**Sarcomatoid Squamous Cell Carcinoma**

Charmaine C. Anderson, Brian H. Le and Bernice Robinson-Bennett *The Reading Hospital and Medical Center USA* 

#### **1. Introduction**

52 Squamous Cell Carcinoma

Vermorken, J. B., R. Mesia, et al. (2008). "Platinum-based chemotherapy plus cetuximab in

Wang, L. X. and M. Agulnik (2008). "Promising newer molecular-targeted therapies in head

Wollina, U., G. Hansel, et al. (2005). "Oral capecitabine plus subcutaneous interferon alpha

in advanced squamous cell carcinoma of the skin." *J Cancer Res Clin Oncol* 131(5):

head and neck cancer." *N Engl J Med* 359(11): 1116-27.

and neck cancer." *Drugs* 68(12): 1609-19.

300-4.

Although much has been characterized about squamous cell carcinoma of the lower female reproductive tract, there is limited knowledge and experience with cases demonstrating squamous cell carcinoma with sarcomatoid features. Sarcomatoid squamous cell carcinoma (SSCC) is mainly found in the upper aerodigestive tract with the larynx being the most common site in the head and neck region. (Otay et al., 2011) The esophagus and skin are other well known affected sites. In these sites, risk factors include, smoking, alcohol consumption, and previous irradiation of the head and neck region. (Otay et al., 2011) Risk factors for skin involvement include prolonged sun exposure and the effects of toxins and irradiation.

True sarcomas of the lower female genital tract arising in the vulva, vagina, and cervix, are extremely rare. They comprise only 1-2% of vulvar cancers, 2% of vaginal cancers (Temkin et.al,2007), 2-3% of cervical cancers, and 3% of endometrial cancers. They tend to be heterogeneous, rapidly progressive, with a high rate of recurrence and distant metastasis to organs such as liver and lungs. For the vulva and vagina, the main sites of occurrence are the labium majus and upper vagina, respectively. Leiomyosarcomas are the most common type of sarcoma in the female genital tract where several factors have been demonstrated to play a role in recurrence including tumor diameter, cytologic atypia, mitotic index, and infiltrating margins. Although there are no specific treatment guidelines, the mainstay of therapy has been surgical excision followed by chemotherapy. Neoadjuvant chemotherapy has been used in patients who have bulky tumors in which surgical debulking had not been optimal. Currently, some believe that neoadjuvant chemotherapy can also be used as primary therapy followed by surgical debulking regardless of tumor. It is thought that this treatment strategy can optimize surgical excision, giving rise to less morbidity, and a longer disease-free interval. (Temkin et.al,2007) The role of radiation therapy has been controversial as some believe that sarcomas themselves are induced by a history of radiation therapy or exposure. Nevertheless, there have been reports of radiation lengthening the time interval to local recurrence.

Sarcomatoid squamous cell carcinoma of the female genital tract has been reported in very small numbers. Human Papilloma Virus (HPV) has been known to be a major causal factor for the development of SCC. High risk subtypes of Human Papilloma Virus, 16 and 18, have been demonstrated in not only the squamous cell component of SSCC but also in the

Sarcomatoid Squamous Cell Carcinoma 55

IF-LN= inguino-femoral lymph node metastasis, P-LN= pelvic lymph node metastasis, DFI= disease free interval, NA= not available, SCC= squamous cell carcinoma, NED= no evidence of disease, RV= radical vulvectomy, LND= lymph node dissection, CTx= chemotherapy, RTx= radiation therapy

Four cases of vaginal SSCC have been reported, with our current case constituting the fifth.

Table 2. SSCC of the Vulva Reported Cases in the Literature (D.-S. Choi et al, 2006)

sarcomatoid component. Making immunohistochemical assays of this cancer a hallmark to diagnosis to differentiate pure squamous cell carcinoma from a pure sarcoma.

Like pure sarcomas, Sarcomatoid Squamous Cell Carcinoma has a very poor prognosis, short disease-free intervals, and is diagnosed at later stages of disease. Even with optimal treatment and follow up, SSCC recur rapidly and metastasize to regions such as the peritoneum, kidney, and subcutaneous tissue. Most cases of SSCC of the female genitalia have been reported to arise from the cervix and vulva. There are currently 16 cases of cervical and vulvar SSCC reported in the English literature to date. (Tae-Wook Kong et. al., 2010 and Dong-Seok Choi et. al., 2006), with our current case of vulvar SSCC making up the 17th case.

SSCC of the Cervix Literature Review


Table 1. **SSCC of the Cervix Reported Cases in the Literature (Tae-Wook King et al, 2010)**  N/A= not available, ER= external pelvic radiation therapy, RAH= radical abdominal hysterectomy, CRT= chemoradiation therapy, TAH= total abdominal hysterectomy, LRH= laparoscopic radical hysterectomy, PD= progressive disease, RD= recurrent disease, CR= complete remission, DOD= dead of disease, NED= no evidence of disease

sarcomatoid component. Making immunohistochemical assays of this cancer a hallmark to

Like pure sarcomas, Sarcomatoid Squamous Cell Carcinoma has a very poor prognosis, short disease-free intervals, and is diagnosed at later stages of disease. Even with optimal treatment and follow up, SSCC recur rapidly and metastasize to regions such as the peritoneum, kidney, and subcutaneous tissue. Most cases of SSCC of the female genitalia have been reported to arise from the cervix and vulva. There are currently 16 cases of cervical and vulvar SSCC reported in the English literature to date. (Tae-Wook Kong et. al., 2010 and Dong-Seok Choi et. al., 2006), with our current case of vulvar SSCC making up the

Table 1. **SSCC of the Cervix Reported Cases in the Literature (Tae-Wook King et al, 2010)**  N/A= not available, ER= external pelvic radiation therapy, RAH= radical abdominal hysterectomy, CRT= chemoradiation therapy, TAH= total abdominal hysterectomy, LRH= laparoscopic radical hysterectomy, PD= progressive disease, RD= recurrent disease, CR=

complete remission, DOD= dead of disease, NED= no evidence of disease

diagnosis to differentiate pure squamous cell carcinoma from a pure sarcoma.

17th case.

SSCC of the Cervix Literature Review


IF-LN= inguino-femoral lymph node metastasis, P-LN= pelvic lymph node metastasis, DFI= disease free interval, NA= not available, SCC= squamous cell carcinoma, NED= no evidence of disease, RV= radical vulvectomy, LND= lymph node dissection, CTx= chemotherapy, RTx= radiation therapy

Table 2. SSCC of the Vulva Reported Cases in the Literature (D.-S. Choi et al, 2006) Four cases of vaginal SSCC have been reported, with our current case constituting the fifth.

