Feature: CME #130 March 2007: Verrucous Carcinoma: The Buschke-Loewenstein Tumor - By Jacob Dudelzak, M.D., Daniel J. Sheehan, M.D., and Omar P. Sangüeza, M.D. CME #130 March 2007 Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for one category 1 physician credit hour. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. Buschke-Loewenstein tumor is a condition that carries a significant risk of morbidity and mortality if left untreated. In this article, authors Jacob Dudelzak, M.D., Daniel Sheehan, M.D., and Omar P. Sangüeza, M.D., discuss its prognosis, clinical and histological features and treatment options to aid in the prompt diagnosis and treatment essential to its cure and/or prevention of the morbidity associated with its advanced stages. At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 66 to NACCME  at (610) 560-0501. We’ll also post this course on our Web site, which you can access at www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: Jacob Dudelzak, M.D., Daniel J. Sheehan, M.D., and Omar P. Sangüeza, M.D. Method of Participation: Physicians may receive one category 1 credit by reading the article on pp. 61 to 65 and successfully answering the questions found on p. 65. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 1 hour Date of Original Release: March 1, 2007 Expiration Date: February 28, 2008 Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Off-Label/Unapproved Usage Discussion: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither NACCME, 3M nor Roche recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclosures: All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose to the meeting audience any real or apparent conflicts of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants. The authors have disclosed that they have no significant financial relationship with any organization that could be perceived as a conflict of interest in the context of this article. Sponsor: This activity is sponsored by the North American Center for Continuing Medical Education. Learning Objectives: 1.Describe the clinical presentation features of verrucous carcinoma and the giant condyloma of Buschke and Lowenstein in particular. 2. Discuss the etiology and histopathologic findings of verrucous carcinoma.. 3. Describe the medical and surgical treatment options for verrucous carcinoma. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None Sponsor: NACCME Verrucous Carcinoma: The Buschke-Loewenstein Tumor Buschke-Loewenstein tumor (BLT), also known as giant condyloma acuminatum (GCA) or condyloma gigantea, is a rare but potentially life-threatening and highly morbid, low-grade variant of squamous cell carcinoma (SCC) of the anogenital region. This tumor belongs to a group of verrucous carcinomas (VC), which includes the oral florid papillomatosis of Ackerman, palmoplantar epithelioma cuniculatum, and cutaneous Gottron’s papillomatosis cutis carcinoides.1-4 BLT is characterized clinically by slow but relentless growth in spite of its seemingly benign histopathologic features. The neoplasm is not generally considered to have an intrinsic metastatic potential, although malignant transformation to a histologically invasive squamous cell carcinoma may account for reports of regional metastasis. Some consider BLT an intermediate neoplasm within the spectrum ranging from condyloma acuminatum (CA) to verrucous carcinoma to invasive squamous cell carcinoma.5-10 Historical Perspective Abraham Buschke and Ludwig Loewenstein stunned the medical community in the early 20th century by proposing that giant condyloma acuminata could display features of a malignant neoplasm by nature of its locally destructive growth pattern while still displaying intrinsically benign behavior. They noted that these tumors tended to have a benign histology, did not tend to recur following excision, and did not tend to result in metastasis or “tumor cachexia.” Subsequently, Lauren V. Ackerman coined the term “verrucous carcinoma” to describe a form of low-grade, non-metastasizing SCC with a relatively favorable behavior.10 Epidemiology The mean age of onset for BLT is 40 to 43.9 years of age (42.9 for males, 46.6 for females). Two-thirds of all cases occur before the age of 50. There is a male predominance that increases from 2.7:1 for those under 50 years of age to 3.5:1 for patients over 50.1,2,11,12 BLT has rarely been reported in children.11 Pathogenesis The pathogenesis of BLT remains incompletely understood to the present day, although a number of etiologic