seem to be responsible for tuberculosis globalization, statement common to others' physicians [3], which is an explanation for a primary men's breast tuberculosis, as it the case of a 44 years old Lithuanian man living in UK [18]. In countries where TB is endemic, young lactating women are more prone to develop breast tuberculosis, being described an incidence that can vary in the limits of 7–33% [31–33]. All types of Mycobacterium spp., and other types of antigens or foreign bodies, as milk during pregnancy or lactational period, are met by a vigorous cell-mediated hypersensitivity reaction involving macrophages, epithelioid and giant cells, Th1 lymphocytes, and their cytokines, which are activated and are developing the granulomas [34].

reaction, or cancer metastases in the endometrium, tubes, ovaries and lymph nodes. Since many years from the first description of the association of these two life-threatening pathologies, host response as the basic mechanism of specific defense against infection and tumor factors that enable such a response are also discussed since long time [39], being not completely known/understood, they may benefit from the host's previously compromised

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The MbT is a facultative intracellular parasite that grows well in non-activated macrophages. When large numbers of these bacilli have grown intracellularly within such macrophages, a cytotoxic immune response, herein called tissue-damaging delayed-type hypersensitivity kills the macrophages, forming the caseous center of the tubercle, where the tubercle is surviving; such a delayed-type hypersensitivity was first described for the pulmonary tuberculosis [40], and this patient have suffered from pulmonary tuberculosis 7 years earlier. The progression of cervical dysplasias to invasive, lethal cervical cancers has been attributed to diverse factors such as immune, hormonal, and nutritional status, or co-infection with other sexually trans-

The contemporary professional societies are sure on primary immune defense system deficiency or incapacities to some infections, bacterial and viral, which were demonstrated in the systemic circulation and in some bodies locations – in the cervix uteri or in the breast. In North America [42], Western Europe [43, 44] and recently in China [45], it was proved the shifted balance between T helper 1 (Th1)-type and Th2-type cytokines in cervical dysplasia [42, 46], the involvement and increase of invariant natural killer T (iNKT) cells (which are in small number in condyloma acuminatum, in mild and moderate dysplasias [47]), and the cytokines production from cervical keratinotytes [48] the main targets of HPV infection as the stratified epithelium cells, and the main source of cytokines [49], as type I interferon (IFN)-γ, tumoral necrosis factor (TNF)-α, transforming growth factor (TGF)-α, interleukin-1 (Il-1), interleukin-6 (Il-6), interleukin 8 (Il-8) expressions are involved in immune system modulation (all of them being parts of innate immune system), in the evolution from persistent high-risk HPV-infected cells to the development of high-grade cervical intraepithelial neoplasia and cervical cancer, because the keratinocytes cannot destroy the fact high-risk HPV, and that may work also on MbT infection evolution, and complications. Parallel to these conditions, it is the individual cellular system of defense [50], involved in early phases of infection [51, 52]. Flow cytometry is revealing an increased level of CD3+ T, CD + 4 cells [53, 54] among both epithelium and stromal layers of the cervical tissues, contributing to the suppression of local immunity. In conjunction to these details is the presence of the population of monocytes/macrophages in the endocervix, with increasing number in cervical high-grade lesions with the parallel decrease in Langerhans cells, in contrary to what occurs in non-infected tissues [55]. All these facts contribute to the escape of HPV to tissue innate and acquired immune system, which is also influenced by the viral epitopes E6 and E7 [56], and evolution from less invasive to more advanced invasive cervical HPV-induced carcinoma is associated to a higher number of T and B lymphocytes, macrophages and induced nitric oxide synthase-expressing cells in the peritumoral stroma, so cell migration being proportional to the progression of the lesion [54]. Some studies show that these high number of inflammatory cells and compounds may open

immunity: MbT and HPV can potentate each other.

mitted agents, supporting data being equivocal [41].

the way to bacterial infections, being additional mediators [57].

In Romania, like in countries with endemic tuberculosis as India, Pakistan, China, Iran and Korea, tubercular infection is seen more frequent secondary to a tubercular focus such as lungs, pleura or lymph nodes, which very frequently actually may not be detected clinical or radiological [26]. The breast infection is acquired usually from lungs by many routes (hematogenous, lymphatic via tracheobronchial, paratracheal, mediastinal lymph trunks or internal mammary nodes), by spread from contiguous structures and by ductal infection [8]. MbT is affecting differently breast structures, according to route of contamination: the epithelium of the ducts (primary) or of the lobules (secondary) with loss of acinar structures; and the entire epithelial lining of the lobules is destroyed, caseating necrosis appearing in the center of the lesion, and the destructive mechanisms are progressing and involving the skin, which may ulcerate and create fistula/sinuses; in other cases, specially in elder women, the mechanisms of repair/restoration are developing excessive dense fibrous tissue.

#### 4.2. Pathophysiology of cervix uteri tuberculosis: Hypothesis on the association to cervical cancer

Pelvic organs are infected from a primary focus, elsewhere in the body, most commonly from lungs, by hematogenous spread. The cervix may be infected, as a part of this process, by lymphatic dissemination from the infected tube, or by direct extension from the endometrium. It is discussed a cervical infection from the sexual partner/partners with tuberculous epididymitis, being discussed the increased risk when there are multiple sexual male partners, especially in China [35]. It is discussed a relative immunity of the cervix to MbT as it was shown previously for other organs, which is probably connected to the inability of the bacillus to penetrate the squamous epithelium of portio vaginalis, and to cervical mucus resistance, but in rare cases, cervical TB may be a primary infection, MbT being introduced by a partner with tuberculous epididymitis or other genitourinary disease [36], but the sexual partner of the reported patient was negative for pulmonary TB. It was suggested the role of the sputum used as a sexual lubricant [22].

In the nineteenth century, it was a controversy as whether tuberculosis and cancer can coexist in the same organ; Carl von Rokitansky (1855) was the first to propose the view that there is a definite antagonism between the two, meaning that tuberculosis and cancer cannot be present in the same organ, but after the influences of Votta J Paul work and through his own further experience, Rokitansky later changed his previous generally accepted view, and admitted that tuberculosis and carcinoma can coexist, but that this coexistence is rather rare. The Romanian report on this pathological association is done for its rarity in Europe, and to the best of authors' knowledge, in the last 45–50 years, two similar cases in Romania (Iaşi) by Luchian et al. [37] and one case in Poland [38] are described. The question is whether tuberculosis is before cancer, or the presence of the viral infection made possible the secondary location of the MbT. The pathological exams of the reported case did not revealed extensive granulomatous reaction, or cancer metastases in the endometrium, tubes, ovaries and lymph nodes. Since many years from the first description of the association of these two life-threatening pathologies, host response as the basic mechanism of specific defense against infection and tumor factors that enable such a response are also discussed since long time [39], being not completely known/understood, they may benefit from the host's previously compromised immunity: MbT and HPV can potentate each other.

types of Mycobacterium spp., and other types of antigens or foreign bodies, as milk during pregnancy or lactational period, are met by a vigorous cell-mediated hypersensitivity reaction involving macrophages, epithelioid and giant cells, Th1 lymphocytes, and their cytokines,

In Romania, like in countries with endemic tuberculosis as India, Pakistan, China, Iran and Korea, tubercular infection is seen more frequent secondary to a tubercular focus such as lungs, pleura or lymph nodes, which very frequently actually may not be detected clinical or radiological [26]. The breast infection is acquired usually from lungs by many routes (hematogenous, lymphatic via tracheobronchial, paratracheal, mediastinal lymph trunks or internal mammary nodes), by spread from contiguous structures and by ductal infection [8]. MbT is affecting differently breast structures, according to route of contamination: the epithelium of the ducts (primary) or of the lobules (secondary) with loss of acinar structures; and the entire epithelial lining of the lobules is destroyed, caseating necrosis appearing in the center of the lesion, and the destructive mechanisms are progressing and involving the skin, which may ulcerate and create fistula/sinuses; in other cases, specially in elder women, the mechanisms of

4.2. Pathophysiology of cervix uteri tuberculosis: Hypothesis on the association to cervical

Pelvic organs are infected from a primary focus, elsewhere in the body, most commonly from lungs, by hematogenous spread. The cervix may be infected, as a part of this process, by lymphatic dissemination from the infected tube, or by direct extension from the endometrium. It is discussed a cervical infection from the sexual partner/partners with tuberculous epididymitis, being discussed the increased risk when there are multiple sexual male partners, especially in China [35]. It is discussed a relative immunity of the cervix to MbT as it was shown previously for other organs, which is probably connected to the inability of the bacillus to penetrate the squamous epithelium of portio vaginalis, and to cervical mucus resistance, but in rare cases, cervical TB may be a primary infection, MbT being introduced by a partner with tuberculous epididymitis or other genitourinary disease [36], but the sexual partner of the reported patient was negative for pulmonary TB. It was suggested the role of the sputum used

In the nineteenth century, it was a controversy as whether tuberculosis and cancer can coexist in the same organ; Carl von Rokitansky (1855) was the first to propose the view that there is a definite antagonism between the two, meaning that tuberculosis and cancer cannot be present in the same organ, but after the influences of Votta J Paul work and through his own further experience, Rokitansky later changed his previous generally accepted view, and admitted that tuberculosis and carcinoma can coexist, but that this coexistence is rather rare. The Romanian report on this pathological association is done for its rarity in Europe, and to the best of authors' knowledge, in the last 45–50 years, two similar cases in Romania (Iaşi) by Luchian et al. [37] and one case in Poland [38] are described. The question is whether tuberculosis is before cancer, or the presence of the viral infection made possible the secondary location of the MbT. The pathological exams of the reported case did not revealed extensive granulomatous

which are activated and are developing the granulomas [34].

repair/restoration are developing excessive dense fibrous tissue.

cancer

140 Tuberculosis

as a sexual lubricant [22].

The MbT is a facultative intracellular parasite that grows well in non-activated macrophages. When large numbers of these bacilli have grown intracellularly within such macrophages, a cytotoxic immune response, herein called tissue-damaging delayed-type hypersensitivity kills the macrophages, forming the caseous center of the tubercle, where the tubercle is surviving; such a delayed-type hypersensitivity was first described for the pulmonary tuberculosis [40], and this patient have suffered from pulmonary tuberculosis 7 years earlier. The progression of cervical dysplasias to invasive, lethal cervical cancers has been attributed to diverse factors such as immune, hormonal, and nutritional status, or co-infection with other sexually transmitted agents, supporting data being equivocal [41].

The contemporary professional societies are sure on primary immune defense system deficiency or incapacities to some infections, bacterial and viral, which were demonstrated in the systemic circulation and in some bodies locations – in the cervix uteri or in the breast. In North America [42], Western Europe [43, 44] and recently in China [45], it was proved the shifted balance between T helper 1 (Th1)-type and Th2-type cytokines in cervical dysplasia [42, 46], the involvement and increase of invariant natural killer T (iNKT) cells (which are in small number in condyloma acuminatum, in mild and moderate dysplasias [47]), and the cytokines production from cervical keratinotytes [48] the main targets of HPV infection as the stratified epithelium cells, and the main source of cytokines [49], as type I interferon (IFN)-γ, tumoral necrosis factor (TNF)-α, transforming growth factor (TGF)-α, interleukin-1 (Il-1), interleukin-6 (Il-6), interleukin 8 (Il-8) expressions are involved in immune system modulation (all of them being parts of innate immune system), in the evolution from persistent high-risk HPV-infected cells to the development of high-grade cervical intraepithelial neoplasia and cervical cancer, because the keratinocytes cannot destroy the fact high-risk HPV, and that may work also on MbT infection evolution, and complications. Parallel to these conditions, it is the individual cellular system of defense [50], involved in early phases of infection [51, 52]. Flow cytometry is revealing an increased level of CD3+ T, CD + 4 cells [53, 54] among both epithelium and stromal layers of the cervical tissues, contributing to the suppression of local immunity. In conjunction to these details is the presence of the population of monocytes/macrophages in the endocervix, with increasing number in cervical high-grade lesions with the parallel decrease in Langerhans cells, in contrary to what occurs in non-infected tissues [55]. All these facts contribute to the escape of HPV to tissue innate and acquired immune system, which is also influenced by the viral epitopes E6 and E7 [56], and evolution from less invasive to more advanced invasive cervical HPV-induced carcinoma is associated to a higher number of T and B lymphocytes, macrophages and induced nitric oxide synthase-expressing cells in the peritumoral stroma, so cell migration being proportional to the progression of the lesion [54]. Some studies show that these high number of inflammatory cells and compounds may open the way to bacterial infections, being additional mediators [57].

Insertional mutagenesis by HPV is another proposed tumor-promoting mechanism, but recent studies have not supported this hypothesis [58]. No common, recurring genetic alterations that cooperate with HPV to promote cervical cancer progression have been identified since Harald Zur Hausen first identified HPV as the causal transmissible agent of cervical cancer nearly 40 years ago [59]. To the pressing question to the biological basis of cervical cancer progression which is to be resolved since long time, the discover of the loss of a major tumor supressor LkB1 [60, 61] or somatically acquired mutations in this tumor supressor LKB1 [62], which is considered to be similar to p53. When LKB1 deficiency/mutations, a primary cervical tumor confined to the cervix at the time of diagnosis has a bad prognosis: early metastasis and patient death, after the initial diagnosis despite aggressive therapy including radiation treatment. These abnormalities were first discovered in connection to Peutz-Jeghers Syndrome [63] and pulmonary cancer [64]. The MbT was proved to reduce host's immunity to high-risk HPV types for cervical cancer. The Chinese study "Shanxi Province Cervical Cancer Screening Study I" [36] showed an increasing magnitude of effect of MbT with increasing severity of disease in an isolated women population from rural China, as is demonstrated by the increasing odds ratios from 1.68 for HPV positivity to 1.75 for persistent HPV and then 2.08 for CIN3+. Associated to these findings, it was showed that TB and cervical inflammation were diagnosed in 1% of the women, and associated with 90% higher odds of oncogenic HPV infection and 113% higher odds of persistent HPV infection. The authors of the "Shanxi Province Cervical Cancer Screening Study I" are considering that their results are consistent with the novel hypothesis that TB may provide an immunological profile that is associated with an increased susceptibility to HPV infection. In conjunction to this hypothesis, we can speculate like that MbT is associated to the loss/mutations in LKB1 tumor suppressor, because persistence of small islands of squamous non-keratinizing cancer cells after radiation and chemotherapies.

multiples; skin thickening; and skin sinus/fistula/multiple discharge sinuses [70], nipple retraction or inversion, nipple hyperpigmentation or focal discoloration –when the disease is long time duration [69], breast shape and sizes change, axillary lymphadenopathy (axillary lymph nodes are found in one-third of cases with breast TB [33]. Constitutional symptoms as fever, weight loss, night sweats or a failing of general health are infrequently encountered [71, 72].

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Irregular vaginal and postcoital bleeding with different aspects could occur at the cervix speculum examination such as exophytic-cauliflower aspect, tumoral-granulomatous, ulcerative and polypoid endocervical [73]. In many countries, even where tuberculosis is endemic, the majority of cases remain asymptomatic, but infected, and are discovered incidentally or remain undiscovered [22, 74]. Cervical examination of cases with cervical tuberculosis is normal in 90% cases, and the rest presents non-specific macroscopic changes, ulcerative/hypertrophic nodular lesions like proliferative cauliflower growth or fistulas/sinuses, or friable papillary growth covering almost the entire ectocervix. All these aspects may simulate invasive cervical cancer, or a miliary appearance [75–77]. There are reported cases with entire genital tract involvement, with myometrial alterations [78, 79], and association with tubercu-

Current hematological and biochemical analysis are minimally influenced in cases with these

The golden standard for TB diagnosis is to detect acid-fast bacilli (AFB) in the infected tissue, but it is well known how difficult is the Ziehl-Neelsen stain or the cultures for BK to become positive [67, 72, 81], because the necessity of a high number MbT in the smear (more than 10,000 bacilli/mL), and the slow growth of all mycobacterial species, including MbT, fact that partially explains the delay of TB diagnosis. It was recommended scanning with high-power oil immersion because these diagnosis difficulties, but the practice proved that scanning with a X 40 objective should suffice in most cases. There were proposed alternative stains to the conventional Ziehl-Neelsen stain, such as auramine/auramine-rhodamine using fluorescence technique [82], which in association to a higher power examination (x 600) may have better

It is known that biopsy specimens that are cultured on Löwenstein-Jensen medium at room temperature yield pigmented mycobacterial colonies in 2–4 weeks. In the literature of bacteriology, it is very important the place for sampling, and leveling that may affect the sensitivity of a stain in the detection of rare organisms as Mycobacterium spp. or fungi. On the other side, for a better discovery for MbT, it is recommended to examine at least two blocks of biopsy instead of one [84]. In India, it is reported that are possible positive cultures of nipple discharge for

MbT locations. It is cited a high level of white blood cells, and of ESV [77].

Staphylococcus aureus associated with positivity for MbT [85].

5.1.2. Clinical diagnosis of cervix uteri tuberculosis

losis of vulva and vagina [80].

5.2. Laboratory assessment

5.2.1. Bacteriological diagnosis

detection for MbT [83].

#### 5. Diagnosis

Regarding the diagnosis, one must consider the clinical presentation, physical examination, laboratory results, specially the microbiological ones and imagistic tools, and after the difficulties of the Romanian first published case of breast tubercular abscess on must reconsider an old concept of diagnosis—the "therapeutic" test.

#### 5.1. Clinical presentation: physical examinations

#### 5.1.1. Clinical presentation of breast TB

Clinical presentation of breast TB is variable regarding symptoms/signs: swelling of the breast 48.1% [65]; painless hard lump in approximately 60% cases [66], or pain is revealed as the first complain of some patients [67, 68] or up to 18.5% of cases [65]; rarely are recorded multiple lumps, the lump being with irregular borders, sometimes with skin fixation or to the underlying muscle or even chest wall, clinical findings imposing differential to breast carcinoma [69], situation which is much more suggested by the presence of an isolated breast mass, sometimes skin fixated "peau d'orange" sign, and without an associated sinus tract; abscess, unique or multiples; skin thickening; and skin sinus/fistula/multiple discharge sinuses [70], nipple retraction or inversion, nipple hyperpigmentation or focal discoloration –when the disease is long time duration [69], breast shape and sizes change, axillary lymphadenopathy (axillary lymph nodes are found in one-third of cases with breast TB [33]. Constitutional symptoms as fever, weight loss, night sweats or a failing of general health are infrequently encountered [71, 72].