Sarcomatoid Squamous Cell Carcinoma 57

immunohistochemistry for p16 and in situ hybridization for high risk human Papilloma virus (HPV) subtypes was performed; this demonstrated that the tumor was, indeed, an HPV-driven malignancy compatible with sarcomatoid squamous cell carcinoma. Following a course of chemotherapy and radiation therapy, the patient presented two years later with deep vein thrombosis and obstructive uropathy, with subsequent biopsy demonstrating

 Fig. 1. Sarcomatoid squamous cell carcinoma of the vagina. (A) The lesion is characterized exclusively by spindled cells, architecturally arranged in fascicles. No in situ or conventional squamous cell morphology is apparent [200x original magnification]. (B) High-power magnification shows spindled cells with abundant mitotic figures [400x original

magnification]. (C) Neoplastic cells show diffuse nuclear reactivity for p16, indicative of a HPV-driven tumor [400x original magnification]. (D) Chromogenic in situ hybridization for high-risk HPV subtypes demonstrates diffuse nuclear chromogenic labeling (in blue dot

Case number two: 78 year old Para 1 woman with long-standing vulvar irritation presented with a 4cm vulvar lesion. She underwent biopsies that demonstrated a high-grade vulvar intraepithelial lesion (VIN III, carcinoma in situ), and subsequent wide local excision showed involved margins. Four years later, she re-presented with a 4cm, enlarging vulva mass; excision of this mass revealed an invasive, poorly differentiated Sarcomatoid Squamous Cell Carcinoma (SSCC), again with positive margins. She subsequently underwent a bilateral simple hemivulvectomy with pathology demonstrating involvement of the urethral margin,

pattern) [400x original magnification].

recurrent metastatic squamous cell carcinoma involving the ureter.

1A 1B

1C 1D


Table 3. SSCC of the Vagina Reported Cases in the Literature (Raptis et al, 1993)

The low volume of cases poses a dilemma in that institutional encounters of such cases are sporadic and as such, there are no established guidelines for diagnosis or treatment. These cancers have traditionally been treated and staged similar to squamous cell carcinomas of their respective sites using the FIGO staging system. There has been reported success in long term survival rates of patients who present earlier in the disease and whose tumors could be fully resected. These presentations are rare, as patients tend to present with long standing bulky tumors and with metastasis.

## **2. Case report**

Two cases of sarcomatoid squamous cell carcinoma, one of the vagina and one of the vulva, will be utilized as illustrative examples of this rare entity.

Case number one: 67 year old, Gravida 7 Para 6 woman status post total abdominal hysterectomy 13 years prior for reportedly benign fibroids, presented with profuse vaginal bleeding. Examination revealed a vaginal lesion which was biopsied, revealing a highgrade, malignant sarcomatoid neoplasm with no concurrent precursor lesion, such as an insitu component. Pathologic assessment suggested that this was a sarcoma, specifically, a leiomyosarcoma, as evidence of smooth muscle differentiation was demonstrated by immunohistochemisty. However, with subsequent demonstration of pelvic sidewall and pelvic lymph node involvement, features not typically associated with sarcomas,

Table 3. SSCC of the Vagina Reported Cases in the Literature (Raptis et al, 1993)

bulky tumors and with metastasis.

will be utilized as illustrative examples of this rare entity.

**2. Case report** 

The low volume of cases poses a dilemma in that institutional encounters of such cases are sporadic and as such, there are no established guidelines for diagnosis or treatment. These cancers have traditionally been treated and staged similar to squamous cell carcinomas of their respective sites using the FIGO staging system. There has been reported success in long term survival rates of patients who present earlier in the disease and whose tumors could be fully resected. These presentations are rare, as patients tend to present with long standing

Two cases of sarcomatoid squamous cell carcinoma, one of the vagina and one of the vulva,

Case number one: 67 year old, Gravida 7 Para 6 woman status post total abdominal hysterectomy 13 years prior for reportedly benign fibroids, presented with profuse vaginal bleeding. Examination revealed a vaginal lesion which was biopsied, revealing a highgrade, malignant sarcomatoid neoplasm with no concurrent precursor lesion, such as an insitu component. Pathologic assessment suggested that this was a sarcoma, specifically, a leiomyosarcoma, as evidence of smooth muscle differentiation was demonstrated by immunohistochemisty. However, with subsequent demonstration of pelvic sidewall and pelvic lymph node involvement, features not typically associated with sarcomas, immunohistochemistry for p16 and in situ hybridization for high risk human Papilloma virus (HPV) subtypes was performed; this demonstrated that the tumor was, indeed, an HPV-driven malignancy compatible with sarcomatoid squamous cell carcinoma. Following a course of chemotherapy and radiation therapy, the patient presented two years later with deep vein thrombosis and obstructive uropathy, with subsequent biopsy demonstrating recurrent metastatic squamous cell carcinoma involving the ureter.

Fig. 1. Sarcomatoid squamous cell carcinoma of the vagina. (A) The lesion is characterized exclusively by spindled cells, architecturally arranged in fascicles. No in situ or conventional squamous cell morphology is apparent [200x original magnification]. (B) High-power magnification shows spindled cells with abundant mitotic figures [400x original magnification]. (C) Neoplastic cells show diffuse nuclear reactivity for p16, indicative of a HPV-driven tumor [400x original magnification]. (D) Chromogenic in situ hybridization for high-risk HPV subtypes demonstrates diffuse nuclear chromogenic labeling (in blue dot pattern) [400x original magnification].

Case number two: 78 year old Para 1 woman with long-standing vulvar irritation presented with a 4cm vulvar lesion. She underwent biopsies that demonstrated a high-grade vulvar intraepithelial lesion (VIN III, carcinoma in situ), and subsequent wide local excision showed involved margins. Four years later, she re-presented with a 4cm, enlarging vulva mass; excision of this mass revealed an invasive, poorly differentiated Sarcomatoid Squamous Cell Carcinoma (SSCC), again with positive margins. She subsequently underwent a bilateral simple hemivulvectomy with pathology demonstrating involvement of the urethral margin,

Sarcomatoid Squamous Cell Carcinoma 59

young 2A 2B Sarcomatoid Squamous Cell Carcinoma 7 women and men are being offered the Gardasil and Cervarix injections. These injections are FDA improved and are aimed at immunizing against some of the "high risk" human papillomavirus types that predispose to cancer and the "low risk" subtypes of human papillomavirus that cause genital warts. Despite relatively wide availability, less than 30% of patients receive the recommended three doses. (NCI Cancer Bulletin, 2011) Even though the rates of HPV infection decrease sharply after 30 years of age, older women are less likely to clear an infection with a high risk subtype of HPV. The older the patient at presentation the more likely the patient will

High risk sexual behavior is a risk factor due to the increase in exposure to sexually transmitted infections (STI). The more sexual partners one has the higher the chance that they will become infected with an STI. This is partly due to the fact that some STI's cause disruption of the epithelial cell layer that can facilitate the transport of infectious material. When the cervix is exposed to infection it undergoes reparative metaplastic changes that can

Cigarette smokers are known to be at increased risk of cancer of the lungs and other body organs including the cervix and vulva. Cigarette smoke is an independent risk factor for cervical cancer. (Nishino, K. et al, 2008) The pathogenesis is due to the elevated levels of genotoxic breakdown products that are in the cigarettes, including nicotine, cotinine, hydrocarbons, and tars, that have mutagenic properties that are present in cervical mucus and cells. (Berek and Hacker, 2010) Coker et al (2009) found that smokers were 21% more likely to succumb to cervical cancer compared to those who did not smoke at all, suggesting

that it expedites the disease process due to the inhibited epithelial immune response.

