A Unique Case of Primary Extranodal Marginal Zone Lymphoma of the Anal Canal.

Marginal zone lymphomas represent approximately 10-12% of all B-cell lymphomas. Extranodal marginal zone lymphomas (EMZL) or mucosa-associated lymphoid tissue (MALT) lymphomas are the most common subtype. Almost half of all MALT lymphomas arise in the gastrointestinal (GI) tract and, while the stomach is the most common site of GI involvement, the small and large intestines can also be involved. Rare cases of MALT lymphoma involving the rectum have been reported; however, to our knowledge, involvement of the anal canal has never been reported in the literature. Here, we describe a unique case of MALT lymphoma of the anal canal. Infectious agents have been implicated in the pathogenesis of MALT lymphomas, possibly through persistent antigenic stimulation of the area; however, in our case no such infection was documented.

Consideraciones prácticas de la anoscopia de alta resolución en pacientes infectados por el virus de la inmunodeficiencia humana / Practical considerations for high resolution anoscopy in patients infected with human immunodeficiency virus

El cáncer de ano, una enfermedad infrecuente en la población general, presenta una incidencia elevada y progresiva en ciertos grupos de riesgo, fundamentalmente en hombres que tienen sexo con hombres, y particularmente en aquellos con infección por el virus de la inmunodeficiencia humana. La anoscopia de alta resolución se considera actualmente la técnica estándar en el diagnóstico de la neoplasia intraepitelial anal, pero su uso protocolizado aún está por consensuar en los sistemas sanitarios. Aunque no está exenta de dificultades, es una técnica asequible que puede llegar a ser fundamental en el cribado del cáncer de ano y sus lesiones precursoras. Actualmente estamos estudiando la estrategia más efectiva para el manejo de las lesiones premalignas anales, y con esta publicación intentamos animar a otros grupos interesados en la reducción de una neoplasia epidemiológicamente en progresión

Anal cancer is uncommon in the general population, however its incidence is increasing significantly in certain risk groups, mainly in men who have sex with men, and particularly those infected with human immunodeficiency virus. High resolution anoscopy technique is currently considered the standard in the diagnosis of anal intraepithelial neoplasia, but at present there is no agreed standard method between health areas. High resolution anoscopy is an affordable technique that can be critical in the screening of anal carcinoma and its precursor lesions, but is not without difficulties. We are currently studying the most effective strategy for managing premalignant anal lesions, and with this article we attempt to encourage other groups interested in reducing the incidence of an increasing neoplasia

[HPV type 16-associated anal intraepithelial neoplasia (AIN)]. / HPV-Typ-16-assoziierte anale intraepitheliale Neoplasie (AIN).

A 25-year-old woman had suffered from a perianal ulcer for approximately 1 year. Topical and systemic treatments had been unsuccessful. Employing virologic and histologic techniques, we confirmed the diagnosis of an intraepithelial neoplasia. Anal intraepithelial neoplasia (AIN) is induced by carcinogenic human papillomaviruses. It can occur anywhere in the anogenital area. Because of its frequency, AIN is a crucial differential diagnosis for lesions of the anogenital area region failing to respond to standard therapies.

Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.

BACKGROUND: The incidence of anal cancer has increased among both men (160%) and women (78%) from 1973 to 2000 in the U.S. The authors conducted a population-based case-control study of anal cancer to examine factors that may account for this increase. METHODS: Men (n = 119 patients) and women (n = 187 patients) who were diagnosed with anal cancer between 1986 and 1998 in the Seattle area were ascertained through the local Surveillance, Epidemiology, and End Results registry. Control participants (n = 1700) were ascertained through random-digit telephone dialing. Participants were interviewed in person and provided blood samples. Archival tumor tissue was tested for human papilloma virus (HPV) DNA, and serum samples were tested for HPV type 16 (HPV-16). RESULTS: Overall, 88% of tumors (all histologies) in the study were found to be positive for HPV. HPV-16 was the most frequent HPV type detected (73% of all tumors), followed by HPV-18 (6.9%), regardless of gender. However, 97.7% of tumors from men who were not exclusively heterosexual contained HPV DNA. The risk of anal cancer increased among men (odds ratio [OR], 5.3; 95% confidence interval [95% CI], 2.4-12.0) and women (OR, 11.0; 95% CI, 5.5-22.1) who had > or = 15 sexual partners during their lifetime. Among men who were not exclusively heterosexual and women, receptive anal intercourse was related strongly to the risk of anal cancer (OR, 6.8 [95% CI, 1.4-33.8] and OR, 2.2 [95% CI, 1.4-3.3], respectively). Current smokers among men and women were at particularly high risk for anal cancer, independent of age and other risk factors (OR, 3.9 [95% CI, 1.9-8.0] and OR, 3.8 [95% CI, 2.4-6.2], respectively). CONCLUSIONS: The high proportion of tumors with detectable HPV suggests that infection with HPV is a necessary cause of anal cancer, similar to that of cervical cancer. Increases in the prevalence of exposures, such as cigarette smoking, anal intercourse, HPV infection, and the number of lifetime sexual partners, may account for the increasing incidence of anal cancer in men and women.