#### 5.1.2. Clinical diagnosis of cervix uteri tuberculosis

Irregular vaginal and postcoital bleeding with different aspects could occur at the cervix speculum examination such as exophytic-cauliflower aspect, tumoral-granulomatous, ulcerative and polypoid endocervical [73]. In many countries, even where tuberculosis is endemic, the majority of cases remain asymptomatic, but infected, and are discovered incidentally or remain undiscovered [22, 74]. Cervical examination of cases with cervical tuberculosis is normal in 90% cases, and the rest presents non-specific macroscopic changes, ulcerative/hypertrophic nodular lesions like proliferative cauliflower growth or fistulas/sinuses, or friable papillary growth covering almost the entire ectocervix. All these aspects may simulate invasive cervical cancer, or a miliary appearance [75–77]. There are reported cases with entire genital tract involvement, with myometrial alterations [78, 79], and association with tuberculosis of vulva and vagina [80].

#### 5.2. Laboratory assessment

Insertional mutagenesis by HPV is another proposed tumor-promoting mechanism, but recent studies have not supported this hypothesis [58]. No common, recurring genetic alterations that cooperate with HPV to promote cervical cancer progression have been identified since Harald Zur Hausen first identified HPV as the causal transmissible agent of cervical cancer nearly 40 years ago [59]. To the pressing question to the biological basis of cervical cancer progression which is to be resolved since long time, the discover of the loss of a major tumor supressor LkB1 [60, 61] or somatically acquired mutations in this tumor supressor LKB1 [62], which is considered to be similar to p53. When LKB1 deficiency/mutations, a primary cervical tumor confined to the cervix at the time of diagnosis has a bad prognosis: early metastasis and patient death, after the initial diagnosis despite aggressive therapy including radiation treatment. These abnormalities were first discovered in connection to Peutz-Jeghers Syndrome [63] and pulmonary cancer [64]. The MbT was proved to reduce host's immunity to high-risk HPV types for cervical cancer. The Chinese study "Shanxi Province Cervical Cancer Screening Study I" [36] showed an increasing magnitude of effect of MbT with increasing severity of disease in an isolated women population from rural China, as is demonstrated by the increasing odds ratios from 1.68 for HPV positivity to 1.75 for persistent HPV and then 2.08 for CIN3+. Associated to these findings, it was showed that TB and cervical inflammation were diagnosed in 1% of the women, and associated with 90% higher odds of oncogenic HPV infection and 113% higher odds of persistent HPV infection. The authors of the "Shanxi Province Cervical Cancer Screening Study I" are considering that their results are consistent with the novel hypothesis that TB may provide an immunological profile that is associated with an increased susceptibility to HPV infection. In conjunction to this hypothesis, we can speculate like that MbT is associated to the loss/mutations in LKB1 tumor suppressor, because persistence of small

islands of squamous non-keratinizing cancer cells after radiation and chemotherapies.

Regarding the diagnosis, one must consider the clinical presentation, physical examination, laboratory results, specially the microbiological ones and imagistic tools, and after the difficulties of the Romanian first published case of breast tubercular abscess on must reconsider an old

Clinical presentation of breast TB is variable regarding symptoms/signs: swelling of the breast 48.1% [65]; painless hard lump in approximately 60% cases [66], or pain is revealed as the first complain of some patients [67, 68] or up to 18.5% of cases [65]; rarely are recorded multiple lumps, the lump being with irregular borders, sometimes with skin fixation or to the underlying muscle or even chest wall, clinical findings imposing differential to breast carcinoma [69], situation which is much more suggested by the presence of an isolated breast mass, sometimes skin fixated "peau d'orange" sign, and without an associated sinus tract; abscess, unique or

5. Diagnosis

142 Tuberculosis

concept of diagnosis—the "therapeutic" test.

5.1.1. Clinical presentation of breast TB

5.1. Clinical presentation: physical examinations

Current hematological and biochemical analysis are minimally influenced in cases with these MbT locations. It is cited a high level of white blood cells, and of ESV [77].

#### 5.2.1. Bacteriological diagnosis

The golden standard for TB diagnosis is to detect acid-fast bacilli (AFB) in the infected tissue, but it is well known how difficult is the Ziehl-Neelsen stain or the cultures for BK to become positive [67, 72, 81], because the necessity of a high number MbT in the smear (more than 10,000 bacilli/mL), and the slow growth of all mycobacterial species, including MbT, fact that partially explains the delay of TB diagnosis. It was recommended scanning with high-power oil immersion because these diagnosis difficulties, but the practice proved that scanning with a X 40 objective should suffice in most cases. There were proposed alternative stains to the conventional Ziehl-Neelsen stain, such as auramine/auramine-rhodamine using fluorescence technique [82], which in association to a higher power examination (x 600) may have better detection for MbT [83].

It is known that biopsy specimens that are cultured on Löwenstein-Jensen medium at room temperature yield pigmented mycobacterial colonies in 2–4 weeks. In the literature of bacteriology, it is very important the place for sampling, and leveling that may affect the sensitivity of a stain in the detection of rare organisms as Mycobacterium spp. or fungi. On the other side, for a better discovery for MbT, it is recommended to examine at least two blocks of biopsy instead of one [84]. In India, it is reported that are possible positive cultures of nipple discharge for Staphylococcus aureus associated with positivity for MbT [85].

Actually many infections are detected by immunological assays proving the host competence, but for TB this aim is still a future desire; a very recently study of North American Universities' Microbiology and Pathology Laboratories [86] have confirmed the limitations of serodiagnosis for active tuberculosis, including poor sensitivity and increased reactivity with non-tuberculous mycobacterium-positive patients.

[97]. In the Romanian case, MbT presence in the endocervix was confirmed by PCR for MbT

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Actually fine needle aspiration cytology (FNAC) is considered a minimally invasive diagnosis method for breast pathology [98], including TB, because is revealing chronic granulomatous inflammation with caseating necrosis, presence of Langhans giant cell, and lymphocytic aggregates [99–101], but some studies are showing that in one quarter of cases FNAC is negative for breast tuberculosis diagnosis [71], because tissue samples collected at FNAC are not usually adequate for evaluation, or because caseating necrosis can be absent on the specimen. The absence of necrosis on breast specimen from FNAC does not exclude tuberculosis, which is sustained by other histological abnormalities [102]. In these situations, the next step for the diagnosis of mammary TB is the pathologic evaluation of specimens collected at open surgical biopsy [71], as it was done in the Romanian case, after the evaluation of the smear from fistula

The Pap smear, a non-invasive procedure, may help in the diagnosis by the discover of epithelioid and multinucleated histiocytic cells, described since many years ago and rediscuss actually [103–105], fact that prompts further investigation. The epithelioid cells are elongated cells with pale eosinophilic cytoplasm, indistinct cell borders having large oval/elongated nuclei with a delicate chromatin pattern in singles/clusters. Multinucleated histiocytic cells, typical of Langhan's cells type, have large number of delicate, often ovoid nuclei, some overlapping, arranged peripherally and often in horseshoe fashion. The presence of those multinucleated histiocytic giant cells may help to differentials to herpes virus infection—the cells have epithelial origin, but lower number of nuclei, and show characteristic crowding/ molding without overlapping with eosinophilic inclusion in nuclei and cytoplasm, and also in post radiotherapy of postmenopausal women smears, where the cells have bad outline, and may contain some phagocytosed debris with radiation-induced changes [104]. In countries with endemic tuberculosis, it is appreciated that the Papanicolaou smear is helping very much the staff, the Ziehl-Neelsen stain of cervical smear, and fluorescent technique and culture are confirming later [105]. The Romanian woman was not postmenopausal, a viral infection with high-risk HPV was clearly demonstrated, by genotyping of the cervix after surgery, but these

There are known two pathological classifications of breast tuberculosis: an old one—McKeown and Wilkinson [106] cited by Bahoroon [107], and a recent one—Tewari and Shukla [7].

performed on archived tissue (formalin-fixed paraffin-embedded uterine tissue).

5.3. Cytological diagnosis

discharge.

5.3.1. Cytological diagnosis of breast tuberculosis

5.3.2. Cytological diagnosis of cervix uteri tuberculosis

type of cells were absent in the smear.

5.4. Pathological diagnosis of MbT infection

5.4.1. Pathological diagnosis in breast MbT infection

#### 5.2.1.1. Bacteriological diagnosis of breast tuberculosis

The molecular diagnosis from clinical specimens is the aim of modern diagnosis of MbT, since many years, and this may be accomplished by nuclear acid amplification (NAA). The used methods allow the detection of mycobacterial DNA or RNA directly from the specimens, before the culture results are available [87]. Food and Drug Administration had accepted since the year 2000, two types of NAA, which were initially used for pulmonary tuberculosis, and later in extrapulmonary cases. The NAA is usually recommended when the smear evaluation is negative for AFB, and when clinical suspicion is very high, or when TB is endemic, but there are controversies on the specificity, sensitivity of the methods regarding the origin of specimen from respiratory tract or other sites [88]. The recommended tests are the enhanced MbT Direct Test (E-MTD; Gen-Probe, San Diego, CA) and Amplicor MbT Test (Amplicor; Roche Diagnostic Systems, Inc., Branchburg, NJ), and associated to these tests there were many studies about each value, specially for differential to granulomatous mastitis [12, 83, 89] or for the value of polymerase chain reaction (PCR) for real time MbT to compare to formalin-fixed, paraffinembedded histologic specimens [90].

The real-time PCR for MbT on paraffin-embedded tissue is available with a high specificity of 99%, but low sensitivity of 65% for breast tissue in contrast to other types of specimens such as cerebral spinal fluid, urine and bronchoalveolar lavage, where sensitivity of more than 90% is reported, with comparable specificity [91, 92].

In the Romanian case, the molecular test—PCR for MbT on paraffin-embedded breast tissue was negative, and there are some researches [83, 93, 94] sustaining that molecular tests are not always relevant for the diagnosis of TB in smear-negative specimens. It is appreciated that realtime PCR for MbT is useful if positive, and confirms the presence of MbT, but if negative does not rule out the possibility of an infection [83]. Breast TB is paucibacillary and consequently tests such as microscopy, culture and NAA tests such as PCR techniques do not have the same diagnostic utility as they do in pulmonary tuberculosis [95]. There are some explanations for the negativity of the described tests for BK identification. One old explanation [84] is that the microorganisms have been killed and/or removed by the inflammatory process. Other explanation for PCR negativity is the existence of non-tuberculous infections such as Corynebacterium spp. [96], or non-tuberculous mycobacterium, which are now more common than tuberculosis in Western countries, and therefore would not be detected by this assay.

#### 5.2.1.2. Bacteriological diagnosis in cervical tuberculosis

The demonstration of the presence of MbT in the cervix uteri with the Ziehl-Neelsen staining was proved to be difficult in many reported cases all over the world, even in India and China [97]. In the Romanian case, MbT presence in the endocervix was confirmed by PCR for MbT performed on archived tissue (formalin-fixed paraffin-embedded uterine tissue).

#### 5.3. Cytological diagnosis

Actually many infections are detected by immunological assays proving the host competence, but for TB this aim is still a future desire; a very recently study of North American Universities' Microbiology and Pathology Laboratories [86] have confirmed the limitations of serodiagnosis for active tuberculosis, including poor sensitivity and increased reactivity with non-tuberculous

The molecular diagnosis from clinical specimens is the aim of modern diagnosis of MbT, since many years, and this may be accomplished by nuclear acid amplification (NAA). The used methods allow the detection of mycobacterial DNA or RNA directly from the specimens, before the culture results are available [87]. Food and Drug Administration had accepted since the year 2000, two types of NAA, which were initially used for pulmonary tuberculosis, and later in extrapulmonary cases. The NAA is usually recommended when the smear evaluation is negative for AFB, and when clinical suspicion is very high, or when TB is endemic, but there are controversies on the specificity, sensitivity of the methods regarding the origin of specimen from respiratory tract or other sites [88]. The recommended tests are the enhanced MbT Direct Test (E-MTD; Gen-Probe, San Diego, CA) and Amplicor MbT Test (Amplicor; Roche Diagnostic Systems, Inc., Branchburg, NJ), and associated to these tests there were many studies about each value, specially for differential to granulomatous mastitis [12, 83, 89] or for the value of polymerase chain reaction (PCR) for real time MbT to compare to formalin-fixed, paraffin-

The real-time PCR for MbT on paraffin-embedded tissue is available with a high specificity of 99%, but low sensitivity of 65% for breast tissue in contrast to other types of specimens such as cerebral spinal fluid, urine and bronchoalveolar lavage, where sensitivity of more than 90% is

In the Romanian case, the molecular test—PCR for MbT on paraffin-embedded breast tissue was negative, and there are some researches [83, 93, 94] sustaining that molecular tests are not always relevant for the diagnosis of TB in smear-negative specimens. It is appreciated that realtime PCR for MbT is useful if positive, and confirms the presence of MbT, but if negative does not rule out the possibility of an infection [83]. Breast TB is paucibacillary and consequently tests such as microscopy, culture and NAA tests such as PCR techniques do not have the same diagnostic utility as they do in pulmonary tuberculosis [95]. There are some explanations for the negativity of the described tests for BK identification. One old explanation [84] is that the microorganisms have been killed and/or removed by the inflammatory process. Other explanation for PCR negativity is the existence of non-tuberculous infections such as Corynebacterium spp. [96], or non-tuberculous mycobacterium, which are now more common than tuberculosis in

The demonstration of the presence of MbT in the cervix uteri with the Ziehl-Neelsen staining was proved to be difficult in many reported cases all over the world, even in India and China

Western countries, and therefore would not be detected by this assay.

5.2.1.2. Bacteriological diagnosis in cervical tuberculosis

mycobacterium-positive patients.

144 Tuberculosis

embedded histologic specimens [90].

reported, with comparable specificity [91, 92].

5.2.1.1. Bacteriological diagnosis of breast tuberculosis

#### 5.3.1. Cytological diagnosis of breast tuberculosis

Actually fine needle aspiration cytology (FNAC) is considered a minimally invasive diagnosis method for breast pathology [98], including TB, because is revealing chronic granulomatous inflammation with caseating necrosis, presence of Langhans giant cell, and lymphocytic aggregates [99–101], but some studies are showing that in one quarter of cases FNAC is negative for breast tuberculosis diagnosis [71], because tissue samples collected at FNAC are not usually adequate for evaluation, or because caseating necrosis can be absent on the specimen. The absence of necrosis on breast specimen from FNAC does not exclude tuberculosis, which is sustained by other histological abnormalities [102]. In these situations, the next step for the diagnosis of mammary TB is the pathologic evaluation of specimens collected at open surgical biopsy [71], as it was done in the Romanian case, after the evaluation of the smear from fistula discharge.

#### 5.3.2. Cytological diagnosis of cervix uteri tuberculosis

The Pap smear, a non-invasive procedure, may help in the diagnosis by the discover of epithelioid and multinucleated histiocytic cells, described since many years ago and rediscuss actually [103–105], fact that prompts further investigation. The epithelioid cells are elongated cells with pale eosinophilic cytoplasm, indistinct cell borders having large oval/elongated nuclei with a delicate chromatin pattern in singles/clusters. Multinucleated histiocytic cells, typical of Langhan's cells type, have large number of delicate, often ovoid nuclei, some overlapping, arranged peripherally and often in horseshoe fashion. The presence of those multinucleated histiocytic giant cells may help to differentials to herpes virus infection—the cells have epithelial origin, but lower number of nuclei, and show characteristic crowding/ molding without overlapping with eosinophilic inclusion in nuclei and cytoplasm, and also in post radiotherapy of postmenopausal women smears, where the cells have bad outline, and may contain some phagocytosed debris with radiation-induced changes [104]. In countries with endemic tuberculosis, it is appreciated that the Papanicolaou smear is helping very much the staff, the Ziehl-Neelsen stain of cervical smear, and fluorescent technique and culture are confirming later [105]. The Romanian woman was not postmenopausal, a viral infection with high-risk HPV was clearly demonstrated, by genotyping of the cervix after surgery, but these type of cells were absent in the smear.

#### 5.4. Pathological diagnosis of MbT infection

#### 5.4.1. Pathological diagnosis in breast MbT infection

There are known two pathological classifications of breast tuberculosis: an old one—McKeown and Wilkinson [106] cited by Bahoroon [107], and a recent one—Tewari and Shukla [7].

McKeown and Wilkinson [106] had classified breast tuberculosis into five pathological varieties: (1) nodular—the most common variety presenting as a localized mass, with extensive caseation, and little fibrosis; (2) diffuse or disseminated—second most common variety, involving the entire breast with multiple intercommunicating foci of tubercles within the breast, which caseate leading to ulceration and discharging sinuses; (3) sclerosing—extensive fibrosis rather than caseation is present, suppuration is rare, the entire breast is hard, the nipple is retracted/inverted, category which is often mistaken for breast carcinoma; (4) tuberculous mastitis obliterans, characterized by duct infection producing proliferation of the lining epithelium, and marked epithelial and periductal fibrosis; and occlusion of the ducts, with appearance of cystic spaces, and all these resemble "cystic mastitis" and (5) acute miliary tuberculous mastitis, which occurs as a part of generalized miliary tuberculosis. The last two entities have only historical importance, being rarely described in the recent medical literature.

associated to caseating necrosis which makes the name of "caseating granulomas", and the difference from "idiopathic "granulomatous mastitis [107, 116], which was named "lobular non caseous granuloma" (Table 2). The isolation of MbT in the central necrosis increases the

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There are mentioned some other types of "necrositing granulomas" in which infectionsinflammation are frequently associated, and are proved with special stains (as Ziehl-Neelsen or Grocott Methamine Silver), and/or by cultures, and other granulomas with infectioninflammatory aspect, but without associated infections as eosinophylic necrosis or basophilic necrosis [83], as is Wegener's granulomatosis, and less commonly rheumatoid nodule, necrotizing sarcoid granulomatosis, infarct and lymphomatoid granulomatosis [83]. The granulomas with eosinophilic necrosis have regular rounded contour, the rim being formed of epithelioid histiocytes with multinucleated giant cells, and the center may have coagulative type of necrosis, which is like an infarct. The Wegener's granulomatosis is characterized by 'dirty' basophilic necrosis with irregular geographic necrosis; the necrosis is rimmed by palisading histiocytes and scattered multinucleated giant cells, with hyperchromatic nuclei and peripheral to the necrosis is the necrotizing vasculitis in vessels. The vessels display transmural fibrinoid necrosis, and the necrosis of the media with admixed necrotic neutrophils, which contributes to the diagnosis with true necrotizing vasculitis. The granuloma of the Romanian case has multiple normal vessels. The parenchymal necrosis of the necrotizing

Characteristic "Idiopathic" granulomatous mastitis Tubercular mastitis

Abscess Common Uncommon

Epithelioid histiocytes, Langhans giant cells, lymphocytes, plasma cells, and occasionally

(modified from Akcan et al. [114]; Baslaim et al. [115]; Bahoroon [107]; Lacambra et al. [109]).

Foamy cells Absent Present Caseating necrosis Absent Present Fibrosis Present Present Fat necrosis Present Present

Structure affected Mammary lobules from one breast, rarely bilateral

eosinophils

Common Common

Absent Present

Absent Present

Type of lesion Granulomas of the lobules Granulomas of all mammary structures

Table 2. Macroscopic and microscopic characteristics of "idiopathic" granulomatous mastitis and tubercular mastitis

All mammary structures: ducts, lobules, fat,

Epithelioid histiocytes, Langhans giant cells, lymphocytes, rare plasma cells, and

commonly bilateral

eosinophils

sensitivity of the diagnosis.