Although there has been a lack of sound evidence that vitamins and minerals has a clinically significant affect on the progression and prevention of cancer (World Cancer Research Fund, 2007), there have been several studies that have shown a benefit of certain nutrients and vitamins. Research continues to find a correlation between essential vitamin and nutrient intake and the progression/prevention of breast, cervical, prostate, and colon cancer. Vitamins A, C, D, and E have been depicted to have protective properties. Vitamin A has some role in regulating differentiation, growth, and apoptosis of normal as well as malignant cells. (Cui et al, 2008) The role of Vitamin C has been in the foraging of free radicals. Vitamin E works in conjunction with vitamins A and C to regulate cell differentiation and proliferation, to scavenge free radicals and oxidants, and may reduce the persistence of HPV as well as inhibit cervical carcinogenesis by augmenting immunological function and modulating the inflammatory response to infection. (Kim et al, 2010) Toner and Milner (2010) found that even though Vitamin D has been shown to be beneficial in cancer prevention the problem lies in finding a standard and most beneficial dosage and

There are several disease states that can result in immunosupression. These include HIV, transplant patients, cancer patients undergoing chemotherapy, congenital immunodeficiency disorders, and immunosuppressive drugs, among others. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. (Bremmes et al, 2011) When the physiologic function of immune cells are interrupted in any way, the body has an impeded response to the recognition and response to cancer cells. This delayed response and recognition aides in the

have a more advanced stage (Berek and Hacker 201

also showed that there were risk with overexposure.

also increase susceptibility of and STI. (Bereck and Hacker, 2010)

with other margins uninvolved. A metastatic evaluation was negative. Other comorbidities rendered the patient to be a poor candidate for additional surgical intervention.

Fig. 2. (A) Sarcomatoid squamous cell carcinoma of the vulva. The lesion has an interface with an in situ component (left side of image), and transitions to a tumor of predominant spindled cell morphology (right side of image) [100x original magnification]. (B) Highpower magnification shows spindle cell morphology in a fascicular architectural pattern, imparting a mesenchymal-like, sarcomatoid morphology [400x original magnification].

### **3. Incidence**

The incidences of SSCC has not been well established but is deemed to be very low from the isolated published case reports, constituting, at most only 1-2% of all gynecologic malignancies overall. There have been more reported cases of vulvar and cervical SSCC than cases from the vagina. This trend is also seen in squamous cell carcinomas of the female genital tract, with cervix and vulvar being more common than vagina. In general, SSCC are observed in more frequency with advancing age, and there is a correlation between vaginal cancers in women who have undergone a hysterectomy for malignant disease. It would be interesting to see if this is also true in SSCC. A possibility for the low incidence of SSCC is that the sarcomatoid component is under recognized, or under reported as part of the pathology report.

## **4. Risk factors**

Risk factors for SSCC of the female genital tract are assumed to be the same as risk factors for Squamous cell carcinoma. This is even more so if the belief that SSCC transforms from SCC. Risk factors include HPV infection, high risk sexual behavior, cigarette smoking, specific vitamin deficiencies, and immunosupression.

Human Papillomavirus (HPV) is a well known causal factor for the development of squamous cell carcinoma of the vulva, vagina, cervix, anus, and oropharynx.It is the most frequently diagnosed sexually transmitted disease in the United States. HPV subtypes 16 and 18 in particular have a high known oncogenic potential and are thus called "high risk"subtypes, accounting for approximately 80% of cases of invasive cervical cancer. (Bereck and Hacker, 2010). HPV has been reported to affect roughly 20 million people in the U.S. and is the most frequently diagnosed STD. This number is expected to decrease as more

with other margins uninvolved. A metastatic evaluation was negative. Other comorbidities

 Fig. 2. (A) Sarcomatoid squamous cell carcinoma of the vulva. The lesion has an interface with an in situ component (left side of image), and transitions to a tumor of predominant spindled cell morphology (right side of image) [100x original magnification]. (B) Highpower magnification shows spindle cell morphology in a fascicular architectural pattern, imparting a mesenchymal-like, sarcomatoid morphology [400x original magnification].

The incidences of SSCC has not been well established but is deemed to be very low from the isolated published case reports, constituting, at most only 1-2% of all gynecologic malignancies overall. There have been more reported cases of vulvar and cervical SSCC than cases from the vagina. This trend is also seen in squamous cell carcinomas of the female genital tract, with cervix and vulvar being more common than vagina. In general, SSCC are observed in more frequency with advancing age, and there is a correlation between vaginal cancers in women who have undergone a hysterectomy for malignant disease. It would be interesting to see if this is also true in SSCC. A possibility for the low incidence of SSCC is that the sarcomatoid component is under recognized, or under reported as part of the

Risk factors for SSCC of the female genital tract are assumed to be the same as risk factors for Squamous cell carcinoma. This is even more so if the belief that SSCC transforms from SCC. Risk factors include HPV infection, high risk sexual behavior, cigarette smoking,

Human Papillomavirus (HPV) is a well known causal factor for the development of squamous cell carcinoma of the vulva, vagina, cervix, anus, and oropharynx.It is the most frequently diagnosed sexually transmitted disease in the United States. HPV subtypes 16 and 18 in particular have a high known oncogenic potential and are thus called "high risk"subtypes, accounting for approximately 80% of cases of invasive cervical cancer. (Bereck and Hacker, 2010). HPV has been reported to affect roughly 20 million people in the U.S. and is the most frequently diagnosed STD. This number is expected to decrease as more

**3. Incidence** 

pathology report.

**4. Risk factors** 

specific vitamin deficiencies, and immunosupression.

rendered the patient to be a poor candidate for additional surgical intervention.