contributors have been proposed including inflammatory conditions such as lichen sclerosus13,14 or lichen planus;15 environmental factors, such as poor hygiene, lack of circumcision, and chronic irritation; and immunosuppression, including HIV disease.2,16 In addition, human papilloma virus (HPV) has been identified in a large proportion of BLT cases. The most frequent isolated serotypes are 6 and 11,3,17-19 although others, including 5, 16, 18, and 54 have also been demonstrated.20-23 The carcinogenic mechanism in the HPV-associated cases has not been firmly established. However, it has been postulated that the E7 protein of HPV type 6 or alteration in the normal function of the p53 tumor suppressor protein by viral peptides may play a role.24-26 A significantly large number of reported cases have no detectable HPV within the tumor.2,22,27,28 HPV has also been implicated in verrucous carcinoma in other locations, including the oral cavity, the foot, and rarely the scalp.29 Transformation to histologically invasive SCC has been associated in some instances with serotypes 16 and 18,2,3,17,30-32 although their absence does not preclude the possibility of a malignant transformation.33 Transformation to invasive SCC has also been documented following radiation therapy.2 The rate of malignant transformation generally reported ranges from 30% to 50%, occurring on average 5 years from disease onset.1,34,35 However, it has been argued that it is neither the isolation of a particular HPV type (whether the “low-risk” 6 and 11 or the “high-risk” 16 and 18), nor the malignant histopathologic features, but rather the local extent of tumor invasion that has the greatest impact on the clinical course of the disease.1,33,34,36 Clinical Features BLT generally presents as a slowly but persistently growing, exophytic, fungating, verrucous, cauliflower-like or polypoid, pebbly, firm to rock-hard, tender malodorous erythematous mass (See Figures 1 and 2). These neoplasms have a propensity to attain enormous size, ulcerate, and hemorrhage.2 The most common location is the penis, usually the glans, and BLT accounts for between 5% and 24% of all penile tumors. However, any anogenital site, including scrotum, vulva, anus, perineum, and buttocks, may be involved.2,3,11 Patients may complain of a painful disfiguring mass, pruritus, burning, bleeding, malodorous discharge, dyschezia, dysuria, pelvic pain, and difficulty sitting or ambulating.1-3,11,37 The locally and deeply infiltrating BLT may involve penile corpus cavernosum, urethra, the anorectal vault, as well as subcutaneous tissues and muscle. Necrosis and bacterial superinfection permit formation of an abscess or fistula draining putrid purulent keratinaceus debris. Regional lymphadenopathy is almost universally reactive to commonly occurring secondary bacterial superinfection, although rare reports of regional metastasis have been reported. Major sources of morbidity in patients with BLT are the result of its locally infiltrating and destructive behavior, bleeding, infection, recurrence, and peri-operative treatment complications. Perforation of the prepuce, urethral fistulation, and anal canal stenosis have all been reported.2,11,22,26 Figure 1: 10-cm tumor in the suprapubic area of a 45-year-old male. This specimen tested positive for HPV type 6. Surgical resection was complicated by post-operative gram-negative wound infection. Figure 2: Massive, locally destructive verrucous tumor in an adult male. Histopathologic Features The histopathologic features of BLT are in sharp contrast to its clinically malignant behavior. The overall histologic picture resembles a benign neoplasm akin to CA. BLT is an exo-endophytic neoplasm exhibiting prominent dense hyperkeratosis and anastomosing papillomatosis of fungating papillary fronds. Massive hyperplasia of the epidermis is characteristic, with downward extension at the base by the thickened, blunted, broad, bulbous rete ridges (see Figure 3). These rete “push,” rather than infiltrate, into the dermis and subcutis, thereby compressing adjacent structures (see Figure 4).1,2,9,10,33,38 Cytologic features of this well-differentiated squamous proliferation include cells with large amounts of ground glass cytoplasm and nuclei with prominent nucleoli, exhibiting minimal pleomorphism, and rare normal mitotic figures. (See Figure 5.) Bizarre mitoses, individual cell necrosis, and multinucleated keratinocytes are distinctively rare. The prominent granular layer contains vacuolated cells resembling koilocytes of