**6. Case reports of MAABD**

As the association between ABD and malignancy is noted in many case reports, the question of causal connection is raised. There are three situations possible concerning the relation: i) malignancy preceding ABD, ii) malignancy coexisting with ABD, iii) malignancy following ABD. For a long months and years, many cases of ABD are undiagnosed, misdiagnosed and subsequently mistreated due to relative rarity and therefore low awareness of ABD and its symptoms. The time period elapsed between the first symptoms and diagnosis, makes the time-onset relation between ABD and cancer usually uncertain.

Here, based on our personal clinical/laboratory/research experience, we present a dozen of memorable/representative patients with association of malignancy, both cutaneous and internal, and ABD over the last decade. Unfortunately, usually there is no experimental data indicating if it is a random coincidence or cause-and-effect relationship in individual patient. Still, the diagnosis of such a concurrence increases mortality.

#### **6.1. Anti-desmosomal autoimmunity circle / pemphigus group cases**

#### *6.1.1. Case 1 — Mucocutaneous pemphigus vulgaris / lung cancer*

relationship of BP180 to malignancy is discussed. BP180 has possible phosphorylation sites and may by phosphorylated in SCC [177]. Enhanced expression and abnormal distribution of BP180 in various precancerous and cancerous tissues was revealed, including e.g. SCCs and

As it was demonstrated that expression of BP180 was decreased or absent in cutaneous neoplasms [184], some authors speculated that some type of carcinomas itself might expose BP180 antigenic epitope, which would normally be hidden, thus inducing the production of autoantibodies that lead to the onset of BP [185]. It was proposed that BP180 neoexpression could be associated with early/malignant transformation of keratinocytes as widely expression of BP180 was demonstrated in SCC in contrast to normal skin, where this protein is restricted

Laminin-322 (previously named laminin-5) is the main autoantigen in anti-epiligrin cicatricial pemphigoid, mucouse membrane pemphigoid. Laminin-332 and alfa6beta4integrin may play an important role in tumor progression via activation of phosphatidylinositol-3 kinase signaling (PI3K) [187]. There was shown, that it is highly expressed in several types of squamous and other epithelial tumours [188]. Moreover, in these tumors, laminin-322 shows tendency to accumulate at the interface of the tumor with the surrounding stroma, and expression of this proteins correlates with tumor invasiveness [188]. Interestingly, keratino‐ cytes from patients with junctional epidermolysis bullosa, that did not express laminin-322 or beta4integrin, showed a lack of tumorigenecity in immunodeficient mice after transformation [188]. Perhaps, the binding of collagen VII to laminin-322 may be essential for tumorigenesis [188]. Furthermore, the laminin-322-derived signaling is an important component of tumori‐ genesis. As mentioned above, constitutive activation of the PI3K pathway leading to RAC1

As the association between ABD and malignancy is noted in many case reports, the question of causal connection is raised. There are three situations possible concerning the relation: i) malignancy preceding ABD, ii) malignancy coexisting with ABD, iii) malignancy following ABD. For a long months and years, many cases of ABD are undiagnosed, misdiagnosed and subsequently mistreated due to relative rarity and therefore low awareness of ABD and its symptoms. The time period elapsed between the first symptoms and diagnosis, makes the

Here, based on our personal clinical/laboratory/research experience, we present a dozen of memorable/representative patients with association of malignancy, both cutaneous and internal, and ABD over the last decade. Unfortunately, usually there is no experimental data indicating if it is a random coincidence or cause-and-effect relationship in individual patient.

GTPase activation may be the triggering factor inducing tumor invasion.

time-onset relation between ABD and cancer usually uncertain.

Still, the diagnosis of such a concurrence increases mortality.

Bowen's disease [177].

172 Highlights in Skin Cancer

to basal keratinocytes [186].

**6. Case reports of MAABD**

An elderly female with painful oral erosions, flat white-speckled infiltrations, mucosal edema and enlarged submandibular lymph nodes was admitted to oncology center outpatients. Histopathological examination of the retromolar mucosa of the left alveolar process of maxilla showed paraepidermoid epithelium with focal high-grade dysplasia and few neoplastic cells.

Due to improper biopsy technique full examination of the material was impossible. Therefore, the patient was readmitted to the oncology ward, with tentative diagnosis of carcinoma planoepitheliale with bilateral metastases to neck lymph nodes, for bilateral selective lymphadenectomy and probational excision of the lesions at right buccal region and left soft palate. Histopathological examination on probational biopsy showed mu‐ cous membrane fragments with features of basement membrane disruption and acantholy‐ sis. There was abundant infiltration consisting of lymphoid cells with plasmocyte prevalence and presence of granulocytes. The overall image did not support the diagno‐ sis of carcinoma planoepitheliale, yet suggested pemphigus. Chest x-ray showed leftsided pleural effusion with costodiaphragmatic recess filling. At the posterolateral side of the lung, thin layer of liquid reaching 7th rib in the posterior axillary line was observed. Ultrasonography of the neck showed non-enlarged thyroid gland (10 ml of volume) with hypoechogenic node (11 mm x 8 mm) and 3 lesser hypoechogenic nodes of diameters up to 4 mm in the left lobe. Enlarged lymph nodes, with narrow lymph sinuses (up to 15 mm x 8 mm) and unclear character, were seen bilaterally in the upper part of the neck vessels beyond mandibular angles.

The patient was directed to dermatological ward for further diagnostics. Laboratory tests showed increased sedimentation rate. DIF of perilesional skin of the vulva revealed IgG(+), IgG1(++) and C3(+) deposits in the intercellular spaces of the spinous layer of epidermis. hDIF on pulled-out hair revealed IgG(+), IgG1(+) and IgG4(+) deposits in the intercellular spaces of the outer root sheath. DIF of larynx mucosa showed fragmented specimen, mainly without epithelium. There was fragmented epithelium consisting of several cells at the specimens margin (evident acantholysis) with surrounding noticeable IgG(+/-) and C3(+/-) deposits. IIF study on monkey esophagus revealed circulating IgG class of pemphigus-type autoantibodies against desmosomal proteins of keratinocytes – titer above 1/80. On the basis of abovemen‐ tioned tests the diagnosis of mucocutaneous PV was reached.

After amelioration of the lesions, due to pulse steroid treatment, she was dismissed from the ward. Two months later, she suffered from aggravation of mucosal erosions, haematopnoe and dyspnoe. The woman was admitted to oncology center, where chest computed tomogra‐ phy (CT) scan visualized solid mass in the left lung (Fig. 1A). Via bronchofiberoscopy, carcinoma planoepitheliale of the left lung (G4) with hepatic metastases was diagnosed. Palliative radiotherapy (20 Gy/T) of the mediastinal/left pulmonary region led to aggravation of mucocutaneous PV (Fig. 1B).

### *6.1.2. Case 2 — Mucocutaneous pemphigus vulgaris / oropharyngeal cancer*

A middle-aged man observed blisters localized in the interscapular region and the posterior aspect of the neck (Fig. 2B, C). Simultaneously, he suffered from excruciating sore throat and dysphagia. He was consulted by ENT-specialist and subsequently was directed to oncology center for further diagnosis and treatment. Histological material obtained during laryngolog‐ ical diagnostics revealed carcinoma planoepitheliale keratodes invasivum of the right palatine tonsil, soft palate and uvula (T3N2M0) with metastatic focus in lymph node (Fig. 2A). Therefore, the patient underwent excision of the lesion with bilateral modified cervical lymphadenectomy. Neck ultrasound imaging visualized hypoechogenic polycyclic tumorous mass (43 mm x 25 mm) associated with lower pole of parotid gland with numerous small satellite nodules of diameter up to 6 mm and dissolved reactive lymph nodes up to 7 mm of length. The patient was treated with Intensity Modulated Radiation Therapy (IMRT) – 6 MeV photons for 34 cycles (68 Gy/t). Due to lesions regarded as notable cutaneous radiation syndrome of the neck (II\* according to EORTC/RTOG scale), the few last cycles were dimin‐ ished by 1 fraction and postradiative topicals were applied. Interestingly, the bullous lesions exacerbated (Fig. 2D) and appeared on the thorax, abdomen and limbs (Fig. 2E). No mucosal involvement was present at that time.

stent implantation due to myocardial infarction, hypertension, hypercholesterolemia, diabetes

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**Figure 1.** A. Chest CT of an elderly PV patient showing tumor in the left lung. B. Aggravation of mucocutaneous PV

after palliative radiotherapy (radiotherapy-induced PV lesions).

mellitus type 2, hiatal hernia and epigastric hernia.

Due to above symptoms, he was consulted by the dermatologist. Histology of the skin revealed suprabasilar separation and acantholysis in the upper epidermis (Fig. 2F). IIF on monkey esophagus revealed circulating IgG class pemphigus-type antibodies against desmosomal proteins of keratinocytes – titer 1/320. DIF on the perilesional skin of the back showed IgG(+), IgG1(+), IgG4(+++) and C3(+) deposits in intracellular spaces of lower layers of epidermis (Fig. 2G). DIF of the plucked hair showed IgG4(+++), IgG1(++), IgG(++) and C3(+/-) deposits in intracellular spaces of outer hair sheath (Fig. 2H). Performed tests supported the diagnosis of mucocutaneous PV.

Four months later, patient was admitted to dermatological ward with numerous blisters and erosions on the skin of the thorax, back, limbs and head. Reddish postradiative aggravated PV lesions, which healed later with aggressive immunosuppressive treatment, with marginal blistering notably limited to the anterior surface of the neck, showed no visible reepitheliali‐ zation. Numerous painful erosions presented on oral mucosa disabling patient's feeding and resulting in 10 kg weight loss. ELISA study revealed the presence of anti-desmoglein 1 (DSG1) IgG of titer 130.34AU/ml (cut-off point 41AU/ml) and anti-desmoglein 3 (DSG3) IgG of titer >150AU/ml (cut-off point 40AU/ml). IIF performed on rat bladder did not reveal serum antibodies of paraneoplastic pemphigus (PNP) type. Consulting laryngologist described numerous erosions of buccal and oral mucosa, yet noticed no features of recurrence of malignancy. The case was reported in literature [189].

#### *6.1.3. Case 3 — Pemphigus foliaceus / pseudomyxoma peritonei*

An elderly female was admitted to dermatological ward with numerous erythematous plaques, blisters and non-healing erosions covered with crusts – on the scalp, trunk and limbs (Fig. 3A, B). Her medical history was significant for angina pectoris, angioplasty (PTCA) with stent implantation due to myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus type 2, hiatal hernia and epigastric hernia.

*6.1.2. Case 2 — Mucocutaneous pemphigus vulgaris / oropharyngeal cancer*

involvement was present at that time.

malignancy. The case was reported in literature [189].

