1Institut Gustave Roussy, Villejuif Cedex; 2Centre Hospitalier de Bicêtre Cedex, France
Received 1 March 2001; revised 16 May 2001; accepted 18 May 2001.
Abstract
We report the case of a 37-year-old man in whom penile cancer was discovered while he was treated for AIDS 4 years after a human papillomavirus (HSV) infection. Despite initially localised disease with T1 N0 staging, he died of metastasis within 3 years. A brief review of the literature regarding HPV-related cancer in HIV-infected patients is presented and therapeutic options are discussed.
Key words: AIDS, HIV, HPV-related cancer, immunodeficiency, penile cancer
Introduction
Although human papillomavirus (HPV)-related squamous cell anorectal and cervical carcinomas are well described in patients infected with HIV [1], data on the association of AIDS and squamous cell penile carcinoma are still scarce. We report the case of an explosive course of squamous cell penile carcinoma in an AIDS patient, review the literature on HPV-related cancer and discuss the mechanisms of cancer progression and therapeutic options in this setting.
Case history
In January 1997, a 37-year-old Caucasian man was referred to the institution for penile cancer associated with AIDS. He was an engineer, married and father of two children, a non-smoker and denied drug abuse or bisexuality. In 1978, he was treated for phimosis. In 1993, his wife was treated for cervix dysplasia related to HPV infection. He was then examined in the same dermatology department, diagnosed as having condylomatous balanitis occupying 40% of the surface of the penis glans and was treated by surgical excision followed by local 5-fluorouracil (5-FU) with good local results.
In February 1995, fever, cough and a 7 kg weight loss led to pneumocystis carinii pneumonia documentation. He was found to be HIV1 positive and diagnosed as having AIDS, stage C of the Center for Disease Control (CDC) classification. His CD4 cell count was 47/µl. He was started on zidovudine (AZT, Retrovir, Glaxo Wellcome, Marly le Roy, France) 500 mg/day and zalcitabine (DDC, Hivid; Roche, Neuilly, France) 750 mg x 3/day.
In October 1995, he presented with a flat erythematous non-ulcerated lesion of the glans. The biopsy specimen showed plasma cell infiltration typical of Zoons plasma cell balanitis (Figure 1). The serum analysis was negative for syphilis. A second biopsy was discussed because of his previous history of condyloma but rejected since the first had caused severe bleeding. Silver nitrate was applied locally.
|
In September 1996, the erythematous lesion on the penis glans recurred. An excisional biopsy was performed that showed squamous cell carcinoma invading only the superficial part of the lamina propria associated with areas of carcinoma in situ in the margins of the biopsy specimen (Figure 2). There was no evidence of corpus cavernosum invasion. Surgical excision was performed followed by CO2 laser coagu-lation repeated 6 weeks later for a suspected recurrence. In December 1996, there was an enlargement of a left inguinal lymph node. An inguinal lymphadenectomy specimen was positive for squamous cell carcinoma.
|
In January 1997, external beam radiotherapy was delivered at a dose of 40 Gy in 16 fractions to the left inguinal chain followed by a boost of 20 Gy of electron beam therapy. In October 1997 a partial amputation of the penis was performed because of urethral stenosis after treatment of two new glans relapses by laser therapy.
HAART was continued. In February 1998 the CD4 cell count had risen to 253/µl but the viral load remained high at 200 000 copies (5.2 log). Hydroxycarbamide 1000 mg/day was added in an attempt to reduce the synthesis of viral DNA.
In June 1998, a right inguinal node biopsy showed evidence of squamous cell carcinoma. The whole-body CT scan confirmed no further dissemination. External beam radiotherapy was delivered to a right inguino-iliac field at a total dose of 45 Gy in 18 fractions.
In March 1999, a chest X-ray showed pleural effusion and several round pulmonary parenchymal images. A pleural biopsy specimen showed metastasis from squamous cell carcinoma. An amplified hybridization antibody capture assay, with an HPV RNA probe cocktail for HPV 16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59 and 68 (Digene HPV Test Hybrid Capture II) was used to investigate HPV infection. It was positive. The CD4 cell count was 150/µl with a viral load of 300 000 copies. Blood counts showed 10.7 g Hb/dl, 10 900 white cells with 8800 neutrophils and 229 000 platelets. Hydroxycar- bamide was interrupted and chemotherapy containing cisplatin (CDDP) 100 mg/m2 day 1 and 5-FU 500 mg/m2 days 15 was administered. No haematological toxicity occurred nor any hair loss or mucositis. After two cycles of chemotherapy with a 21-day interval between cycles, numerous subcutaneous nodules appeared. The biopsy of a scalp nodule showed squamous cell carcinoma. The patient died in June 1999 with evidence of extensive disease (pleuro-pericardic effusion, bone and lung metastases).