Screening for anal dysplasia associated with human papillomavirus.

Anal dysplasia associated with human papillomavirus (HPV) infection occurs in substantial proportions of HIV-infected men and women and poses risk for anal carcinoma. Whether to routinely screen for HPV-associated anal dysplasia in this population, however, remains a debated question. Anal dysplasia is detectable by Pap screening and colposcopic biopsy; as Pap testing results have relatively low reproducibility, 2 baseline tests may be prudent. Screening should also ascertain risk factors for dysplasia, degree of immunosuppression, and history of prior anal disease. Although treatment options for anal dysplasia are limited by morbidity and high recurrence rates, early detection may permit better tolerance of therapy, and current estimates indicate that routine screening for the condition would be cost-effective. In addition, emerging immunologic therapies offer hope of more effective future treatment. This article summarizes a presentation given by Wm. Christopher Mathews, MD, MSPH, at the November 2002 International AIDS Society-USA course in San Diego.

Buschke-Loewenstein tumour infiltrating pelvic organs.

We report a 42-year-old HIV-negative patient with a 12-year history of exceptionally extensive genital warts and coexisting verrucous carcinoma of the anogenital region (Buschke-Loewenstein tumour). Masses of both tumour and viral papillomas infiltrated the external genitalia, perineum and buttocks, pelvic diaphragm and parts of the lesser pelvis, as well as the urethra, prostate and parts of the urinary bladder, necessitating repeated surgical intervention and plastic reconstruction. Adjuvant interferon-alpha therapy was given without any lasting effects. Human papillomavirus type 6 was detected by DNA in situ hybridization and Southern blot analysis.

Cervical and anal neoplasia and HPV infection in persons with HIV infection.

Prolonged, severe immunodeficiency provides the necessary milieu for the emergence of anogenital neoplasia caused by human papillomaviruses. Cervical and anal neoplasia are likely to become more common manifestations of HIV disease as patients with profound immunodeficiency, who would have succumbed to opportunistic infections earlier in the epidemic, are now surviving for extended periods of time because of increasingly effective antiretroviral, prophylactic, and antimicrobial therapies. Cervical cancer in the setting of HIV infection appears to be a more aggressive disease, less likely to be successfully treated by standard therapies, and consequently associated with a poorer prognosis than in comparable non-HIV-infected women. Anecdotal observations suggest that anal cancer in HIV-infected persons may share these features. Strategies need to be developed for earlier detection and treatment of neoplasia and anogenital cancer in the setting of HIV-induced immunodeficiency.

Localization of p53 protein and human papillomavirus in anogenital squamous lesions: immunohistochemical and in situ hybridization studies in benign, dysplastic, and malignant epithelia.

p53 Protein is a 53-kd nuclear phosphoprotein believed to play an important role in controlling proliferation of neoplastic and normal cells. This "natural tumor suppressor" can be rendered ineffective (or oncogenic) by mutations in the p53 gene or by interactions with proteins synthesized by DNA-transforming viruses, including specific subtypes of human papillomavirus (HPV). We describe the localization of p53 protein in association with HPV in paraffin sections of a spectrum of benign, dysplastic, and malignant anogenital squamous epithelia using immunohistochemical and in situ hybridization techniques. p53 Was detected in 81% of the 48 cases studied. Immunoreactivity for p53 was seen in 83% of the benign and low-grade squamous intraepithelial lesions (SILs), in 73% of the high-grade SILs, and in 86% of the infiltrating squamous carcinomas. In high-grade SILs p53 staining was frequently observed in individual nuclei at various levels of the abnormal epithelium and in the basal layer of the adjacent epithelium, while in squamous metaplasia and low-grade SILs immunostaining for p53 was limited to the basal layer of the epithelium. p53 Was detected in a slightly higher percentage of HPV-positive than HPV-negative epithelia as determined by in situ hybridization. No correlation was observed between p53 immunoreactivity and HPV subtypes. p53 Protein and HPV were detected in anal lesions from a small group of human immunodeficiency virus-positive individuals. Antibodies currently available mainly demonstrate mutant forms of p53 protein that are associated with longer half-lives than the wild-type protein, but demonstration of p53 protein overexpression is not necessarily indicative of malignancy.