*6.1.3. Case 3 — Pemphigus foliaceus / pseudomyxoma peritonei*

mucocutaneous PV.

174 Highlights in Skin Cancer

A middle-aged man observed blisters localized in the interscapular region and the posterior aspect of the neck (Fig. 2B, C). Simultaneously, he suffered from excruciating sore throat and dysphagia. He was consulted by ENT-specialist and subsequently was directed to oncology center for further diagnosis and treatment. Histological material obtained during laryngolog‐ ical diagnostics revealed carcinoma planoepitheliale keratodes invasivum of the right palatine tonsil, soft palate and uvula (T3N2M0) with metastatic focus in lymph node (Fig. 2A). Therefore, the patient underwent excision of the lesion with bilateral modified cervical lymphadenectomy. Neck ultrasound imaging visualized hypoechogenic polycyclic tumorous mass (43 mm x 25 mm) associated with lower pole of parotid gland with numerous small satellite nodules of diameter up to 6 mm and dissolved reactive lymph nodes up to 7 mm of length. The patient was treated with Intensity Modulated Radiation Therapy (IMRT) – 6 MeV photons for 34 cycles (68 Gy/t). Due to lesions regarded as notable cutaneous radiation syndrome of the neck (II\* according to EORTC/RTOG scale), the few last cycles were dimin‐ ished by 1 fraction and postradiative topicals were applied. Interestingly, the bullous lesions exacerbated (Fig. 2D) and appeared on the thorax, abdomen and limbs (Fig. 2E). No mucosal

Due to above symptoms, he was consulted by the dermatologist. Histology of the skin revealed suprabasilar separation and acantholysis in the upper epidermis (Fig. 2F). IIF on monkey esophagus revealed circulating IgG class pemphigus-type antibodies against desmosomal proteins of keratinocytes – titer 1/320. DIF on the perilesional skin of the back showed IgG(+), IgG1(+), IgG4(+++) and C3(+) deposits in intracellular spaces of lower layers of epidermis (Fig. 2G). DIF of the plucked hair showed IgG4(+++), IgG1(++), IgG(++) and C3(+/-) deposits in intracellular spaces of outer hair sheath (Fig. 2H). Performed tests supported the diagnosis of

Four months later, patient was admitted to dermatological ward with numerous blisters and erosions on the skin of the thorax, back, limbs and head. Reddish postradiative aggravated PV lesions, which healed later with aggressive immunosuppressive treatment, with marginal blistering notably limited to the anterior surface of the neck, showed no visible reepitheliali‐ zation. Numerous painful erosions presented on oral mucosa disabling patient's feeding and resulting in 10 kg weight loss. ELISA study revealed the presence of anti-desmoglein 1 (DSG1) IgG of titer 130.34AU/ml (cut-off point 41AU/ml) and anti-desmoglein 3 (DSG3) IgG of titer >150AU/ml (cut-off point 40AU/ml). IIF performed on rat bladder did not reveal serum antibodies of paraneoplastic pemphigus (PNP) type. Consulting laryngologist described numerous erosions of buccal and oral mucosa, yet noticed no features of recurrence of

An elderly female was admitted to dermatological ward with numerous erythematous plaques, blisters and non-healing erosions covered with crusts – on the scalp, trunk and limbs (Fig. 3A, B). Her medical history was significant for angina pectoris, angioplasty (PTCA) with

**Figure 1.** A. Chest CT of an elderly PV patient showing tumor in the left lung. B. Aggravation of mucocutaneous PV after palliative radiotherapy (radiotherapy-induced PV lesions).

Initially, lesional skin sample examined by the cutaneous pathologist showed thin epidermis with fissures and flat vesicles in upper layer with slight acantholysis. Perivascular inflamma‐ tory infiltrates with prevalence of lymphocytes and eosinophils, focally involving the epider‐ mis, were seen in the dermis. DIF test revealed deposits of IgG(+), IgG4(++) and C3(++) in intercellular spaces of epidermis. Marked acantholysis was visible and upper layers of epidermis were absent. Serum IgG, but not IgG4, autoantibodies of pemphigus type against desmosomal proteins of keratinocytes were present in IIF on rabbit labial mucosa and normal human skin, of titers respectively 1/40 and 1/160. The diagnosis of PF was made. She was treated with oral steroids and cyclophosphamide achieving remission before dismissal.

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Six years later she was readmitted to dermatological ward due to aggravation of PF. IIF study on monkey esophagus showed serum IgG4 autoantibodies of pemphigus type against desmo‐ somal proteins of keratinocytes – titer 1/80 (Fig. 3C). Abdominal ultrasonography revealed oval hyperechogenic solid mass (12 mm x 14 mm) in the middle part of the right kidney medulla suggesting kidney tumor. Two-phased abdominal CT scan visualized hypodensic welldelineated lesion (transverse diameter ca. 10 mm) in right renal medulla (suggestive of angio‐ myolipoma) characterized by density of adipose tissue, without contrast intensification.

The patient was supervised for years by dermatology practitioner. Due to increase of waist circumference, she was suggested to visit gynecologist. In gynecological control, the physician found right adnexal mass. The patient was directed urgently to gynecologic ward with tentative diagnosis of ovarian cancer, where she underwent hysterectomy with adnexotomy, omentectomy and appendectomy. The tumor was described by the histopathologist as low grade appendiceal mucinous neoplasm (pseudomyxoma peritonei) with metastasis to right

**Figure 3.** A. Erythematous plaques and crusts on the scalp of the head. B. Erosions and blisters on the back. C. IIF on monkey esophagus: pemphigus IgG4 autoantibodies. PF recurrence in the course of ACE-inhibitor treatment for myo‐

A middle-aged man was consulted by dermatological specialist due to disseminated eryth‐ ematous plaques. The lesions were preceded by three months of uncomfortable itching on hands and feet. He was not diagnosed beforehand and was solely treated with topical steroids.

ovary and omentum. Since then, she regularly visited gynecological oncologist.

*6.1.4. Case 4 — Pemphigus foliaceus / squamous cell carcinoma of the thorax*

cardial infarction.

#### Published in [189]

**Figure 2.** A. Carcinoma planoepitheliale keratodes invasivum in lymphoid tissue. H+E staining. Courtesy of Prof. J. Brę‐ borowicz. B. Numerous erosions on non-inflammatory skin of the back, some of them covered with brownish-greenish crusts. C. Erosions on non-inflammatory skin of the face and neck. Scar after the surgical excision of the cancer. D. Nu‐ merous merging erosions, some covered with bloody and greenish crusts on the skin of the neck area subjected to radiotherapy. E. Erosions covered with crusts around the nipple (a natural body orifice area). F. Suprabasilar separation and acantholytic blister in the upper epidermis. H+E staining. G. DIF of perilesional skin of the back: pemphigus IgG4 deposits in lower epidermis. H. DIF of plucked scalp hair: pemphigus IgG4 deposits in outer root sheath.

Initially, lesional skin sample examined by the cutaneous pathologist showed thin epidermis with fissures and flat vesicles in upper layer with slight acantholysis. Perivascular inflamma‐ tory infiltrates with prevalence of lymphocytes and eosinophils, focally involving the epider‐ mis, were seen in the dermis. DIF test revealed deposits of IgG(+), IgG4(++) and C3(++) in intercellular spaces of epidermis. Marked acantholysis was visible and upper layers of epidermis were absent. Serum IgG, but not IgG4, autoantibodies of pemphigus type against desmosomal proteins of keratinocytes were present in IIF on rabbit labial mucosa and normal human skin, of titers respectively 1/40 and 1/160. The diagnosis of PF was made. She was treated with oral steroids and cyclophosphamide achieving remission before dismissal.

Six years later she was readmitted to dermatological ward due to aggravation of PF. IIF study on monkey esophagus showed serum IgG4 autoantibodies of pemphigus type against desmo‐ somal proteins of keratinocytes – titer 1/80 (Fig. 3C). Abdominal ultrasonography revealed oval hyperechogenic solid mass (12 mm x 14 mm) in the middle part of the right kidney medulla suggesting kidney tumor. Two-phased abdominal CT scan visualized hypodensic welldelineated lesion (transverse diameter ca. 10 mm) in right renal medulla (suggestive of angio‐ myolipoma) characterized by density of adipose tissue, without contrast intensification.

The patient was supervised for years by dermatology practitioner. Due to increase of waist circumference, she was suggested to visit gynecologist. In gynecological control, the physician found right adnexal mass. The patient was directed urgently to gynecologic ward with tentative diagnosis of ovarian cancer, where she underwent hysterectomy with adnexotomy, omentectomy and appendectomy. The tumor was described by the histopathologist as low grade appendiceal mucinous neoplasm (pseudomyxoma peritonei) with metastasis to right ovary and omentum. Since then, she regularly visited gynecological oncologist.

**Figure 3.** A. Erythematous plaques and crusts on the scalp of the head. B. Erosions and blisters on the back. C. IIF on monkey esophagus: pemphigus IgG4 autoantibodies. PF recurrence in the course of ACE-inhibitor treatment for myo‐ cardial infarction.

#### *6.1.4. Case 4 — Pemphigus foliaceus / squamous cell carcinoma of the thorax*

Published in [189]

176 Highlights in Skin Cancer

**Figure 2.** A. Carcinoma planoepitheliale keratodes invasivum in lymphoid tissue. H+E staining. Courtesy of Prof. J. Brę‐ borowicz. B. Numerous erosions on non-inflammatory skin of the back, some of them covered with brownish-greenish crusts. C. Erosions on non-inflammatory skin of the face and neck. Scar after the surgical excision of the cancer. D. Nu‐ merous merging erosions, some covered with bloody and greenish crusts on the skin of the neck area subjected to radiotherapy. E. Erosions covered with crusts around the nipple (a natural body orifice area). F. Suprabasilar separation and acantholytic blister in the upper epidermis. H+E staining. G. DIF of perilesional skin of the back: pemphigus IgG4

deposits in lower epidermis. H. DIF of plucked scalp hair: pemphigus IgG4 deposits in outer root sheath.

A middle-aged man was consulted by dermatological specialist due to disseminated eryth‐ ematous plaques. The lesions were preceded by three months of uncomfortable itching on hands and feet. He was not diagnosed beforehand and was solely treated with topical steroids. Therefore, he was directed do dermatological ward with tentative diagnosis of pemphigus/PNP for further diagnostics and treatment.

painful erosions on oral mucosa dating back several months (Fig. 5A). Subsequently, the blistering lesions and oozing erosions appeared on the skin (Fig. 5B, C). He called the derma‐ tology professional and was directed to dermatological ward for diagnosis and treatment.