Macroscopic characteristic Isolated or multiple breast masses

Multiple sinuses or

Focal discoloration of

Microscopic characteristic

components of breast's

fistulas

areola

Histological

granulomas

The Indian pathologists [108] have introduced a new pathological classification of breast tuberculosis, with three categories: (1) nodulo-caseous tubercular mastitis; (2) disseminated/ confluent tubercular mastitis and (3) tubercular breast abscess.

There are some controversial discussions about the "granulomatous mastitis", diagnosed during childbearing period, usually in parous women, in early 1930s, which are frequently misdiagnosed as tuberculosis or carcinoma [108], with negative culture for MbT, and with cytological and immunocytochemical findings definitely for differential diagnosis from breast tuberculosis at fine needle aspiration cytology [109] or at open surgery. The pathological changes induced by MbT in breast make the differences to other breast pathology, "idiopathic granulomatous mastitis", which is also a "masquerader" [25, 28]. Tuberculous mastitis is often considered a form of "granulomatous mastitis" secondary to breast MbT infection, and some authors reserve the term of "granulomatous mastitis" to "idiopathic granulomatous mastitis", a chronic breast inflammatory entity [110]. Granuloma is a defense mechanism against antigens, which stay in many organs without inactivation. The granulomatous lesions are classified into infectious, vasculitis, immunological, chemicals and neoplasia [35], or the recent classification is more simple: infectious and non-infectious granulomas, with the prove from new studies that pathogenic microorganism are suspected to be a cause of granuloma in noninflammatory diseases [111].

The etiology of "granulomatous mastitis" is unclear, being postulated, and sometimes proved, the autoimmune factors [112], sarcoidosis, fat necrosis, undetected organisms (as blastomycosis, actinomycosis, cryptococcosis, histoplasmosis, filarial infection and corynebacterium), Wegener's granulomatosis, reaction to childbirth, and use of oral contraceptives, ductular ectasis [113] the last two factors are present in the reported case. "Granulomatous mastitis" was the first diagnosis in authors' mind at the beginning of investigations, and this is partially an explanation of the delay in diagnosis, and late specific antitubercular treatment, as in other cases from literature in the last years [12]. These breast pathologies – tuberculosis and "idiopathic" granulomatous mastitis are considered "masquerader" [28] or "imitator" [89].

There are described some pathological characteristics [107, 114, 115], which make the differentiation between the "idiopathic "granulomatous mastitis"—first described by Kessler and Wolloc [113], and breast TB. TB is affecting all breast structures (lobules, ducts, fat; some pathologists consider that ducts are specially affected), and the tubercular granulomas are associated to caseating necrosis which makes the name of "caseating granulomas", and the difference from "idiopathic "granulomatous mastitis [107, 116], which was named "lobular non caseous granuloma" (Table 2). The isolation of MbT in the central necrosis increases the sensitivity of the diagnosis.

McKeown and Wilkinson [106] had classified breast tuberculosis into five pathological varieties: (1) nodular—the most common variety presenting as a localized mass, with extensive caseation, and little fibrosis; (2) diffuse or disseminated—second most common variety, involving the entire breast with multiple intercommunicating foci of tubercles within the breast, which caseate leading to ulceration and discharging sinuses; (3) sclerosing—extensive fibrosis rather than caseation is present, suppuration is rare, the entire breast is hard, the nipple is retracted/inverted, category which is often mistaken for breast carcinoma; (4) tuberculous mastitis obliterans, characterized by duct infection producing proliferation of the lining epithelium, and marked epithelial and periductal fibrosis; and occlusion of the ducts, with appearance of cystic spaces, and all these resemble "cystic mastitis" and (5) acute miliary tuberculous mastitis, which occurs as a part of generalized miliary tuberculosis. The last two entities have only historical importance, being rarely described in the recent medical literature. The Indian pathologists [108] have introduced a new pathological classification of breast tuberculosis, with three categories: (1) nodulo-caseous tubercular mastitis; (2) disseminated/

There are some controversial discussions about the "granulomatous mastitis", diagnosed during childbearing period, usually in parous women, in early 1930s, which are frequently misdiagnosed as tuberculosis or carcinoma [108], with negative culture for MbT, and with cytological and immunocytochemical findings definitely for differential diagnosis from breast tuberculosis at fine needle aspiration cytology [109] or at open surgery. The pathological changes induced by MbT in breast make the differences to other breast pathology, "idiopathic granulomatous mastitis", which is also a "masquerader" [25, 28]. Tuberculous mastitis is often considered a form of "granulomatous mastitis" secondary to breast MbT infection, and some authors reserve the term of "granulomatous mastitis" to "idiopathic granulomatous mastitis", a chronic breast inflammatory entity [110]. Granuloma is a defense mechanism against antigens, which stay in many organs without inactivation. The granulomatous lesions are classified into infectious, vasculitis, immunological, chemicals and neoplasia [35], or the recent classification is more simple: infectious and non-infectious granulomas, with the prove from new studies that pathogenic microorganism are suspected to be a cause of granuloma in non-

The etiology of "granulomatous mastitis" is unclear, being postulated, and sometimes proved, the autoimmune factors [112], sarcoidosis, fat necrosis, undetected organisms (as blastomycosis, actinomycosis, cryptococcosis, histoplasmosis, filarial infection and corynebacterium), Wegener's granulomatosis, reaction to childbirth, and use of oral contraceptives, ductular ectasis [113] the last two factors are present in the reported case. "Granulomatous mastitis" was the first diagnosis in authors' mind at the beginning of investigations, and this is partially an explanation of the delay in diagnosis, and late specific antitubercular treatment, as in other cases from literature in the last years [12]. These breast pathologies – tuberculosis and "idio-

pathic" granulomatous mastitis are considered "masquerader" [28] or "imitator" [89].

There are described some pathological characteristics [107, 114, 115], which make the differentiation between the "idiopathic "granulomatous mastitis"—first described by Kessler and Wolloc [113], and breast TB. TB is affecting all breast structures (lobules, ducts, fat; some pathologists consider that ducts are specially affected), and the tubercular granulomas are

confluent tubercular mastitis and (3) tubercular breast abscess.

inflammatory diseases [111].

146 Tuberculosis

There are mentioned some other types of "necrositing granulomas" in which infectionsinflammation are frequently associated, and are proved with special stains (as Ziehl-Neelsen or Grocott Methamine Silver), and/or by cultures, and other granulomas with infectioninflammatory aspect, but without associated infections as eosinophylic necrosis or basophilic necrosis [83], as is Wegener's granulomatosis, and less commonly rheumatoid nodule, necrotizing sarcoid granulomatosis, infarct and lymphomatoid granulomatosis [83]. The granulomas with eosinophilic necrosis have regular rounded contour, the rim being formed of epithelioid histiocytes with multinucleated giant cells, and the center may have coagulative type of necrosis, which is like an infarct. The Wegener's granulomatosis is characterized by 'dirty' basophilic necrosis with irregular geographic necrosis; the necrosis is rimmed by palisading histiocytes and scattered multinucleated giant cells, with hyperchromatic nuclei and peripheral to the necrosis is the necrotizing vasculitis in vessels. The vessels display transmural fibrinoid necrosis, and the necrosis of the media with admixed necrotic neutrophils, which contributes to the diagnosis with true necrotizing vasculitis. The granuloma of the Romanian case has multiple normal vessels. The parenchymal necrosis of the necrotizing


Table 2. Macroscopic and microscopic characteristics of "idiopathic" granulomatous mastitis and tubercular mastitis (modified from Akcan et al. [114]; Baslaim et al. [115]; Bahoroon [107]; Lacambra et al. [109]).

sarcoid granulomatosis is variable, usually eosinophilic but can be irregular and basophilic, mimicking Wegener's granulomatosis.

is very important to distinguish between the granulomatous reaction and tuberculosis by more specific methods [120]. The presence of stroma caseous necrosis was sufficient for the positive diagnosis of cervical TB in the Romanian authors' opinion. The granuloma diagnosis is a microscopic diagnosis. The microscopy of the cervical specimen after radical hysterectomy reveals an aggregate of immune cells, appearing as epithelioid macrophages, and if a foreign body or a parasite is not observed inside the granuloma, stains for acid-fast bacilli, and fungi are ordered as mycobacteria and fungi (such as Cryptococcus, Blastomyces, Coccidioides and Aspergillus can be seen on hematoxyline-eosine, preferentially in the area of necrosis rather than the surrounding viable area) are frequently the cause of this type of inflammation [31]. In cases with samples fixed in formalin the detection of the infectious agent is recommended to be done by molecular analysis, PCR for MbT in the Romanian

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Radiological imaging of breast tuberculosis is appreciated not to be diagnostic, and the described mammographic images are in connection to three patterns of breast tuberculosis: nodular, disseminated and sclerosing patterns [121]. Some radiological characteristics are common for all patterns, like the change in shape, and outline of the breast mass—seen in the standard views, the reduction in size of the affected breast, skin thickening, nipple retraction and ill-defined breast mass [122]. In previous radiological studies, the skin bulge and sinus tract sign, which connects the breast density to a localized skin thickening or to the skin bulge

In the Romanian case, the mammography was not recommended, because authors thinking was dominated by a chronic inflammation with repeated episodes of recurrence, as a granulo-

Some clinicians [123] recommend computed tomography scan, when are doubtful cases, for the differentiation of primary and secondary lesions, to evaluate accompanying pulmonary disease, if it is present or to detect the continuity of the breast lesions with the thoracic wall or

In the literature, there are controversies about the value of ultrasonography for breast TB diagnosis. On one side, it is mentioned no specificity of the ultrasound examination [121]: the breasts' lesions may appear as heterogeneous, hypoechoic, irregularly or ill-bordered masses of different sizes, but usually small sizes, with internal echoes or thick-walled cystic lesions, some mass may present posterior acoustic enhancement, in association to the fistula formation, and the thickening of Cooper's ligaments and subcutaneous tissues, as it was revealed in the Romanian case. On the other side, it is mentioned an unique finding strongly suggestive for breast TB: the presence of a dense sinus tract connecting an ill-defined breast mass to localized

are the radiological features strongly suggestive for tubercular breast abscess [66].

case [91, 118].

5.5. Imaging diagnosis of rare tuberculosis locations

5.5.1. Radiological imaging of breast tuberculosis

matous mastitis or a plasma cell mastitis.

pleura, and associated lesions of the lungs.

5.5.2. Ultrasonography for breast tuberculosis

skin thickening and bulge [14].

The pathological characteristics of the "idiopathic" lobular non-caseating granulomas and of tuberculosis caseating granuloma of the breast are listed in Table 2, and it is considered [83] that no single histological feature may distinguish infectious necrotizing granulomas from other specific disorder as Wegener's granulomatosis or sarcoidosis, being necessary a combination of multiple pathological features to establish the specific diagnosis.

The first reported case of this chapter is a primary breast TB, with no personal history, or other focus on the systemic physical/radiological examinations for TB. The diagnosis of breast TB must follow the general principles: clinical and laboratory. The clinical presentation of breast TB is variable regarding symptoms/signs: swelling of the breast—48.1% [10]; painless hard lump—approximately 60% cases, or pain is revealed as the first complain of some patients [67, 68] or up to 18.5% of cases [10]; rarely are recorded multiple lumps, with irregular borders, sometimes with skin fixation or areola fixation, or to the underlying muscle or even chest wall, clinical findings imposing differential to breast carcinoma [69], situation which is much more suggested by the presence of an isolated breast mass, sometimes skin fixated-"peau d'orange" sign, and without an associated sinus tract; ulceration of areola [117], or of the skin covering the mammary gland [118]; abscess, unique or multiples [85]; skin thickening and skin sinus/ fistula/multiple discharge sinuses [70], nipple retraction or inversion, nipple hyperpigmentation or focal discoloration—when the disease is long time duration [69], or distruction of nipple-areola region [19], breast shape and sizes are changed, axillary lymphadenopathy (axillary lymph nodes are found in one-third of cases with breast TB). Constitutional symptoms as fever, weight loss, night sweats or a failing of general health are infrequently encountered [71, 72].

#### 5.4.2. Pathological diagnosis of cervical tuberculosis

The cervical tuberculosis diagnosis is commonly established by the Papanicolaou smear without any dysplasia, positivity for acid-fast bacilli, and the cervical biopsy (punch, loop excision biopsy) showing granulomatous inflammation with caseous necrosis, facts that were absent in the Romanian case. The presence of the viral infection is clearly proved by genotyping of the cervix after surgery. The endocervical curettage which has the possibility to diagnose associated endocervical tuberculosis was not done, because they believe that exocervical lesion was the only cause of abnormal bleeding. The pulmonary tuberculosis was 7 years previously registered, and the genital location was diagnosed in the endocervical glands, on the specimen collected at hysterectomy—after radiotherapy and chemotherapy. The presence of the endocervical tubercle bacillus was indirectly diagnosed by the pathologic examination the presence of caseous necrosis and Langhans multinuclear giant cells, and by PCR for MbT. The diagnosis of TB depends also upon the isolation of the MbT on microscopy, and culture, and by the PCR. Culture of MbT and acid-fast staining was not done, the cervical granulomas were noted at pathological examination after surgery, on a formalin-fixed specimen. The presence of characteristic, typical caseous granuloma was appreciated sufficient to make the diagnosis [77, 119], but many researchers consider that it is very important to distinguish between the granulomatous reaction and tuberculosis by more specific methods [120]. The presence of stroma caseous necrosis was sufficient for the positive diagnosis of cervical TB in the Romanian authors' opinion. The granuloma diagnosis is a microscopic diagnosis. The microscopy of the cervical specimen after radical hysterectomy reveals an aggregate of immune cells, appearing as epithelioid macrophages, and if a foreign body or a parasite is not observed inside the granuloma, stains for acid-fast bacilli, and fungi are ordered as mycobacteria and fungi (such as Cryptococcus, Blastomyces, Coccidioides and Aspergillus can be seen on hematoxyline-eosine, preferentially in the area of necrosis rather than the surrounding viable area) are frequently the cause of this type of inflammation [31]. In cases with samples fixed in formalin the detection of the infectious agent is recommended to be done by molecular analysis, PCR for MbT in the Romanian case [91, 118].

#### 5.5. Imaging diagnosis of rare tuberculosis locations

#### 5.5.1. Radiological imaging of breast tuberculosis

sarcoid granulomatosis is variable, usually eosinophilic but can be irregular and basophilic,

The pathological characteristics of the "idiopathic" lobular non-caseating granulomas and of tuberculosis caseating granuloma of the breast are listed in Table 2, and it is considered [83] that no single histological feature may distinguish infectious necrotizing granulomas from other specific disorder as Wegener's granulomatosis or sarcoidosis, being necessary a combi-

The first reported case of this chapter is a primary breast TB, with no personal history, or other focus on the systemic physical/radiological examinations for TB. The diagnosis of breast TB must follow the general principles: clinical and laboratory. The clinical presentation of breast TB is variable regarding symptoms/signs: swelling of the breast—48.1% [10]; painless hard lump—approximately 60% cases, or pain is revealed as the first complain of some patients [67, 68] or up to 18.5% of cases [10]; rarely are recorded multiple lumps, with irregular borders, sometimes with skin fixation or areola fixation, or to the underlying muscle or even chest wall, clinical findings imposing differential to breast carcinoma [69], situation which is much more suggested by the presence of an isolated breast mass, sometimes skin fixated-"peau d'orange" sign, and without an associated sinus tract; ulceration of areola [117], or of the skin covering the mammary gland [118]; abscess, unique or multiples [85]; skin thickening and skin sinus/ fistula/multiple discharge sinuses [70], nipple retraction or inversion, nipple hyperpigmentation or focal discoloration—when the disease is long time duration [69], or distruction of nipple-areola region [19], breast shape and sizes are changed, axillary lymphadenopathy (axillary lymph nodes are found in one-third of cases with breast TB). Constitutional symptoms as fever, weight loss, night sweats or a failing of general health are infrequently encoun-

The cervical tuberculosis diagnosis is commonly established by the Papanicolaou smear without any dysplasia, positivity for acid-fast bacilli, and the cervical biopsy (punch, loop excision biopsy) showing granulomatous inflammation with caseous necrosis, facts that were absent in the Romanian case. The presence of the viral infection is clearly proved by genotyping of the cervix after surgery. The endocervical curettage which has the possibility to diagnose associated endocervical tuberculosis was not done, because they believe that exocervical lesion was the only cause of abnormal bleeding. The pulmonary tuberculosis was 7 years previously registered, and the genital location was diagnosed in the endocervical glands, on the specimen collected at hysterectomy—after radiotherapy and chemotherapy. The presence of the endocervical tubercle bacillus was indirectly diagnosed by the pathologic examination the presence of caseous necrosis and Langhans multinuclear giant cells, and by PCR for MbT. The diagnosis of TB depends also upon the isolation of the MbT on microscopy, and culture, and by the PCR. Culture of MbT and acid-fast staining was not done, the cervical granulomas were noted at pathological examination after surgery, on a formalin-fixed specimen. The presence of characteristic, typical caseous granuloma was appreciated sufficient to make the diagnosis [77, 119], but many researchers consider that it

nation of multiple pathological features to establish the specific diagnosis.

mimicking Wegener's granulomatosis.

148 Tuberculosis

tered [71, 72].

5.4.2. Pathological diagnosis of cervical tuberculosis

Radiological imaging of breast tuberculosis is appreciated not to be diagnostic, and the described mammographic images are in connection to three patterns of breast tuberculosis: nodular, disseminated and sclerosing patterns [121]. Some radiological characteristics are common for all patterns, like the change in shape, and outline of the breast mass—seen in the standard views, the reduction in size of the affected breast, skin thickening, nipple retraction and ill-defined breast mass [122]. In previous radiological studies, the skin bulge and sinus tract sign, which connects the breast density to a localized skin thickening or to the skin bulge are the radiological features strongly suggestive for tubercular breast abscess [66].

In the Romanian case, the mammography was not recommended, because authors thinking was dominated by a chronic inflammation with repeated episodes of recurrence, as a granulomatous mastitis or a plasma cell mastitis.

Some clinicians [123] recommend computed tomography scan, when are doubtful cases, for the differentiation of primary and secondary lesions, to evaluate accompanying pulmonary disease, if it is present or to detect the continuity of the breast lesions with the thoracic wall or pleura, and associated lesions of the lungs.