2A 2B

young 2A 2B Sarcomatoid Squamous Cell Carcinoma 7 women and men are being offered the Gardasil and Cervarix injections. These injections are FDA improved and are aimed at immunizing against some of the "high risk" human papillomavirus types that predispose to cancer and the "low risk" subtypes of human papillomavirus that cause genital warts. Despite relatively wide availability, less than 30% of patients receive the recommended three doses. (NCI Cancer Bulletin, 2011) Even though the rates of HPV infection decrease sharply after 30 years of age, older women are less likely to clear an infection with a high risk subtype of HPV. The older the patient at presentation the more likely the patient will have a more advanced stage (Berek and Hacker 201

High risk sexual behavior is a risk factor due to the increase in exposure to sexually transmitted infections (STI). The more sexual partners one has the higher the chance that they will become infected with an STI. This is partly due to the fact that some STI's cause disruption of the epithelial cell layer that can facilitate the transport of infectious material. When the cervix is exposed to infection it undergoes reparative metaplastic changes that can also increase susceptibility of and STI. (Bereck and Hacker, 2010)

Cigarette smokers are known to be at increased risk of cancer of the lungs and other body organs including the cervix and vulva. Cigarette smoke is an independent risk factor for cervical cancer. (Nishino, K. et al, 2008) The pathogenesis is due to the elevated levels of genotoxic breakdown products that are in the cigarettes, including nicotine, cotinine, hydrocarbons, and tars, that have mutagenic properties that are present in cervical mucus and cells. (Berek and Hacker, 2010) Coker et al (2009) found that smokers were 21% more likely to succumb to cervical cancer compared to those who did not smoke at all, suggesting that it expedites the disease process due to the inhibited epithelial immune response.

Although there has been a lack of sound evidence that vitamins and minerals has a clinically significant affect on the progression and prevention of cancer (World Cancer Research Fund, 2007), there have been several studies that have shown a benefit of certain nutrients and vitamins. Research continues to find a correlation between essential vitamin and nutrient intake and the progression/prevention of breast, cervical, prostate, and colon cancer. Vitamins A, C, D, and E have been depicted to have protective properties. Vitamin A has some role in regulating differentiation, growth, and apoptosis of normal as well as malignant cells. (Cui et al, 2008) The role of Vitamin C has been in the foraging of free radicals. Vitamin E works in conjunction with vitamins A and C to regulate cell differentiation and proliferation, to scavenge free radicals and oxidants, and may reduce the persistence of HPV as well as inhibit cervical carcinogenesis by augmenting immunological function and modulating the inflammatory response to infection. (Kim et al, 2010) Toner and Milner (2010) found that even though Vitamin D has been shown to be beneficial in cancer prevention the problem lies in finding a standard and most beneficial dosage and also showed that there were risk with overexposure.

There are several disease states that can result in immunosupression. These include HIV, transplant patients, cancer patients undergoing chemotherapy, congenital immunodeficiency disorders, and immunosuppressive drugs, among others. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. (Bremmes et al, 2011) When the physiologic function of immune cells are interrupted in any way, the body has an impeded response to the recognition and response to cancer cells. This delayed response and recognition aides in the

Sarcomatoid Squamous Cell Carcinoma 61

An excisional biopsy is one in which the entire mass is removed with a margin of normal tissue. This is done in the OR for the most part under sedation or if the lesion is small enough in the office with local anesthesia. Since the lesion is friable, supplies for bleeding should be readily available. Excisional biopsy is preferred for smaller lesions in which margins are available and do not interfere with surrounding structures. An incisional biopsy, in which the surgeon removes a portion of the mass, may be done in the office or in the operating room. This is utilitized in the event the mass is too large to obtain normal

In general, the histopathological diagnosis of SSCC rests upon demonstration of a malignancy with regions of classic squamous cell carcinoma morphology, merging with those exhibiting a prominent spindle cell component. In cases where such a transition occurs, and/or where a squamous cell carcinoma in situ interface is evident, the diagnosis

However, in situations where the spindled cell component predominates, without areas of classic squamous morphology or an interface with an in situ carcinoma component, the diagnosis is particularly challenging, as key differential diagnostic considerations would include a sarcoma. Such was the case with the current vaginal lesion, which was a tumor demonstrating exclusive spindled cell morphology; as immunohistochemistry for muscle markers (smooth muscle actin) was positive, the lesion was initially thought to reflect a leiomyosarcoma. In review of the cases, some report round to polygonal cells, scanty eosinophilic cytoplasm, irregular nuclei, prominent nucleoli, numerous mitosis, and areas of

There are many tools in modern immunohistochemistry that may aid in facilitating the diagnosis of SSCC, but may also pose significant nuances. In our case of SSCC of the vagina, tumor cells which are exclusively spindled in morphology, were positive for markers associated with both, mesenchymal and epithelial differentiation, including cytokeratin, vimentin, desmin and smooth muscle actin. Indeed, while one report indicates that neoplastic cells of SSCC do not show reactivity for smooth muscle actin (C-P, Lin et al. 2006), another reports that this marker may be positive in tumor cells. (Brown et al., 2003). In our particular case of SSCC from the vagina, the tumor initially thought to reflect a leiomyosarcoma, was ultimately demonstrated to harbor high-risk HPV subtypes by in situ hybridization, as well as expression of p16, a tumor suppressor protein implicated in the HPV tumorigenesis pathway. These latter findings, despite the morphologic appearance of the tumor and the ambiguous immunophenotype, permitted a definitive final diagnosis of

Due to the rarity of this cancer, the FIGO staging system that is used for squamous cell

can be confidently rendered on morphologic grounds alone.

necrosis with interlacing bundles of spindle cells on microscopic exam.

**7.2 Immunohistochemical methodologies including HPV detection**

carcinoma is also used to stage SSCC of the vulva, vagina, and cervix.

margin of surrounding tissue.

**7.1 Histology** 

SSCC.

**8. Staging** 

more rapid progression of cancer. Studies on immunotherapy in cancer patients have been ongoing and there have been great advances, giving validity that the immune response is an important mediator in preventing and fighting off cancer.

