—  SLIDE SEMINAR #11  —

Genitourinary Pathology
Moderators: John R. Srigley and Rodolfo Montironi

Case 2 - Carcinoma Cuniculatum of Penis

Antonio Cubilla MD
Institute de Patologia e Investigaticion
Asuncion, Paraguay


Clinical History:
An 83-year-old patient presented with a foul smelling exophytic mass involving the distal portion of the glans. The lesion was slowly-growing for the past 4 years. A biopsy revealed a well-differentiated verrucous squamous cell carcinoma. A partial penectomy was performed.


Case 2 - Slide 1
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Pathological Findings:
Grossly there was a large white/gray granular exophytic mass involving the foreskin, coronal sulcus and part of ventral and dorsal glans. The cut surface revealed irregular sinuses of tumor invaginations from the surface to deep anatomical structures, corpora spongiosa and cavernosa with fistula formation to the skin of the foreskin and shaft. The tumor grew along the tunica albuginea forming a long tract.

Microscopically there was a labyrinthine burrowing pattern with surface fistulization. Individual crypts had a jagged inner surface containing hyperkeratotic material and a sharply delineated external border. The histological features resembled those of mixed verrucous- squamous cell carcinoma (hyperkeratosis, papillomatosis, acanthosis, and squamous cell differentiation with lack of koilocytosis). Deeply located keratin filled cyst-like spaces on serial gross sectioning were found to be connected and continuous with either the crypts or the tumor surface. The interface between tumor and stroma was sharply delineated or jagged with an invasive border.

Diagnosis:
Carcinoma cuniculatum of penis.

Discussion:
We recently found some penile tumors with a burrowing growth pattern similar to plantar epithelioma cuniculatum described by Ayrd in 1954 [1]. Other sites affected are esophagus [2], jaw [3], oropharynx [4], sacrum [5], oral cavity [6], nasal cavity and sinuses [7], buttock [8], hands [9], toes [10], thumb [11], abdominal wall [12], and intertriginous areas [13]. They were also reported in association with leprosy [14, 15], pilonidal cysts, necrobiosis lipoidica [16] and chronic skin ulcers [17].

Carcinoma cuniculatum of the penis is an unusual verruciform tumor characterized by a labyrinthine exo- endophytic growth with irregular and deep sinusesand tracts simulating rabbits' burrows from which this entity derives its name.

In our report of 7 cases [18] affected patients were older males (rage of 73-83 years) in comparison to the relatively younger age of patients with usual SCC (62 years), closer to the age of patients with verrucous carcinoma (69 years) [19] and similar to the age of pseudohyperplastic SCC [20]. The duration of the disease prior to pathological diagnosis ranged from 12 to 60 months. At diagnosis tumors were large (ave. 6.3 cm) , affecting multiple epithelial compartments (glans, coronal sulcus and foreskin).

Grossly the outer surfaces of carcinoma cuniculata were indistinguishable from other verruciform tumors but the cut surface was characteristic revealing deeply penetrating sinuses connecting the surface with corpora spongiosa or cavernosa. Considering that superficial invaginations are not unusual in low grade penile carcinomas we required for the diagnosis both a verruciform configuration and a deep penetration beyond lamina propria. The deepest point of the tumor is a cul de sac equally broadly based at the surface and in deeper areas. Microscopically the tumor showed some cytologic features of verrucous carcinoma [21] but the overall growth pattern was different. There was an absence of koilocytosis.

The differential diagnoses of carcinoma cuniculatum includes classical verrucous carcinoma, mixed verrucous carcinoma and warty (condylomatous) carcinoma. We have recently reviewed a large number of penile tumors originally classified as verrucous carcinoma and found the classical (pure) verrucous carcinoma to be unusual. Most commonly we observed admixed with features of classical verrucous carcinoma, a heterogeneous spectrum of morphological patterns: those of usual, papillary NOS, warty (condylomatous) and sarcomatoid squamous cell carcinomas. The diagnosis of classical or "pure" verrucous carcinoma should be restricted to neoplasms with extreme differentiation throughout, absence of koilocytosis, and a broad base with sharply delineated base. Pure verrucous carcinomas in our experience do not involve the corpus cavernosa. The deep penetration of carcinoma cuniculatum into corpora cavernosa and the frequent presence of at least focally jagged invasive borders makes the distinction possible. Carcinoma cuniculatum shares some features of mixed verrucous carcinoma but in addition shows the characteristic sinuous burrowing pattern absent in mixed verrucous carcinomas. Another tumor with a complex endophytic growth pattern which may be confused with carcinoma cuniculatum is the warty (condylomatous) carcinoma including the recently described endophytic "non invasive" variant [22]. Warty carcinoma is an uncommon HPV related tumor [23] that may be grossly indistinguishable from carcinoma cuniculatum. Microscopically, especially in its endophytic variant, warty carcinoma may show an inverted nodular growth of otherwise typical condylomatous papillae affecting lamina propria and corpus spongiosum. Higher histologic grade and prominent koilocytotic atypia throughout the tumor aid to differentiate warty carcinoma from carcinoma cuniculatum. Presence and absence of HPV has been reported in carcinoma cuniculata [24, 25].

Rarely, metastases have been reported in carcinoma cuniculatum of the skin [26, 27]. but despite deep invagination by tumors involving the tunica albuginea and corpora cavernosa in 6 cases, inguinal node metastases were not present in our penile cases.