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His laboratory tests showed increased sedimentation rate. Chest x-ray revealed fine atelectasis in the inferior aspect of the right lung. Ultrasonography of the abdomen showed non-echogenic area (16 mm x 18 mm) with intramural calcification and features of a cyst within VII segment and hypoechogenic lesion (dia. of 12 mm), probably angioma, in VI/VII segment of the of the right lobe of the liver. Two lesser cysts (up to dia. 5 mm) were found in left lobe. Gallstone (dia. 18 mm) was depicted in gall bladder, while right kidney showed sonographic features of hydronephrosis. An intravenous urogram (IVU) proved the presence of renal stone in right ureteropelvic junction, causing obstruction and dilatation of the pelvicalyceal system. In Tzanck test rounded acantholytic cells were present (Fig. 5D). Skin bioptate was characterized by the pathologist as PV material. hDIF showed IgG(++) and IgG4(+) deposits in intercellular spaces of outer root sheath (Fig. 5G). DIF on skin lesion margin showed IgG(+), IgG4(++) and C3(+) deposits in intercellular spaces of the lower spinous layer of epidermis (Fig. 5H). IIF on monkey esophagus revealed circulating IgG pemphigus-type antibodies against desmosomal proteins of keratinocytes – titer 1/320. ELISA test with patient's serum revealed serum anti-DSG1 and anti-DSG3 IgG class autoantibodies – levels respectively 133.81 RU/ml (cut-off point 41 RU/ml) and > 150 RU/ml (cut-off point 40 RU/ml). The diagnosis of mucocutaneous PV (shifting from mucosal dominant PV) was established. He was treated with pulses of high dose intravenous steroids combined with oral/topical steroids and doxycycline as a fundamental

An elderly female, five years after right-side mastectomy due to breast cancer (invasive ductal carcinoma; G1; pT1cpN1Mx), was admitted to dermatological ward with painful non-healing erosions of oral and tongue mucosa. Her medical history was significant for diabetes mellitus type 2, arterial hypertension, diverticulosis, hemorrhagic gastritis and past episodes of deep vein thrombosis in the legs and thrombosis of the right central retinal vein. hDIF revealed IgG (+++), IgG1(++), IgG4(+++) and C3 deposits in intercellular spaces of outer root sheath (Fig. 6A). DIF on the perilesional mucosa showed IgG(+), IgG1(++), IgG4(+)and C3 deposits in intercellular spaces of lower layers of oral epithelium (Fig. 6B). IIF on monkey esophagus showed circulating IgG pemphigus-type antibodies binding spinous layer desmosomal proteins of keratinocytes – titer 1/160. Serum PNP-type autoantibodies were absent in IIF study on rat bladder transitional epithelium. ELISA study revealed elevated anti-DSG3 IgG level: 112.83 AU/ml (cut-off point 40 AU/ml), while IgG anti-DSG1 level was normal: 34.49 AU/ml (cut-off point 41AU/ml). Both laboratory tests and immunopathological findings supported the diagnosis of mucosal dominant PV. She was treated with oral methyloprednisolone,

Because of her medical history, she was gradually deprived of methyloprednisolone, that resulted in an aggravation of PV within a month and need for urgent hospitalization. She was admitted with diffused erosions and blisters both on the skin and oral mucosa. Laboratory

therapy with satisfactory effect.

doxycycline and cyclophosphamide.

*6.1.6. Case 6 — Mucosal dominant pemphigus vulgaris / breast cancer*

On admission, he presented erythroderma (Fig. 4A) and notable exophytic tumor on anterior surface of the thorax (c.a. 13 cm of diameter), clinically carcinoma verrucosum (Fig. 4B). Laboratory tests showed anemia, increased sedimentation rate and CRP. Histology of the perilesional skin showed marked acantholysis (Fig. 4C). Tumor margin bioptate showed clustered isles of atypic cells with fine keratin pearls giving overall image of highly differentiat‐ ed squamous cell carcinoma (SCC) G1 (Fig. 4D). IIF on monkey esophagus proved the pres‐ ence of serum IgG pemphigus-type antibodies against desmosomal proteins of keratinocytes – titer1/160,yetIIFonratbladderforserumPNP-typeIgGwasnegative.ELISAtestshowedserum anti-DSG1 IgG level >200 RU/ml (cut-off point 20 RU/ml), yet did not revealed serum anti-DSG3IgG–level0RU/ml(cut-offpoint20RU/ml).DIFoftheperilesional skinvisualizedIgG(+), IgG1(++) andIgG4(++)deposits inthe intercellular spaces ofhigherlayers of epidermis andC3(+ +)deposits inthe intercellular spacesoflowerlayersof epidermis (Fig. 4E).hDIFshowedIgG(+), IgG1(+) and C3(+) deposits in the intercellular spaces of outer root sheath (Fig. 4F). With clinical and histological findings and molecular findings, the diagnosis of PF was made. After achiev‐ ing dermatological improvement with doxycycline, antihistamine drugs and oral/topical steroids, patient was directed to oncology ward for SCC therapy.

**Figure 4.** A. Disseminated erythematous plaques and crusts on the back. B. Exophytic tumor on anterior surface of the chest. C. Histology of the perilesional skin: Acantholysis. H+E staining. D. Histology of the tumor margin: Clustered isles of atypical cells with fine keratin pearls. Highly differentiated SCC. H+E staining. E. DIF of perilesional skin: IgG4(++) deposits in the intercellular spaces of higher layers of epidermis. F. hDIF of plucked scalp hair: IgG(+) deposits in the intercellular spaces of outer root sheath.

*6.1.5. Case 5 — Mucocutaneous pemphigus vulgaris shifting from mucosal dominant form / lower lip squamous cell carcinoma*

An elderly man treated for lower lip squamous cell carcinoma (SCC planoepitheliale kerato‐ des; G2) that developed in lesions showing histological features of PV (Fig. 5E, F) suffered from painful erosions on oral mucosa dating back several months (Fig. 5A). Subsequently, the blistering lesions and oozing erosions appeared on the skin (Fig. 5B, C). He called the derma‐ tology professional and was directed to dermatological ward for diagnosis and treatment.

His laboratory tests showed increased sedimentation rate. Chest x-ray revealed fine atelectasis in the inferior aspect of the right lung. Ultrasonography of the abdomen showed non-echogenic area (16 mm x 18 mm) with intramural calcification and features of a cyst within VII segment and hypoechogenic lesion (dia. of 12 mm), probably angioma, in VI/VII segment of the of the right lobe of the liver. Two lesser cysts (up to dia. 5 mm) were found in left lobe. Gallstone (dia. 18 mm) was depicted in gall bladder, while right kidney showed sonographic features of hydronephrosis. An intravenous urogram (IVU) proved the presence of renal stone in right ureteropelvic junction, causing obstruction and dilatation of the pelvicalyceal system. In Tzanck test rounded acantholytic cells were present (Fig. 5D). Skin bioptate was characterized by the pathologist as PV material. hDIF showed IgG(++) and IgG4(+) deposits in intercellular spaces of outer root sheath (Fig. 5G). DIF on skin lesion margin showed IgG(+), IgG4(++) and C3(+) deposits in intercellular spaces of the lower spinous layer of epidermis (Fig. 5H). IIF on monkey esophagus revealed circulating IgG pemphigus-type antibodies against desmosomal proteins of keratinocytes – titer 1/320. ELISA test with patient's serum revealed serum anti-DSG1 and anti-DSG3 IgG class autoantibodies – levels respectively 133.81 RU/ml (cut-off point 41 RU/ml) and > 150 RU/ml (cut-off point 40 RU/ml). The diagnosis of mucocutaneous PV (shifting from mucosal dominant PV) was established. He was treated with pulses of high dose intravenous steroids combined with oral/topical steroids and doxycycline as a fundamental therapy with satisfactory effect.

#### *6.1.6. Case 6 — Mucosal dominant pemphigus vulgaris / breast cancer*

Therefore, he was directed do dermatological ward with tentative diagnosis of

On admission, he presented erythroderma (Fig. 4A) and notable exophytic tumor on anterior surface of the thorax (c.a. 13 cm of diameter), clinically carcinoma verrucosum (Fig. 4B). Laboratory tests showed anemia, increased sedimentation rate and CRP. Histology of the perilesional skin showed marked acantholysis (Fig. 4C). Tumor margin bioptate showed clustered isles of atypic cells with fine keratin pearls giving overall image of highly differentiat‐ ed squamous cell carcinoma (SCC) G1 (Fig. 4D). IIF on monkey esophagus proved the pres‐ ence of serum IgG pemphigus-type antibodies against desmosomal proteins of keratinocytes – titer1/160,yetIIFonratbladderforserumPNP-typeIgGwasnegative.ELISAtestshowedserum anti-DSG1 IgG level >200 RU/ml (cut-off point 20 RU/ml), yet did not revealed serum anti-DSG3IgG–level0RU/ml(cut-offpoint20RU/ml).DIFoftheperilesional skinvisualizedIgG(+), IgG1(++) andIgG4(++)deposits inthe intercellular spaces ofhigherlayers of epidermis andC3(+ +)deposits inthe intercellular spacesoflowerlayersof epidermis (Fig. 4E).hDIFshowedIgG(+), IgG1(+) and C3(+) deposits in the intercellular spaces of outer root sheath (Fig. 4F). With clinical and histological findings and molecular findings, the diagnosis of PF was made. After achiev‐ ing dermatological improvement with doxycycline, antihistamine drugs and oral/topical

**Figure 4.** A. Disseminated erythematous plaques and crusts on the back. B. Exophytic tumor on anterior surface of the chest. C. Histology of the perilesional skin: Acantholysis. H+E staining. D. Histology of the tumor margin: Clustered isles of atypical cells with fine keratin pearls. Highly differentiated SCC. H+E staining. E. DIF of perilesional skin: IgG4(++) deposits in the intercellular spaces of higher layers of epidermis. F. hDIF of plucked scalp hair: IgG(+) deposits in the

*6.1.5. Case 5 — Mucocutaneous pemphigus vulgaris shifting from mucosal dominant form / lower lip*

An elderly man treated for lower lip squamous cell carcinoma (SCC planoepitheliale kerato‐ des; G2) that developed in lesions showing histological features of PV (Fig. 5E, F) suffered from

pemphigus/PNP for further diagnostics and treatment.

178 Highlights in Skin Cancer

steroids, patient was directed to oncology ward for SCC therapy.

intercellular spaces of outer root sheath.