## **5. Pathogenesis**

There have been many hypotheses about the pathogenesis of SSCC, including the basis of its aggressiveness. The theory that is longstanding and the most accepted is that there is a transformation from the squamous cell carcinoma component into a spindle cell cancer. This is mainly due to parallel immunohistochemical, molecular, and ultrastructural characteristics. In 1960, Hay-Roe et al found that the epithelial portion of SSCC of the esophagus had an apparent tendency to become spindled in tissue culture. This was also reported by Sherwin et al (1963) which also stated there is a probable loss of unity of the epithelial cells in the basal layer and this was the major feature causing the spindle cell transformation. Raptis et. al (1993) showed a relative decrease in desmosomes and tonofilaments within the spindled component therefore lacking the structural foundation of ordinary squamous cell carcinoma and might be more susceptible to the compressing effect of surrounding stroma. The fact that the spindle cells have desmosomes and tonofilaments confirms the squamous cell origin. Lastly, there has been speculation that the spindle cell component and the squamous cell component arise concurrently from distinct stem cell lines and thus SSCC has been termed a "collision" tumor and not a single tumor with conversion to a spindled cell type. (Otay et al. 2011)

## **6. Presentation**

The disease process of Sarcomatoid Squamous Cell Carcinoma is very aggressive, patients typically present with extensive local disease or with metastasis on imaging and during surgery. The clinical signs and symptoms do not correlate to the severity of disease. Early nonspecific symptoms can include fatigue, anemia, pelvic pain, pelvic pressure, constipation, bloating, weight loss, and loss of appetite.

The most common presenting symptom of cervical SSCC was abnormal vaginal bleeding. There have also been cases of patients complaining of a foul smelling discharge (Brown et al 2003), postcoital spotting (Kong et al, 2010). In all of the cases of cervical SSCC there was a visible cervical lesion ranging from 1.6cm to 10cm. Vaginal lesions can present in a similar fashion with vaginal bleeding and a yellowish-white vaginal discharge. On physical exam a mass was usually palpable. Vulvar lesions usually present with the patient reporting a lesion that bleeds, is expanding, and/or is worrisome. In a small percentage of patients, there were no signs or symptoms of a genital mass. SSCC lesions of the cervix, vagina, and vulva, were all described similarly in the text as being ulceroproliferative, friable, of polypoid configuration, and necrotic in areas.

## **7. Diagnosis**

The hallmark of diagnosing this disease is biopsy of the lesion. It is important to get an adequate specimen to increase the probability of accurately diagnosing the cancer. There is no consensus as to the diameter and depth of specimen that gives the highest yield for proper pathological evaluation.

An excisional biopsy is one in which the entire mass is removed with a margin of normal tissue. This is done in the OR for the most part under sedation or if the lesion is small enough in the office with local anesthesia. Since the lesion is friable, supplies for bleeding should be readily available. Excisional biopsy is preferred for smaller lesions in which margins are available and do not interfere with surrounding structures. An incisional biopsy, in which the surgeon removes a portion of the mass, may be done in the office or in the operating room. This is utilitized in the event the mass is too large to obtain normal margin of surrounding tissue.

#### **7.1 Histology**

60 Squamous Cell Carcinoma

more rapid progression of cancer. Studies on immunotherapy in cancer patients have been ongoing and there have been great advances, giving validity that the immune response is an

There have been many hypotheses about the pathogenesis of SSCC, including the basis of its aggressiveness. The theory that is longstanding and the most accepted is that there is a transformation from the squamous cell carcinoma component into a spindle cell cancer. This is mainly due to parallel immunohistochemical, molecular, and ultrastructural characteristics. In 1960, Hay-Roe et al found that the epithelial portion of SSCC of the esophagus had an apparent tendency to become spindled in tissue culture. This was also reported by Sherwin et al (1963) which also stated there is a probable loss of unity of the epithelial cells in the basal layer and this was the major feature causing the spindle cell transformation. Raptis et. al (1993) showed a relative decrease in desmosomes and tonofilaments within the spindled component therefore lacking the structural foundation of ordinary squamous cell carcinoma and might be more susceptible to the compressing effect of surrounding stroma. The fact that the spindle cells have desmosomes and tonofilaments confirms the squamous cell origin. Lastly, there has been speculation that the spindle cell component and the squamous cell component arise concurrently from distinct stem cell lines and thus SSCC has been termed a "collision" tumor and not a single tumor with

The disease process of Sarcomatoid Squamous Cell Carcinoma is very aggressive, patients typically present with extensive local disease or with metastasis on imaging and during surgery. The clinical signs and symptoms do not correlate to the severity of disease. Early nonspecific symptoms can include fatigue, anemia, pelvic pain, pelvic pressure,

The most common presenting symptom of cervical SSCC was abnormal vaginal bleeding. There have also been cases of patients complaining of a foul smelling discharge (Brown et al 2003), postcoital spotting (Kong et al, 2010). In all of the cases of cervical SSCC there was a visible cervical lesion ranging from 1.6cm to 10cm. Vaginal lesions can present in a similar fashion with vaginal bleeding and a yellowish-white vaginal discharge. On physical exam a mass was usually palpable. Vulvar lesions usually present with the patient reporting a lesion that bleeds, is expanding, and/or is worrisome. In a small percentage of patients, there were no signs or symptoms of a genital mass. SSCC lesions of the cervix, vagina, and vulva, were all described similarly in the text as being ulceroproliferative, friable, of

The hallmark of diagnosing this disease is biopsy of the lesion. It is important to get an adequate specimen to increase the probability of accurately diagnosing the cancer. There is no consensus as to the diameter and depth of specimen that gives the highest yield for

important mediator in preventing and fighting off cancer.

conversion to a spindled cell type. (Otay et al. 2011)

constipation, bloating, weight loss, and loss of appetite.

polypoid configuration, and necrotic in areas.

**5. Pathogenesis** 

**6. Presentation** 

**7. Diagnosis** 

proper pathological evaluation.

In general, the histopathological diagnosis of SSCC rests upon demonstration of a malignancy with regions of classic squamous cell carcinoma morphology, merging with those exhibiting a prominent spindle cell component. In cases where such a transition occurs, and/or where a squamous cell carcinoma in situ interface is evident, the diagnosis can be confidently rendered on morphologic grounds alone.

However, in situations where the spindled cell component predominates, without areas of classic squamous morphology or an interface with an in situ carcinoma component, the diagnosis is particularly challenging, as key differential diagnostic considerations would include a sarcoma. Such was the case with the current vaginal lesion, which was a tumor demonstrating exclusive spindled cell morphology; as immunohistochemistry for muscle markers (smooth muscle actin) was positive, the lesion was initially thought to reflect a leiomyosarcoma. In review of the cases, some report round to polygonal cells, scanty eosinophilic cytoplasm, irregular nuclei, prominent nucleoli, numerous mitosis, and areas of necrosis with interlacing bundles of spindle cells on microscopic exam.