#### 5.5.2. Ultrasonography for breast tuberculosis

In the literature, there are controversies about the value of ultrasonography for breast TB diagnosis. On one side, it is mentioned no specificity of the ultrasound examination [121]: the breasts' lesions may appear as heterogeneous, hypoechoic, irregularly or ill-bordered masses of different sizes, but usually small sizes, with internal echoes or thick-walled cystic lesions, some mass may present posterior acoustic enhancement, in association to the fistula formation, and the thickening of Cooper's ligaments and subcutaneous tissues, as it was revealed in the Romanian case. On the other side, it is mentioned an unique finding strongly suggestive for breast TB: the presence of a dense sinus tract connecting an ill-defined breast mass to localized skin thickening and bulge [14].

Regarding the vascularisation of the breast tubercular masses, the blood flow was not observed within the lesions, while increased circumferential vascularization was seen in the color Doppler ultrasound, and the spectral evaluation shows a low resistance monophasic flow pattern [121].

breast carcinoma and axillary tuberculous lymphadenitis [126]. In postmenopausal women is considered that the diagnosis of breast TB does not exclude a concomitent cancer [3], situation

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In cases with discharging sinuses associated to a breast lump it is necessary to make the differentiation from actinomycosis by the absence of sulfur granules in the discharge and by

For women from countries with endemic tuberculosis from Asia and Africa, or immigrated from that countries, the association of breast carcinoma and tuberculosis must be thought, specially when the data are confusing [3, 127, 128], as it is when on records tuberculosis of axillary lymph nodes with primary breast cancer [129], or axillary lymph nodes with granulo-

Beside carcinoma there are other misdiagnosis risks as "idiopathic" granulomatous mastitis (Table 2, for pathological differential), or plasma cell mastitis (which may mimic histological the tuberculosis by the presence of foreign body giant cells, epithelioid cells which are arranged in tubercles, besides plasma cells, polymorphs, lymphocytes and few foamy macrophages, but is missing the caseation which makes the differential from tuberculosis- [131],

In the last years there are described recurrent breast abscess to be more frequent due to nontuberculous mycobacterial infection [20, 134], cases with similar clinical presentation, with

When women's complaints are present, and cervical examination shows cervical changes it is considered to think about both pathologies, separately or associated in countries with high risks for these pathologies. There are discussed other viral cervical infections as HIV, herpes virus simplex, other sexual transmitted (Treponema pallidum, Trichomonas vaginalis, Neisseria gonorrhea) or parasitic diseases as schistosomal, amoebic, brucella, tularaemia which may induce chronic cervical granulomas, sarcoidosis, and foreign body reaction [77],

When not adequate treated, TB mastitis is followed by abscesses, which can penetrate the retromammary space [135], or to the ribs [136], formation of sinuses, and nipple retraction, and irreversible inversion, recurrences even with surgical drainage/excision, and breast muti-

In the case with the association of two severe immunosuppressive diseases as tuberculosis and cancer there are risks for reactivating the lung tuberculosis, for lung metastases from cervical

that was first reported by Pilliet and Piatot in (cited by [27]).

fungal culture [9].

granulomas.

lation [26].

mas and a breast carcinoma [72, 130].

lupus mastitis [132], eritema nodosus [133].

6.2. Differentials for cervix uteri tuberculosis

or more rare an epithelioid granulomas in Hodgkin's disease [39].

7. Complications of breast/cervix uteri tuberculosis

cancer, and of high mortality in patients with coexistent disease [137, 138].

#### 5.5.3. Magnetic resonance imaging (MRI) for breast/cervix uteri tuberculosis diagnosis

If on recommend MRI imaging for breast TB, it is possible to detect parenchymal asymmetry with enhancement, micro-abscesses, and peripherally enhanced masses. MRI may reveal lymphadenopathy along the pelvic walls, with an abnormal signal to the entire body of the uterus and sometimes when the entire uterus is infected by MbT, the endometrial cavity, myometrium, and junctional zone could not be differentiated and thus the radiological appearance was consistent with Asherman's syndrome [77].

#### 5.6. Antitubercular therapeutic test for rare location tuberculosis diagnosis

There are cases with pulmonary and extrapulmonary TB with negative molecular test—PCR for MbT from clinical specimens or it is not possible to recommend and use the rapid very efficient modern molecular NAA for detection of mycobacterial DNA or RNA directly from the specimens as it was previously discussed. In countries with endemic TB, it is since long time discussed and recently it is recalled an empirical antitubercular therapy even in the absence of positive acid-fast bacilli, and without culture—positive results, or when it is the suspicion of TB or when the "idiopathic" granulomatous mastitis is found and it is not responding to metothrexate or corticosteroids [108, 117].

TB is considered to be actually under-diagnosed in Romania, and the Romanian health history had a similar management in cases which are mentioned before, and in these conditions, the final diagnosis of the case with primary recurrent non-gestational breast abscess was done after the antitibercular" therapeutic" test, which was efficient after the first two months. More details are in the subsection 8 on "Treatment".

#### 6. Differential diagnosis

#### 6.1. Differentials for breast tuberculosis

The breast tuberculosis can be confused with breast carcinoma, specially in elder women [27, 28, 69, 124], who present an isolated ill defined, irregular, occasionally hard breast lump without sinuses/fistula, but pain is present more frequently in the tuberculous lump than in carcinoma. Involvement of the nipple and areola is rare in tuberculosis, but fixation of the lump to the skin may be present as a part of the inflammatory process, which is present in both pathological entities A high index of suspicion needs to be maintained if a breast lump is associated with a sinus or indolent lump in an immigrant women if this is encountered in the western countries. The coexistence of tubercular axillary lymphadenitis with breast carcinoma can falsely over-stage the disease [125], and is reported an association of the metastasis of breast carcinoma and axillary tuberculous lymphadenitis [126]. In postmenopausal women is considered that the diagnosis of breast TB does not exclude a concomitent cancer [3], situation that was first reported by Pilliet and Piatot in (cited by [27]).

In cases with discharging sinuses associated to a breast lump it is necessary to make the differentiation from actinomycosis by the absence of sulfur granules in the discharge and by fungal culture [9].

For women from countries with endemic tuberculosis from Asia and Africa, or immigrated from that countries, the association of breast carcinoma and tuberculosis must be thought, specially when the data are confusing [3, 127, 128], as it is when on records tuberculosis of axillary lymph nodes with primary breast cancer [129], or axillary lymph nodes with granulomas and a breast carcinoma [72, 130].

Beside carcinoma there are other misdiagnosis risks as "idiopathic" granulomatous mastitis (Table 2, for pathological differential), or plasma cell mastitis (which may mimic histological the tuberculosis by the presence of foreign body giant cells, epithelioid cells which are arranged in tubercles, besides plasma cells, polymorphs, lymphocytes and few foamy macrophages, but is missing the caseation which makes the differential from tuberculosis- [131], lupus mastitis [132], eritema nodosus [133].

In the last years there are described recurrent breast abscess to be more frequent due to nontuberculous mycobacterial infection [20, 134], cases with similar clinical presentation, with granulomas.

#### 6.2. Differentials for cervix uteri tuberculosis

Regarding the vascularisation of the breast tubercular masses, the blood flow was not observed within the lesions, while increased circumferential vascularization was seen in the color Doppler ultrasound, and the spectral evaluation shows a low resistance monophasic flow

If on recommend MRI imaging for breast TB, it is possible to detect parenchymal asymmetry with enhancement, micro-abscesses, and peripherally enhanced masses. MRI may reveal lymphadenopathy along the pelvic walls, with an abnormal signal to the entire body of the uterus and sometimes when the entire uterus is infected by MbT, the endometrial cavity, myometrium, and junctional zone could not be differentiated and thus the radiological appear-

There are cases with pulmonary and extrapulmonary TB with negative molecular test—PCR for MbT from clinical specimens or it is not possible to recommend and use the rapid very efficient modern molecular NAA for detection of mycobacterial DNA or RNA directly from the specimens as it was previously discussed. In countries with endemic TB, it is since long time discussed and recently it is recalled an empirical antitubercular therapy even in the absence of positive acid-fast bacilli, and without culture—positive results, or when it is the suspicion of TB or when the "idiopathic" granulomatous mastitis is found and it is not

TB is considered to be actually under-diagnosed in Romania, and the Romanian health history had a similar management in cases which are mentioned before, and in these conditions, the final diagnosis of the case with primary recurrent non-gestational breast abscess was done after the antitibercular" therapeutic" test, which was efficient after the first two months. More

The breast tuberculosis can be confused with breast carcinoma, specially in elder women [27, 28, 69, 124], who present an isolated ill defined, irregular, occasionally hard breast lump without sinuses/fistula, but pain is present more frequently in the tuberculous lump than in carcinoma. Involvement of the nipple and areola is rare in tuberculosis, but fixation of the lump to the skin may be present as a part of the inflammatory process, which is present in both pathological entities A high index of suspicion needs to be maintained if a breast lump is associated with a sinus or indolent lump in an immigrant women if this is encountered in the western countries. The coexistence of tubercular axillary lymphadenitis with breast carcinoma can falsely over-stage the disease [125], and is reported an association of the metastasis of

5.5.3. Magnetic resonance imaging (MRI) for breast/cervix uteri tuberculosis diagnosis

5.6. Antitubercular therapeutic test for rare location tuberculosis diagnosis

ance was consistent with Asherman's syndrome [77].

responding to metothrexate or corticosteroids [108, 117].

details are in the subsection 8 on "Treatment".

6.1. Differentials for breast tuberculosis

6. Differential diagnosis

pattern [121].

150 Tuberculosis

When women's complaints are present, and cervical examination shows cervical changes it is considered to think about both pathologies, separately or associated in countries with high risks for these pathologies. There are discussed other viral cervical infections as HIV, herpes virus simplex, other sexual transmitted (Treponema pallidum, Trichomonas vaginalis, Neisseria gonorrhea) or parasitic diseases as schistosomal, amoebic, brucella, tularaemia which may induce chronic cervical granulomas, sarcoidosis, and foreign body reaction [77], or more rare an epithelioid granulomas in Hodgkin's disease [39].

#### 7. Complications of breast/cervix uteri tuberculosis

When not adequate treated, TB mastitis is followed by abscesses, which can penetrate the retromammary space [135], or to the ribs [136], formation of sinuses, and nipple retraction, and irreversible inversion, recurrences even with surgical drainage/excision, and breast mutilation [26].

In the case with the association of two severe immunosuppressive diseases as tuberculosis and cancer there are risks for reactivating the lung tuberculosis, for lung metastases from cervical cancer, and of high mortality in patients with coexistent disease [137, 138].

#### 8. Treatment of breast/cervix uteri tuberculosis

Treatment may cure the disease with antitubercular drugs, and surgery is rarely required, being used in cases resistant to medical treatment. The specific antitubercular treatment was delayed in the Romanian case with breast abscess as is frequently mentioned in literature [24], because the difficulties of the positive and differential diagnosis, and because tuberculosis is under-diagnosis in contemporary Romania, but the attitude regarding tuberculosis was similar in the Romanian health history to that from tuberculosis endemic countries: to recommend empirical antitubercular therapy even in the absence of positive AFB, and without positive culture results, when it is a suspicion of TB or when the granuloma is found. In many cases, the decision for the antitubercular treatment is taken after the failure of corticoids and methotrexate therapy for "idiopathic" granulomatous mastitis [108, 117, 139].

In the Romanian primary recurrent non-gestational breast abscess was recalled as the old concept of the "antitubercular therapeutic" test, for the final diagnosis and it was proved to be efficient after the first 2 months, and the association of isoniazid and rifampin was contin-

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Surgery was imposed in the Romanian case because of abscess complications in the conditions of MbT late diagnosis. It was a minimal surgical intervention required for drainage and excision biopsy of abscesses' wall. Surgery is commonly reserved for selected cases, in partic-

• According to the presence of breast masses/lump and abscesses with fistula: simple or segmental mastectomy or quadrantectomy or drainage of abscess with large excision of the necrotic tissue of the breast and excision of the axillary lymph nodes when

• Breast abscesses with negative bacteriological tests in order to diagnose by excision biopsy

A special mention is for the percutaneous treatment with drainage controlled by CT and specific antibiotic antitubercular drugs [123], especially when resistance to ATT is discovered

The ATT are usually recommended for cervix uteri tuberculosis for minimum 6 months [146], healing being proved by repeated biopsy. The chemo and radiotherapy, and the radical surgical intervention done in the Romanian case were imposed by the initial diagnosis of squamous non-keratinized cervical carcinoma stage IB, tubercular cervicitis being a postoperative surprise, and it was decided to avoid a new cure of AAT because the postoperative assessments for MbT lung or general reactivation were negative.

• Breast tuberculosis should be considered as a differential diagnosis of breast inflammatory disease or masses, all over the world, not only where tuberculosis is endemic.

• Tuberculosis must be suspected in recurrent breast inflammatory disease with negative current cultures, and negative tests as Ziehl-Neelsen stain, culture and PCR for

• The pathologic examination of the open biopsy in the reported case is suggesting the diagnosis of a granulomatous mastitis, and the multinuclear giant cells of Langhans type presence ensure the diagnosis of tubercular granulomatous mastitis even in the absence of

of the abscess wall and drainage of abscess with fistula [16, 21, 67].

• Residual lumps after antitubercular therapy, excision of sinus [9, 10].

[144], as it is done for pulmonary TB and for abdominal collections [145].

ued with excellent results up to 9 months.

ular situations, and in different manner:

• In cases refractory to medication [69].

• Mastectomy when is severe breast destruction [14].

involved [25].

9. Conclusions

MbT.

the characteristic caseous necrosis.

Based on patient profile, clinical features and lack of response to usual antibiotic therapy, it is recommended a four-drug (isoniazid, rifampin, ethambutol and pyrazinamide) 6-month course of Directly Observed Therapy Short-Term (DOTS) - Category I [117], but the response to treatment is variable and not dramatic. There are reported excellent results with such management [101].

There are no specific available guidelines for chemotherapy of breast TB, and the therapy generally follows guidelines that are used for pulmonary TB. The regimen consists of a 2 month intensive phase (isoniazid, rifampicin, pyrazinamide and ethambutol), followed by a 4 month continuation phase (isoniazid and rifampin). It is recommended another regimen with extension of continuation therapy for a longer period to 7 months [9, 140–142] or more up to 12–18 months [140], because the wish to lower the relapse rate. There is also a regimen which combines first and second lines antitubercular drugs, including kanamycin, ofloxacin, ethionamide, para-amino salicylic acid (PAS), pyrazinamide and isoniazid, with the reason of the risk of multidrug resistant strains [143]. The breast lesions and tenderness are steadily improved after 2 months of intensive therapy the breast lesions and tenderness are steadily improved [83] (Table 3).


\* Al-Marri et al. [122]; Jalali et al. [102]; Mirsaeidi et al. [6], Bahoroon [107]; Gon et al. [28]; Singal, et al. [13]. \*\*Daali et al. [141]; Khanna et al. [9]; Kumar et al. [143].

Table 3. Breast antitubercular regimens.

In the Romanian primary recurrent non-gestational breast abscess was recalled as the old concept of the "antitubercular therapeutic" test, for the final diagnosis and it was proved to be efficient after the first 2 months, and the association of isoniazid and rifampin was continued with excellent results up to 9 months.

Surgery was imposed in the Romanian case because of abscess complications in the conditions of MbT late diagnosis. It was a minimal surgical intervention required for drainage and excision biopsy of abscesses' wall. Surgery is commonly reserved for selected cases, in particular situations, and in different manner:


A special mention is for the percutaneous treatment with drainage controlled by CT and specific antibiotic antitubercular drugs [123], especially when resistance to ATT is discovered [144], as it is done for pulmonary TB and for abdominal collections [145].

The ATT are usually recommended for cervix uteri tuberculosis for minimum 6 months [146], healing being proved by repeated biopsy. The chemo and radiotherapy, and the radical surgical intervention done in the Romanian case were imposed by the initial diagnosis of squamous non-keratinized cervical carcinoma stage IB, tubercular cervicitis being a postoperative surprise, and it was decided to avoid a new cure of AAT because the postoperative assessments for MbT lung or general reactivation were negative.

#### 9. Conclusions

8. Treatment of breast/cervix uteri tuberculosis

ate therapy for "idiopathic" granulomatous mastitis [108, 117, 139].

improved [83] (Table 3).

152 Tuberculosis

6 months\* 2 months of:

9 months\*\* 2 months of:

Table 3. Breast antitubercular regimens.

\*

Treatment may cure the disease with antitubercular drugs, and surgery is rarely required, being used in cases resistant to medical treatment. The specific antitubercular treatment was delayed in the Romanian case with breast abscess as is frequently mentioned in literature [24], because the difficulties of the positive and differential diagnosis, and because tuberculosis is under-diagnosis in contemporary Romania, but the attitude regarding tuberculosis was similar in the Romanian health history to that from tuberculosis endemic countries: to recommend empirical antitubercular therapy even in the absence of positive AFB, and without positive culture results, when it is a suspicion of TB or when the granuloma is found. In many cases, the decision for the antitubercular treatment is taken after the failure of corticoids and methotrex-

Based on patient profile, clinical features and lack of response to usual antibiotic therapy, it is recommended a four-drug (isoniazid, rifampin, ethambutol and pyrazinamide) 6-month course of Directly Observed Therapy Short-Term (DOTS) - Category I [117], but the response to treatment is variable and not dramatic. There are reported excellent results with such management [101].

There are no specific available guidelines for chemotherapy of breast TB, and the therapy generally follows guidelines that are used for pulmonary TB. The regimen consists of a 2 month intensive phase (isoniazid, rifampicin, pyrazinamide and ethambutol), followed by a 4 month continuation phase (isoniazid and rifampin). It is recommended another regimen with extension of continuation therapy for a longer period to 7 months [9, 140–142] or more up to 12–18 months [140], because the wish to lower the relapse rate. There is also a regimen which combines first and second lines antitubercular drugs, including kanamycin, ofloxacin, ethionamide, para-amino salicylic acid (PAS), pyrazinamide and isoniazid, with the reason of the risk of multidrug resistant strains [143]. The breast lesions and tenderness are steadily improved after 2 months of intensive therapy the breast lesions and tenderness are steadily

Treatment duration Initial phase treatment (intensive therapy) Continuation treatment

Al-Marri et al. [122]; Jalali et al. [102]; Mirsaeidi et al. [6], Bahoroon [107]; Gon et al. [28]; Singal, et al. [13].

4 months of isoniazid, rifampin

7 months of isoniazid, rifampin

300 mg isoniazid, 600 mg rifampin, 1500 mg pyrazinamide, 1000 mg ethambutol or streptomycin 1 g per day

300 mg isoniazid, 600 mg rifampin, 1500 mg pyrazinamide, 1000 mg ethambutol

per day

\*\*Daali et al. [141]; Khanna et al. [9]; Kumar et al. [143].


• The final diagnosis of breast TB was established by specific antitubercular drugs, which represents a Tuberculosis Diagnosis Test, and may avoid or delay breast characteristic mutilations when treatment is not adequate.

[7] Tewari M, Shukla HS. Breast tuberculosis: Diagnosis, clinical features, and management.