CA. Multiple fistulous tracts lined by neoplastic epithelium are common. No vascular, lymphatic, or neural invasion is evident, correlating well with the lack of metastasis. Foci of histologically invasive SCC may be evident in some cases. Marked lymphohistiocytic infiltrate is generally present in the adjacent stroma.1,2,9,10,33,38 Differential Diagnosis Like a conventional SCC, BLT may deeply penetrate the underlying tissues. However, in contrast to typical SCC, the entire tumor is composed of well-differentiated squamous epithelium displaying orderly maturation and cell polarity with clear delineation of epidermal layers. The epidermis lacks significant cellular pleomorphism, with only infrequent mitoses. An intact basement membrane with lack of histologic infiltration further delineates this neoplasm from conventional SCC, and tissue destruction in BLT occurs via compression and displacement rather than by direct infiltration. Vascular and neural invasion are not present, and no metastases are observed as a rule despite the enormous size of the tumor. In contrast, conventional SCC of comparable dimensions frequently results in metastasis and generally carries a poor prognosis.1,2,10,33 Although papillary and condylomatous (warty) squamous cell carcinomas, referred by Loewenstein as condyloma-like carcinomas, may resemble BLT architecturally, they lack the broad bulbous retes of a VC. Papillary and warty SCC instead display elongated irregularly penetrating rete ridges made up of crowded pleomorphic keratinocytes with bizarre mitotic figures. The keratinocytes of these neoplasms display large, wrinkled, hyperchromatic nuclei with bi- or multinucleation, perinuclear halos, and single cell necrosis. Both neoplasms have pronounced tendency to metastasize.2,10 Features shared by both BLT and CA include marked hyperkeratosis, parakeratosis, papillomatosis and acanthosis, normal keratinocyte maturation, variable vacuolization of cells in the superficial tiers of the epidermis, infrequent mitoses, and a variable degree of inflammation. BLT lacks the connective tissue core in the papillary dermal processes characteristically displayed by CA. Although CA may also attain a large size, the growth always remains superficial and no destruction of the underlying structures takes place. In contrast, BLT has great tendency to infiltrate deeply with underlying tissue compression and displacement.1,2,10,22 Unlike BLT, pseudoepitheliomatous hyperplasia is characterized by a deep margin of narrow, jagged, uneven, sharp-pointed and elongated rete ridges.10 Condyloma lata of syphilis is typically smooth, flat, and resembles granulation tissue. Biopsies of condyloma lata generally teem with spirochetes.1,2,10 Ancillary Diagnostic Modalities The immunohistochemical testing for proliferating cell nuclear antigen (PCNA) has been reported useful in the histopathologic diagnosis of some BLT cases to help distinguish them from conventional well-differentiated SCC. Whereas in the former the staining is generally observed only at the periphery, in the latter it has a widespread distribution. Preoperative patient imaging with CT scan or MRI may help delineate the extent of pelvic involvement and detect evidence of possible metastasis.6 Figure 3: Tremendous epidermal hyperplasia and papillomatosis. Hematoxylin and eosin, 20x. Figure 4: “Pushing” border of broad-based rete ridges. Hematoxylin and eosin, 40x. Figure 5: Well-differentiated keratinocytes with ample eosinophilic cytoplasm. One normal mitotic figure is visible in this field. Hematoxylin and eosin, 200x. Treatment Most authorities agree that the first line of therapy and the only potentially curative option is radical excision, the success and perioperative moribidity of which is greatly dependent on the size of the tumor at the time of diagnosis. Abdomino-perineal resection is recommended in cases of recurrence, sphincter ani muscle infiltration, multiple fistulas, pelvic invasion, or malignant transformation.1,2,11,12,34,35,37-44 Some authors also advocate regional lymph node dissection.7,35 Given that surgery in the intrinsically contaminated perineum carries a considerable risk of post-operative wound infection, a major source of morbidity in patients with BLT, temporary loop colostomy is commonly designed for fecal diversion, especially in cases of extensive disease or multiple fistulas.1,12,38 Options for defect closure include island flaps, such as S-plasty and V-Y plasty, myocutaneous flaps, split-thickness grafts, and second-intent