#### **7.2 Immunohistochemical methodologies including HPV detection**

There are many tools in modern immunohistochemistry that may aid in facilitating the diagnosis of SSCC, but may also pose significant nuances. In our case of SSCC of the vagina, tumor cells which are exclusively spindled in morphology, were positive for markers associated with both, mesenchymal and epithelial differentiation, including cytokeratin, vimentin, desmin and smooth muscle actin. Indeed, while one report indicates that neoplastic cells of SSCC do not show reactivity for smooth muscle actin (C-P, Lin et al. 2006), another reports that this marker may be positive in tumor cells. (Brown et al., 2003). In our particular case of SSCC from the vagina, the tumor initially thought to reflect a leiomyosarcoma, was ultimately demonstrated to harbor high-risk HPV subtypes by in situ hybridization, as well as expression of p16, a tumor suppressor protein implicated in the HPV tumorigenesis pathway. These latter findings, despite the morphologic appearance of the tumor and the ambiguous immunophenotype, permitted a definitive final diagnosis of SSCC.

#### **8. Staging**

Due to the rarity of this cancer, the FIGO staging system that is used for squamous cell carcinoma is also used to stage SSCC of the vulva, vagina, and cervix.

Sarcomatoid Squamous Cell Carcinoma 63

**Stage I** The carcinoma is strictly confined to the cervix (extension to the corpus

**Stage II** Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or

**Stage III** The tumor extends to the pelvic wall and/or involves lower third of the vagina

**IIIA** Tumor involves lower third of vagina, with no extension to the pelvic

 **IIIB** Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney **Stage IV** The carcinoma has extended beyond the true pelvis or has involved (biopsy

*\*All macroscopically visible lesions-even with superficial invasion-are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissue-squamous or glandular. The depth of invasion should always be reported in mm, even in those cases with "early (minimal) stromal invasion" (~1 mm). the involvement of vascular/lymphatic spaces should not change the stage allotment) \*\*On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another cause.* 

The rarity of these malignancies makes recommendations for standard treatments a

In early stage disease of the vulva, vagina and cervix the role for surgery is more clearly defined. These lesions are usually treated with radical surgery followed by radiation therapy and/or chemotherapy in certain cases. Size, margin status, and local tumor biology might dictate the need for radiotherapy. Brown et al (2003) treated all Stage I and Stage II women with radiation therapy alone and this was successfully able to eradicate the tumor. This proves radiation to be an effective treatment option, even though some believe it to be a

formidable endeavor. In general, the stage of the cancer will dictate therapy.

proven) the mucosa of the bladder or rectum. A bullous edema, as such, does

deepest invasion ≤5 mm and largest extension ≤7 mm

Clinically visible lesion ≤4.0 cm in greatest dimension Clinically visible lesion >4.0 cm in greatest dimension

Clinically visible lesion ≤4.0 cm in greatest dimension Clinically visible lesion >4.0 cm in greatest dimension

and/or causes hydronephrosis or non-functioning kidney\*\*

not permit a case to be allotted to Stage IV

Invasive carcinoma which can be diagnosed only by microscopy, with

Clinically visible lesions limited to the cervix uteri or pre-clinical cancers

Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension

would be disregarded)

greater than stage IA\*

**IIB** With obvious parametrial invasion

**IVA** Spread of the growth to adjacent organs

sidewall

**IVB** Spread to distant organs

(**FIGO Committee on Gynecologic Oncology.** 2009) Table 6. Carcinoma of the Cervix Uteri (2008)

to the lower third of the vagina

Without parametrial invasion

of not >7 mm

**IA** 

 **IA1** 

 **IA2** 

**IB** 

 **IB1 IB2** 

 **IIA IIA1 IIA2** 

**9. Therapy** 


**\***The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. (**FIGO Committee on Gynecologic Oncology.** 2009)


Table 4. Carcinoma of the Vulva FIGO Staging. (2008)

#### (**FIGO Annual Report.** 2006)

Table 5. Carcinoma of the Vagina FIGO Nomenclature

Cervical cancer is still staged clinically, which is not always very accurate in portraying the extent of the disease. Clinical staging can include palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and e-ray examination of the lungs and skeletal system. (Berek and Hacker, 2010) CT and MRI are also utilized often as this can give a better idea of extent of disease, margins, lymphadenopathy, and other organ involvement. Positron emission tomography (PET) is mainly utilized for nodal status.

**IA** Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal

**IB** Lesions >2 cm in size or with stromal invasion >1.0 mm\*, confined to the

**Stage II** Tumor of any size with extension to adjacent perineal structures (1/3 lower

**Stage III** Tumor of any size with or without extension to adjacent perineal structures

**Stage IV** Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or

**\***The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. (**FIGO Committee on** 

**Stage II** The carcinoma has involved the subvaginal tissue but has not extended to

**Stage IV** The carcinoma has extended beyond the true pelvis or has involved the

**IVA** Tumor invades bladder and/or rectal mucosa and/or direct extension

Cervical cancer is still staged clinically, which is not always very accurate in portraying the extent of the disease. Clinical staging can include palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and e-ray examination of the lungs and skeletal system. (Berek and Hacker, 2010) CT and MRI are also utilized often as this can give a better idea of extent of disease, margins, lymphadenopathy, and other organ involvement. Positron emission tomography (PET) is

mucosa of the bladder or rectum; bullous edema as such does not permit a

(1/3 lower urethra, 1/3 lower vagina, anus) with positive inguino-femoral

i. upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa,

**Stage I** Tumor confined to the vulva

lymph nodes

distant structures **IVA** Tumor invades any of the following:

**Gynecologic Oncology.** 2009)

invasion ≤1.0 mm\*, no nodal metastasis

vulva or perineum, with negative nodes

urethra, 1/3 lower vagina, anus)

**IIIA** i. With 1 lymph node metastasis (≥5 mm), or

**IIIC** With positive nodes with extracapsular spread

or fixed to pelvic bone, or

Table 4. Carcinoma of the Vulva FIGO Staging. (2008)

the pelvic wall

**IVB** Spread to distant organs

(**FIGO Annual Report.** 2006)

mainly utilized for nodal status.

**Stage I** The carcinoma is limited to the vaginal wall

**Stage III** The carcinoma has extended to the pelvic wall

case to be allotted to stage IV

Table 5. Carcinoma of the Vagina FIGO Nomenclature

beyond the true pelvis

**IVB** Any distant metastasis including pelvic lymph nodes

ii. fixed or ulcerated inguino-femoral lymph nodes

ii. 1-2 lymph node metastasis(es) (<5 mm) **IIIB** i. With 2 or more lymph node metastases (≥5 mm), or ii. 3 or more lymph node metastases (<5 mm)


*\*All macroscopically visible lesions-even with superficial invasion-are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissue-squamous or glandular. The depth of invasion should always be reported in mm, even in those cases with "early (minimal) stromal invasion" (~1 mm). the involvement of vascular/lymphatic spaces should not change the stage allotment) \*\*On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another cause.* 

(**FIGO Committee on Gynecologic Oncology.** 2009)

Table 6. Carcinoma of the Cervix Uteri (2008)

## **9. Therapy**

The rarity of these malignancies makes recommendations for standard treatments a formidable endeavor. In general, the stage of the cancer will dictate therapy.