Immunohistochemical detection of mutant P53 protein and human papillomavirus-related E6 protein in anal cancers.

PURPOSE: The wild-type P53 protein, a product of the P53 gene, is a normal growth controlling protein. Mutation of the P53 gene generates a mutant P53 protein which promotes tumor formation through loss of growth suppression. Some of the agents responsible for P53 gene mutation are known, one of which may be tumorigenic human papillomavirus (HPV) infection. Anal cancers are demonstrating a changing trend in the affected population, from older females in the older reported series to younger males more recently. This may be a reflection of infection with tumorigenic HPV types 16 and 18. The E6 oncoprotein of these viruses inactivates the growth-controlling wild-type P53 protein. In this study, our purpose was to determine the incidence of mutant P53 and HPV-16 and 18-related E6 protein and their coexpression in anal cancers. METHODS: We examined 29 anal cancers immunohistochemically for mutant P53 protein, HPV 16 and 18 E6 protein, and coexpression of the two. RESULTS: Mutant P53 protein was present in 58.6 percent of anal cancers overall and in 85.7 percent of anal adenocarcinomas. E6 oncoprotein was present in five cases (17.2 percent), all of which were squamous-cell carcinomas. Coexpression of both mutant P53 and E6 proteins was seen in only three cases (10.3 percent). CONCLUSION: Although tumorigenic HPV may be an important cause for P53 gene mutation in anal cancers, perhaps other mutagenic factors play a predominant role.

Human papillomavirus, type 16, DNA in multicentric anogenital neoplasia associated with idiopathic panmyelopathy. A case report.

A 27-year-old woman suffering from panmyelopathy for six years presented with a cervical low grade squamous intraepithelial lesion (SIL), vulvar high grade SIL and perianal squamous cell carcinoma with an inguinal metastasis. Southern blot hybridization with 32P-labeled human papillomavirus (HPV) DNA revealed HPV 16 DNA in varying copy numbers in material from the four locations. HPV 16 genomes persisting after surgery on the perianal tumor area were no longer detectable after betatron radiotherapy.

NK-cell activity in patients with HPV16-associated anogenital tumors: defective recognition of HPV16-harboring keratinocytes and restricted unresponsiveness to immunostimulatory cytokines.

Peripheral blood mononuclear cells (PBMC) from patients with active HPV16-associated pre-malignant and malignant anogenital lesions display a significantly decreased NK-cell activity against HPV16-harboring SKv keratinocytes (NK/SKv) while their cytotoxicity against erythroleukemic K562 cells (NK/K562) remains unaffected. A similar defect can also be seen in some healthy individuals displaying no symptoms of HPV infection (low responders). Analysis with specific Leu IIa monoclonal antibodies (MAbs) has revealed that all patients as well as weakly responding control subjects had normal numbers of circulating CD16+ NK cells. However, PBMC from patients with active disease and weakly responding controls displayed a significantly decreased ability to bind SKv cells. Binding of K562 was in the normal range. In patients in whom the lesions were successfully removed or regressed spontaneously (patients with no lesions), NK/SKv activity did not differ from that of normally responding healthy subjects and the ability of their PBMC to bind SKv cells was unaffected. To determine whether an abrogated NK/SKv cytotoxicity may be corrected by NK-cell stimulatory cytokines. PBMC were pre-incubated overnight with IL-2 and interferon-alpha. Both cytokines stimulated NK/K562 activity in all tested groups. Significant stimulation of NK/SKv activity was observed in PBMC from normal and weakly responding controls as well as patients with no lesions. No increase could be seen in patients with active disease. Evaluations of NK-cell activity before and after surgical removal or spontaneous regression of the lesions showed normalization of primarily depressed NK/SKv activity. Malignant progression was associated with a significant drop in SKv cell killing. Our results suggest that abrogation of NK-cell activity against HPV16-harboring targets in patients with HPV16-associated anogenital neoplasia is associated with restricted inability to recognize the disease-specific target cells, and may depend on persistence of the lesions.

[HPV in oncogenesis]. / HPV in der Onkogenese.