*squamous cell carcinoma*

An elderly female, five years after right-side mastectomy due to breast cancer (invasive ductal carcinoma; G1; pT1cpN1Mx), was admitted to dermatological ward with painful non-healing erosions of oral and tongue mucosa. Her medical history was significant for diabetes mellitus type 2, arterial hypertension, diverticulosis, hemorrhagic gastritis and past episodes of deep vein thrombosis in the legs and thrombosis of the right central retinal vein. hDIF revealed IgG (+++), IgG1(++), IgG4(+++) and C3 deposits in intercellular spaces of outer root sheath (Fig. 6A). DIF on the perilesional mucosa showed IgG(+), IgG1(++), IgG4(+)and C3 deposits in intercellular spaces of lower layers of oral epithelium (Fig. 6B). IIF on monkey esophagus showed circulating IgG pemphigus-type antibodies binding spinous layer desmosomal proteins of keratinocytes – titer 1/160. Serum PNP-type autoantibodies were absent in IIF study on rat bladder transitional epithelium. ELISA study revealed elevated anti-DSG3 IgG level: 112.83 AU/ml (cut-off point 40 AU/ml), while IgG anti-DSG1 level was normal: 34.49 AU/ml (cut-off point 41AU/ml). Both laboratory tests and immunopathological findings supported the diagnosis of mucosal dominant PV. She was treated with oral methyloprednisolone, doxycycline and cyclophosphamide.

Because of her medical history, she was gradually deprived of methyloprednisolone, that resulted in an aggravation of PV within a month and need for urgent hospitalization. She was admitted with diffused erosions and blisters both on the skin and oral mucosa. Laboratory

tests revealed elevated CEA level – 8.05 ng/ml (cut-off point 5 ng/ml) with normal levels of other cancer biomarkers (CA19-9, Ca125, AFP). She was treated with cyclophosphamide,

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She was readmitted to the ward six months later with erosions on buccal mucosa, base of the mouth, soft palate and epiglottis. Laboratory tests revealed elevated CA19-9 level: 843.8 U/ml (cut-off point 37 U/ml). After achieving remission of lesions, she was directed to oncology

**Figure 6.** A. hDIF visualizing IgG1(++) deposits in the outer root sheath. B. DIF of perilesional mucosa revealing IgG1(+

A middle-aged man with exophytic ulcerative nasal tumor was diagnosed with paranasal sinuses roentgenogram revealing massive shade of polycyclic outline. Surgical excision of the external nose tumor infiltrating upper lip was performed in oncology center (Fig. 7A). Exophytic lesion was described by a pathologist as carcinoma planoepitheliale keratodes (G2). The patient was frequently monitored in oncology outpatients finding no features of tumor

Two years afterward, erythemous plaques with flaccid serous blisters, oozing erosions and crusts appeared on lower limbs. It took several weeks until lesions generalized and occupied trunk, limbs, head and intertriginous regions forming vast desquamative surfaces of flaky puff pastry-like appearance (Fig. 7B). Mucous membranes remained free of lesions. Due to ineffective ambulatory management, he was directed to dermatological ward with

Histological features of perilesional skin supported PF diagnosis. IIF on monkey esopha‐ gus revealed serum IgG pemphigus-type antibodies against desmosomal proteins of spinous layer of epidermis – titer 1/320, yet IIF on rat bladder epithelium as a substrate did not detected circulating PNP-type autoantibodies. DIF of perilesional skin visualized

*6.1.7. Case 7 — Pemphigus foliaceus / squamous cell carcinoma of external nose and upper lip*

doxycycline and high doses of both intravenous and oral steroids.

outpatients to screen for malignancy.

+) deposits in intercellular spaces of lower layers of oral epithelium.

recurrence.

tentative diagnosis of PF.

Published in [190].

**Figure 5.** A. Mucosal erosions in patient with lower lip SCC and mucocutaneous PV. B. Fragile blister on the hand. C. Pemphigus vulgaris imitating paronychia. D. Positive Tzanck test: rounded acantholytic cells suggestive for PV. E. Su‐ prabasilar cleft with acantholysis in the lower lip specimen showing also features of SCC. H+E staining. F. Lower lip SCC. H+E staining. Courtesy of Prof. J. Bręborowicz. G. hDIF: pemphigus IgG deposits in intercellular spaces of outer root sheath. H.DIF showing IgG pemphigus-type deposits.

tests revealed elevated CEA level – 8.05 ng/ml (cut-off point 5 ng/ml) with normal levels of other cancer biomarkers (CA19-9, Ca125, AFP). She was treated with cyclophosphamide, doxycycline and high doses of both intravenous and oral steroids.

She was readmitted to the ward six months later with erosions on buccal mucosa, base of the mouth, soft palate and epiglottis. Laboratory tests revealed elevated CA19-9 level: 843.8 U/ml (cut-off point 37 U/ml). After achieving remission of lesions, she was directed to oncology outpatients to screen for malignancy.

#### *6.1.7. Case 7 — Pemphigus foliaceus / squamous cell carcinoma of external nose and upper lip*

A middle-aged man with exophytic ulcerative nasal tumor was diagnosed with paranasal sinuses roentgenogram revealing massive shade of polycyclic outline. Surgical excision of the external nose tumor infiltrating upper lip was performed in oncology center (Fig. 7A). Exophytic lesion was described by a pathologist as carcinoma planoepitheliale keratodes (G2). The patient was frequently monitored in oncology outpatients finding no features of tumor recurrence.

Two years afterward, erythemous plaques with flaccid serous blisters, oozing erosions and crusts appeared on lower limbs. It took several weeks until lesions generalized and occupied trunk, limbs, head and intertriginous regions forming vast desquamative surfaces of flaky puff pastry-like appearance (Fig. 7B). Mucous membranes remained free of lesions. Due to ineffective ambulatory management, he was directed to dermatological ward with tentative diagnosis of PF.

Published in [190].

180 Highlights in Skin Cancer

root sheath. H.DIF showing IgG pemphigus-type deposits.

**Figure 5.** A. Mucosal erosions in patient with lower lip SCC and mucocutaneous PV. B. Fragile blister on the hand. C. Pemphigus vulgaris imitating paronychia. D. Positive Tzanck test: rounded acantholytic cells suggestive for PV. E. Su‐ prabasilar cleft with acantholysis in the lower lip specimen showing also features of SCC. H+E staining. F. Lower lip SCC. H+E staining. Courtesy of Prof. J. Bręborowicz. G. hDIF: pemphigus IgG deposits in intercellular spaces of outer

Histological features of perilesional skin supported PF diagnosis. IIF on monkey esopha‐ gus revealed serum IgG pemphigus-type antibodies against desmosomal proteins of spinous layer of epidermis – titer 1/320, yet IIF on rat bladder epithelium as a substrate did not detected circulating PNP-type autoantibodies. DIF of perilesional skin visualized well-defined IgG(+++) and IgG4(+++) deposits in intercellular spaces of lower layers of epidermis and linear C3(+) deposits alongside DEJ (Fig. 7C). Serum anti-DSG1 IgG ELISA was positive – level >150 AU/ml (cut-off point 41 AU/ml), whereas serum anti-DSG3 IgG ELISA proved negative – level 6.20 AU/ml (cut-off point 40 AU/ml). The molecular tests confirmed the PF diagnosis. He was treated with oral/intravenous steroids and cyclophos‐ phamide, azathioprine and doxycycline as adjuvant treatment. The compliance in ambula‐ tory care was poor as the patient repeatedly was treated in dermatological ward with IIF IgG pemphigus-type antibody titer reaching 1/2560.

BP tend to manifest in natural and iatrogenic orifices featured by transient epithelium (e.g. the scar or the stomy site). It may be possible, that malignant tumor causing pathological immu‐ nization triggered the onset of this subepidermal dermatosis. The case is a hallmark of

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A middle-aged female was directed to dermatological ward for diagnostics and treatment of disseminated itchy blisters and vesicles on erythematous skin (Fig. 9A, B) dating back two months. Her family history was significant for renal cancer coexisting with a subepidermal IgG-mediated bullous dermatosis, most likely BP, in grandmother. Her laboratory test were noncontributory. Immunohistochemical study showed subepidermal blister with neutrophil elastase (NE) deposits (Fig. 9C). IIF on monkey esophagus was positive for serum IgG pemphigoid-type antibody against DEJ proteins – titer 1/80. DIF of the perilesional skin revealed IgG1(+), IgG4(+) and C3(++) deposits along DEJ (Fig. 9D). Direct immunofluorescence test on salt-split skin (ssDIF) showed IgG4(+) and C3 deposits on epidermal side of the split. Aforementioned methods made it possible to diagnose BP and begin treatment with oral/ topical steroids, cyclophosphamide, doxycycline and antihistamines. Because of family history of autoimmune blistering dermatosis coexistent with cancer, the patient was advised to

undergo meticulous follow-up to reveal any signs of malignancy as soon as possible.

An elderly female, with swollen left supraclavicular lymph nodes, weight loss, fatigue, low grade fever and night sweats, was admitted to internal diseases ward for diagnostics. Both clinical symptoms, laboratory tests and histological examination of lymph node supported the diagnosis of Hodgkin lymphoma (IIB). She was treated with ABVD chemotherapy regimen (adriamycin, bleomycin, vinblastine, dacarbazine) and COPP regimen (cyclophosphamide, vincristin, procarbazine, prednisone) - due to bad tolerance of anthracyclines, achieving

Six years later, she called ENT professional due to dysphagia, oral itching and numerous painfull erosions on oral mucosa covered with whitish coating (Fig. 10A). The lesions were diagnosed mycologically as oral candidiasis (Candida famata, Candida glabrata). Antimyco‐ logical treatment seemed ineffective and another erosive lesion (3 cm in diameter) appeared in umbilical region (Fig. 10B). She was directed to dermatological ward for further diagnostics and treatment six months later. Her medical history was also significant for total hysterectomy and episode of upper gastrointestinal bleeding (diffused intestinal metaplasia of the stomach mucosa; coagulated). Laboratory blood tests showed increased sedimentation rate and CRP. IIF on monkey esophagus did not revealed circulating IgG antibodies against desmosomal proteins of keratinocytes and basement membrane antigens (Fig. 10C). DIF of the perilesional skin from the umbilical region showed linear deposits of IgG(+/-), IgG1(+), and C3(+) along dermal-epidermal junction (Fig. 10D). In natural blister, autoantibody deposits were seen on epidermal side of the split. The diagnosis of MMP was based on clinical and DIF findings

*6.2.2. Case 9 — Bullous pemphigoid / family history of renal cancer*

*6.2.3. Case 10 — Mucous membrane pemphigoid / hodgkin lymphoma*

literature data [191–193].

lymphoma remission.

fulfilling the criteria of this dermatosis.

**Figure 7.** A. Nose stump after tumor excision. Courtesy of S. Stusek MD. B. Flaky puff pastry-like desquamative lesions on the trunk. Courtesy of S. Stusek MD. C. DIF of perilesional skin: intense pemphigus IgG4(+++) deposits.