In early stage disease of the vulva, vagina and cervix the role for surgery is more clearly defined. These lesions are usually treated with radical surgery followed by radiation therapy and/or chemotherapy in certain cases. Size, margin status, and local tumor biology might dictate the need for radiotherapy. Brown et al (2003) treated all Stage I and Stage II women with radiation therapy alone and this was successfully able to eradicate the tumor. This proves radiation to be an effective treatment option, even though some believe it to be a

Sarcomatoid Squamous Cell Carcinoma 65

screening modalities, it is difficult to discern which squamous cell cancers will transition to SSCC so no risk prevention can be done. One would assume that with the reduction in squamous cell carcinoma cases of the female genital tract that there will be a parallel

Diagnosis has traditionally been difficult due to the large ratio of sarcomatous to squamous cell component. Immunohistochemistry and ancillary testing, such as in situ hybridization for high-risk HPV subtypes are very important for the precise diagnosis which can guide treatment and counseling of the patient. One should perform immunohistochemistry for squamous epithelial markers as well as in situ hybridization for HPV when encountering a

As with any cancer, the lower the FIGO stage at diagnosis the better the prognosis. Unfortunately even when adequately treated according to unset standards, recurrence is very prevalent with disease free interval to death being very rapid. Once recurrence occurs there is very little recourse as the cancer does not respond to second line therapy and has usually extended out of the pelvis to distant organs. There have been few cases of a FIGO stage greater than II in which there has been long term survival but not enough to

Bereck, J.; Hacker, N. (2010) *Gynecologic Oncology* (5th), Lippincott, Williams, and Wilkins, ISBN

Bremnes, R.; Al-Shibli, K.; Donnem, T.; Sirera, R.; Al-Saad, S.; Anderson, S.; Stenvold, H.;

Brown, J.; Broaddus, R.; Koeller, M.; Burke,T.; Gershenson, D.; Bodurka, D. (2003).

Choi, D.-S.; Lee, J.-W.; Lee, S.-J.; Choi, C.-H., Kim, T.-J.; Lee, J.-H.; Bae, D.-S.; Ahn, G.; Kim, B.-

Coker, AL; DeSimone, CP; Eggleston, KS; Hopenhayn, C; Nee, J; Tucker, T. (2009) Smoking And

Hay-Roe, V.; Hill, R.; Civin, W. (1960) An Unclassified Tumor of the Esophagus: Case Review.

*Nutrition.* Vol. 87, No. 4, (April 2008), pp. 1009-18, ISSN 0002-9165

Camps, C.; Busund, L. (2011) The Role of Tumor-Infiltrating Immune Cells And Chronic Inflammation at the Tumor Site on Cancer Development, Progression, and Prognosis: Emphasis on Non-small Cell Lung Cancer. *Journal of Thoracic Oncology.* 

Sacrcomatoid Carcinoma of the Cervix. *Gynecologic Oncology,* Vol. 90, No. 1,(July

G. (2006). Squamous Cell Carcinoma with Sarcomatoid Features of the Vulva: A case Report and Review of the Literature. *Gynecologic Oncology,* Vol. 103, No. 1, (October

survival among Kentucky women diagnosed with invasive cervical Cancer: 1995-2005. *Gynecologic Oncology,* Vol. 112, No. 2, (February 2009), pp. 365-69, ISSN 1095-6859. Cui, Y.; Shikany, JM.; Liu, S.; Shagufta, Y.; Rohan, TE. (2008) Selected antioxidants and risk Of

hormone receptor-defined invasive breast cancers among post menopausal Women in the Women's Health Initiative Observational Study. *American Journal of Clinical* 

*Journal of Thoracic and Cardiovascular Surgery.* Vol. 40, (July 1960), pp. 107-13, ISSN

reduction of SSCC.

sarcomatoid neoplasm to rule out SSCC.

effectively alter the inevitable outcome.

The authors of this chapter have no financial acknowledgments.

978-0-7817-9512-8, Philadelphia, Pennsylvania.

2003), pp. 23-28, ISSN 0090-8258

2006), pp. 363-67, ISSN 0090-8258

Vol. 6, No. 4, (April 2011), pp. 824-33, ISSN 1556-0864

**12. Acknowledgements** 

0022-5223

**13. References** 

source of the transition of this cancer from SCC to the intermingling of the spindle shaped cells. In 2010, Kong et al reported a case of IB1 SSCC of the cervix in a young patient, being treated by laparoscopic radical hysterectomy, bilateral pelvic lymph node biopsy, peritoneal washing cytology and transposition of both ovaries without adjuvant therapy. Despite the initial treatment for low stage cancers, recurrent cancer did not respond to second line therapy (Brown et al, 2003) which leads some to take a more aggressive approach with surgery and adjuvant therapy, especially since time from recurrence to death is less than a year as reported in the literature.

In more advanced stages, patients present with such extensive disease that surgery is usually done on a palliative basis if indicated. These tumors are usually treated with concurrent chemotherapy and radiation, extrapolating from the pure squamous counterparts. In contradiction to these lesions where there exist more robust standard treatment recommendations the response to similar treatment is largely unknown and the risk for recurrence is very significant with a very short disease free interval.

## **10. Prognosis**

Prognosis of SSCC is very poor. It is a very aggressive cancer, is usually diagnosed at a later stage, and most recur within one year despite aggressive combined therapy. As with the majority of solid tumors, the survival of patients that were detected at early stages is very reassuring. Patients who are diagnosed at Stage I have a higher survival rate at 5 years, approaching 90%. In contrast, those who present at Stage IV, according to the studies, have a survival rate of less than 5% at five years, according to the review of the case reports. Prognostic factors have not been uniformed in any of the studies. Lane believed the extent of the grossly carcinomatous element was the best predictor of survival. Friedel et al found that not only was the degree of differentiation of the carcinomatous component an important prognostic factor but also the extent of invasiveness. Some suggest size and location are the sole factors impacting prognosis. (Randall et al.) Brown et al found that the younger patients tended to present at an earlier stage. Of these women who presented at stage 1, all were free of disease with the longest interval reported at 42 months. They also found that all patients less than 40 presented at Stage I and not a more advanced stage III or IV. One explanation for the fact that younger patients present at a lesser stage is that they are more prone to go to the doctors for acute visits and are more likely to voice there concerns over abnormal changes in their bodies. This is different to the belief that women >40 are more apt to cope with the symptoms and only present when the condition is debilitating or they are urged by family.