healing.37,45,46 Recently, mesh-skin grafts have been advocated for promoting drainage and providing a source of epithelium.37 Tissue preserving techniques promoted for the treatment of BLT include glansectomy, as an alternative for penectomy in penile tumors,47 and Mohs micrographic surgery.48-50 Any surgical approach, however, must strive to preserve normal anorectal function. Several lasers, including the carbon dioxide, argon, and neodymium:yttrium-aluminum-garnet (Nd:YAG), have been utilized for recurrent or inoperable cases. Advantages provided by the CO2 laser include operative hemostasis and wound sterilization, improved healing, and its ability to destroy deeper lesions by adjusting the power. Laser therapy also allows treatment of BLT on an outpatient basis.33,51,52 Chemotherapy and radiation have also been utilized, separately or in combination, to shrink and render operable an otherwise unresectable tumor.44 Mitomycin C and 5-fluorouracil have been used with success in non-BLT-associated anal SCC, as well as cisplatin, bleomycin and methotrexate in polychemotherapy regimens. Chemotherapy or radiotherapy, alone or in combination, have also been reported successful in select cases.1,12,53-55 In light of the previous reports of radiation-induced malignant transformation with risk of subsequent metastasis, some advocate that the use of this modality be limited.56-58 However, others promote its utility in the treatment of inoperable tumors and in chemoradiation protocols.54,55 Intralesional chemotherapy with cisplatin and 5-fluorouracil has also been used in the treatment of BLT.34 Long-term therapy with interferon as well as acitretin has been reported effective in the (off-label) treatment of BLT.6,59,60 More recently, imiquimod cream was used (off-label) prior to carbon dioxide laser surgery to delineate the extent of the tumor, and presumably decrease viral load in the surrounding clinically normal-appearing skin, thus decreasing the risk of recurrence.61 Immunotherapy with autogenous vaccine was also reported to be efficacious.62 For smaller lesions, cryosurgery and topical 5-fluorouracil (off-label) have been found useful.20 However, in contrast to its effectiveness in CA, results with topical podophyllin (off-label) have been found to be disappointing.1 Prognosis BLT is a condition that carries a significant risk of morbidity and mortality if left untreated. The overall mortality rate is 20% to 30%.12,34,35,44 Major causes of morbidity include local spread of the disease, recurrence, postoperative complications including hemorrhage, cachexia, and failed colostomy-associated peritonitis. The risk of recurrence reported in the literature ranges from 60% to 67% following excision.12,34,35,44 Risk factors for recurrence include long duration of the disease and HIV co-infection.1,34 Preventing morbidity High clinical suspicion, prompt diagnosis, and early aggressive treatment are of paramount importance in the management of BLT to maximize the chance for a cure and prevent the morbidity associated with advanced disease. Dedication This manuscript is dedicated in memoriam to Dan K. Chalker, M.D., one of the founding fathers of the American Academy of Dermatology, a caring physician, a great dermatologist, a devoted teacher, a mentor, and a friend. Dr. Dudelzak is a Resident in the Division of Dermatology at the Medical College of Georgia, Augusta. CME Course #130 — March 2007: The Buschke-Loewenstein Tumor—Giant Condyloma Acuminatum 1. Which of the following belong to the group of verrucous carcinomas? a. The Buschke-Loewenstein Tumor (BLT) b. Oral florid papillomatosis of Ackerman c. Palmoplantar epithelioma cuniculatum d. Cutaneous Gottron’s papillomatosis cutis carcinoides e. All of the above 2. The Buschke-Loewenstein Tumor is: a. Seen more commonly in males b. Seen more commonly in females c. Has an equal sex distribution 3. The most frequently isolated HPV types in BLT are: a. 16 and 18 b. 1 and 3 c. 6 and 11 d. 7 4. Which viral protein of HPV type 6 has been postulated in the pathogenesis? a. E7 b. E2 c. L1 d. L2 5. Which factor has the greatest impact on clinical course? a. HPV type b. Histopathology c. Local extent of the tumor 6. What is the most common site of BLT? a. Penis b. Scrotum c. Inguinal folds d. Perineum 7. What does the base of the Buschke-Loewenstein tumor usually look like histologically? a. Infiltrating cords of cells b. Infiltrating single atypical keratinocytes c. Pushing broad rete ridges d. Poorly differentiated spindle cells 8. Which treatment modality should be used with caution as it has been linked to malignant transformation and metastasis? a. Radiation b. Chemotherapy c. Interferon-_ d. Etretinate 9. What is the mortality of this tumor? a. 1% to 2% b. 20% to 30% c. 50% to 75% d. 80% to 95% 10. What is the risk of recurrence after excision? a. <2% b. 10% c. 25% d. 60%       References: 1. Trombetta LJ, Place RJ. Giant condyloma acuminatum of the anorectum: trends in epidemiology and management: report of a case and review of the literature. Dis Colon Rectum. 