During recent years, advances have been made in understanding the functions of the viral oncoproteins E6 and E7. E6 und E7 code for proteins forming complexes with cellular proteins, which regulate the cell cycle. This leads to a disturbance of the physiological control mechanism and to increased proliferation of the infected cells. Enhanced expression of viral oncogenes in cells infected by genital "high risk" HPV types results in chromosomal instability and in an accumulation of mutational events. Cutaneous HPV types apparently follow other strategies to transform their host cells.

Anal cancer--current perspectives.

Anal cancer is uncommon accounting for only 2% of anorectal cancers. The recognition of many similarities between cervical and anal cancer has stimulated research into the identification of a common aetiological agent. DNA from human papillomaviruses has consistently been found in both of these cancers and is thought to be an important factor in the development of both of these tumours. Simultaneously, epidemiological data from the west coast of America have indicated that the demography of anal cancer may be changing. Further studies in the USA and the UK have identified certain groups at high risk of developing anal cancer. These high-risk groups include 'never married' men and immunosuppressed patients both from iatrogenic immunosuppression in transplant patients and those infected with HIV. The potential increase in anal cancer cases, due to the ever increasing numbers of patients who have received transplants and the spiralling number of the population infected with HIV make it timely to review what is known of the aetiology, presentation and management of this cancer.

Childhood condyloma acuminatum: association with genital and cutaneous human papillomaviruses.

We studied 25 children, age 7 months to 12 years 6 months, with anogenital warts, and their parents. In most children the warts were localized in the anal area, in 3 of 18 girls perianally and on the vulva, and in 4 girls exclusively on the vulva. Southern blot hybridization studies disclosed an association of condylomata with human papillomaviruses (HPV) 6 and 11 in 74% and HPV 2 in 17.4% of patients. The clinical features were similar in warts induced by genital and cutaneous HPVs. Even the HPV 2-associated warts in the vulva of two girls were typical of condyloma acuminatum. In all children with HPV 2-induced condylomata, cutaneous common warts coexisted, also induced by HPV 2. However, three mothers had cutaneous warts, and the children's condylomata were associated with HPV 6. Thus, the mere presence of skin warts in family members does not rule out other sources of infection. Sexual abuse was suspected in four girls and two boys, but was not confirmed in any. Nonsexual transmission could occur by persons with the lesions taking care of children. Perinatal transmission also appears to be an important route of infection in small babies. Infection in utero was probable in one girl in whom anal warts appeared in the first week of life and whose mother had cervical condylomata during pregnancy. This study provides further confirmation of possible nonsexual transmission of genital HPVs and the not infrequent association of childhood condylomata with HPV 2.

Cancer and viruses.

Viruses implicated in the development of human cancers include hepatitis B (and C) viruses in hepatocellular carcinoma; human papillomaviruses in anogenital cancers; Epstein-Barr virus in nasopharyngeal carcinoma and Burkitt's lymphoma; human T-cell leukaemia/lymphoma viruses in adult T-cell leukaemia/lymphoma; and indirectly, human immunodeficiency viruses in Kaposi's sarcoma and B-cell lymphoma. Together, they contribute significantly to the cancer statistics in the Southeast Asian region. Neoplastic proliferation may be instigated by the presence and expression of viral oncogenes which may be integrated into the host genome and/or exist in episomal molecules. Critical viral genes may also interfere with host genes, resulting in the activation of cellular proto-oncogenes and/or the inactivation of anti-oncogenes and their products. The molecular pathogenesis of virally-induced cancers has led to major breakthroughs in the understanding of carcinogenesis at a molecular level. The occurrence of some of these viruses in a significant proportion of normal individuals suggests long latency periods necessitating multi-step co-operating events arising from multi-factorial agents such as host genetic susceptibility, immunological and hormonal status, as well as chemical and physical cocarcinogens in the environment. Successful intervention achieved with effective vaccines such as the hepatitis B vaccine and measures to severe the chain of viral transmission culminating in reduced incidence of the corresponding cancer will provide conclusive evidence for the virus-cancer relationship.

Molecular and serological studies of human papillomavirus among patients with anal epidermoid carcinoma.