#### **6.2. Subepidermal autoimmune blistering diseases**

#### *6.2.1. Case 8 — Bullous pemphigoid / colon cancer*

An elderly man was directed to chirurgical ward due to ileus. He underwent left hemicolec‐ tomy and forming of colostomy because of appendicitis, chronic peritonitis and colon cancer. Histopathological examination of the excised material revealed partially gelatinous tubular adenocarcinoma (G2; T4N0M0) infiltrating pericolic adipose tissue (Fig. 8B).

After the surgery, eczematous vesicular oozing eruption appeared on the surrounding of the stomy (Fig. 8A), while itchy well-tense bullae occurred on the skin of the back covering trunk and limbs in a few weeks. Histopathological and immunopathological tests were performed in dermatological outpatient ward two years after operation. Histology of the perilesional skin showed subepidermal vesicle filled with inflammatory cells with predominance of eosinoi‐ phils (Fig. 8C). Perilesional skin DIF revealed linear deposits of IgG4(++) and C3(+++) along dermal-epidermal junction (DEJ) (Fig. 8D). IIF, performed on monkey esophagus as a sub‐ strate, was negative for IgG serum autoantibodies against desmosomal proteins of keratino‐ cytes and basement membrane antigens. ELISA anti-BP180NC16a examination was positive for serum IgG antibodies against BP180 – titer 60.47 U/ml (cut-off point 9 U/ml), that enabled the diagnosis of trauma-induced and paraneoplastic BP at the molecular level. Control chest X-ray and ultrasonography of the abdomen did not showed neoplasm.

BP tend to manifest in natural and iatrogenic orifices featured by transient epithelium (e.g. the scar or the stomy site). It may be possible, that malignant tumor causing pathological immu‐ nization triggered the onset of this subepidermal dermatosis. The case is a hallmark of literature data [191–193].

#### *6.2.2. Case 9 — Bullous pemphigoid / family history of renal cancer*

well-defined IgG(+++) and IgG4(+++) deposits in intercellular spaces of lower layers of epidermis and linear C3(+) deposits alongside DEJ (Fig. 7C). Serum anti-DSG1 IgG ELISA was positive – level >150 AU/ml (cut-off point 41 AU/ml), whereas serum anti-DSG3 IgG ELISA proved negative – level 6.20 AU/ml (cut-off point 40 AU/ml). The molecular tests confirmed the PF diagnosis. He was treated with oral/intravenous steroids and cyclophos‐ phamide, azathioprine and doxycycline as adjuvant treatment. The compliance in ambula‐ tory care was poor as the patient repeatedly was treated in dermatological ward with IIF

**Figure 7.** A. Nose stump after tumor excision. Courtesy of S. Stusek MD. B. Flaky puff pastry-like desquamative lesions

An elderly man was directed to chirurgical ward due to ileus. He underwent left hemicolec‐ tomy and forming of colostomy because of appendicitis, chronic peritonitis and colon cancer. Histopathological examination of the excised material revealed partially gelatinous tubular

After the surgery, eczematous vesicular oozing eruption appeared on the surrounding of the stomy (Fig. 8A), while itchy well-tense bullae occurred on the skin of the back covering trunk and limbs in a few weeks. Histopathological and immunopathological tests were performed in dermatological outpatient ward two years after operation. Histology of the perilesional skin showed subepidermal vesicle filled with inflammatory cells with predominance of eosinoi‐ phils (Fig. 8C). Perilesional skin DIF revealed linear deposits of IgG4(++) and C3(+++) along dermal-epidermal junction (DEJ) (Fig. 8D). IIF, performed on monkey esophagus as a sub‐ strate, was negative for IgG serum autoantibodies against desmosomal proteins of keratino‐ cytes and basement membrane antigens. ELISA anti-BP180NC16a examination was positive for serum IgG antibodies against BP180 – titer 60.47 U/ml (cut-off point 9 U/ml), that enabled the diagnosis of trauma-induced and paraneoplastic BP at the molecular level. Control chest

on the trunk. Courtesy of S. Stusek MD. C. DIF of perilesional skin: intense pemphigus IgG4(+++) deposits.

adenocarcinoma (G2; T4N0M0) infiltrating pericolic adipose tissue (Fig. 8B).

X-ray and ultrasonography of the abdomen did not showed neoplasm.

IgG pemphigus-type antibody titer reaching 1/2560.

182 Highlights in Skin Cancer

**6.2. Subepidermal autoimmune blistering diseases**

*6.2.1. Case 8 — Bullous pemphigoid / colon cancer*

A middle-aged female was directed to dermatological ward for diagnostics and treatment of disseminated itchy blisters and vesicles on erythematous skin (Fig. 9A, B) dating back two months. Her family history was significant for renal cancer coexisting with a subepidermal IgG-mediated bullous dermatosis, most likely BP, in grandmother. Her laboratory test were noncontributory. Immunohistochemical study showed subepidermal blister with neutrophil elastase (NE) deposits (Fig. 9C). IIF on monkey esophagus was positive for serum IgG pemphigoid-type antibody against DEJ proteins – titer 1/80. DIF of the perilesional skin revealed IgG1(+), IgG4(+) and C3(++) deposits along DEJ (Fig. 9D). Direct immunofluorescence test on salt-split skin (ssDIF) showed IgG4(+) and C3 deposits on epidermal side of the split. Aforementioned methods made it possible to diagnose BP and begin treatment with oral/ topical steroids, cyclophosphamide, doxycycline and antihistamines. Because of family history of autoimmune blistering dermatosis coexistent with cancer, the patient was advised to undergo meticulous follow-up to reveal any signs of malignancy as soon as possible.

#### *6.2.3. Case 10 — Mucous membrane pemphigoid / hodgkin lymphoma*

An elderly female, with swollen left supraclavicular lymph nodes, weight loss, fatigue, low grade fever and night sweats, was admitted to internal diseases ward for diagnostics. Both clinical symptoms, laboratory tests and histological examination of lymph node supported the diagnosis of Hodgkin lymphoma (IIB). She was treated with ABVD chemotherapy regimen (adriamycin, bleomycin, vinblastine, dacarbazine) and COPP regimen (cyclophosphamide, vincristin, procarbazine, prednisone) - due to bad tolerance of anthracyclines, achieving lymphoma remission.

Six years later, she called ENT professional due to dysphagia, oral itching and numerous painfull erosions on oral mucosa covered with whitish coating (Fig. 10A). The lesions were diagnosed mycologically as oral candidiasis (Candida famata, Candida glabrata). Antimyco‐ logical treatment seemed ineffective and another erosive lesion (3 cm in diameter) appeared in umbilical region (Fig. 10B). She was directed to dermatological ward for further diagnostics and treatment six months later. Her medical history was also significant for total hysterectomy and episode of upper gastrointestinal bleeding (diffused intestinal metaplasia of the stomach mucosa; coagulated). Laboratory blood tests showed increased sedimentation rate and CRP. IIF on monkey esophagus did not revealed circulating IgG antibodies against desmosomal proteins of keratinocytes and basement membrane antigens (Fig. 10C). DIF of the perilesional skin from the umbilical region showed linear deposits of IgG(+/-), IgG1(+), and C3(+) along dermal-epidermal junction (Fig. 10D). In natural blister, autoantibody deposits were seen on epidermal side of the split. The diagnosis of MMP was based on clinical and DIF findings fulfilling the criteria of this dermatosis.

#### Published in [191].

**Figure 8.** A. Blisters and their evolutionary lesions on inflamed skin around colostomy. B. A part of neoplastic infiltrate in the wall of large intestine showing cramped glandular ducts with irregular shapes. Epithelium cells with high-grade atypical cells. Inflammation of the periphery. H+E staining. Courtesy of I. Turczuk-Bierła MD. C. Histology of perilesional skin: Subepidermal vesicle with admixture of eosinophils within it. H+E staining. D. DIF of the blister skin margin: linear IgG4(++) deposits along DEJ.

> **Figure 10.** A. Mucosal erosions in oral cavity. B. Erosion in the navel. C. IIF study revealing no IgG antibodies binding either desmosomal proteins of keratinocytes or basement membrane antigens. D. DIF of the perilesional navel skin:

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An elderly man visited the dermatologist due to disseminated erythematous itchy lesions, papules, erosions and a few well-tensed blisters filled with serous exudate on the forearms, arms and trunk (Fig. 11A, B). He was treated without clinical effect with antibiotics, antihist‐ amine drugs and oral steroids. After a month, he was directed to dermatological ward for

His medical history was significant for nephrectomy because of carcinoma clarocellulare, prostate adenocarcinoma (Gleason 1+3=4) treated with brachytherapy (HDR; 20 Gy) and radiotherapy, two hypermetabolic abdominal foci at level of kidney vessels in PET (suppos‐ edly metastatic lymph nodes), thyroid nodule and testis hydrocele. Laboratory tests revealed

Histology of the perilesional skin showed subepidermal blistering and inflammatory mixed infiltrate with neutrophils and eosinophils (Fig. 11C). DIF of the perilesional skin of gluteal region showed linear deposits of IgG1(+), IgG4(++) and C3(+) along DEJ. DIF performed on vesicle margin skin showed linear deposits of IgG(+), IgG1(+), IgG4(+++) and C3(++) along dermal-epidermal junction. (Fig. 11D). IIF on monkey esophagus did not revealed

linear IgG1(+) deposits alongside DEJ. Autoantibody deposits on epidermal side.

*6.2.4. Case 11 — Bullous pemphigoid / renal cancer / prostate cancer*

increased CRP levels, monocytosis, eosinocytosis, hypertriglyceridemia.

further diagnostics.

**Figure 9.** A. Erosions and bullae on erythematous skin forming "string of beans". B. Group of small blisters forming "cluster of jewels". C. Immunohistochemical study of the lesional skin. Visualization of neutrophil elastase (NE) depos‐ its in the subepidermal blister. D. DIF on the perilesional skin: linear IgG4(+) deposits along DEJ.

**Figure 10.** A. Mucosal erosions in oral cavity. B. Erosion in the navel. C. IIF study revealing no IgG antibodies binding either desmosomal proteins of keratinocytes or basement membrane antigens. D. DIF of the perilesional navel skin: linear IgG1(+) deposits alongside DEJ. Autoantibody deposits on epidermal side.

#### *6.2.4. Case 11 — Bullous pemphigoid / renal cancer / prostate cancer*

Published in [191].

184 Highlights in Skin Cancer

IgG4(++) deposits along DEJ.