2001;44(12):1878-86. 2. Micali G, Nasca MR, Innocenzi D, Schwartz RA. Penile cancer. J Am Acad Dermatol. 2006;54:369-91. 3. Schwartz RA. Buschke-Loewenstein tumor: verrucous carcinoma of the penis. J Am Acad Dermatol. 1990;23:723-7. 4. Majewski S, Jablonska S. Human papillomavirus-associated tumors of the skin and mucosa. J Am Acad Dermatol. 1997;36:659-85. 5. Bogomoletz WV, Potet F, Molas G. Condylomata acuminata, giant condyloma acuminatum (Buschke-Loewenstein tumour) and verrucous squamous carcinoma of the perianal and anorectal region: a continuous precancerous spectrum? Histopathology. 1985;9(11):155-69. 6. Geusau A, Heinz-Peer G, Volc-Platzer B, Stingl G, Kirnbauer R. Regression of deeply infiltrating giant condyloma (Buschke-Lowenstein tumor) following long-term intralesional interferon alfa therapy. Arch Dermatol. 2000;136(6):707-10. 7. Grassegger A, Hopfl R, Hussl H, Wicke K, Fritsch P. Buschke-Loewenstein tumour infiltrating pelvic organs. Br J Dermatol. 1994;130(2):221-5. 8. Cubilla AL, Velazques EF, Reuter VE, Oliva E, Mihm MC Jr, Young RH. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of 'verruciform' penile tumors. Am J Surg Pathol. 2000;24(4):505-12. 9. Anadolu R, Boyvat A, Calikoglu E, Gurler A. Buschke-Loewenstein tumour is not a low-grade carcinoma but a giant verruca. Acta Derm Venereol. 1999;79(3):253-4. 10. Steffen C. The men behind the eponym--Abraham Buschke and Ludwig Lowenstein: giant condyloma (Buschke-Loewenstein). Am J Dermatopathol. 2006;28(6):526-36. 11. Ambriz-Gonzalez G, Escobedo-Zavala LC, Carrillo de la Mora F, Ortiz-Arriaga A, Cordero-Zamora A, Corona-Nakamura A, Lopez Ramirez MK, Velazquez Ramirez GA. Buschke-Lowenstein tumor in childhood: a case report. J Pediatr Surg. 2005;40(9):e25-7. 12. Chao MW, Gibbs P. Squamous cell carcinoma arising in a giant condyloma acuminatum (Buschke-Lowenstein tumour). Asian J Surg. 2005;28(3):238-40. 13. Micali G, Nasca MR, Innocenzi D. 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J Urol. 1994;152:1476-8. 40. Grussendorf-Conen EI. Anogenital premalignant and malignant tumors (including Buschke-Lowenstein tumors). Clin Dermatol. 1997;15(3):377-88. 41. Lee SH, McGregor DH, Kuziez MN. Malignant transformation of perianal condyloma acuminatum: a case report with review of the literature. Dis Colon Rectum. 1981;24(6):462-7. 42. Lock MR, Katz DR, Samoorian S, Parks AG. Giant condyloma of the rectum: report of a case. Dis Colon Rectum. 1977;20(2):154-7. 43. Bjorck M, Athlin L, Lundskog B. Giant condyloma acuminatum (Buschke-Loewenstein tumour) of the anorectum with malignant transformation. Eur J Surg. 1995;161(9):691-4. 44. Bertram P, Treutner KH, Rubben A, Hauptmann S, Schumpelick V. Invasive squamous-cell carcinoma in giant anorectal condyloma (Buschke-Lowenstein tumor). Langenbecks Arch Chir. 1995;380(2):115-8. 45. Uribe N, Millan M, Flores J, Asencio F, Diaz F, Del Castillo JR. Excision and V-Y plasty reconstruction for giant condyloma acuminatum. Tech Coloproctol. 2004;8(2):99-101. 46. Sasaki K, Nozaki M, Kikutchi Y, Yamaki T, Soejima K. Reconstruction of perianal skin defect using a V-Y advancement of bilateral gluteus maximus musculocutaneous flaps: reconstruction considering anal cleft and anal function. Br J Plast Surg. 1999;52(6):471-5. 46: Hatzichristou DG, Apostolidis A, Tzortzis V, Hatzimouratidis K, Ioannides E, Yannakoyorgos K. Glansectomy: an alternative surgical treatment for Buschke-Lowenstein tumors of the penis. Urology. 2001;57(5):966-9. 47. Davis JW, Schellhammer PF. Glansectomy: an alternative surgical treatment for Buschke-Lowenstein tumours of the penis. BJU Int. 2001;88(6):647. 48. Mohs FE, Sahl WJ. Chemosurgery for verrucous carcinoma. J Dermatol Surg Oncol. 1979;5(4):302-6. 49. Muro Vidaurre I, Hernaez Manrique I, Sanz Jaka JP, Rekarte Barriola JA, Lluch Costa A. Verrucous carcinoma of the penis: local excision with the Mohs micrographic technique. Arch Esp Urol. 1996;49(9):959-64. 50. 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