Discussion
Penile carcinoma is a rare neoplasm in Europe and North America [2]. According to epidemiological data it arises in non-circumcised individuals and is associated with HPV, a member of the human herpes virus family [3]. This patient had been treated for phimosis at 20 and 11 years later for condylomatous balanitis while his wife had evidence of HPV infection associated with cervical dysplasia. Usually, the latency period between a suspected HPV genital infection and invasive penile cancer lasts several decades [2]. The peak incidence is in the sixth decade of life. Typically tumours present as controllable local lesions and the disease stage is the main prognostic factor. The unusual features of this case are the rapid progression from condylomatous balanitis to invasive squamous cell carcinoma and from superficial to metastatic disease. Pathologically the aspect of the first glans biopsy specimen was typical of Zoons plasma cell balanitis, characterised by a plasma cell infiltration. This inflammatory infiltrate may have been close to foci of carcinoma in situ, which may not have been removed during the biopsy. The role of the systemic CD4 lymphocyte depletion could also be questioned since it may be responsible for a plasma cell activation. Months later only a superficial squamous cell carcinoma (still surrounded by an inflammatory infiltrate) was found on the second biopsy specimen after a clinically diagnosed relapse. The extension work-up was negative. The lesion was defined as a stage T1N0M0 lesion according to the Union Internationale contre le Cancer TNM classification [4]. Such tumours are usually well controlled by local treatments. However, within weeks inguinal lymph node extension was histologically documented. Owing to the patients refusal to undergo radical surgery, his poor performance status and the inefficiency of HAART, he was treated with conservative surgery, laser ablation of local recurrences and an inguinal lymphadenectomy followed by radiotherapy. He never developed a left iliac node relapse. The following relapses on the glans may have been related to incomplete surgery since cancer may have invaded the glans more extensively or may have even extended to the shaft of the penis in which case the tumour would have been a stage T2 lesion. The recurrent disease that developed in the controlateral lymph nodes 8 months after the partial penectomy indicates that the patient was not disease free after surgery. After a limited local lymphadenectomy and radiotherapy, local control was obtained again but it has been shown that nodal irradiation does not prevent the risk of subsequent metastases [5]. The 5-year survival rate for N2 patients with bilateral nodal involvement was only 17% in a series of 118 patients [6] and 20% in another series of 102 patients [7]. However, most deaths due to penile cancer are caused by uncontrolled regional recurrences rather than by distant metastases, which remain rare [8]. Systemic chemotherapy has only limited activity in advanced penile cancer [9]. However, its complete lack of toxicity with no changes in blood counts and no alopecia raises the question of interactions between HAART and anticancer drugs such as 5-FU or CDDP.
The unusually accelerated progression in our patient raises the question of the role of the HIV infection itself and immune deficiency.
The role of co-infection by HIV-1 and HPV in malignant transformation has been discussed previously. Suspected mechanisms of interaction between HPV and HIV include the attenuation of a systemic cell-mediated immune response to HPV antigens [10] and interaction between HIV-infected cells circulating below the basement membrane and HPV-infected keratinocytes above the basement membrane, which could be mediated by aberrant expression of cytokines such as interleukin 6, known to modulate HPV gene expression. Finally, in vitro studies suggest the HIV-encoded Tat protein may enhance the expression of HPV-induced E6 and E7 transforming proteins [11].
Other malignant conditions related to HPVs have been described in patients infected with HIV and there has been considerable debate about the respective impacts of lifestyle factors associated with both infections and that of the immune deficiency following HIV infection.
Cervix carcinoma is one of the AIDS-defining malignancies since Maiman [12] reported a series of women with invasive cervical neoplasia infected with HIV. All of these patients died of cervical intra-epithelial neoplasia with a median survival of 10 months. Case reports of rapid progression of cervical intra-epithelial neoplasia to invasive cervix carcinoma exist [13]. In contrast, regression of low-grade squamous intra-epithelial lesions (SIL) has been reported in 43 of 69 women with HIV infection with progression in only nine over a period of 31 months [14]. The degree of immune suppression has been reported to be related to the severity of cervical neoplasia in women infected with HIV [15].