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155

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• The cervix uteri tuberculosis presence and its association to ecto/endocervical cancer is to be suspected not only in developing countries with endemic tuberculosis and high rates of HPV/HIV infections, in patients with primary lung/other organs tuberculosis.

#### Author details

Manuela Cristina Russu<sup>1</sup> \*, Şerban Nastasia<sup>2</sup> , Daniela Degeratu<sup>3</sup> and Ruxandra Viorica Stănculescu<sup>4</sup>

\*Address all correspondence to: manuela\_russu@yahoo.com

1 "Dr. I. Cantacuzino" Clinical Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

2 "Dr. I. Cantacuzino" Clinic of Obstetrics and Gynaecology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

3 "Dr. I. Cantacuzino" Laboratory of Pathology, Bucharest, Romania

4 Department of Pathological Obstetrics, Emergency "St Pantelimon" Clinical Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

#### References


[7] Tewari M, Shukla HS. Breast tuberculosis: Diagnosis, clinical features, and management. The Indian Journal of Medical Research. 2005;122:103-110

• The final diagnosis of breast TB was established by specific antitubercular drugs, which represents a Tuberculosis Diagnosis Test, and may avoid or delay breast characteristic muti-

• The cervix uteri tuberculosis presence and its association to ecto/endocervical cancer is to be suspected not only in developing countries with endemic tuberculosis and high rates of

, Daniela Degeratu<sup>3</sup> and

HPV/HIV infections, in patients with primary lung/other organs tuberculosis.

1 "Dr. I. Cantacuzino" Clinical Hospital, "Carol Davila" University of Medicine and

2 "Dr. I. Cantacuzino" Clinic of Obstetrics and Gynaecology, "Carol Davila" University of

4 Department of Pathological Obstetrics, Emergency "St Pantelimon" Clinical Hospital,

[1] World Health Organization. Global Tuberculosis Report 2017. Geneva, Switzerland:

[2] Prezzemolo T, Guggino G, Pio La Manna M, Di Liberto D, Dieli F, Caccamo N. Functional signatures of human CD4 and CD8 T cell responses to Mycobacterium tuberculosis.

[3] Bouti K, Soualhi M, Marc K, Zahraoui R, Benamor J, Bourkadi E, Iraqi G. Postmenopausal breast tuberculosis – Report of 4 cases. Breast Care (Basel). 2012;7(5):411-413 [4] Micha JP, Brown JV 3rd, Birk C, Van Horn D, Retenmaier MA, Golstein BH. Tuberculosis mimicking cervical carcinoma-case report. European Journal of Obstetrics & Gynecology.

[5] Agrawal S, Madan M, Leekha N, Raghunandan C. A rare case of cervical tuberculosis

[6] Mirsaeidi SM, Masjedi MR, Mansouri SD, Velayati AA. Tuberculosis of the breast: Report of 4 clinical cases and literature review. Eastern Mediterranean Health Journal.

\*, Şerban Nastasia<sup>2</sup>

3 "Dr. I. Cantacuzino" Laboratory of Pathology, Bucharest, Romania

simulating carcinoma cervix. Cases Journal. 2009;2:161

"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

Licence CCBY-NC-SA0IGO. Available from: http://apps.who.int/iris

\*Address all correspondence to: manuela\_russu@yahoo.com

lations when treatment is not adequate.

Author details

154 Tuberculosis

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162 Tuberculosis

15(3):437-439


**Chapter 8**

**Provisional chapter**

**Urinary Tract Tuberculosis**

**Urinary Tract Tuberculosis**

http://dx.doi.org/10.5772/intechopen.76063

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

tuberculosis, genitourinary tuberculosis

genitourinary tuberculosis (GUTB) represents 27% [1].

DOI: 10.5772/intechopen.76063

Urinary tract tuberculosis (UTTB) is an insidious disease with non-specific constitutional symptoms that are often unrecognized and lead to delayed diagnosis. Advanced UTTB may cause loss of kidney function. In the majority of literature, UTTB is reviewed together with genital tuberculosis because often both sites are involved simultaneously; "Genitourinary tuberculosis" (GUTB) is the most common term used in the literature. However, the term may cause confusion because the clinical presentation and diagnosis approach is very different, and does not always occur simultaneously. UTTB is the term used here as we encountered tuberculosis involvement of urinary tract only. This book chapter is a comprehensive review of the epidemiology, pathophysiology, clinical pre-

**Keywords:** tuberculosis, urinary tract infection, renal tuberculosis, extra-pulmonary

Throughout history, tuberculosis (TB) has been identified as a respiratory disease, with prominent symptoms as cough, fever, and wasting. Current clinical experience reveals that the lungs are involved in 80–90% of all TB patients not infected by human immunodeficiency virus (HIV). Extra-pulmonary forms are more common in people co-infected with HIV where

GUTB is a term coined by Wildbolz in 1937 [2]; it is a worldwide disease, but shows a more destructive behavior in developing countries. The kidney is the most common site of GUTB [3], and it usually affects adults between the second and fourth decades of life and is reported

sentation, diagnosis approach, and current treatment of this disease.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Gerardo Amaya-Tapia and Guadalupe Aguirre-Avalos

**Abstract**

**1. Introduction**

Gerardo Amaya-Tapia and Guadalupe Aguirre-Avalos

**Chapter 8 Provisional chapter**

#### **Urinary Tract Tuberculosis Urinary Tract Tuberculosis**

Gerardo Amaya-Tapia and Guadalupe Aguirre-Avalos Gerardo Amaya-Tapia and Guadalupe Aguirre-Avalos

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76063

#### **Abstract**

Urinary tract tuberculosis (UTTB) is an insidious disease with non-specific constitutional symptoms that are often unrecognized and lead to delayed diagnosis. Advanced UTTB may cause loss of kidney function. In the majority of literature, UTTB is reviewed together with genital tuberculosis because often both sites are involved simultaneously; "Genitourinary tuberculosis" (GUTB) is the most common term used in the literature. However, the term may cause confusion because the clinical presentation and diagnosis approach is very different, and does not always occur simultaneously. UTTB is the term used here as we encountered tuberculosis involvement of urinary tract only. This book chapter is a comprehensive review of the epidemiology, pathophysiology, clinical presentation, diagnosis approach, and current treatment of this disease.

DOI: 10.5772/intechopen.76063

**Keywords:** tuberculosis, urinary tract infection, renal tuberculosis, extra-pulmonary tuberculosis, genitourinary tuberculosis

#### **1. Introduction**

Throughout history, tuberculosis (TB) has been identified as a respiratory disease, with prominent symptoms as cough, fever, and wasting. Current clinical experience reveals that the lungs are involved in 80–90% of all TB patients not infected by human immunodeficiency virus (HIV). Extra-pulmonary forms are more common in people co-infected with HIV where genitourinary tuberculosis (GUTB) represents 27% [1].

GUTB is a term coined by Wildbolz in 1937 [2]; it is a worldwide disease, but shows a more destructive behavior in developing countries. The kidney is the most common site of GUTB [3], and it usually affects adults between the second and fourth decades of life and is reported

as being rare in children [4, 5]. Clinical renal TB is a chronic process that can start many years after the initial lung infection [6].

**3. Pathogenesis**

Pulmonary infection is the primary focus in most cases of TB. After exposition, the bacilli remain stored in macrophages, where they slowly multiply, UTTB is the result of hematogenous spread from the lungs. Once the bacilli reach the circulation system, it can be distributed to all parts of the body, especially those sites with adequate conditions for its multiplication and with local immune deficiencies [18, 19]. The lymphatic nodes, encephalus, and urinary

Urinary Tract Tuberculosis

167

http://dx.doi.org/10.5772/intechopen.76063

The kidneys, and possibly the prostate and seminal vesicles, are often the primary sites of GUTB. All other genital organs, including the epididymis and bladder, become involved by ascent or descent of *Mtb* from a source elsewhere in the genitourinary tract [22]. *Mtb* bacilli are shed into the urine; they spread into the urinary tract, involving the renal pelvis, ureters and bladder; the urinary tract mucosa may be ulcerated, thin and without contractility [4]. In most patients, acquired cellular immunity develops and there is inhibition of bacilli multiplication and containment of the disease by the formation of microscopic granulomas, leading caseous

The infection occurs initially in the medullary region, where granulomatous lesions can occur. If, in the course of primary infection, cell-mediated immunity develops and the proliferation of organisms is limited by competitive macrophages, this results in the formation of granulomas in which dormant bacilli can be maintained for long periods, leading caseous necrosis with local tissue destruction. When the bacilli are spilling down into the nephrons, they are trapped in the loop of Henle, establishing new foci of infection [18]. The multiple focus of microscopic necrosis lead macroscopic lesions that rapidly involve the renal papilla, causing fibrosis that can cause ureteral damage, with dilations intercalated with strictures, which con-

Sites of the urinary tract where there are natural narrow strictures, such as the calyceal neck, the pelvi-ureteric junction, and the uretero-vesical junction are the sites that suffer strictures more frequently. Steroid therapy may be useful in the early stages of scarring and could reduce the risk of stenosis that can lead to urinary obstruction and irreversible kidney damage [24]. A mass lesion may result from massive destruction and coalescence of granulomas,

Hypercalcemia may occur, usually secondary to abnormal cortisol production by granulomatous tissue [26]. Although calcification is unusual in the early stages of the disease, nearly every end-stage tuberculosis kidney contains calcification. Hydronephrosis or hydrocalicosis may be the final stage, and may lead to a non-functioning, calcified kidney of any size; this

UTTB has an insidious onset, no specific symptoms with atypical presentations [27], which lead to difficulty and delay the diagnosis in most health care centers [19, 20, 22, 28]. The majority

tract are some of the most frequent sites involved [20, 21].

necrosis with local tissue destruction [18].

stitutes an important TB sign on the pyelogram [23].

if they do not rupture into the adjoining calyx [25].

process is called autonephrectomy [24].

**4. Clinical presentation**

Renal involvement in TB can be part of a disseminated infection or a localized GUTB disease. With renal disease progression, extensive areas of papillary necrosis can cause formation of cavities that destroy the renal parenchyma and can migrate into the collecting system. Advanced disease may cause obstructive uropathy, bladder defects, and loss of kidney function [7].

UTTB is underdiagnosed in most health care centers; the clinicians must have a high degree of suspicion for UTTB in patients presenting with non-specific symptoms, culture-negative, pyuria, and for whom imaging studies show some typical findings of UTTB. Acid fast bacilli (AFB) microscopy and Lowenstein Jensen (LJ) culture are the tests most used in health institutions. AFB stain has a poor sensitivity and false positive can result from mycobacteria external genital colonization or by the presence of precipitates that resemble AFB. Although, LJ cultures have a better sensitivity, it may require around 8 weeks to obtain growth and identification [8]. In addition to other forms of extra-pulmonary tuberculosis, the amplification tests of deoxyribonucleic acid (DNA) have been used with good results, increasing the sensitivity, specificity and shortening the time to obtain the results. However, UTTB diagnostic requires a comprehensive approach and not just the use of a single test.

The initial treatment for TB in adults consists of the association of three or four different drugs, an intensive phase of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a continuation phase of 4 months of INH and RIF [9].

## **2. Epidemiology**

The 2017 edition of the World Health Organization global TB report includes data available from 201 countries and territories that account for over 99% of the world's population. In 2016, a total of 6.3 million new cases of TB were reported and extra-pulmonary TB represented 15% of the cases notified, ranging from 8% in the Western Pacific Region to 24% in the Eastern Mediterranean Region [10]. According to other registers, of the total TB cases reported, the most frequent types of extra-pulmonary TB were lymphatic (14.8–40.4%), pleural (7.8–19.8%), bones and/or joints (3.5–11%), and GUTB (1.7–6.5%) [11, 12]. Involvement of the kidneys is the most common form of tuberculosis of the genitourinary tract [13].

In UTTB, a history of pulmonary TB is present in 17.7–25.8% [14–16]. The time interval between the onset of primary pulmonary TB and development of GUTB has a mean interval of 3–10 years in more than 50% of patients [14, 15]. In frequency, renal involvement is the most common finding following by ureteric and bladder involvement [16]. Simultaneous involvement of kidney, ureter, and bladder has been reported until a 25.8% [15, 16]. The incidence of active pulmonary TB concurrent with UTTB varied from 10 to 25.8%.

The proportion of immune-compromising conditions, such as malignancy, diabetes mellitus, chronic renal failure, and immunosuppressive drug use, are found as 46.7% [14]. The incidence of TB has been estimated to be as much as 10-fold higher among renal failure patients than among the general population [17].

#### **3. Pathogenesis**

as being rare in children [4, 5]. Clinical renal TB is a chronic process that can start many years

Renal involvement in TB can be part of a disseminated infection or a localized GUTB disease. With renal disease progression, extensive areas of papillary necrosis can cause formation of cavities that destroy the renal parenchyma and can migrate into the collecting system. Advanced disease may cause obstructive uropathy, bladder defects, and loss of kidney function [7].

UTTB is underdiagnosed in most health care centers; the clinicians must have a high degree of suspicion for UTTB in patients presenting with non-specific symptoms, culture-negative, pyuria, and for whom imaging studies show some typical findings of UTTB. Acid fast bacilli (AFB) microscopy and Lowenstein Jensen (LJ) culture are the tests most used in health institutions. AFB stain has a poor sensitivity and false positive can result from mycobacteria external genital colonization or by the presence of precipitates that resemble AFB. Although, LJ cultures have a better sensitivity, it may require around 8 weeks to obtain growth and identification [8]. In addition to other forms of extra-pulmonary tuberculosis, the amplification tests of deoxyribonucleic acid (DNA) have been used with good results, increasing the sensitivity, specificity and shortening the time to obtain the results. However, UTTB diagnostic requires

The initial treatment for TB in adults consists of the association of three or four different drugs, an intensive phase of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and

The 2017 edition of the World Health Organization global TB report includes data available from 201 countries and territories that account for over 99% of the world's population. In 2016, a total of 6.3 million new cases of TB were reported and extra-pulmonary TB represented 15% of the cases notified, ranging from 8% in the Western Pacific Region to 24% in the Eastern Mediterranean Region [10]. According to other registers, of the total TB cases reported, the most frequent types of extra-pulmonary TB were lymphatic (14.8–40.4%), pleural (7.8–19.8%), bones and/or joints (3.5–11%), and GUTB (1.7–6.5%) [11, 12]. Involvement of the kidneys is the

In UTTB, a history of pulmonary TB is present in 17.7–25.8% [14–16]. The time interval between the onset of primary pulmonary TB and development of GUTB has a mean interval of 3–10 years in more than 50% of patients [14, 15]. In frequency, renal involvement is the most common finding following by ureteric and bladder involvement [16]. Simultaneous involvement of kidney, ureter, and bladder has been reported until a 25.8% [15, 16]. The incidence of

The proportion of immune-compromising conditions, such as malignancy, diabetes mellitus, chronic renal failure, and immunosuppressive drug use, are found as 46.7% [14]. The incidence of TB has been estimated to be as much as 10-fold higher among renal failure patients

ethambutol (EMB) followed by a continuation phase of 4 months of INH and RIF [9].

a comprehensive approach and not just the use of a single test.

most common form of tuberculosis of the genitourinary tract [13].

active pulmonary TB concurrent with UTTB varied from 10 to 25.8%.

than among the general population [17].

after the initial lung infection [6].

166 Tuberculosis

**2. Epidemiology**

Pulmonary infection is the primary focus in most cases of TB. After exposition, the bacilli remain stored in macrophages, where they slowly multiply, UTTB is the result of hematogenous spread from the lungs. Once the bacilli reach the circulation system, it can be distributed to all parts of the body, especially those sites with adequate conditions for its multiplication and with local immune deficiencies [18, 19]. The lymphatic nodes, encephalus, and urinary tract are some of the most frequent sites involved [20, 21].

The kidneys, and possibly the prostate and seminal vesicles, are often the primary sites of GUTB. All other genital organs, including the epididymis and bladder, become involved by ascent or descent of *Mtb* from a source elsewhere in the genitourinary tract [22]. *Mtb* bacilli are shed into the urine; they spread into the urinary tract, involving the renal pelvis, ureters and bladder; the urinary tract mucosa may be ulcerated, thin and without contractility [4]. In most patients, acquired cellular immunity develops and there is inhibition of bacilli multiplication and containment of the disease by the formation of microscopic granulomas, leading caseous necrosis with local tissue destruction [18].

The infection occurs initially in the medullary region, where granulomatous lesions can occur. If, in the course of primary infection, cell-mediated immunity develops and the proliferation of organisms is limited by competitive macrophages, this results in the formation of granulomas in which dormant bacilli can be maintained for long periods, leading caseous necrosis with local tissue destruction. When the bacilli are spilling down into the nephrons, they are trapped in the loop of Henle, establishing new foci of infection [18]. The multiple focus of microscopic necrosis lead macroscopic lesions that rapidly involve the renal papilla, causing fibrosis that can cause ureteral damage, with dilations intercalated with strictures, which constitutes an important TB sign on the pyelogram [23].

Sites of the urinary tract where there are natural narrow strictures, such as the calyceal neck, the pelvi-ureteric junction, and the uretero-vesical junction are the sites that suffer strictures more frequently. Steroid therapy may be useful in the early stages of scarring and could reduce the risk of stenosis that can lead to urinary obstruction and irreversible kidney damage [24]. A mass lesion may result from massive destruction and coalescence of granulomas, if they do not rupture into the adjoining calyx [25].

Hypercalcemia may occur, usually secondary to abnormal cortisol production by granulomatous tissue [26]. Although calcification is unusual in the early stages of the disease, nearly every end-stage tuberculosis kidney contains calcification. Hydronephrosis or hydrocalicosis may be the final stage, and may lead to a non-functioning, calcified kidney of any size; this process is called autonephrectomy [24].

#### **4. Clinical presentation**

UTTB has an insidious onset, no specific symptoms with atypical presentations [27], which lead to difficulty and delay the diagnosis in most health care centers [19, 20, 22, 28]. The majority


studies revealed urinalysis with pyuria and hematuria. Two serologies for antibodies to HIV were positive. The smear of urine staining with Ziehl-Neelsen (ZN) demonstrated AFB, and mycobacteria cultures were performed. Her chest x-ray showed diffuse bilateral infiltrates consistent with pulmonary tuberculosis (**Figures 1** and **2**). Renal ultrasonography (USG) showed both kidneys enlargement with marked dilation of renal pelvis and calyces. The findings on conventional urography were stricture sites of the ureters and renal pelvis with severe hydronephrosis and ureter distortion (**Figures 3** and **4**). An abdominal computed tomography (CT) showed a large abscess in psoas muscle (**Figures 5** and **6**). Initial empiric antimicrobial therapy with ceftriaxone, ciprofloxacin, and anti-TB therapy were started. The abscess was aspirated by external incision with complete drainage. Cultures for pyogenic bacteria of the psoas abscess and urine were both negatives. A polymerase chain reaction (PCR) test for *Mtb* in urine was

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positive (**Figure 7**). The patient was discharged home after 8 days of hospital stay.

