—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 3 - Angiosarcomatoid Squamous Cell Carcinoma of the Penis

Elsa F. Velazquez
New York University School of Medicine
New York, NY


Click on each slide thumbnail image for an enlarged view
Clinical History
A 49-year-old man was seen for a large, ulcerated and hemorrhagic penile mass. The lesion that affected the glans, coronal sulcus and foreskin deeply invaded the corpora cavernosa and was rapidly growing for the past year.


Case 3 - Figure 1 - Gross features of a large, ulcerated and hemorrhagic penile mass that affects the glans, coronal sulcus and foreskin and deeply invades the corpora cavernosa.
Case 3 - Figure 2 - Low-power view of the neoplasm showing the ulcerated surface and interanastomosing channels lined by neoplastic cells.
Case 3 - Figure 3 - Microscopic views illustrating the interanastomosing channels lined by tumor cells dissecting through the stroma. The neoplastic cells vary from flat to hobnail to polygonal with hyperchromatic and pleomorphic nuclei. There are fibrovascular tufts lined by neoplastic cells. Some of the spaces contain detached neoplastic cells and erythrocytes. Occasional intracytoplasmic vacuoles are seen. Cords of more cohesive undifferentiated epithelioid cells are focally present.



Case 3 - Figure 4 - Microscopic views illustrating the interanastomosing channels lined by tumor cells dissecting through the stroma. The neoplastic cells vary from flat to hobnail to polygonal with hyperchromatic and pleomorphic nuclei. There are fibrovascular tufts lined by neoplastic cells. Some of the spaces contain detached neoplastic cells and erythrocytes. Occasional intracytoplasmic vacuoles are seen. Cords of more cohesive undifferentiated epithelioid cells are focally present.
Case 3 - Figure 5 - Microscopic views illustrating the interanastomosing channels lined by tumor cells dissecting through the stroma. The neoplastic cells vary from flat to hobnail to polygonal with hyperchromatic and pleomorphic nuclei. There are fibrovascular tufts lined by neoplastic cells. Some of the spaces contain detached neoplastic cells and erythrocytes. Occasional intracytoplasmic vacuoles are seen. Cords of more cohesive undifferentiated epithelioid cells are focally present.

Histopathological Findings:
The tumor in most areas exhibited a pseudovascular growth pattern characterized by interanastomosing channels lined by tumor cells dissecting through the stroma. The neoplastic cells varied from flat to hobnail to polygonal with hyperchromatic and pleomorphic nuclei. There were areas of villiform growth within the pseudolumina (in which cores or tufts of fibrovascular tissue were lined by neoplastic cells). The non-neoplastic vascular endothelium in the stromal blood vessels was cytologically bland. The neoplastic cells were focally multinucleated with syncytial pattern. Some of the pseudoluminal spaces contained detached neoplastic cells and erythrocytes. Occasional intracytoplasmic vacuoles mimicking primitive vascular lumina were seen. Foci of cohesive undifferentiated epithelial cells, spindle cells and frankly squamous cells were also present. Mitotic figures and focal necrosis were identified. Perineural, perivascular and lymphovascular invasion were present. The adjacent mucosa showed lichen sclerosus with foci of squamous hyperplasia.

Immunohistochemical Features:
The neoplastic cells in the angiosarcomatoid areas were diffusely positive for vimentin, 34βE12 and p63, and focally positive for AE1/AE3 and EMA. The squamous component was negative for vimentin and positive for AE1/AE3, CAM 5.2, 34βE12, EMA and p63. The neoplastic cells were negative for CD31, CD34, Factor VIII, muscle specific actin, smooth muscle actin, desmin and S100.

Molecular Studies: HPV DNA was not detected by in situ hybridization.