**Figure 8.** A. Blisters and their evolutionary lesions on inflamed skin around colostomy. B. A part of neoplastic infiltrate in the wall of large intestine showing cramped glandular ducts with irregular shapes. Epithelium cells with high-grade atypical cells. Inflammation of the periphery. H+E staining. Courtesy of I. Turczuk-Bierła MD. C. Histology of perilesional skin: Subepidermal vesicle with admixture of eosinophils within it. H+E staining. D. DIF of the blister skin margin: linear

**Figure 9.** A. Erosions and bullae on erythematous skin forming "string of beans". B. Group of small blisters forming "cluster of jewels". C. Immunohistochemical study of the lesional skin. Visualization of neutrophil elastase (NE) depos‐

its in the subepidermal blister. D. DIF on the perilesional skin: linear IgG4(+) deposits along DEJ.

An elderly man visited the dermatologist due to disseminated erythematous itchy lesions, papules, erosions and a few well-tensed blisters filled with serous exudate on the forearms, arms and trunk (Fig. 11A, B). He was treated without clinical effect with antibiotics, antihist‐ amine drugs and oral steroids. After a month, he was directed to dermatological ward for further diagnostics.

His medical history was significant for nephrectomy because of carcinoma clarocellulare, prostate adenocarcinoma (Gleason 1+3=4) treated with brachytherapy (HDR; 20 Gy) and radiotherapy, two hypermetabolic abdominal foci at level of kidney vessels in PET (suppos‐ edly metastatic lymph nodes), thyroid nodule and testis hydrocele. Laboratory tests revealed increased CRP levels, monocytosis, eosinocytosis, hypertriglyceridemia.

Histology of the perilesional skin showed subepidermal blistering and inflammatory mixed infiltrate with neutrophils and eosinophils (Fig. 11C). DIF of the perilesional skin of gluteal region showed linear deposits of IgG1(+), IgG4(++) and C3(+) along DEJ. DIF performed on vesicle margin skin showed linear deposits of IgG(+), IgG1(+), IgG4(+++) and C3(++) along dermal-epidermal junction. (Fig. 11D). IIF on monkey esophagus did not revealed circulating IgG antibodies against desmosomal proteins of keratinocytes and basement membrane antigens. ELISA test revealed increased serum anti-BP230 IgG level – 81.356 RU/ml (cut-off point 20 RU/ml), yet circulating anti-BP180 IgG level was normal – 8.037 RU/ml (cut-off point 20 RU/ml). Vesicular and paraneoplastic BP was confirmed at the molecular level.

DIF of perilesional skin revealed linear deposits of IgG4(+) and C3(++) along dermal-epidermal junction (Fig. 12C). IIF on monkey esophagus did not revealed circulating IgG antibodies against either desmosomal proteins of keratinocytes or basement membrane antigens. The patient was directed to dermatological ward for further diagnostics. Laboratory tests showed leukocytosis, increased sedimentation rate and CRP. Apart of slightly increased CEA (6.79 ng/ ml; cut-off for non-smokers 5.00 ng/ml, for smokers 6.50 ng/ml), other cancer biomarkers (AFP, CA19-9, Ca125, PSA) were negative. ELISA study was positive for serum anti-BP180 IgG – 19.50 RU/ml (cut-off point 9 RU/ml), yet negative for serum anti-BP230 IgG – 0.00 RU/ml (cutoff point 9 RU/ml). The diagnosis of BP was established. Abdominal ultrasound displayed enlarged liver without visible focal changes. Chest x-ray revealed a tumorous mass (7.0 cm x 6.6 cm), in middle lobe of the right lung, infiltrating lower root (Fig. 12D). Chest CT showed heterogeneous tumor of the right lung with consequent emphysema and metastatic mediasti‐

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Consulting pulmonologist ordered further diagnostics and treatment in pulmonological ward, where bronchofiberoscopy was performed. With the histological diagnosis of carcinoma planoepitheliale akeratodes (G3; T4N2M0; IIIB) the patient began chemotherapy (cisplatin/

**Figure 12.** A. Painful well-tensed blisters, crusts and erosions on erythematous skin of the axillary area. B. Histology: subepidermal vesicle with abundant eosinophil infiltrate. H+E staining. C. DIF: linear deposits of IgG4 along DEJ. D.

Chest x-ray: solid mass in middle lobe of the right lung, Tumor infiltration of lower lung root.

nal lymph nodes.

vinorelbine regimen), yet he died within months.

Published in [220].

**Figure 11.** A. Erythemous/oedematous lesions and erosions on the back in patient with vesiculous form of BP. Sticking plaster marks the site of biopsy. B. Vesicular lesions on posteriomedial surface of the left arm. C. Histology of subepi‐ dermal blister. Inflammatory mixed infiltrate with neutrophils and eosinophils. H+E staining. D. DIF on perilesional skin: IgG4 deposits along DEJ.

#### *6.2.5. Case 12 — Bullous pemphigoid / lung cancer*

A middle-aged heavy smoker visited dermatologist because of disseminated eruption of welltensed painful blisters (Fig. 12A). Histological examination was suggestive of BP (Fig. 12B). DIF of perilesional skin revealed linear deposits of IgG4(+) and C3(++) along dermal-epidermal junction (Fig. 12C). IIF on monkey esophagus did not revealed circulating IgG antibodies against either desmosomal proteins of keratinocytes or basement membrane antigens. The patient was directed to dermatological ward for further diagnostics. Laboratory tests showed leukocytosis, increased sedimentation rate and CRP. Apart of slightly increased CEA (6.79 ng/ ml; cut-off for non-smokers 5.00 ng/ml, for smokers 6.50 ng/ml), other cancer biomarkers (AFP, CA19-9, Ca125, PSA) were negative. ELISA study was positive for serum anti-BP180 IgG – 19.50 RU/ml (cut-off point 9 RU/ml), yet negative for serum anti-BP230 IgG – 0.00 RU/ml (cutoff point 9 RU/ml). The diagnosis of BP was established. Abdominal ultrasound displayed enlarged liver without visible focal changes. Chest x-ray revealed a tumorous mass (7.0 cm x 6.6 cm), in middle lobe of the right lung, infiltrating lower root (Fig. 12D). Chest CT showed heterogeneous tumor of the right lung with consequent emphysema and metastatic mediasti‐ nal lymph nodes.

circulating IgG antibodies against desmosomal proteins of keratinocytes and basement membrane antigens. ELISA test revealed increased serum anti-BP230 IgG level – 81.356 RU/ml (cut-off point 20 RU/ml), yet circulating anti-BP180 IgG level was normal – 8.037 RU/ml (cut-off point 20 RU/ml). Vesicular and paraneoplastic BP was confirmed at the

**Figure 11.** A. Erythemous/oedematous lesions and erosions on the back in patient with vesiculous form of BP. Sticking plaster marks the site of biopsy. B. Vesicular lesions on posteriomedial surface of the left arm. C. Histology of subepi‐ dermal blister. Inflammatory mixed infiltrate with neutrophils and eosinophils. H+E staining. D. DIF on perilesional

A middle-aged heavy smoker visited dermatologist because of disseminated eruption of welltensed painful blisters (Fig. 12A). Histological examination was suggestive of BP (Fig. 12B).

molecular level.

186 Highlights in Skin Cancer

Published in [220].

skin: IgG4 deposits along DEJ.

*6.2.5. Case 12 — Bullous pemphigoid / lung cancer*

Consulting pulmonologist ordered further diagnostics and treatment in pulmonological ward, where bronchofiberoscopy was performed. With the histological diagnosis of carcinoma planoepitheliale akeratodes (G3; T4N2M0; IIIB) the patient began chemotherapy (cisplatin/ vinorelbine regimen), yet he died within months.

**Figure 12.** A. Painful well-tensed blisters, crusts and erosions on erythematous skin of the axillary area. B. Histology: subepidermal vesicle with abundant eosinophil infiltrate. H+E staining. C. DIF: linear deposits of IgG4 along DEJ. D. Chest x-ray: solid mass in middle lobe of the right lung, Tumor infiltration of lower lung root.

#### *6.2.6. Case 13 — Bullous pemphigoid / prostate cancer*

An elderly man consulted dermatology outpatient clinic due to itchy and painful well-tense blisters on the legs and subsequently on flexural surfaces of the forearms dating back four months (Fig. 13A). Perilesional skin bioptate and patient's blood sample were obtained for diagnostic purposes. Histology showed subepidermal blister. Major basic protein was visualized with immunohistochemical method marking eosinophil infiltrate (Fig. 13B). DIF study revealed linear deposits of IgG1(+), IgG4(+) and C3(++) along DEJ (Fig. 13C). IIF on monkey esophagus revealed circulating pemphigoid-type IgG, IgG1 and IgG4 antibodies against basement membrane antigens, of titers respectively 1/320, 1/160 and 1/160 (Fig. 13D). He was treated with limecycline, antihistamine drugs and incidental intramuscular steroids and was directed to dermatological ward, with tentative diagnosis of BP, for further diagnos‐ tics and treatment.

On admission he presented oozing erosions and well-tensed blisters filled with serosangui‐ neous exudate on the right forearm. His medical history was significant for prostatic cancer (treated for 8-year-period with hormonal therapy) and orchidectomy. He was treated by urologist with tamsulosin, cyproterone, finasteride, flutamide, leuprorelin and goserelin. Several months before lesions' appearance, the urologist ceased the hormonal treatment, finding it purposeless. Laboratory tests revealed erythrocytopenia, increased sedimentation rate and PSA (17.49 ng/ml; cut-off 4.00). Other cancer biomarkers (CEA, AFP), FOBT and stool examination for parasite infestation were negative. ELISA test performed on patient's serum and blister fluid showed increased anti-BP180 IgG level: 14.01 RU/ml and 13.21 RU/ml respectively (cut-off 9 RU/ml) and increased anti-BP230 IgG level: 90.66 RU/ml and 75.85 RU/ ml respectively. The diagnosis of BP as a paraneoplastic syndrome was made. Due to previous oncologic history, patient was urgently directed to urologist. Leuproreline readministration with immunosuppressive and anti-inflammatory treatment enabled remission of cutaneous lesions.

*6.2.8. Case 15 — Bullous pemphigoid / breast cancer*

IgG4 antibodies against epithelial basement membrane antigens.

Published in [21].