**Figure 1.** Chest radiograph showing diffuse micro-nodular infiltrates in both lung fields.

**Figure 2.** Magnified view of the left down lobe shows multiple micro-nodular infiltrates.

The patient was re-admitted to the hospital 6 days after home stay. She continues with fever and abdominal discomfort. On the hospital day seven, her condition started to deteriorate

\*Year of publication; NR, not reported.

**Table 1.** Clinical and laboratory features in UTTB (percent).

of patients present local symptoms such as frequent voiding, dysuria, pyuria, pain (back, flank or abdominal), and microscopic or macroscopic hematuria [4, 28–31]. Systemic symptoms of fever, night sweats, weight loss, and anorexia are less common [4, 29–31].

In a series of 115 cases with GUTB, the most common symptoms were reported to be flank pain, nicturia, frequent voiding and dysuria [32]. Figueiredo and Lucon [33] reported that storage symptoms (urinary frequency, urgency, urgency incontinence, nocturia), dysuria, and hematuria were the most common symptoms on admission, affecting 50.5, 37.9 and 35.6% of cases, respectively. Loin pain and fever were reported less frequent (34.4 and 21.9%, respectively).

Lower urinary symptoms occur whenever the disease spreads down to the ureters and bladder. Urinary symptoms suggestive of urinary tract infection, accompanied by pyuria and hematuria with no bacterial growth, suggest UTTB [7, 21, 34]. Pyuria and/or microscopic hematuria are present in more than 90% of cases. Heavy proteinuria and cellular casts are not generally seen and the plasma creatinine concentration is usually normal [21]. Advanced disease may cause obstructive uropathy, bladder defects, and loss of kidney function [7]. **Table 1** summarized the most frequent findings in large recent series of UTTB.

#### **5. Case report**

A 43-year-old woman was admitted to the hospital for fever, dysuria, and gross hematuria. She has a history of 2 years with progressive malaise, weight loss, and recurrent episodes of fever and dysuria that were treated with different antibiotics. Renal TB was diagnosed 1.5 years prior, receiving treatment during 6 months, improving her clinical conditions. However, despite anti-TB therapy, she continued having recurrent episodes of fever and dysuria. She also reports having intermittent diarrhea for 1 year and fever with flank pain for 3 months. Her physical examination revealed a chronically ill woman with fever and oral candidosis. Cardiothoracic examination was normal with the exception of tachycardia. Abdominal examination revealed diffuse abdominal tenderness with flank pain, and lower limb edema was noted. Laboratory studies revealed urinalysis with pyuria and hematuria. Two serologies for antibodies to HIV were positive. The smear of urine staining with Ziehl-Neelsen (ZN) demonstrated AFB, and mycobacteria cultures were performed. Her chest x-ray showed diffuse bilateral infiltrates consistent with pulmonary tuberculosis (**Figures 1** and **2**). Renal ultrasonography (USG) showed both kidneys enlargement with marked dilation of renal pelvis and calyces. The findings on conventional urography were stricture sites of the ureters and renal pelvis with severe hydronephrosis and ureter distortion (**Figures 3** and **4**). An abdominal computed tomography (CT) showed a large abscess in psoas muscle (**Figures 5** and **6**). Initial empiric antimicrobial therapy with ceftriaxone, ciprofloxacin, and anti-TB therapy were started. The abscess was aspirated by external incision with complete drainage. Cultures for pyogenic bacteria of the psoas abscess and urine were both negatives. A polymerase chain reaction (PCR) test for *Mtb* in urine was positive (**Figure 7**). The patient was discharged home after 8 days of hospital stay.

The patient was re-admitted to the hospital 6 days after home stay. She continues with fever and abdominal discomfort. On the hospital day seven, her condition started to deteriorate

**Figure 1.** Chest radiograph showing diffuse micro-nodular infiltrates in both lung fields.

of patients present local symptoms such as frequent voiding, dysuria, pyuria, pain (back, flank or abdominal), and microscopic or macroscopic hematuria [4, 28–31]. Systemic symp-

**Fever Flank pain**

[13] Krishnamoorthy, India 2017 110 NR 27.3 25.5 11 NR 1.8 [14] Altiparmak, Turkey 2015 79 43 38 51 79.1 67.1 19 [15] Wagaskar, India 2016 31 29 45.1 32 19.4 NR 35.4 [16] Zhang, China 2016 120 22.5 49.1 60.8 25 NR NR [35] García-Rodríguez, Spain 1994 81 34.6 56.8 67.9 4.9 19.8 1.2 [36] Gokce, Turkey 2002 174 19.5 43.5 43.1 39.6 NR NR [37] Ye, China 2016 193 NR 49.2 61.1 63.2 19.2 NR

**Dysuria Hematuria Pyuria Renal** 

**failure**

In a series of 115 cases with GUTB, the most common symptoms were reported to be flank pain, nicturia, frequent voiding and dysuria [32]. Figueiredo and Lucon [33] reported that storage symptoms (urinary frequency, urgency, urgency incontinence, nocturia), dysuria, and hematuria were the most common symptoms on admission, affecting 50.5, 37.9 and 35.6% of cases, respectively. Loin pain and fever were reported less frequent (34.4 and 21.9%, respectively). Lower urinary symptoms occur whenever the disease spreads down to the ureters and bladder. Urinary symptoms suggestive of urinary tract infection, accompanied by pyuria and hematuria with no bacterial growth, suggest UTTB [7, 21, 34]. Pyuria and/or microscopic hematuria are present in more than 90% of cases. Heavy proteinuria and cellular casts are not generally seen and the plasma creatinine concentration is usually normal [21]. Advanced disease may cause obstructive uropathy, bladder defects, and loss of kidney function [7]. **Table 1**

A 43-year-old woman was admitted to the hospital for fever, dysuria, and gross hematuria. She has a history of 2 years with progressive malaise, weight loss, and recurrent episodes of fever and dysuria that were treated with different antibiotics. Renal TB was diagnosed 1.5 years prior, receiving treatment during 6 months, improving her clinical conditions. However, despite anti-TB therapy, she continued having recurrent episodes of fever and dysuria. She also reports having intermittent diarrhea for 1 year and fever with flank pain for 3 months. Her physical examination revealed a chronically ill woman with fever and oral candidosis. Cardiothoracic examination was normal with the exception of tachycardia. Abdominal examination revealed diffuse abdominal tenderness with flank pain, and lower limb edema was noted. Laboratory

toms of fever, night sweats, weight loss, and anorexia are less common [4, 29–31].

**no.**

**Ref Author, country Year\* Patients** 

168 Tuberculosis

\*Year of publication; NR, not reported.

**Table 1.** Clinical and laboratory features in UTTB (percent).

summarized the most frequent findings in large recent series of UTTB.

**5. Case report**

**Figure 2.** Magnified view of the left down lobe shows multiple micro-nodular infiltrates.

**Figure 3.** Intravenous urography revealing a non-functioning left kidney. Important deformity and dilatation of the collecting system, with ureteral tortuosity.

**Figure 4.** Left renal pelvis with severe hydronephrosis and ureteral distortion.

and she died despite aggressive support Mycobacterial culture media subsequently yielded

**Figure 7.** A representative image of PCR showing a DNA product of 200 base pairs for the first amplification. A positive

**Figure 6.** Axial CT revealing left psoas muscle abscess of 7 × 5 cm (1) and para-aortic lymph nodes (2).

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The diagnosis of UTTB is a challenge owing to the insidious onset of UTTB with few and nonspecific symptoms, technical difficulties to isolate *Mtb* and the long time required to confirm the diagnosis by classical conventional methods of cultivation, lack of awareness of physi-

The diagnosis of UTTB is usually performed in patients with clinical manifestations or abnormal urinalysis with findings that suggest UTTB. Urinalysis may vary from mild changes, such

*Mtb* susceptible to all primary anti-TB drugs.

control on the first line with a positive test on line 5.

cians, and poor care-seeking behavior [33, 38].

**6. Diagnostic approach**

**Figure 5.** Axial CT revealing involvement of left psoas muscle and para-aortic space with displacement of the left kidney.

**Figure 6.** Axial CT revealing left psoas muscle abscess of 7 × 5 cm (1) and para-aortic lymph nodes (2).

and she died despite aggressive support Mycobacterial culture media subsequently yielded *Mtb* susceptible to all primary anti-TB drugs.

#### **6. Diagnostic approach**

**Figure 4.** Left renal pelvis with severe hydronephrosis and ureteral distortion.

collecting system, with ureteral tortuosity.

170 Tuberculosis

**Figure 5.** Axial CT revealing involvement of left psoas muscle and para-aortic space with displacement of the left kidney.

**Figure 3.** Intravenous urography revealing a non-functioning left kidney. Important deformity and dilatation of the

The diagnosis of UTTB is a challenge owing to the insidious onset of UTTB with few and nonspecific symptoms, technical difficulties to isolate *Mtb* and the long time required to confirm the diagnosis by classical conventional methods of cultivation, lack of awareness of physicians, and poor care-seeking behavior [33, 38].

The diagnosis of UTTB is usually performed in patients with clinical manifestations or abnormal urinalysis with findings that suggest UTTB. Urinalysis may vary from mild changes, such as proteinuria and leukocyturia, to extreme pyuria, sometimes accompanied by hematuria. There are some characteristics in urine examination that suggest a diagnosis of renal TB, such as acid pH, leukocyturia and/or hematuria, associated with negative urine culture for the usual bacteria that causes urinary tract infection [23].

culture. The authors concluded that the nested PCR is superior in sensitivity and rapidity than the traditional methods [57]. Nested PCR display a better sensitivity than the first DNA amplification, increasing the detection limit from 10 pg to 10 fg that is equivalent to two cells in the second amplification. The great amount of DNA in the second step of the nested PCR make easy the detection; it has been reported that during the first amplification, many positive samples gave a relatively weak or doubtful band. In contrast, in the second amplification

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Although it is usually stated that imaging studies are only suggestive of the disease and should not be used for the confirmation or exclusion of UTTB [58], the intravenous urography (IVU) has been the image study more used for this entity; anatomical alterations of the collecting system can be seen with some facility. USG, CT, and magnetic resonance imaging (MRI) are less invasive methods that are better for detecting lesions in organs and tissues, including

UTTB commonly results from hematogenous spread from a pulmonary focus; nevertheless, only 36.5% of patients with UTTB have a previous diagnosis of TB or abnormal imaging studies [5]. Chest radiograph will be normal in half the patients [60]. But, only 10% of chest radio-

The greatest use of simple radiography is to demonstrate calcifications that can represent infections in extra-pulmonary sites, such as lymph nodes, liver, and spleen. Also, simple radiography can identify psoas abscesses and abnormalities of the spine [4, 62]. In UTTB, calcified lesions are mainly located in renal and upper collector system in 24–44% of cases [61], and this finding may be the first sign that TB is present [60]. Fine calcifications that were previously

Calcifications can be small calcifications, multiple, or large single calcifications [63]. These are usually amorphous calcifications located in the renal parenchyma or can take the form of the collecting system where they lodge and tend to be granular or curvilinear [22, 64]. The calcified caseous tissue in the kidneys may look like ground glass, known as "putty kidney". Premkumar et al. [65] termed "putty kidney" if the uniform calcification was greater than 1 cm in diameter. Apperson et al. [66] emphasized the difficulty of differentiating calcifications from calculi in renal TB. In their cases of renal TB, 9.3% had discrete calculi and 8.7% had parenchymal calcification.

IVU has been considered the radiographic procedure of choice due to its ability to show the collector system like no other, and less frequently modern techniques such as computerized axial tomography and magnetic resonance are also used [67]. Early findings are best demonstrated on contrast-enhanced tomography which is replacing IVU as the investigation of choice in that situation. In a retrospective study conducted in Spain, IVU guided the diagnosis

tumors, abscesses and calcifications; these can be done in addition to the IVU [59].

a a strong positive band was observed [57].

graph will show signs of active TB [60, 61].

unidentifiable are now much better seen with CT [59].

**6.3. Imaging studies**

*6.3.1. Plain radiograph*

*6.3.2. Intravenous urography*

There are several diagnostic methods for this entity. Here, we review the most common procedures used: (1) ZN staining and cultures isolation for *Mtb* in urine, (2) PCR for *Mtb*, (3) imaging studies, and (4) histopathological evidence for TB [14].

#### **6.1. ZN stain and cultures for** *Mtb* **in urine**

AFB can be seen in centrifuged urine by ZN staining, but it has low sensitivity when only few bacilli are seen. Also, it can be the result of urine contamination by non-pathogenic *Mycobacterium* spp., which can lead to false positive results [21].

Culture and identification provide a specific diagnosis, but might not be available for 2–3 weeks or longer. Multiple samplings should be obtained to increase test sensitivity; at least three different samples on LJ solid culture medium are recommended to maximize the likelihood of a positive result. Urine cultures are regularly negative, unless there is severe bladder dysfunction. Among patients with active renal TB, 30–40% of single urine specimens will be positive by *Mycobacterium* culture [39, 40]. BACTEC showed to be a better culture method compared to LJ, with a sensitivity of 37.5% and a specificity of 100% and the mean detection time for *Mtb* was 24.0 days by L-J medium culture versus only 12.8 days by BACTEC [41, 42].

#### **6.2. Polymerase chain reaction for** *Mtb*

The PCR assay has been extensively used as diagnosis in many forms of extra-pulmonary TB [43, 44], including some UTTB case reports [45, 46].

As a rapid and sensitive diagnostic method, PCR for *Mtb* identification in the urine has become the ideal diagnostic tool in recent years. It allows to make a diagnosis even when there are few bacilli and AFB detection is not possible. The sensitivity of AFB detection by ZN technique is between 42.1 and 52.1%. The sensitivities of culture methods vary from 10 to 90% while PCR in detecting *Mtb* in urine have a sensitivity that varies from 25 to 93% and a high specificity of 95–100% [38, 47–50]. In a prospective study in 42 patients where PCR was used, it showed a better sensitivity than the urine culture (80.9% against 30.9%); the author concludes that the PCR is far superior diagnosis technique for UTTB with high sensitivity and specificity, avoiding the retard of the start of therapy [51].

In the recent years, there has been important effort to increase the PCR for *Mtb* detection capacity, to avoid false positives by contamination and to determine his utility in different clinical samples [52–54]. In comparison with the traditional PCR of a single amplification, nested PCR consists of performing a second DNA step in order to increase sensitivity. According to the amount of DNA that is obtained, the nested PCR can enhance the sensitivity in approximately 1000 times than the PCR of a single amplification [55–57].

In a study with 417 clinical samples (including 28 of urine), the nested PCR for *Mtb* had a sensitivity of 97% and a specificity of 92% including positive results in some patients with negative culture. The authors concluded that the nested PCR is superior in sensitivity and rapidity than the traditional methods [57]. Nested PCR display a better sensitivity than the first DNA amplification, increasing the detection limit from 10 pg to 10 fg that is equivalent to two cells in the second amplification. The great amount of DNA in the second step of the nested PCR make easy the detection; it has been reported that during the first amplification, many positive samples gave a relatively weak or doubtful band. In contrast, in the second amplification a a strong positive band was observed [57].

#### **6.3. Imaging studies**

as proteinuria and leukocyturia, to extreme pyuria, sometimes accompanied by hematuria. There are some characteristics in urine examination that suggest a diagnosis of renal TB, such as acid pH, leukocyturia and/or hematuria, associated with negative urine culture for the

There are several diagnostic methods for this entity. Here, we review the most common procedures used: (1) ZN staining and cultures isolation for *Mtb* in urine, (2) PCR for *Mtb*, (3)

AFB can be seen in centrifuged urine by ZN staining, but it has low sensitivity when only few bacilli are seen. Also, it can be the result of urine contamination by non-pathogenic

Culture and identification provide a specific diagnosis, but might not be available for 2–3 weeks or longer. Multiple samplings should be obtained to increase test sensitivity; at least three different samples on LJ solid culture medium are recommended to maximize the likelihood of a positive result. Urine cultures are regularly negative, unless there is severe bladder dysfunction. Among patients with active renal TB, 30–40% of single urine specimens will be positive by *Mycobacterium* culture [39, 40]. BACTEC showed to be a better culture method compared to LJ, with a sensitivity of 37.5% and a specificity of 100% and the mean detection time for *Mtb*

The PCR assay has been extensively used as diagnosis in many forms of extra-pulmonary TB

As a rapid and sensitive diagnostic method, PCR for *Mtb* identification in the urine has become the ideal diagnostic tool in recent years. It allows to make a diagnosis even when there are few bacilli and AFB detection is not possible. The sensitivity of AFB detection by ZN technique is between 42.1 and 52.1%. The sensitivities of culture methods vary from 10 to 90% while PCR in detecting *Mtb* in urine have a sensitivity that varies from 25 to 93% and a high specificity of 95–100% [38, 47–50]. In a prospective study in 42 patients where PCR was used, it showed a better sensitivity than the urine culture (80.9% against 30.9%); the author concludes that the PCR is far superior diagnosis technique for UTTB with high sensitivity and specificity, avoid-

In the recent years, there has been important effort to increase the PCR for *Mtb* detection capacity, to avoid false positives by contamination and to determine his utility in different clinical samples [52–54]. In comparison with the traditional PCR of a single amplification, nested PCR consists of performing a second DNA step in order to increase sensitivity. According to the amount of DNA that is obtained, the nested PCR can enhance the sensitivity in approximately

In a study with 417 clinical samples (including 28 of urine), the nested PCR for *Mtb* had a sensitivity of 97% and a specificity of 92% including positive results in some patients with negative

was 24.0 days by L-J medium culture versus only 12.8 days by BACTEC [41, 42].

usual bacteria that causes urinary tract infection [23].

**6.1. ZN stain and cultures for** *Mtb* **in urine**

172 Tuberculosis

**6.2. Polymerase chain reaction for** *Mtb*

ing the retard of the start of therapy [51].

1000 times than the PCR of a single amplification [55–57].

[43, 44], including some UTTB case reports [45, 46].

imaging studies, and (4) histopathological evidence for TB [14].

*Mycobacterium* spp., which can lead to false positive results [21].

Although it is usually stated that imaging studies are only suggestive of the disease and should not be used for the confirmation or exclusion of UTTB [58], the intravenous urography (IVU) has been the image study more used for this entity; anatomical alterations of the collecting system can be seen with some facility. USG, CT, and magnetic resonance imaging (MRI) are less invasive methods that are better for detecting lesions in organs and tissues, including tumors, abscesses and calcifications; these can be done in addition to the IVU [59].

#### *6.3.1. Plain radiograph*

UTTB commonly results from hematogenous spread from a pulmonary focus; nevertheless, only 36.5% of patients with UTTB have a previous diagnosis of TB or abnormal imaging studies [5]. Chest radiograph will be normal in half the patients [60]. But, only 10% of chest radiograph will show signs of active TB [60, 61].

