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
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.
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
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
Diagnosis: Angiosarcomatoid squamous cell carcinoma of the penis
Angiosarcomatoid carcinomas are unusual epithelial neoplasms that share histologic, and
sometimes immunohistochemical features with those of angiosarcomas
. These lesions have been
described in different locations such as skin, breast, lung and thyroid and have generated controversy
and diagnostic confusion . The distinction between them is important based on the likehood of more
aggressive behavior of angiosarcomas, as compared with carcinomas . The separation of
angiosarcomatoid carcinomas from angiosarcomas appears to be particularly complex in the thyroid, where
lesions with intermediate features have been described
. 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
. 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 . Sarcomatoid carcinomas in the
genitourinary tract (with the exception of the kidney) are relatively uncommon
, and there is
only a series of 5 cases  and a few case reports on the penile location
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 . 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
. 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 .
Sarcomatoid carcinomas are aggressive tumors frequently associated with local recurrences
. 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 . Tumors with a predominant angiosarcomatous pattern are exceptional and should be
distinguished from true penile angiosarcomas. Angiosarcomas of the penis are extremely unusual lesions
. In a review of 46 soft tissue tumors of the penis by Dehner et al, 41% were
angiomatous in origin: these included 3 angiosarcomas  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 . The most common malignant penile mesenchymal tumors are Kaposi sarcoma and
. Other reported sarcomas in this location are fibrosarcomas, malignant fibrous
histiocytomas and osteosarcomas . 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
. 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 .Finally, electron microscopy  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 . When dealing with an angiomatous tumor, it should be kept in mind that
neoplastic endothelial cells may focally express some keratins and EMA .
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 .
- Antonini C, Zucconelly R, Forgiarini O et al. Carcinosarcoma of the penis. Case report and review of the literature. Adv Clin Pathol 1997; 1:281-5.
- Banerjee SS, Eyden BP, Wells S et al. Pseudoangiosarcomatous carcinoma: a clinicopathological study of seven cases. Histopathology 1992; 21: 13-23.
- Choi HR, Sturgis EM, Rosenthal DI et al. Sarcomatoid carcinoma of the head and neck. Molecular evidence for evolution and progression from conventional squamous cell carcinomas. Am J Surg Pathol 2003; 27:1216-20.
- Cubilla AL, Reuter VE, Velazquez E et al. Histologic Classification of Penile Carcinomas and its relation to outcome in 61 patients with primary resection. Int J Surg Pathol 2001; 9: 111-20.
- Cubilla AL, Velazquez EF, Barreto JE et al. The penis. In: Sternberg's Diagnostic Surgical Pathology. Editor: Stacey EMillsMD. Fourth Edition.Lippincott Williams & Wilkins, Philadelphia, March 2004.
- Dehner LP, Smith BH. Soft tissue tumors of the penis. A clinicopathologic study of 46 cases. Cancer 1970; 143-47.
- Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in human normal and tumor tissues.Clin Cancer Res 2002; 8:494-501.
- Fetsch JF, Davis Jr CJ, Miettinen M, et al. Leiomyosarcoma of the penis: a clinicopathologic study of 14 cases with review of the literature and discussion of the differential diagnosis. Am J Surg Pathol. 2004; 28:115-25.
- Fetsch JF, Miettinen M. Mesenchymal tumours. In: Tumours of the urinary system and male genital organs. World Health Organization Classification of Tumours. IARC Press, Lyon, 2004.
- Ghandur-Mnaymneh L, Gonzalez MS. Angiosarcoma of the penis with hepatic angiomas in a patient with low vinyl chloride exposure. Cancer 1981; 15: 1318-24.
- Inai K, Nishida T, Nishina H, et al. [Spindle cell carcinoma of the penis--a case report] Gan No Rinsho. 1984 ; 30:99-104.
- Lont AP, Gallee MP, Snijders P, et al.Sarcomatoid squamous cell carcinoma of the penis: a clinical and pathological study of 5 cases. J Urol 2004; 172: 932-5
- Manglani, KS, Manaligod JR, Ray B. Spindle cell carcinoma of the glans penis: a light and electron microscopy study. Cancer 1980; 46: 2266-72.
- Miettinen M, Fetsch JF. Distribution of keratins in normal endothelial cells and a spectrum of vascular tumors: implications in tumor diagnosis. Hum Pathol 2000; 31: 1062-7.
- Mills SE, Gaffey MJ, Watts JC et al. Angiomatoid carcinoma and "angiosarcoma" of the thyroid gland. A spectrum of endothelial differentiation. Am J Clin Pathol 1994; 102: 322-30.
- Morinaga S, Nakamura S, Moro K et al. Carcinosarcoma (carcinoma with sarcomatous metaplasia) of the penis. J Urol Pathol 1995; 3: 369-76.
- Patel B, Hashmat A, Reddy V, et al. Spindle cell carcinoma of penis. Urology. 1982; 19:93-5.
- Prescott RJ, Mainwaring AR. Irradiation-induced penile angiosarcoma. Postgrad Med 1990; 66: 576-9.
- Rasbridge SA, Parry JR. Angiosarcoma of the penis. Br J Urol. 1989; 63:440-1.
- Reuter VE. Sarcomatoid lesions of the urogenital tract. Seminars in Diagnostic Pathol 1993; 10: 188-201.
- Ritter JH, Mills SE, Nappi O et al. Angiosarcoma-like neoplasms of epithelial organs: true endothelial tumors or variants of carcinoma? Seminars in Diagnostic Pathol 1995; 12: 270-82.
- Rubin MA, Kleter B, Zhou M et al. Detection and typing of human papillomavirus DNA in penile carcinoma. Evidence of multiple independent pathways of penile carcinogenesis. Am J Pathol 2001; 159: 1211-8.
- Ung JO, Padera RF and O'Leary MP. Angiosarcoma of the penis masquerading as a Peyronie's plaque. J Urol 2002; 167: 1785-6.
- Velazquez EF, Cubilla AL. Lichen sclerosus in 68 patients with squamous cell carcinoma of the penis. Frequent atypias and correlation with special carcinoma variants suggests a precancerous role. Am J Surg Pathol 2003; 27: 1448-53.
- Velazquez EF, Melamed J, Barreto JE et al. Sarcomatoid carcinoma of the penis. A clinico-pathological study of 15 cases. Submitted for publication.
- Velazquez EF, Reuter V, Torres J, et al. Comparison of morphological features and outcomes of resected primary and recurrent squamous cell carcinomas of the penis. Mod Pathol 2004; 17: 770 (A).
- Webber RJS, Alsaffar N, Bissett D et al. Angiosarcoma of the penis. Urology 1998; 51: 130-1.
- Wick MR, Swanson PE. Carcinosarcomas: Current perspectives and an historical review of nosological concepts. Seminars in Diagnostic Pathol 1993; 10: 118-27.
- Wood EW, Gardner WA, Brown FM. Spindle cell squamous carcinoma of the penis. J Urol 1972; 107: 990-1.
- Young RH, Wick MR, Mills SE. Sarcomatoid carcinoma of the urinary bladder. A clinicopathological analysis of 12 cases and review of the literature. Am J Clin Pathol 1988; 90: 653-61.