**6.3. Discussion on MAABD cases**

Anelderly female withitchy bullous eruptiononacralparts ofthe limbsvisitedthedermatolog‐ icaloutpatient clinic.The lesionsdatedbackfourmonths andsuggestedBP.Hermedicalhistory was significant for mastectomy due to breast cancer (infiltrating desmoplastic ductal and intraductal carcinoma of intermediate grade of malignancy; G2 according to Bloom-Richard‐ son Grading System). DIF study of the perilesional skin sample revealed linear IgG4(+/-) and C3(++)deposits alongDEJ.IIF, onmonkeyesophagus as a substrate,revealedneither serumIgG nor IgG4 antibodies against desmosomal proteins of keratinocytes and basement membrane antigens. ELISA study defined serum anti-BP180 IgG level as >200 RU/ml (cut-off point 20 RU/ ml), yet serum anti-BP230 IgG level was normal – 3.182 RU/ml (cut-off point 20 RU/ml). With molecular methods, the tentative clinical diagnosis of BP was confirmed. The patient re‐

**Figure 13.** A. Blisters and their evolutionary lesions on urticarial skin on the flexural surface of a forearm. B. Eosinophil major basic protein (MBP) deposits in lesional skin. Immunohistochemistry of subepidermal blister showing histologi‐ cal features of regeneration. C. DIF of perilesional skin: linear IgG1(+) deposits along DEJ. D. IIF on monkey esophagus:

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189

ABD can insidiously don the masks of other diseases imitating e.g. ulcerative carcinomas, paronychia, eczema or pruritus. Generalized or localized, the eruption may remain disguised for many months and years until the diagnosis is reached. In the light of contemporary data, ABDcircleshiftinonepatientbyacquiringautoimmunitytonewepitopes(viaepitopespreading or bystander effect) is possible. It should be concluded, that every circle is not a coherent group of diseases, yet forms a continuum of autoimmune blistering dermatoses within autoimmune

mained in control of both dermatology and oncology outpatient clinics.

#### *6.2.7. Case 14 — Ocular mucous membrane pemphigoid / endometrial cancer*

A middle-aged woman was admitted to dermatological dispensary due to erosive lesions on oral mucosa lasting for 2 years. She was treated by stomatologist, but without effect. Moreover, due to involvement of conjunctivae two months earlier, she called the ophthalmologist, yet the administered treatment seemed insufficient.

She was directed to dermatological ward for diagnostics. Her medical history was significant for hysterectomy and adnexotomy with fistula and colon partial resection and transversosto‐ my due to endometrial adenocarcinoma infiltrating colon, causing recto-vaginal fistula (G2; pT3aNx). She was planned for chemotherapy by gynaeco-oncologist. Her laboratory tests showed increased sedimentation rate and increased antinuclear antibodies (ANA) titer. IIF on monkey esophagus was negative for serum IgG autoantibodies against both desmosomal proteins of keratinocyte and basement membrane antigens. DIF on oral mucous membrane bioptate revealed scant linear C3 deposits along DEJ. Both clinical and immunopathological findings supported the diagnosis of ocular MMP.

#### Published in [21].

*6.2.6. Case 13 — Bullous pemphigoid / prostate cancer*

tics and treatment.

188 Highlights in Skin Cancer

lesions.

An elderly man consulted dermatology outpatient clinic due to itchy and painful well-tense blisters on the legs and subsequently on flexural surfaces of the forearms dating back four months (Fig. 13A). Perilesional skin bioptate and patient's blood sample were obtained for diagnostic purposes. Histology showed subepidermal blister. Major basic protein was visualized with immunohistochemical method marking eosinophil infiltrate (Fig. 13B). DIF study revealed linear deposits of IgG1(+), IgG4(+) and C3(++) along DEJ (Fig. 13C). IIF on monkey esophagus revealed circulating pemphigoid-type IgG, IgG1 and IgG4 antibodies against basement membrane antigens, of titers respectively 1/320, 1/160 and 1/160 (Fig. 13D). He was treated with limecycline, antihistamine drugs and incidental intramuscular steroids and was directed to dermatological ward, with tentative diagnosis of BP, for further diagnos‐

On admission he presented oozing erosions and well-tensed blisters filled with serosangui‐ neous exudate on the right forearm. His medical history was significant for prostatic cancer (treated for 8-year-period with hormonal therapy) and orchidectomy. He was treated by urologist with tamsulosin, cyproterone, finasteride, flutamide, leuprorelin and goserelin. Several months before lesions' appearance, the urologist ceased the hormonal treatment, finding it purposeless. Laboratory tests revealed erythrocytopenia, increased sedimentation rate and PSA (17.49 ng/ml; cut-off 4.00). Other cancer biomarkers (CEA, AFP), FOBT and stool examination for parasite infestation were negative. ELISA test performed on patient's serum and blister fluid showed increased anti-BP180 IgG level: 14.01 RU/ml and 13.21 RU/ml respectively (cut-off 9 RU/ml) and increased anti-BP230 IgG level: 90.66 RU/ml and 75.85 RU/ ml respectively. The diagnosis of BP as a paraneoplastic syndrome was made. Due to previous oncologic history, patient was urgently directed to urologist. Leuproreline readministration with immunosuppressive and anti-inflammatory treatment enabled remission of cutaneous

A middle-aged woman was admitted to dermatological dispensary due to erosive lesions on oral mucosa lasting for 2 years. She was treated by stomatologist, but without effect. Moreover, due to involvement of conjunctivae two months earlier, she called the ophthalmologist, yet

She was directed to dermatological ward for diagnostics. Her medical history was significant for hysterectomy and adnexotomy with fistula and colon partial resection and transversosto‐ my due to endometrial adenocarcinoma infiltrating colon, causing recto-vaginal fistula (G2; pT3aNx). She was planned for chemotherapy by gynaeco-oncologist. Her laboratory tests showed increased sedimentation rate and increased antinuclear antibodies (ANA) titer. IIF on monkey esophagus was negative for serum IgG autoantibodies against both desmosomal proteins of keratinocyte and basement membrane antigens. DIF on oral mucous membrane bioptate revealed scant linear C3 deposits along DEJ. Both clinical and immunopathological

*6.2.7. Case 14 — Ocular mucous membrane pemphigoid / endometrial cancer*

the administered treatment seemed insufficient.

findings supported the diagnosis of ocular MMP.

**Figure 13.** A. Blisters and their evolutionary lesions on urticarial skin on the flexural surface of a forearm. B. Eosinophil major basic protein (MBP) deposits in lesional skin. Immunohistochemistry of subepidermal blister showing histologi‐ cal features of regeneration. C. DIF of perilesional skin: linear IgG1(+) deposits along DEJ. D. IIF on monkey esophagus: IgG4 antibodies against epithelial basement membrane antigens.

#### *6.2.8. Case 15 — Bullous pemphigoid / breast cancer*

Anelderly female withitchy bullous eruptiononacralparts ofthe limbsvisitedthedermatolog‐ icaloutpatient clinic.The lesionsdatedbackfourmonths andsuggestedBP.Hermedicalhistory was significant for mastectomy due to breast cancer (infiltrating desmoplastic ductal and intraductal carcinoma of intermediate grade of malignancy; G2 according to Bloom-Richard‐ son Grading System). DIF study of the perilesional skin sample revealed linear IgG4(+/-) and C3(++)deposits alongDEJ.IIF, onmonkeyesophagus as a substrate,revealedneither serumIgG nor IgG4 antibodies against desmosomal proteins of keratinocytes and basement membrane antigens. ELISA study defined serum anti-BP180 IgG level as >200 RU/ml (cut-off point 20 RU/ ml), yet serum anti-BP230 IgG level was normal – 3.182 RU/ml (cut-off point 20 RU/ml). With molecular methods, the tentative clinical diagnosis of BP was confirmed. The patient re‐ mained in control of both dermatology and oncology outpatient clinics.

#### **6.3. Discussion on MAABD cases**

ABD can insidiously don the masks of other diseases imitating e.g. ulcerative carcinomas, paronychia, eczema or pruritus. Generalized or localized, the eruption may remain disguised for many months and years until the diagnosis is reached. In the light of contemporary data, ABDcircleshiftinonepatientbyacquiringautoimmunitytonewepitopes(viaepitopespreading or bystander effect) is possible. It should be concluded, that every circle is not a coherent group of diseases, yet forms a continuum of autoimmune blistering dermatoses within autoimmune multiorgan syndrome. The causative relation between ABD and cancer is difficult to establish, as both malignancy and ABD develops and stay undiagnosed over some time period.

secondary to surgical procedures exposing sequestered antigens of colon mucosa (particularly BP180) [185,203–206]. The case is a hallmark of literature data [191–193]. As pemphigus and pemphigoid may occur as a paraneoplastic syndrome accompanying malignant tumor, it might be reasonable to form an online national registry of patients with ABD. Case 9 was included to visualize that need. Although both ABD may not contain "paraneoplastic" attribute, it is highly advisable to monitor all the patients with all ABD as group of high risk of developing malignancy [16]. There is scant data on coexistence of MMP and Hodgkin lymphoma (case 10) [207,208]. Moreover, the association between pemphigoid and non-Hodgkin lymphoma may seem to be better exemplified [19,209,210]. Nonetheless, each malignant lymphoproliferation may lead to impairment of immunological mechanisms via the change of antigen suit, cytokine production, distorted antibody production and abnormal cytokine production affecting many molecular pathways, both known and unknown. As far as case 11 is concerned, practising dermatologist, perhaps suspecting Cottini form of DH, obtained skin sample for DIF from lesion-free gluteal region (Fig. 11A). However, that area should be regarded as non-optimal for diagnosing that form of DH with DIF [211]. Luckily, BP-indicative deposits of immunoreactants were present at both lesion-free and perilesional sites. The link between malignancy and pemphigoid in case 11 may be multi-sided. Both renal and prostate cancer might be suspicious of contribution to autoaggression [23,67,71,180,212,213] and the role of radiotherapy should not be considered irrelevant. Renal cancer elicits paraneoplastic syndromes in 40% of patients, although dermatological manifes‐ tations seem to be extremely rare [70]. Cancerous lung involvement in BP (as in case 12) was previously reported [34], yet pulmonary cancer seems to be more PV-associated. The cessation of hormonal treatment seemed to trigger BP as a symptom of recurrence of prostate malignancy (case 13) [21]. BP and prostate adenocarcinoma might be interrelated by BP180 issue. It was observed, that prostatic malignant tumors may lack of hemidesmosomal structures – BP180 and less commonly BP230 [180]. Abnormal composition of detectable basement membrane antigens participating in multiple molecular pathways may disbalance mechanisms of selftolerance consequently stimulating the pathological autoimmunity. Induction of pemphigoid by trauma (in case 14 – by hysterectomy with partial colon resection), as reported in literature [214], may seem a reasonable explanation. There is one similar report on anti-laminin-332 MMP presumably associated with endometrial carcinoma [215]. BP in case 15 may be regarded secondary to breast cancer. It may be possible, that the distortion of cell cohesion in neoplastic cells leads to exposing normally hidden antigens or new epitopes are recognized by the immunocompetent cells. There are reports mentioning overlapped breast cancer and BP [20,84] as well as reports describing the evoking of autoimmune blistering dermatosis after

Malignancy in Relation to Autoimmune Blistering Dermatoses: Molecular and Clinical Aspects

http://dx.doi.org/10.5772/55240

191

breast radiotherapy [216–218], that may change antigenicity of the malignant cells.

eradicated in early phase.