The greatest use of simple radiography is to demonstrate calcifications that can represent infections in extra-pulmonary sites, such as lymph nodes, liver, and spleen. Also, simple radiography can identify psoas abscesses and abnormalities of the spine [4, 62]. In UTTB, calcified lesions are mainly located in renal and upper collector system in 24–44% of cases [61], and this finding may be the first sign that TB is present [60]. Fine calcifications that were previously unidentifiable are now much better seen with CT [59].

Calcifications can be small calcifications, multiple, or large single calcifications [63]. These are usually amorphous calcifications located in the renal parenchyma or can take the form of the collecting system where they lodge and tend to be granular or curvilinear [22, 64]. The calcified caseous tissue in the kidneys may look like ground glass, known as "putty kidney". Premkumar et al. [65] termed "putty kidney" if the uniform calcification was greater than 1 cm in diameter.

Apperson et al. [66] emphasized the difficulty of differentiating calcifications from calculi in renal TB. In their cases of renal TB, 9.3% had discrete calculi and 8.7% had parenchymal calcification.

#### *6.3.2. Intravenous urography*

IVU has been considered the radiographic procedure of choice due to its ability to show the collector system like no other, and less frequently modern techniques such as computerized axial tomography and magnetic resonance are also used [67]. Early findings are best demonstrated on contrast-enhanced tomography which is replacing IVU as the investigation of choice in that situation. In a retrospective study conducted in Spain, IVU guided the diagnosis in 28/32 cases (87.5%), with calculus lesions, bladder alterations, hydronephrosis, calcifications and ureteral stenosis as the most common alterations [68]. However, 10–15% of patients with active UTTB may have normal urographic findings [69].

implementation of CT urography with multidetector technology improves the assessment of

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The disadvantages of CT include its inability to identify very early changes of TB such as small parenchymal and subtle papillary necrosis. UTTB is characterized by a vast presentation that is of great diagnostic value [19, 62, 81]. In early disease, CT can detect obstruction of a single major or a group of minor calyces as well as abnormalities in the collector system (dilatation or contraction of the renal pelvis). In advance disease, the kidneys are small with replacement of parenchyma by one or more low density areas. Parenchyma or calyces calcifications are seen at 37% [81]. Newer scanners, if used meticulously, may be able to identify small granulomas. The needs to use contrast and radiation issues, especially in young patients, are other

MRI provides morphological details of the kidneys as well as excellent delineation of the ureters [67]. It allows characterization of various renal masses and can provide valuable information contributing to their clinical management [82, 83]. It is particularly useful in pediatric or pregnant patients or when ionizing radiation and iodinated contrast cannot be administered.

Magnetic resonance urography (MRU) comprises an evolving group of techniques with the potential for optimal non-invasive evaluation of urinary tract abnormalities. Both static-fluid (non-contrast, heavily T2W sequences) and excretory MRU (performed during the excretory phase of enhancement after intravenous gadolinium) can be combined with conventional MRI for comprehensive evaluation of the urinary tract. MRU demonstrates the ureters in their entirety and is useful for confirming the presence of stenosis [84]. It is most successful in patients with moderately to severely dilated or obstructed collecting systems and in impaired renal function situations [84, 85]. MRU performed with a distended urinary bladder allows better visualization of the upper urinary tract [86]. Time-resolved dynamic contrast-enhanced MRU has been used in the evaluation of ureteral peristalsis in GUTB [87]. In view of the possibility of nephrogenic systemic, fibrosis/nephrogenic, fibrosing dermopathy, caution should be exercised while administering gadolinium in patients with compromised renal function [88]. There are very few articles available in the literature on MRU in renal TB and hence the

Sonographically guided FNAC is useful as a means of diagnosing of renal and genital (epididymitis and epididymo-orchitis) abscess or masses, and is of value in defining the granulomatous nature of sonographically visible lesions [72]. Histologic findings of renal or genital TB are similar to those of TB elsewhere in the body (granuloma formation, non-specific inflammatory infiltrate). The granulomas appear with central Langerhans cells surrounded by lymphocytes, fibrocytes, and epithelioid cells, which later progress to central caseous formation and varying degrees of fibrosis and calcification. AFB may be detected on FNAC smears in up

renal and urinary tract lesions using reformatted images [17].

limitations of CT studies that are not encountered on USG [78].

Non-contrast MRI is especially useful in patients with renal failure [67].

appearance of the same is still not widely known.

*6.3.6. Fine-needle aspiration cytology*

to 60% of these patients [72, 89].

*6.3.5. Magnetic resonance imaging*

Early alterations of UTTB are located mainly in calyces, UVI can show minimal calyceal dilation and loss of calyceal sharpness [61]. Although the calyceal damage is an early sign of UTTB, papillary necrosis could be the first sign observed [59]. As the disease progresses, the irregularity of the calices increases and may have a moth-eaten appearance [4, 25]. Other advanced manifestations include extensive cavitation, fibrotic strictures, cortical scars, mass lesions, calcification, autonephrectomy, perinephric abscess, and fistula formation [60].

#### *6.3.3. Ultrasonography*

USG is a readily available technique for demonstrating the various morphologic abnormalities found in renal TB [18, 70] and is a convenient method for guiding needles for fine-needle aspiration cytology (FNAC) [71, 72]. USG has convenient, low-priced, and non-invasive advantages; a disadvantage is that a mass may be missed if its echogenicity is similar to the renal parenchyma.

Traditionally, USG has been considered of less value than IVU or CT in UTTB cases [6, 73]. USG has limitations in detecting subtle urothelial lesions, as well as isoechoic parenchymal masses and is not useful for evaluating renal function [65, 69]. However, a well-detailed study can provide valuable information. In a large retrospective study, the coincidence rate of USG in the diagnosis of renal TB was 58.9% [74]. As the disease progresses, both an infiltrative pattern affecting the tissues and a pattern that affects the collecting system can be observed. In the first case, papillary destruction, calcifications, infected debris, hypoechoic masses or abscesses can be observed, in the second case dilated calyces, small renal pelvis, hydronephrosis, distortion of renal morphology, deformity of the ureters, and bladder atrophy can be found [75, 76].

On the USG, renal abscess is presented as a semi-solid echogenicity and a thick ill-defined wall that can extend and drain, causing perinephric abscess that later may cause a cutaneous fistula [21, 68].

#### *6.3.4. Computed tomography*

CT is useful both in the diagnosis of renal TB and in assessing its severity in terms of loss of renal function and involvement of other organs in the abdomen [77]. It directly visualizes the renal parenchyma, irrespective of renal function and, in addition, assesses extrarenal spread of the disease. The CT nephrogram is not as dependent on renal function as is an IVU. CT is also useful in identifying renal scars, mass lesions, and urothelial thickening, all of which are common findings in renal TB [78].

In general, CT shows more details of pathologic anatomy due to the availability of axial images for review and is superior to retrograde pyelography, IVU, and USG in detecting multiple small urothelial lesions [79]. It can detect calcification with greater accuracy, precision, and sensitivity [61] and is the most sensitive modality for identifying renal calcifications, which occur in over 50% of cases of GUTB [80]. CT is also the best modality for demonstrating the extent, nature, and distribution of calcification within the abnormal kidney [65]. The implementation of CT urography with multidetector technology improves the assessment of renal and urinary tract lesions using reformatted images [17].

The disadvantages of CT include its inability to identify very early changes of TB such as small parenchymal and subtle papillary necrosis. UTTB is characterized by a vast presentation that is of great diagnostic value [19, 62, 81]. In early disease, CT can detect obstruction of a single major or a group of minor calyces as well as abnormalities in the collector system (dilatation or contraction of the renal pelvis). In advance disease, the kidneys are small with replacement of parenchyma by one or more low density areas. Parenchyma or calyces calcifications are seen at 37% [81]. Newer scanners, if used meticulously, may be able to identify small granulomas. The needs to use contrast and radiation issues, especially in young patients, are other limitations of CT studies that are not encountered on USG [78].

#### *6.3.5. Magnetic resonance imaging*

in 28/32 cases (87.5%), with calculus lesions, bladder alterations, hydronephrosis, calcifications and ureteral stenosis as the most common alterations [68]. However, 10–15% of patients

Early alterations of UTTB are located mainly in calyces, UVI can show minimal calyceal dilation and loss of calyceal sharpness [61]. Although the calyceal damage is an early sign of UTTB, papillary necrosis could be the first sign observed [59]. As the disease progresses, the irregularity of the calices increases and may have a moth-eaten appearance [4, 25]. Other advanced manifestations include extensive cavitation, fibrotic strictures, cortical scars, mass lesions, calcification, autonephrectomy, perinephric abscess, and fistula formation [60].

USG is a readily available technique for demonstrating the various morphologic abnormalities found in renal TB [18, 70] and is a convenient method for guiding needles for fine-needle aspiration cytology (FNAC) [71, 72]. USG has convenient, low-priced, and non-invasive advantages; a disadvantage is that a mass may be missed if its echogenicity is similar to the renal parenchyma. Traditionally, USG has been considered of less value than IVU or CT in UTTB cases [6, 73]. USG has limitations in detecting subtle urothelial lesions, as well as isoechoic parenchymal masses and is not useful for evaluating renal function [65, 69]. However, a well-detailed study can provide valuable information. In a large retrospective study, the coincidence rate of USG in the diagnosis of renal TB was 58.9% [74]. As the disease progresses, both an infiltrative pattern affecting the tissues and a pattern that affects the collecting system can be observed. In the first case, papillary destruction, calcifications, infected debris, hypoechoic masses or abscesses can be observed, in the second case dilated calyces, small renal pelvis, hydronephrosis, distortion of renal morphology, deformity of the ureters, and bladder atrophy can be found [75, 76]. On the USG, renal abscess is presented as a semi-solid echogenicity and a thick ill-defined wall that can extend and drain, causing perinephric abscess that later may cause a cutaneous

CT is useful both in the diagnosis of renal TB and in assessing its severity in terms of loss of renal function and involvement of other organs in the abdomen [77]. It directly visualizes the renal parenchyma, irrespective of renal function and, in addition, assesses extrarenal spread of the disease. The CT nephrogram is not as dependent on renal function as is an IVU. CT is also useful in identifying renal scars, mass lesions, and urothelial thickening, all of which are

In general, CT shows more details of pathologic anatomy due to the availability of axial images for review and is superior to retrograde pyelography, IVU, and USG in detecting multiple small urothelial lesions [79]. It can detect calcification with greater accuracy, precision, and sensitivity [61] and is the most sensitive modality for identifying renal calcifications, which occur in over 50% of cases of GUTB [80]. CT is also the best modality for demonstrating the extent, nature, and distribution of calcification within the abnormal kidney [65]. The

with active UTTB may have normal urographic findings [69].

*6.3.3. Ultrasonography*

174 Tuberculosis

fistula [21, 68].

*6.3.4. Computed tomography*

common findings in renal TB [78].

MRI provides morphological details of the kidneys as well as excellent delineation of the ureters [67]. It allows characterization of various renal masses and can provide valuable information contributing to their clinical management [82, 83]. It is particularly useful in pediatric or pregnant patients or when ionizing radiation and iodinated contrast cannot be administered. Non-contrast MRI is especially useful in patients with renal failure [67].

Magnetic resonance urography (MRU) comprises an evolving group of techniques with the potential for optimal non-invasive evaluation of urinary tract abnormalities. Both static-fluid (non-contrast, heavily T2W sequences) and excretory MRU (performed during the excretory phase of enhancement after intravenous gadolinium) can be combined with conventional MRI for comprehensive evaluation of the urinary tract. MRU demonstrates the ureters in their entirety and is useful for confirming the presence of stenosis [84]. It is most successful in patients with moderately to severely dilated or obstructed collecting systems and in impaired renal function situations [84, 85]. MRU performed with a distended urinary bladder allows better visualization of the upper urinary tract [86]. Time-resolved dynamic contrast-enhanced MRU has been used in the evaluation of ureteral peristalsis in GUTB [87]. In view of the possibility of nephrogenic systemic, fibrosis/nephrogenic, fibrosing dermopathy, caution should be exercised while administering gadolinium in patients with compromised renal function [88]. There are very few articles available in the literature on MRU in renal TB and hence the appearance of the same is still not widely known.

#### *6.3.6. Fine-needle aspiration cytology*

Sonographically guided FNAC is useful as a means of diagnosing of renal and genital (epididymitis and epididymo-orchitis) abscess or masses, and is of value in defining the granulomatous nature of sonographically visible lesions [72]. Histologic findings of renal or genital TB are similar to those of TB elsewhere in the body (granuloma formation, non-specific inflammatory infiltrate). The granulomas appear with central Langerhans cells surrounded by lymphocytes, fibrocytes, and epithelioid cells, which later progress to central caseous formation and varying degrees of fibrosis and calcification. AFB may be detected on FNAC smears in up to 60% of these patients [72, 89].

The advantages of USG-guided FNAC are that it is rapid, inexpensive, versatile, does not require the injection of any contrast medium, and can be easily repeated when necessary [90]. USG-guided FNAC is now widely accepted as a safe diagnostic procedure in various neoplastic and non-neoplastic disorders [91, 92].

#### **7. Treatment**

A multidisciplinary approach with infectious disease and urology teams is crucial to provide optimal patient care; tuberculosis medications remain the cornerstone of treatment and surgical management is reserved for specific indications. There is lack of standardized treatment regimen for UTTB, it is accepted that pulmonary and extra-pulmonary TB should be treated with the same regimens.

The objectives of TB therapy are (1) to rapidly reduce the number of actively growing bacilli in the patient, thereby decreasing severity of the disease and preventing death (2) to eradicate populations of persisting bacilli in order to achieve durable cure (prevent relapse) after completion of therapy; and (3) to prevent acquisition of drug resistance during therapy.

#### **7.1. Medical treatment**

Clinical judgment and the index of suspicion for TB are critical in making a decision to initiate treatment [9, 14]. Therapy should be initiated promptly even before the results of AFB smear microscopy, molecular tests, and mycobacterial culture are known. It is particularly important in cases admitted with episodes of cystitis concomitant with sterile pyuria and progressive renal parenchymal damage not related to other clinical diseases [14]. If the diagnosis has been made while renal function still remains, it may be possible to arrest the fall in glomerular filtration rate or even produce improvement, using a combination of anti-TB treatment and corticosteroids [21].

Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (e.g., pregnant women; breastfeeding infants; persons infected with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or those who are of advanced age) [102, 103]. Although there is no studies that compare 5 with 7 daily doses, experts believe that the treatment of

**Table 3.** Recommended drug regimen for tuberculosis caused by drug-susceptible organisms when DOT is difficult to

**Drugs Interval and dose (minimum** 

doses (18 wk), or 5 d/wk for 90 doses (18 wk)

**Drugs Interval and dose (minimum** 

INH 3 times weekly for 54 doses (18 wk) 110–94

**duration)**

**Range of total doses**

Urinary Tract Tuberculosis

177

**Range of total doses**

182–130

http://dx.doi.org/10.5772/intechopen.76063

**duration)**

INH 7 d/wk for 126

DOT, directly observed therapy; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

DOT, directly observed therapy; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

**Table 2.** Recommended drug regimen for tuberculosis caused by drug-susceptible organisms.

Some authors propose that prolonged anti-TB treatment effectively sterilizes caseous and calcified masses of the involved kidney, whereas others believe that the sequestered caseous material should be removed to shorten the duration of medical therapy and to prevent late

Adequately controlled, randomized studies specific to UTTB comparing different treatment regimens have not been performed. Such studies would establish if short-course therapies are adequate to ensure eradication of UTTB, including patients with prostatic infection. There is little information about the vigilance and follow-up of patients with UTTB that may include at least monthly function renal tests, urine ZN smear, and *Mtb* cultures. ADN amplification tests for *Mtb* and imaging studies should be used on clinical judgment and probably performed at the end of both intensive and continues phases. Response to treatment may be difficult to assess and should be based on clinical, radiologic, and eradication of *Mtb* on subsequent

intensive phase with 5-days-a-week is as effective as 7-days-a-week [9].

**Intensive phase Continuation phase**

**Intensive phase Continuation phase**

**Drugs Interval and dose (minimum** 

5 d/wk for 40 doses

**Drugs Interval and dose (minimum** 

5 d/wk for 40 doses

RIF RIF

**duration)**

INH 7 d/wk for 56 doses (8 wk), or

(8 wk)

RIF RIF

**duration)**

INH 7 d/wk for 56 doses (8 wk), or

(8 wk)

PZA EMB

PZA EMB

achieve.

TB reactivation [28, 104].

cultures [94].

Fibrotic alterations can be decreased by use of corticosteroids in association with anti-TB drugs. However, despite these strategies, patients with advanced disease or those with a delayed diagnosis might require surgery [93]. The use of corticosteroids in addition to stenting for ureteral obstruction is discussed in the literature, and its efficacy in this setting remains unclear [94].

Regarding the duration of the UTTB treatment, the expert recommendation is that a standard daily 6-month regimen is adequate [12, 29, 31, 95, 96]. In countries where new cases of tuberculosis are resistant to organisms (resistant to isoniazid ≥4%), it is recommended to use four drugs in the intensive phase: INH, RIF, PZA, and EMB [97–101].

Two regimens can be used. The first-line regimen, which is used for 6 months, is with INH, RIF, PZA, and EMB administered daily or 5 days per week for 2 or 3 months, followed by INH and RIF daily or 5 days per week for 3 or 4 months [93]. The second-line regimen, which is recommended for TB caused by drug-susceptible organisms when directly observed therapy (DOT) is difficult to achieve, it consist of INH, RIF, PZA, and EMB daily or 5 days per week for 2 or 3 months, followed by INH and RIF 3 times a week, for 3 or 4 months (**Tables 2** and **3**) [9].


DOT, directly observed therapy; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

**Table 2.** Recommended drug regimen for tuberculosis caused by drug-susceptible organisms.

The advantages of USG-guided FNAC are that it is rapid, inexpensive, versatile, does not require the injection of any contrast medium, and can be easily repeated when necessary [90]. USG-guided FNAC is now widely accepted as a safe diagnostic procedure in various neoplas-

A multidisciplinary approach with infectious disease and urology teams is crucial to provide optimal patient care; tuberculosis medications remain the cornerstone of treatment and surgical management is reserved for specific indications. There is lack of standardized treatment regimen for UTTB, it is accepted that pulmonary and extra-pulmonary TB should be treated

The objectives of TB therapy are (1) to rapidly reduce the number of actively growing bacilli in the patient, thereby decreasing severity of the disease and preventing death (2) to eradicate populations of persisting bacilli in order to achieve durable cure (prevent relapse) after completion of therapy; and (3) to prevent acquisition of drug resistance during therapy.