References:
  1. Ayrd I, Johnson HD, Lennox B, et al. Epithelioma cuniculatum: a variety of squamous carcinoma peculiar to the foot. B rJ Surg. 1954; 42: 245-50.

  2. De Petris G, Lewin M, Shoji T. Carcinoma cuniculatum of the esophagus. Ann Diagn Pathol, 2005; 9:134-8.

  3. Allon D, Kaplan I, Manor R, et al. Carcinoma cuniculatum of the jaw: a rare variant of oral carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002; 94: 601-8.

  4. Kuffer R, Brocheriou C, Rougier M, et al. Buccopharyngeal localizations of carcinoma cuniculatum. Apropos of 5 cases. Arch Anat Cytol Pathol. 1984; 32: 184.

  5. D'Aniello C, Grimaldi L, Meschino N, et al. Verrucous 'cuniculatum' carcinoma of the sacral region. Br J Dermatol. 2000; 143: 459-60.

  6. Gassler N, Helmke B, Schweigert HG, et al. Carcinoma cuniculatum of the oral cavity. A contribution to the differential diagnosis of potentially malignant papillary lesions of mouth mucosa. Pathologe. 2002; 23: 313-7.

  7. Szmeja Z, Szyfter W, Golusinski W, et al. A rare case of carcinoma cuniculatum within the nasal cavity and paranasal sinuses. Otolaryngol Pol. 1996; 5: 325-8.

  8. Melo CR, Melo IS. Carcinoma cuniculatum of the buttock. An unusual case with an inverted growth. Dermatologica. 1989; 179: 38-41.

  9. Collison DW, Mikhail GR. Carcinoma cuniculatum of the hand. Arch Dermatol. 1989; 125:1335-6.

  10. Hitti IF, Sadowski G, Statsinger AL, et al. Inverted variant of carcinoma cuniculatum of the toe. Cutis. 1987; 39: 250-2.

  11. Coldiron BM, Brown FC, Freeman RG. Epithelioma cuniculatum (carcinoma cuniculatum) of the thumb: a case report and literature review. J Dermatol Surg Oncol. 1986; 12:1150-5.

  12. Lawrence-Brown MM, Gollow IJ, Lam T, et al. Carcinoma cuniculatum of the abdominal wall. Med J Aust. 1984; 140: 668-9.

  13. Melo CR, Melo LS. Carcinoma cuniculatum originating from intertriginous lesions. Int J Dermatol. 1991; 30: 707-9.

  14. Ochsner PE , Hausman R, Olsthoorn PG. Epithelioma cuniculatum developing in a neuropathic ulcer of leprous etiology. Arch Orthop Trauma Surg. 1979; 94: 227-31.

  15. Ramadan WM, el-Aiat A, Hassan MH. Epithelioma cuniculatum in leprotic foot. Int J Lepr Other Mycobact Dis. 1986; 54: 127-9.

  16. Porneuf M, Monpoint S, Barneon G. Carcinoma cuniculatum arising in necrobiosis lipoidica. Ann Dermatol Venereol. 1991; 118: 461-4.

  17. Grenier JM, Barriere I, Rouffy J. Malignant transformation of leg ulcers. Rev Med Interne. 1993; 14 : 51-3.

  18. Barreto JE, Velazquez EF, Ayala E et al. Carcinoma cinuculatum: a distinctive variant of penile squamous cell carcinoma. Am J Surg Path. 2006 (in press).

  19. Cubilla AL, Velazquez EF, Soskin A, et al. The heterogeneous spectrum of penile verrucous carcinoma: morphological features of classical type and mixed variants. A report of 36 cases. Mod Pathol. 2004; 610 (A).

  20. Cubilla AL, Velazquez EF, Young RH. Pseudohyperplastic squamous cell carcinoma of the penis associated with lichen sclerosus. An extremely well-differentiated, nonverruciform neoplasm that preferentially affects the foreskin and is frequently misdiagnosed: a report of 10 cases of a distinctive clinicopathologic entity. Am J Surg Pathol. 2004; 28: 895-900.

  21. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948; 23: 670-8.

  22. Rodriguez IM, Velázquez EF, Torres J et al. The morphological spectrum of penile condylomatous tumors. A report of 44 cases and a re evaluation of the Buschke Lowenstein tumor-giant condyloma concept. Mod Pathol. 2005;18: 161A.

  23. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001; 159:1211-8.

  24. Knobler RM, Schneider S, Neumann, et al. DNA dot-blot hybridization implicates human papillomavirus type 11-DNA in epithelioma cuniculatum. J Med Virol. 1989; 29: 33-7.

  25. Petersen CS, Sjolin, KE, Rosman N, et al. Lack of human papillomavirus DNA in carcinoma cuniculatum. Acta Derm Venereol. 1994; 74: 231-2.

  26. Kao GF, Graham JH, Helwig EB. Carcinoma cuniculatum (verrucous carcinoma of the skin): a clinicopathologic study of 46 cases with ultrastructural observations. Cancer. 1982; 49: 2395-403.

  27. McKee PH, Wilkinson JD, Corbett MF, et al. Carcinoma cuniculatum: a cast metastasizing to skin and lymph nodes. Clin Exp Dermatol. 1981; 6: 613-8.