Cancer research gives molecular evidence for tumor genetic instability. Vast array of unique tumor-specific neoantigens are presented on tumor's MHC molecules. Their recognition by Tcells could induce anti-tumor immunity [219]. Antibody-assisted defense against tumor may explain the fact of spontaneous cancer remissions. The other side of the coin may be the autoimmunity caused by unspecific tumor antigens, that are displayed in many tissues being easily accessible for T-cells. Hypothetically, some ABD might be really MAABD with tumor

In review based on PubMed, Scopus and EMBASE literature data, SCC has been found responsible of projection the majority of paraneoplastic syndromes, with pemphigus being one of the commonest dermatological conditions among them [194]. Case 1 and 2 both presented carcinoma planoepitheliale/SCC with PV. The latter entity, by imitating mucosal neoplastic process, presumably confused the clinicist and elongated the onset-diagnosis period. Interestingly, both cases showed recrudescence of their pemphigus lesions after radiotherapy. It seems to be a common finding in ABD, thus supports the role of radiotraumainduced denudation of formerly hidden epitopes in disease pathogenesis. The issue of SCC driving autoimmunity is still enigmatic, yet change in DSG profile promoting tumor cell migration may play a role in autoaggresion [177]. Similar cases to abovementioned ones were reported in literature [17,195]. As pseudomyxoma peritonei classification still causes contro‐ versy [196], the association between PF and ovarian/appendiceal tumor in case 3 is disputable. Some researchers speculated on the role of HPV16 and bacteria in development of this tumor of appendiceal origin [197,198]. A single case of PNP, breast tumor and pseudomyxoma peritonei was mentioned in literature [53]. To our best knowledge, case 3 is the first report on coexistence of these two conditions. The concomitance of exophytic thoracic SCC-tumor and PF (case 4) seem to be well-defined, yet behavior of the patient is difficult to comprehend since his stinky tumor was present for years. Apparently, his PF lesions finally prompted him to seek dermatological advise, but not the tumor itself. Apart of that, the case 5 is no less enigmatic. PV may imitate multiple conditions and it should be noted, that his lip lesion (described correctly as SCC by general pathologist) coexisted at the same site with the lesion of PV initially missed by general pathologist but diagnosed as such by cutaneous pathologist by reevaluation of initial specimen. Both above cases are portrayal of suspicious association of SCC preceding pemphigus, whereas case 5 features additionally shifting PV phenotype, supposedly because of active long-term pathological autoimmunization syndrome involving epitope spreading phenomenon. Case 5 was mentioned in literature [190]. CA19-9 marker is tumor-associated, but not tumor-specific marker. It is used as a screening test for gastrointes‐ tinal adenocarcinomas (colorectal, hepatic, lung, ovarian carcinoma and few non-malignant conditions), first of all for pancreatic cancer [199]. Association of PV with breast cancer (case 6) or potential gastrointestinal tract adenocarcinoma is disputable. The case may be considered a model for post-cancer ABD eruption and stands as an evidence for strong need of regular screening for malignancy in ABD patients. As far as case 7 is concerned, once again we find it questionable whether excised nasal/labial tumor was assessed properly as a cancerous or was it just a limited exophytic lesion heralding PF – chancre of pemphigus [200]. There is limited data concerning SCC, second commonest skin cancer coexistent with PF [201]. The negative correlation between DSG1 expression and degree of dysplasia in SCC is an interesting issue indicating contribution of desmosomal adhesion glycoproteins in cancerogenesis [202].

BP tends to manifest in natural and iatrogenic orifices featured by transient epithelium (e.g. iatrogenic – the scar or the stomy site) (case 8). It seems coherent that malignant tumor causing pathological immunization triggered the onset of BP. It was suggested that BP may be secondary to surgical procedures exposing sequestered antigens of colon mucosa (particularly BP180) [185,203–206]. The case is a hallmark of literature data [191–193]. As pemphigus and pemphigoid may occur as a paraneoplastic syndrome accompanying malignant tumor, it might be reasonable to form an online national registry of patients with ABD. Case 9 was included to visualize that need. Although both ABD may not contain "paraneoplastic" attribute, it is highly advisable to monitor all the patients with all ABD as group of high risk of developing malignancy [16]. There is scant data on coexistence of MMP and Hodgkin lymphoma (case 10) [207,208]. Moreover, the association between pemphigoid and non-Hodgkin lymphoma may seem to be better exemplified [19,209,210]. Nonetheless, each malignant lymphoproliferation may lead to impairment of immunological mechanisms via the change of antigen suit, cytokine production, distorted antibody production and abnormal cytokine production affecting many molecular pathways, both known and unknown. As far as case 11 is concerned, practising dermatologist, perhaps suspecting Cottini form of DH, obtained skin sample for DIF from lesion-free gluteal region (Fig. 11A). However, that area should be regarded as non-optimal for diagnosing that form of DH with DIF [211]. Luckily, BP-indicative deposits of immunoreactants were present at both lesion-free and perilesional sites. The link between malignancy and pemphigoid in case 11 may be multi-sided. Both renal and prostate cancer might be suspicious of contribution to autoaggression [23,67,71,180,212,213] and the role of radiotherapy should not be considered irrelevant. Renal cancer elicits paraneoplastic syndromes in 40% of patients, although dermatological manifes‐ tations seem to be extremely rare [70]. Cancerous lung involvement in BP (as in case 12) was previously reported [34], yet pulmonary cancer seems to be more PV-associated. The cessation of hormonal treatment seemed to trigger BP as a symptom of recurrence of prostate malignancy (case 13) [21]. BP and prostate adenocarcinoma might be interrelated by BP180 issue. It was observed, that prostatic malignant tumors may lack of hemidesmosomal structures – BP180 and less commonly BP230 [180]. Abnormal composition of detectable basement membrane antigens participating in multiple molecular pathways may disbalance mechanisms of selftolerance consequently stimulating the pathological autoimmunity. Induction of pemphigoid by trauma (in case 14 – by hysterectomy with partial colon resection), as reported in literature [214], may seem a reasonable explanation. There is one similar report on anti-laminin-332 MMP presumably associated with endometrial carcinoma [215]. BP in case 15 may be regarded secondary to breast cancer. It may be possible, that the distortion of cell cohesion in neoplastic cells leads to exposing normally hidden antigens or new epitopes are recognized by the immunocompetent cells. There are reports mentioning overlapped breast cancer and BP [20,84] as well as reports describing the evoking of autoimmune blistering dermatosis after breast radiotherapy [216–218], that may change antigenicity of the malignant cells.

multiorgan syndrome. The causative relation between ABD and cancer is difficult to establish,

In review based on PubMed, Scopus and EMBASE literature data, SCC has been found responsible of projection the majority of paraneoplastic syndromes, with pemphigus being one of the commonest dermatological conditions among them [194]. Case 1 and 2 both presented carcinoma planoepitheliale/SCC with PV. The latter entity, by imitating mucosal neoplastic process, presumably confused the clinicist and elongated the onset-diagnosis period. Interestingly, both cases showed recrudescence of their pemphigus lesions after radiotherapy. It seems to be a common finding in ABD, thus supports the role of radiotraumainduced denudation of formerly hidden epitopes in disease pathogenesis. The issue of SCC driving autoimmunity is still enigmatic, yet change in DSG profile promoting tumor cell migration may play a role in autoaggresion [177]. Similar cases to abovementioned ones were reported in literature [17,195]. As pseudomyxoma peritonei classification still causes contro‐ versy [196], the association between PF and ovarian/appendiceal tumor in case 3 is disputable. Some researchers speculated on the role of HPV16 and bacteria in development of this tumor of appendiceal origin [197,198]. A single case of PNP, breast tumor and pseudomyxoma peritonei was mentioned in literature [53]. To our best knowledge, case 3 is the first report on coexistence of these two conditions. The concomitance of exophytic thoracic SCC-tumor and PF (case 4) seem to be well-defined, yet behavior of the patient is difficult to comprehend since his stinky tumor was present for years. Apparently, his PF lesions finally prompted him to seek dermatological advise, but not the tumor itself. Apart of that, the case 5 is no less enigmatic. PV may imitate multiple conditions and it should be noted, that his lip lesion (described correctly as SCC by general pathologist) coexisted at the same site with the lesion of PV initially missed by general pathologist but diagnosed as such by cutaneous pathologist by reevaluation of initial specimen. Both above cases are portrayal of suspicious association of SCC preceding pemphigus, whereas case 5 features additionally shifting PV phenotype, supposedly because of active long-term pathological autoimmunization syndrome involving epitope spreading phenomenon. Case 5 was mentioned in literature [190]. CA19-9 marker is tumor-associated, but not tumor-specific marker. It is used as a screening test for gastrointes‐ tinal adenocarcinomas (colorectal, hepatic, lung, ovarian carcinoma and few non-malignant conditions), first of all for pancreatic cancer [199]. Association of PV with breast cancer (case 6) or potential gastrointestinal tract adenocarcinoma is disputable. The case may be considered a model for post-cancer ABD eruption and stands as an evidence for strong need of regular screening for malignancy in ABD patients. As far as case 7 is concerned, once again we find it questionable whether excised nasal/labial tumor was assessed properly as a cancerous or was it just a limited exophytic lesion heralding PF – chancre of pemphigus [200]. There is limited data concerning SCC, second commonest skin cancer coexistent with PF [201]. The negative correlation between DSG1 expression and degree of dysplasia in SCC is an interesting issue indicating contribution of desmosomal adhesion glycoproteins in cancerogenesis [202].

BP tends to manifest in natural and iatrogenic orifices featured by transient epithelium (e.g. iatrogenic – the scar or the stomy site) (case 8). It seems coherent that malignant tumor causing pathological immunization triggered the onset of BP. It was suggested that BP may be

as both malignancy and ABD develops and stay undiagnosed over some time period.

190 Highlights in Skin Cancer

Cancer research gives molecular evidence for tumor genetic instability. Vast array of unique tumor-specific neoantigens are presented on tumor's MHC molecules. Their recognition by Tcells could induce anti-tumor immunity [219]. Antibody-assisted defense against tumor may explain the fact of spontaneous cancer remissions. The other side of the coin may be the autoimmunity caused by unspecific tumor antigens, that are displayed in many tissues being easily accessible for T-cells. Hypothetically, some ABD might be really MAABD with tumor eradicated in early phase.