Diagnosis: Angiosarcomatoid squamous cell carcinoma of the penis

Discussion
Angiosarcomatoid carcinomas are unusual epithelial neoplasms that share histologic, and sometimes immunohistochemical features with those of angiosarcomas [2, 21] . These lesions have been described in different locations such as skin, breast, lung and thyroid and have generated controversy and diagnostic confusion [2]. The distinction between them is important based on the likehood of more aggressive behavior of angiosarcomas, as compared with carcinomas [21]. The separation of angiosarcomatoid carcinomas from angiosarcomas appears to be particularly complex in the thyroid, where lesions with intermediate features have been described [15, 21] . The angiosarcomatoid pattern in carcinomas is part of the spectrum of sarcomatoid carcinoma. Sarcomatoid carcinoma is a rare morphological variant of carcinoma that presents in either a purely sarcomatoid form or in association with a typical epithelial phenotype [3, 28] . They commonly appear as biphasic neoplasms with a carcinoma intermingled with a sarcomatoid component, sometimes with heterologous differentiation. Recent molecular studies of these tumors in different organs sites have shown evidence for the sarcomatoid transformation from the epithelial component, thereby supporting a monoclonal origin [3]. Sarcomatoid carcinomas in the genitourinary tract (with the exception of the kidney) are relatively uncommon [20, 30] , and there is only a series of 5 cases [12] and a few case reports on the penile location [1, 11, 13, 16, 17, 29] . In a review of 400 cases of squamous cell carcinoma of the penis, we identified a series of 15 sarcomatoid carcinomas (3.75%), one of which (the tumor we are presenting in this conference) had a prominent angiosarcomatoid appearance [25]. Most sarcomatoid carcinomas in our series were large, polypoid and ulcerated, deeply invasive lesions. They frequently affected the glans, either exclusively or in combination with the coronal sulcus and foreskin. Most tumors invaded the corpora cavernosa in the glans, and the skin in the prepuce. Intrapenile satellite nodules were identified in the corpora cavernosa and skin in 4 cases. All cases showed a predominance of atypical spindle cells with variable patterns reminiscent of fibrosarcoma, malignant fibrous histiocytoma or leiomyosarcoma associated with a minor component of squamous cell carcinoma. Osteosarcomatous, angiosarcomatous and hemangioperitic-like patterns were less frequent. These sarcomatoid changes were typically associated with the usual variant of squamous cell carcinoma, but a variety of other histologic subtypes such as verrucous, low-grade papillary and basaloid carcinomas were also noted. The presence of foci of special types of squamous cell carcinoma would indicate a secondary sarcomatoid transformation from a pre-existing tumor in at least some of the cases. HPV in situ hybridization was negative in 5 of our cases in which it was performed, supporting the hypothesis of a non-HPV related alternative pathway in the development of a subset of penile carcinomas [12, 22, 25] . It is noteworthy that the association of lichen sclerosus and squamous hyperplasia in the current case are findings supporting the hypothesis of a precancerous role for these lesions, especially in non-HPV related neoplasms [24].

Sarcomatoid carcinomas are aggressive tumors frequently associated with local recurrences [4, 25, 26] . Inguinal lymph node metastases were seen in 89% of the patients in our study. Lont et al reported that 4 of 5 patients in their series had distant metastatic disease and died within 1 year after diagnosis [12]. Tumors with a predominant angiosarcomatous pattern are exceptional and should be distinguished from true penile angiosarcomas. Angiosarcomas of the penis are extremely unusual lesions [10, 18, 19, 23, 27] . In a review of 46 soft tissue tumors of the penis by Dehner et al, 41% were angiomatous in origin: these included 3 angiosarcomas [6] and, from a series of 116 soft tissue tumors of the penis from the Tissue Registry of the Armed Forces Institute of Pathology, 3 angiosarcomas were identified [9]. The most common malignant penile mesenchymal tumors are Kaposi sarcoma and leiomyosarcoma [8, 9] . Other reported sarcomas in this location are fibrosarcomas, malignant fibrous histiocytomas and osteosarcomas [5]. The distinctions between sarcomatoid carcinomas and sarcomas are based on gross examination, histological and immunhistochemical features. The first distinctive feature of sarcomas (with the exception of Kaposi sarcoma) is their most common location in the deep penile shaft, usually involving corpora cavernosa or subcutaneous tissue, which would be a highly unusual location for carcinomas [5, 19, 23] . Histologically, the presence of in situ or invasive squamous cell carcinoma, admixed with the sarcomatoid component, is very helpful in making a diagnosis of sarcomatoid carcinoma. In a predominantly sarcomatous lesion, it is important to extensively sample the tumor surface and junction with adjacent intact skin to enable detection of what may often be a very focal squamous component. These squamous areas are more frequently found at or near the surface of the lesion, sometimes adjacent to the ulcerated surface [25].Finally, electron microscopy [13] and immunohistochemical studies can be contributory in making this distinction. Sarcomatoid carcinomas are usually strongly positive for vimentin, but they are usually negative for markers of specific mesenchymal, neural or vascular differentiation, such as muscle specific actin, smooth muscle actin, desmin, S100, CD31, Factor VIII, and CD34. Sarcomatoid carcinomas also express, at least focally, keratins, p63 or EMA. p63 is a recently identified p53 homologue that is highly expressed in embryonic ectoderm. p63 expression in normal adult tissues is restricted to epithelial cells of stratified epithelia and to certain subpopulations of basal cells in glandular structures. p63 is expressed predominantly in basal cell and squamous cell carcinomas, as well as transitional cell carcinomas, but not in soft tissue sarcomas [7]. When dealing with an angiomatous tumor, it should be kept in mind that neoplastic endothelial cells may focally express some keratins and EMA [14].

The tumor presented in this conference was selected to highlight one end of the spectrum of penile squamous cell carcinomas - the poorly differentiated and highly aggressive sarcomatoid lesions that should be distinguished from other less common tumors such as spindle cell melanomas and penile sarcomas. In summary, sarcomatoid carcinoma of the penis is an infrequent but distinct variant of squamous cell carcinoma, most likely HPV unrelated, characterized by a prominent or even exclusive spindle cell component exceptionally with prominent pseudovascular pattern mimicking an angiosarcoma. It manifests as a large and aggressive tumor usually associated with lymph node metastases and poor outcome. In our experience, p63 and keratin 34βE12 were the most frequently expressed epithelial markers in the sarcomatoid component [25].

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