Squamous cell carcinoma of the anus is also caused by oncogenic HPVs and the role of immune deficiency in the progression of SIL to invasive cancer was also questioned. In a recently published study among men infected with HIV with low-grade anal SIL at the time of HAART initiation those who regressed to normal had a mean CD4 level of 272/µl compared with 208/µl among men who did not change and 169/µl among men who progressed to high-grade anal SIL [16].
Squamous cell carcinoma of the conjunctiva (SCCC) is associated with HPV infection and also intense ultraviolet exposure. In Uganda the incidence of SCCC increased from six cases per million in 1972 to 36 cases per million in 19901992. Case-control studies comparing age- and sex-matched controls with other eye diseases found HIV antibodies in 82% of those with SCCC compared with 24% among controls [17]. Other HPV-related neoplastic diseases include tonsillar and vulvo-vaginal cancers [18].
The CDC recently published data on HPV-associated cancers in patients with HIV infection and with AIDS in order to determine if the high frequency of these cancers was due to lifestyle factors associated with both HPV and HIV infections, or to immunosuppression following HIV infection. The relative risk defined as the sex, age and race-matched ratios of observed to expected cancers was studied from 5 years before the onset of AIDS to 5 years after this date. All HPV-associated cancers in AIDS patients occurred in statistically significant excess compared with the expected cancers. For in situ cancers, overall risks were significantly increased for cervical, vulvar/vaginal, anal and penile cancers, and relative risks increased during the 10 years spanning AIDS onset. For invasive cancers, overall risks were significantly increased in cervical, vulvar/vaginal and anal cancers in women and in anal, penile, tonsillar and conjonctival cancers in men. However, relative risks for invasive cancers changed little during the 10 years spanning AIDS onset [19]. It was concluded that advancing immunosuppression caused a gradual loss of control over HPV-infected keratinocytes and was responsible for the increase in relative risks of in situ cancers but late-stage cancer invasion was not greatly influenced by immunosuppression. However, other factors were not considered such as the impact of screening and of surgical removal of in situ cancers, and the importance of the immunosuppression.
In the present case the role of severe immune deficiency despite HAART, rather than the HIV infection itself, seems to have determined the course of disease. Indeed, one case of condyloma acuminata and one case of carcinoma in situ with moderate dysplasia and koilocytosis progressing rapidly to invasive penile carcinoma were described in HIV-infected men. However, both cases were limited stage-disease, which was controlled by local treatment [20, 21]. Even though penile carcinoma is less common than cervical or anal carcinoma (probably because of a cell origin different from that of cervix and anal cancers that originate from cloacogenic cells, likely to be better hosts for HPV) it is noteworthy that a similar increase of relative risk has been demonstrated with a relative risk of 6.9 [95% confidence interval (CI) 4.210.6] for carcinoma in situ and a relative risk of 3.7 (95% CI 26.2) for invasive cancer [19], warranting early treatment and careful surveillance of in situ lesions.
Finally, the complete lack of toxicity with no changes in blood counts and no alopecia raises the question of drug interactions between HAART and 5-FU or CDDP. In men with testicular cancer infected with HIV, CDDP has exhibited similar activity and toxicity to that observed in HIV-negative patients [22]. However, the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors with chemotherapy has not yet been adequately studied. As regards drugdrug interaction, both protease inhibitors and non-nucleoside reverse transcriptase inhibitors are cleared by the liver via the cytochrome p450-3A family. Eighty percent of 5-FU is metabolised by the liver while CDDP is excreted in the urine as the result of glomerular filtration of unbound platinum coordinate complexes. So far, concerns about interactions between HAART and anticancer chemotherapy are essentially related to additional toxicities particularly with cyclophosphamide, doxorubicin, vincristine and pednisone (CHOP) combination chemotherapy for lymphoma. Trials of chemotherapy combined with stavidine, indinavir and lamivudine have recently been published [23] but data are still lacking on the association of saquinavir with chemotherapy.
Conclusion
AIDS patients with a previous history of HPV-related penile pre-neoplastic cutaneous lesions should be considered at high risk for developing invasive penile carcinoma and offered biopsies and radical treatments early on during the course of their disease. More data are needed on the concomitant administration of HAART and anticancer chemotherapy.
Acknowledgements
We would like to thank Ms Saint-Ange for editorial assistance, Ms Molinazzi for typing assistance and Drs Carlotti, Viellefond and Bedossa for transmission of pathological material.