Certain types of human papillomavirus (HPV) are associated with anogenital carcinomas, including carcinomas of the anal canal. Whereas several serological studies have found an association between papillomavirus antibody responses and cervical carcinoma, the antibody response against papillomavirus antigens among patients with anal carcinoma has not been investigated. The present study has examined the antibody responses to a panel of papillomavirus-derived antigens and compared the serological profile with the histology and HPV carrier state of the tumor, as well as with the stage and prognosis of the disease. Sera from 64 patients with anal cancer and from 79 healthy blood donors were studied in ELISA for the presence of IgA and IgG antibodies to 5 previously described HPV16-derived synthetic peptide antigens. Serum IgA antibodies to a peptide antigen derived from the E2 region of HPV16 were found in 89% of patients with anal cancer as compared to 24% of controls (p = 0.0001). The IgA reactivity to the 4 other antigens showed only low and non-significant increases in mean titer. Serum IgG responses were similar among patients and controls. Among patients who had progressive disease, 21/21 were seropositive for IgA anti-E2 at diagnosis, as compared to 36/43 patients who were in remission after a mean follow-up of 41 months (p = 0.05). Forty-seven cases of anal carcinoma were also studied for the presence of HPV by in situ hybridization using a probe mix of 7 anogenital HPV types. Sixteen patients (35%) carried HPV in their anal cancer and one patient had an HPV-positive benign lesion adjacent to the tumor. Patients with HPV-carrying anal cancer were significantly younger than those with HPV-negative anal cancers (mean age: 57 and 68 years, respectively, p = 0.03). No differences in seroreactivity or HPV carrier state were seen depending on the stage or histological type of the tumor.

Presence of human papillomavirus DNA in condylomata acuminata in children and adolescents.

The presence of human papillomavirus (HPV) DNA of types 6, 11, 16, 18, 31 and 33 was determined by in situ hybridization on archival paraffin-embedded tissue sections in 21 condylomata acuminata observed in patients aged 20 or less. HPV DNA was detected in 17 of 21 cases: all of these contained HPV 6, five also contained HPV 11, and one also contained HPV 16 and 18. HPVs 31 and 33 were not observed. Among 21 cases, 4 cases were in children under 6 yrs one of whom had a history of sexual abuse. The hybridization data indicate that condylomata acuminata in young people are associated with the same HPV types found in anogenital lesions in adults.

Detection of human papillomavirus DNA in the urogenital tracts of men with anogenital warts.

Increasing evidence suggests that human papillomavirus (HPV) infection of the female anogenital tract is multifocal. Less is known of the distribution of HPVs in men. To investigate this, a prospective study was conducted of 116 men consecutively attending a clinic for ablative treatment of anogenital warts. Wart tissue, urethral swabs, and urine were obtained from each patient. HPV DNA was extracted from the specimens and amplified using the polymerase chain reaction (PCR). HPV types 6, 11, 16, 18, 31, and 33 were identified using Southern blotting of the PCR product, followed by hybridization. HPV DNA was detected in 112 (96.6%) of 116 wart specimens and there was urethral infection with HPV in 26 (22.4%) of the men. Eleven (61.1%) of 18 urethral specimens taken with a loop and 22 (20.0%) of 116 urethral specimens taken using a cotton-tipped swab contained HPV DNA. One (6.3%) of 16 urine samples tested contained HPV DNA. HPV types 6 and 11 were found in the urethra most commonly when warts were seen near the urinary meatus, although HPV occurred in the urethras of men without clinically apparent meatal warts. The proportion of urethral samples with HPV DNA, including HPV types 16, 18, 31, and 33, was independent of the location of visible warts at the time of sampling.

Papillomaviruses in human disease: Part II. Molecular biology and immunology of papillomavirus infections and carcinogenesis.

As summarized in the last issue of the EJM, human papillomaviruses induce a great variety of neoplastic lesions of mucosal epithelia and the skin. Particular types of these viruses are associated with specific human cancers, most notably anogenital carcinomas. These tumours account for about fifteen percent of the whole worldwide cancer burden. However, recent epidemiological studies revealed that papillomavirus infections including those with the cancer-related papillomavirus types are very widespread even among asymptomatic healthy individuals. Here, the current understanding of the molecular events leading to papillomavirus-induced tumours will be reviewed. It is assumed that these tumours arise as a consequence of several molecular modifications of persistently papillomavirus-infected epithelial cells. Experimental studies revealed that the virus types associated with anogenital cancers harbour two potential oncogenes referred to as E6 and E7. These viral genes are consistently expressed in HPV-associated anogenital carcinoma cells. HPV-associated cervical carcinoma cells loose their neoplastic growth properties if the expression of the E6 and E7 genes is inhibited. The proteins encoded by these viral genes thus appear to be ideal targets for a specific pharmacological approach to treat papillomavirus associated cancers or their respective precursor lesions. Recent studies in animals furthermore suggest that active vaccination with the viral oncoprotein E7 prevents growth of papillomavirus associated tumours. Hence, the possibility arises that also in man, vaccination with the viral transforming proteins might prevent the development of papillomavirus associated cancers.