Clinical judgment and the index of suspicion for TB are critical in making a decision to initiate treatment [9, 14]. Therapy should be initiated promptly even before the results of AFB smear microscopy, molecular tests, and mycobacterial culture are known. It is particularly important in cases admitted with episodes of cystitis concomitant with sterile pyuria and progressive renal parenchymal damage not related to other clinical diseases [14]. If the diagnosis has been made while renal function still remains, it may be possible to arrest the fall in glomerular filtration rate or even produce improvement, using a combination of anti-TB treatment and

Fibrotic alterations can be decreased by use of corticosteroids in association with anti-TB drugs. However, despite these strategies, patients with advanced disease or those with a delayed diagnosis might require surgery [93]. The use of corticosteroids in addition to stenting for ureteral obstruction is discussed in the literature, and its efficacy in this setting remains unclear [94].

Regarding the duration of the UTTB treatment, the expert recommendation is that a standard daily 6-month regimen is adequate [12, 29, 31, 95, 96]. In countries where new cases of tuberculosis are resistant to organisms (resistant to isoniazid ≥4%), it is recommended to use four

Two regimens can be used. The first-line regimen, which is used for 6 months, is with INH, RIF, PZA, and EMB administered daily or 5 days per week for 2 or 3 months, followed by INH and RIF daily or 5 days per week for 3 or 4 months [93]. The second-line regimen, which is recommended for TB caused by drug-susceptible organisms when directly observed therapy (DOT) is difficult to achieve, it consist of INH, RIF, PZA, and EMB daily or 5 days per week for 2 or 3 months, followed by INH and RIF 3 times a week, for 3 or 4 months (**Tables 2** and **3**) [9].

drugs in the intensive phase: INH, RIF, PZA, and EMB [97–101].

tic and non-neoplastic disorders [91, 92].

**7. Treatment**

176 Tuberculosis

with the same regimens.

**7.1. Medical treatment**

corticosteroids [21].


**Table 3.** Recommended drug regimen for tuberculosis caused by drug-susceptible organisms when DOT is difficult to achieve.

Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (e.g., pregnant women; breastfeeding infants; persons infected with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or those who are of advanced age) [102, 103]. Although there is no studies that compare 5 with 7 daily doses, experts believe that the treatment of intensive phase with 5-days-a-week is as effective as 7-days-a-week [9].

Some authors propose that prolonged anti-TB treatment effectively sterilizes caseous and calcified masses of the involved kidney, whereas others believe that the sequestered caseous material should be removed to shorten the duration of medical therapy and to prevent late TB reactivation [28, 104].

Adequately controlled, randomized studies specific to UTTB comparing different treatment regimens have not been performed. Such studies would establish if short-course therapies are adequate to ensure eradication of UTTB, including patients with prostatic infection. There is little information about the vigilance and follow-up of patients with UTTB that may include at least monthly function renal tests, urine ZN smear, and *Mtb* cultures. ADN amplification tests for *Mtb* and imaging studies should be used on clinical judgment and probably performed at the end of both intensive and continues phases. Response to treatment may be difficult to assess and should be based on clinical, radiologic, and eradication of *Mtb* on subsequent cultures [94].

To maximize completion of therapy, management strategies should utilize a broad range of approaches. Among these, DOT is the practice of observing the patient swallow their anti-TB drugs and has been widely used as the standard of practice in many TB programs. DOT can be advantageous for early recognition of adverse drug reactions and treatment irregularities. DOT remains the standard of practice in the majority of TB programs in the United States [105, 106] and Europe [107].

of adverse events. Whenever possible, the use of combination formulations, both antitubercu-

Urinary Tract Tuberculosis

179

http://dx.doi.org/10.5772/intechopen.76063

The recommendation for HIV-infected patients receiving ARV and initial TB disease with susceptible *Mtb* is a short course of 6 months of therapy. During the first 2 months of daily regimen (initial phase), patients should be treated with INH, RIF, PZA, and EMB. This is followed by a continuation phase of 4 months of INH plus RIF thrice-weekly regimen. HIV-infected patients that still do not receive ARV; the recommendation is to extend the continuation phase with INH and RIF for additional 3 months (i.e., a continuation phase of 7 months in duration,

Once a week, TB continuation phase regimen can be safe and effective treating pulmonary TB in HIV-negative patients without cavitation on chest radiography [116]. However, relapses and rifamycin monoresistant tuberculosis occurs among HIV infected patients treated with a once-weekly isoniazid/rifapentine during continuation phase regimen [117]. A study with 169 HIV-infected patients and pulmonary TB, nine (5.3%) had failure or relapse, eight of these nine isolates were detected with acquired rifamycin resistance, low CD4 lymphocyte counts and the use of twice-weekly therapy during intensive phase were the most important factors associated [118]. Lower plasma rifabutin and INH concentrations are associated with acquir-

HIV/TB co-infected patients treated during continuation phases with thrice-weekly anti-TB regimen showed a higher risk of relapse and death as well as emergence of rifamycin resistance compared with HIV-uninfected patients. ARV therapy reduces but does not eliminate the risk of these complications [120]. A prompt diagnosis of HIV, earlier ARV initiation, and avoiding intermittent TB treatment regimens could prevent relapses and drug resistance emergence. Rifabutin can be substituted for RIF to decrease drug interactions with drugs used in the treatment of HIV

Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical clinical worsening of a known or new condition occurring shortly after initiating ARV therapy, mainly in patients with low CD4+ cell counts [121]. *Mtb* is among the most frequently reported pathogen associated with IRIS; signs may include high fever, lymphadenopathy, worsening of respiratory symptoms, new pulmonary infiltrates, and pleural effusions. Extra-pulmonary presentations are also possible expanding to central nervous system, intra-abdominal abscesses, osteomyelitis, and others [122]. For more severe cases of IRIS, treatment with corticosteroids is effective. In a placebo-controlled trial of prednisone for patients with moderate IRIS, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures [123].

Renal TB can result in acute or chronic renal failure with an incidence of 24%. If renal TB progresses to chronic kidney disease (CKD), it has effects in the immune system too. The alterations on systemic immunity included persistent systemic inflammation and acquired immunosuppression state [124]. The mechanisms associated with end-stage renal disease

include obliterative endarteritis, renal amyloidosis, and obstructive uropathy [7, 93].

infection (protease inhibitors and transcriptase reverse non-nucleoside inhibitors) [9].

lous and ARV drugs, is recommended in order to simplify the treatment.

corresponding to a total of 9 months of therapy) [9].

ing rifamycin resistance [119].

*7.3.2. Renal failure*

Gastrointestinal and skin disorders adverse reactions are common; the frequency can reach up to 30% especially early in therapy. Less frequent adverse events are muscle-joints disorders, fever, headache, hepatic problems, and even death [108, 109]. Four-drug fixed-doses therapy may reduce the incidence of gastrointestinal adverse effects and the use of antacids or proton pump inhibitors for reducing gastrointestinal can contribute to better tolerance with minor impact on drugs absorption [110]. INH, RIF, and PZA can cause drug-induced liver injury that is the most frequent serious adverse event [111]. It is necessary to promote some strategies that improve the quality of patient care and to control TB safely, treating preexisting diseases or dysfunctions, such as diabetes and alcoholism. These strategies may improve the patient adherence to treatment and therapeutic outcome.

#### **7.2. Invasive procedures**

Invasive procedures or surgery are indicated in certain situations: hydronephrosis drainage (ureter dilation or percutaneous nephrostomy), abscesses and collection drainage, definitive treatment of renal TB (partial nephrectomy), superior urinary tract reconstruction, bladder dilation, ureter reconstruction and others [112]. In a study of 4298 patients with GUTB, 2364 (37%) underwent surgery: remove or preserve an organ and reconstruction surgery were the most frequent interventions. Other surgical modalities included ureteral neoimplantation using intestinal transplants (ileocystoplasty, sigmoidocystoplasty, and cecocystoplasty) [113].

Other surgical intervention can be double-J stenting use and percutaneous nephrostomy for hydronephrosis cases, drainage of abscesses, partial or polar nephrectomy, reconstruction of the upper urinary tract, and bladder augmentation with ileum replacement [114].

The standard treatment for a unilateral nonfunctional kidney secondary to renal TB is a nephrectomy combined with anti-TB therapy [16]. The patients that end up in nephrectomy have an advanced stage [13, 37]. Nephrectomy is recommended only in cases of secondary sepsis, bleeding, pain, uncontrollable hypertension, and continued positive urinary cultures for *Mtb* [38].

Radical or reconstructive surgical interventions are recommended be carried out in the first 2 months of intensive GUTB therapy [115].

#### **7.3. Treatment of special situations**

#### *7.3.1. Patients with HIV infection*

HIV and TB create a deadly synergy, speeding the progression of both diseases. HIV enhances the reactivation and progression of latent TB to overt TB disease. The treatment represents a challenge were the most significant concern is to avoid drug-drug interactions and the control of adverse events. Whenever possible, the use of combination formulations, both antituberculous and ARV drugs, is recommended in order to simplify the treatment.

The recommendation for HIV-infected patients receiving ARV and initial TB disease with susceptible *Mtb* is a short course of 6 months of therapy. During the first 2 months of daily regimen (initial phase), patients should be treated with INH, RIF, PZA, and EMB. This is followed by a continuation phase of 4 months of INH plus RIF thrice-weekly regimen. HIV-infected patients that still do not receive ARV; the recommendation is to extend the continuation phase with INH and RIF for additional 3 months (i.e., a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) [9].

Once a week, TB continuation phase regimen can be safe and effective treating pulmonary TB in HIV-negative patients without cavitation on chest radiography [116]. However, relapses and rifamycin monoresistant tuberculosis occurs among HIV infected patients treated with a once-weekly isoniazid/rifapentine during continuation phase regimen [117]. A study with 169 HIV-infected patients and pulmonary TB, nine (5.3%) had failure or relapse, eight of these nine isolates were detected with acquired rifamycin resistance, low CD4 lymphocyte counts and the use of twice-weekly therapy during intensive phase were the most important factors associated [118]. Lower plasma rifabutin and INH concentrations are associated with acquiring rifamycin resistance [119].

HIV/TB co-infected patients treated during continuation phases with thrice-weekly anti-TB regimen showed a higher risk of relapse and death as well as emergence of rifamycin resistance compared with HIV-uninfected patients. ARV therapy reduces but does not eliminate the risk of these complications [120]. A prompt diagnosis of HIV, earlier ARV initiation, and avoiding intermittent TB treatment regimens could prevent relapses and drug resistance emergence. Rifabutin can be substituted for RIF to decrease drug interactions with drugs used in the treatment of HIV infection (protease inhibitors and transcriptase reverse non-nucleoside inhibitors) [9].

Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical clinical worsening of a known or new condition occurring shortly after initiating ARV therapy, mainly in patients with low CD4+ cell counts [121]. *Mtb* is among the most frequently reported pathogen associated with IRIS; signs may include high fever, lymphadenopathy, worsening of respiratory symptoms, new pulmonary infiltrates, and pleural effusions. Extra-pulmonary presentations are also possible expanding to central nervous system, intra-abdominal abscesses, osteomyelitis, and others [122]. For more severe cases of IRIS, treatment with corticosteroids is effective. In a placebo-controlled trial of prednisone for patients with moderate IRIS, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures [123].

#### *7.3.2. Renal failure*

To maximize completion of therapy, management strategies should utilize a broad range of approaches. Among these, DOT is the practice of observing the patient swallow their anti-TB drugs and has been widely used as the standard of practice in many TB programs. DOT can be advantageous for early recognition of adverse drug reactions and treatment irregularities. DOT remains the standard of practice in the majority of TB programs in the United States

Gastrointestinal and skin disorders adverse reactions are common; the frequency can reach up to 30% especially early in therapy. Less frequent adverse events are muscle-joints disorders, fever, headache, hepatic problems, and even death [108, 109]. Four-drug fixed-doses therapy may reduce the incidence of gastrointestinal adverse effects and the use of antacids or proton pump inhibitors for reducing gastrointestinal can contribute to better tolerance with minor impact on drugs absorption [110]. INH, RIF, and PZA can cause drug-induced liver injury that is the most frequent serious adverse event [111]. It is necessary to promote some strategies that improve the quality of patient care and to control TB safely, treating preexisting diseases or dysfunctions, such as diabetes and alcoholism. These strategies may improve the

Invasive procedures or surgery are indicated in certain situations: hydronephrosis drainage (ureter dilation or percutaneous nephrostomy), abscesses and collection drainage, definitive treatment of renal TB (partial nephrectomy), superior urinary tract reconstruction, bladder dilation, ureter reconstruction and others [112]. In a study of 4298 patients with GUTB, 2364 (37%) underwent surgery: remove or preserve an organ and reconstruction surgery were the most frequent interventions. Other surgical modalities included ureteral neoimplantation using intestinal transplants (ileocystoplasty, sigmoidocystoplasty, and cecocystoplasty) [113]. Other surgical intervention can be double-J stenting use and percutaneous nephrostomy for hydronephrosis cases, drainage of abscesses, partial or polar nephrectomy, reconstruction of

the upper urinary tract, and bladder augmentation with ileum replacement [114].

The standard treatment for a unilateral nonfunctional kidney secondary to renal TB is a nephrectomy combined with anti-TB therapy [16]. The patients that end up in nephrectomy have an advanced stage [13, 37]. Nephrectomy is recommended only in cases of secondary sepsis, bleeding, pain, uncontrollable hypertension, and continued positive urinary cultures for *Mtb* [38].

Radical or reconstructive surgical interventions are recommended be carried out in the first

HIV and TB create a deadly synergy, speeding the progression of both diseases. HIV enhances the reactivation and progression of latent TB to overt TB disease. The treatment represents a challenge were the most significant concern is to avoid drug-drug interactions and the control

[105, 106] and Europe [107].

178 Tuberculosis

**7.2. Invasive procedures**

patient adherence to treatment and therapeutic outcome.

2 months of intensive GUTB therapy [115].

**7.3. Treatment of special situations**

*7.3.1. Patients with HIV infection*

Renal TB can result in acute or chronic renal failure with an incidence of 24%. If renal TB progresses to chronic kidney disease (CKD), it has effects in the immune system too. The alterations on systemic immunity included persistent systemic inflammation and acquired immunosuppression state [124]. The mechanisms associated with end-stage renal disease include obliterative endarteritis, renal amyloidosis, and obstructive uropathy [7, 93].

The patients with CKD by other etiology are at increased risk of TB than those with normal renal function. Drug-induced hepatitis and all-cause mortality are more common among TB patients with CKD [125]. One of principal factors to consider in TB treatment with CKD included drug pharmacokinetics, drugs removed by hemodialysis that should be dosed after dialysis [126]. INH, RIF, and EMB are not significantly dialyzed. However, PZA is removed by hemodialysis and should be administered after hemodialysis [127]. Other factors included co-existent illnesses, dosage adjustment, drug interactions, and drug accumulate predisposing to toxicities. Initial regimen with standard doses and no more than three times weekly for PZA, EMB, and aminoglycosides is recommended [128].

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The fluoroquinolones used for TB treatment are levofloxacin, moxifloxacin, and gatifloxacin. According to degree of renal impairment, levofloxacin dosage adjustment is required. Nevertheless, neither hemodialysis nor continuous ambulatory peritoneal dialysis removed levofloxacin [129]. Moxifloxacin may be administered at the normal dosage even with severe renal failure [130].

#### *7.3.3. Advanced age*

Age over 60 years is significantly associated with serious adverse events related to INH, PZA, and RIF, with greater frequency of hepatitis episodes and gastrointestinal intolerance [131, 132]. However, the risk of hepatotoxicity in advanced age might not increase after 12 weeks with standard treatment containing INH and RIF [133]. The severity of INHinduced hepatitis has been associated with higher mortality in this patient population [131]. Dose adjustments or alternative regiments should be considered to avoid stopping the treatment, increasing the probability of failure and mortality [9, 134]. The duration of TB treatment depends of initial regimen during the intensive phase [9].

#### **Author details**

Gerardo Amaya-Tapia1,2\* and Guadalupe Aguirre-Avalos1,3

\*Address all correspondence to: gamaya@cencar.udg.mx

1 Centro Universitario Ciencias de la Salud at Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

2 Infectious Diseases Department at Hospital General de Occidente, Guadalajara, Jalisco, Mexico

3 Intensive Care Unit at Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico

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The patients with CKD by other etiology are at increased risk of TB than those with normal renal function. Drug-induced hepatitis and all-cause mortality are more common among TB patients with CKD [125]. One of principal factors to consider in TB treatment with CKD included drug pharmacokinetics, drugs removed by hemodialysis that should be dosed after dialysis [126]. INH, RIF, and EMB are not significantly dialyzed. However, PZA is removed by hemodialysis and should be administered after hemodialysis [127]. Other factors included co-existent illnesses, dosage adjustment, drug interactions, and drug accumulate predisposing to toxicities. Initial regimen with standard doses and no more than three times weekly for

The fluoroquinolones used for TB treatment are levofloxacin, moxifloxacin, and gatifloxacin. According to degree of renal impairment, levofloxacin dosage adjustment is required. Nevertheless, neither hemodialysis nor continuous ambulatory peritoneal dialysis removed levofloxacin [129]. Moxifloxacin may be administered at the normal dosage even with severe

Age over 60 years is significantly associated with serious adverse events related to INH, PZA, and RIF, with greater frequency of hepatitis episodes and gastrointestinal intolerance [131, 132]. However, the risk of hepatotoxicity in advanced age might not increase after 12 weeks with standard treatment containing INH and RIF [133]. The severity of INHinduced hepatitis has been associated with higher mortality in this patient population [131]. Dose adjustments or alternative regiments should be considered to avoid stopping the treatment, increasing the probability of failure and mortality [9, 134]. The duration of TB treatment

1 Centro Universitario Ciencias de la Salud at Universidad de Guadalajara, Guadalajara,

2 Infectious Diseases Department at Hospital General de Occidente, Guadalajara, Jalisco,

3 Intensive Care Unit at Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara,

[1] Rieder HL, Snider DE Jr, Cauthen GM. Extrapulmonary tuberculosis in the United

States. The American Review of Respiratory Disease. 1990;**141**:347-351

PZA, EMB, and aminoglycosides is recommended [128].

depends of initial regimen during the intensive phase [9].

Gerardo Amaya-Tapia1,2\* and Guadalupe Aguirre-Avalos1,3

\*Address all correspondence to: gamaya@cencar.udg.mx

renal failure [130].

180 Tuberculosis

*7.3.3. Advanced age*

**Author details**

Jalisco, Mexico

Jalisco, Mexico

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## *Edited by Jean-Marie Ntumba Kayembe*

Tuberculosis is an ancient disease with a high incidence and mortality rate, unequally distributed worldwide. Epidemiological indicators, but also risk factors, play a key role in the natural history of the disease and need to be regulary addressed. Low and middle income countries are not prepared for appropriate response and are also the most affected. The incidence of this extrapulmonary disease is far from being clearly established. Epidemiological studies in different geographical areas will help in this field.

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Tuberculosis

Tuberculosis