Footnotes
+ Correspondence to: Dr C. Théodore, Institut Gustave-Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel: +33-1-4211-4322; Fax: +33-1-4211-5219; E-mail: theodore@igr.fr
References
1. Goedert JJ, Cote TR, Virgo P et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998; 351: 18331839.[ISI][Medline]
2. Burgers JK, Badalament RA, Drago JR. Penile cancer. Clinical presentation, diagnosis and staging. Urol Clin North Am 1992; 19: 247256.[ISI][Medline]
3. Laimins LA. The biology of human papillomaviruses: From warts to cancer. Infect Agents Dis 1993; 2: 7486.[ISI][Medline]
4. Hermanek P, Sobin LH. TNM Classification of Malignant Tumours, 4th edition. Berlin: Springer 1987.
5. Jones WG, Fossa SD, Harmers H, van den Bogaert W. Penis cancer: a review by the Joint Radiotherapy Committee of the European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary and Radiotherapy Groups. J Surg Oncol 1989; 40: 227231.[ISI][Medline]
6. Horenblas S. Prognostic factors of survival. Analysis of the TNM classification and staging in the management of penile squamous cell carcinoma. A retrospective and prospective study thesis. PhD Thesis. Amsterdam: Zoetermeer, Export drukkerij BV 1993; 145160.
7. Soria JC, Fizazi K, Piron D et al. Squamous cell carcinoma of the penis: multivariate analysis of prognostic factors and natural history in a monocentric study with a conservative policy. Ann Oncol 1997; 8: 10891098.[Abstract]
8. Pizzocaro G, Piva L, Bandieramonte G, Tana S. Up-to-date management of carcinoma of the penis. Eur Urol 1997; 32: 515.[ISI][Medline]
9. Eisenberger MA. Chemotherapy for carcinomas of the penis and urethra. Urol Clin North Am 1992; 19: 333338.[ISI][Medline]
10. Nakagawa M, Stites DP, Farhat S et al. T cell proliferative response to human papilloma virus type 16 peptides: relationship to cervical intra-epithelial neoplasia. Clin Diagn Lab Immunol 1996; 3: 205210.[Abstract]
11. Takeshita S, Breen EC, Ivashchenko M et al. Induction of IL-6 and IL-10 production by recombinant HIV-1 envelope glycoprotein 41 (gp41) and the THP-1 human monocytic cell line. Cell Immunol 1995; 165: 234242.[ISI][Medline]
12. Maiman M, Fruchter RG, Serur E, Boyce JG. Prevalence of human immunodeficiency virus in a colposcopy clinic. JAMA 1988; 260: 22142215.[ISI][Medline]
13.
Holcomb K, Maiman M, Dimaio T, Gates J. Rapid progression to invasive cervix cancer in a woman infected with the human immunodeficiency virus. Obstet Gynecol 1998; 91: 848850.
14. Belafsky P, Clark RA, Kissinger P, Torres J. Natural history of low-grade squamous intra-epithelial lesions in women infected with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11: 511512.[ISI][Medline]
15. Robinson W 3rd. Invasive and preinvasive cervical neoplasia in human immunodeficiency virus-infected women. Semin Oncol 2000; 27: 463470.[ISI][Medline]
16. Palefsky JM. Anal squamous intra-epithelial lesions in human immunodeficiency virus-positive men and women. Semin Oncol 2000; 27: 471479.[ISI][Medline]
17. Ateenyi-Agaba C. Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda. Lancet 1995; 345: 695696.[ISI][Medline]
18. Goedert JJ, Cote TR. Conjunctival malignant disease with AIDS in USA. Lancet 1995; 346: 257258.
19.
Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000; 92: 15001510.
20. Sanders CJ. Condylomata acuminata of the penis progressing rapidly to invasive squamous cell carcinoma. Genitourin Med 1997; 73: 402403.[ISI][Medline]
21. Yoganathan K, Patel RN, Maitland N et al. Carcinoma of the penis in an HIV positive patient. Genitourin Med 1995; 71: 4142.[ISI][Medline]
22. Bernardi D, Salvioni R, Vaccher E et al. Testicular germ cell tumors and human immunodeficiency virus infection: a report of 26 cases. Italian Cooperative Group on AIDS and Tumors. J Clin Oncol 1995; 13: 27052711.[Abstract]
23. Ratner L, Redden D, Hamzeh F et al. Chemotherapy for AIDS associated non-Hodgkins lymphoma in combination with highly active retroviral therapy(HAART) is not associated with excessive toxicity. Third National AIDS Malignancy Conference, Bethesda, MD,1999. J AIDS 1999; 21: A32.