## **11. Conclusion**

SSCC is a very rare cancer that has an aggressive and rapidly fatal course. Due to its rarity, there is no distinct staging or guidelines to direct therapy and care. As more cases become available and follow up is documented on patients with early FIGO stages, treatments, and surveillance decisions there will be a better chance of developing a set of guidelines based on the evidence. Since this cancer is most accepted as being a variant of SCC, the FIGO staging and treatment guidelines for squamous cell carcinoma are also used for SSCC.

Human papillomavirus has been implicated in SCC and is also found in the spindle cell component of SSCC. Even with the use of the widely available HPV vaccine and better

source of the transition of this cancer from SCC to the intermingling of the spindle shaped cells. In 2010, Kong et al reported a case of IB1 SSCC of the cervix in a young patient, being treated by laparoscopic radical hysterectomy, bilateral pelvic lymph node biopsy, peritoneal washing cytology and transposition of both ovaries without adjuvant therapy. Despite the initial treatment for low stage cancers, recurrent cancer did not respond to second line therapy (Brown et al, 2003) which leads some to take a more aggressive approach with surgery and adjuvant therapy, especially since time from recurrence to death is less than a

In more advanced stages, patients present with such extensive disease that surgery is usually done on a palliative basis if indicated. These tumors are usually treated with concurrent chemotherapy and radiation, extrapolating from the pure squamous counterparts. In contradiction to these lesions where there exist more robust standard treatment recommendations the response to similar treatment is largely unknown and the

Prognosis of SSCC is very poor. It is a very aggressive cancer, is usually diagnosed at a later stage, and most recur within one year despite aggressive combined therapy. As with the majority of solid tumors, the survival of patients that were detected at early stages is very reassuring. Patients who are diagnosed at Stage I have a higher survival rate at 5 years, approaching 90%. In contrast, those who present at Stage IV, according to the studies, have a survival rate of less than 5% at five years, according to the review of the case reports. Prognostic factors have not been uniformed in any of the studies. Lane believed the extent of the grossly carcinomatous element was the best predictor of survival. Friedel et al found that not only was the degree of differentiation of the carcinomatous component an important prognostic factor but also the extent of invasiveness. Some suggest size and location are the sole factors impacting prognosis. (Randall et al.) Brown et al found that the younger patients tended to present at an earlier stage. Of these women who presented at stage 1, all were free of disease with the longest interval reported at 42 months. They also found that all patients less than 40 presented at Stage I and not a more advanced stage III or IV. One explanation for the fact that younger patients present at a lesser stage is that they are more prone to go to the doctors for acute visits and are more likely to voice there concerns over abnormal changes in their bodies. This is different to the belief that women >40 are more apt to cope with the symptoms and only present when the condition is debilitating or they are urged by family.

SSCC is a very rare cancer that has an aggressive and rapidly fatal course. Due to its rarity, there is no distinct staging or guidelines to direct therapy and care. As more cases become available and follow up is documented on patients with early FIGO stages, treatments, and surveillance decisions there will be a better chance of developing a set of guidelines based on the evidence. Since this cancer is most accepted as being a variant of SCC, the FIGO staging and treatment guidelines for squamous cell carcinoma are also used for SSCC.

Human papillomavirus has been implicated in SCC and is also found in the spindle cell component of SSCC. Even with the use of the widely available HPV vaccine and better

risk for recurrence is very significant with a very short disease free interval.

year as reported in the literature.

**10. Prognosis** 

**11. Conclusion** 

screening modalities, it is difficult to discern which squamous cell cancers will transition to SSCC so no risk prevention can be done. One would assume that with the reduction in squamous cell carcinoma cases of the female genital tract that there will be a parallel reduction of SSCC.

Diagnosis has traditionally been difficult due to the large ratio of sarcomatous to squamous cell component. Immunohistochemistry and ancillary testing, such as in situ hybridization for high-risk HPV subtypes are very important for the precise diagnosis which can guide treatment and counseling of the patient. One should perform immunohistochemistry for squamous epithelial markers as well as in situ hybridization for HPV when encountering a sarcomatoid neoplasm to rule out SSCC.

As with any cancer, the lower the FIGO stage at diagnosis the better the prognosis. Unfortunately even when adequately treated according to unset standards, recurrence is very prevalent with disease free interval to death being very rapid. Once recurrence occurs there is very little recourse as the cancer does not respond to second line therapy and has usually extended out of the pelvis to distant organs. There have been few cases of a FIGO stage greater than II in which there has been long term survival but not enough to effectively alter the inevitable outcome.

## **12. Acknowledgements**

The authors of this chapter have no financial acknowledgments.

## **13. References**


**4** 

Jasim Radhi

*Canada* 

*Hamilton, Ontario* 

*Department of Pathology and* 

*Molecular Medicine McMaster University* 

**Basaloid Squamous Cell Carcinoma** 

**Squamous cell carcinoma is** the second most common cancer of the skin. This tumor arises predominantly in sun exposed actinically damaged areas. Implicated as predisposing factors, in addition to sunlight, these are industrial carcinogens, chronic ulcers, and ionizing radiation [1]. They are common cancer in immunocompromised and renal transplant patients [2]. Squamous cell carcinomas are known to be the most prevalent malignant tumor of the head and neck region [3]. They are also reported in many organs including cervix,

Squamous cell carcinoma is characterized by squamous cells with large nuclei and abundant eosinophilic cytoplasm. The cells exhibit prominent intracellular bridges and variable keratin formation, depending on the degree of differentiation. Poorly differentiated tumors lack keratinization and usually form solid sheets of cells with marked pleomorphism to the

Several histologic variant of squamous cell carcinoma are identified. These variants are based on certain morphological features accordingly, which may or may not have prognostic implications. The following are the most reported variant in the literature and include basaloid, warty verrucous, papillary, spindle cell, adenosquamous, clear cell,

**Spindle cell carcinoma** is rather rare and is composed of atypical spindle cells with whorled arrangement (Fig 1), which mostly come from immunosuppressed renal transplant patients. The tumor needs to be differentiated from desmoplastic melanoma, atypical fibroxanthoma or metastatic carcinoma with spindle cell features. Immunohistochemistry is of value in

**Clear squamous cell carcinoma** is another variant first described as squamous cell carcinoma with extensive hydropic changes. The cells appear glassy looking, due to accumulation of fluid, and can be easily mistaken for sebaceous cell carcinoma. The differential also includes other clear cell tumors such as clear cell acanthoma, clear cell

hidradenoma, metastatic renal cell carcinoma, balloon cell nevus and melanoma [9].

lung, bladder, uterus, ovary, esophagus and teratomas [4;5;6,7].

extent that require special studies to establish the nature of the tumor.

**2. Histologic variants of squamous cell carcinoma** 

acantholytic and lymphoepithelioma-like type.

differentiating these entities [8].

**1. Introduction** 

