Pathology of human immunodeficiency virus infection: Noninfectious conditions

REVIEW ARTICLE

Pathology of Human Immunodeficiency Virus Infection: Noninfectious Conditions Mary K. Klassen, MD, Michael Lewin-Smith, MB, BS, Sarah S. Frankel, MD, and Ann Marie Nelson, MD Diagnostic anatomic pathologists play a crucial role in the battle against acquired immunodeficiency syndrome (AIDS). Not only are they intimately involved in the treatment of individual patients with human immunodeficiency virus (HIV) infection, but also they make important observations that result in the expansion of the scientific understanding of its pathogenesis. Pathologists studying tissue from patients with HIV infection should be familiar with the conditions to which these patients are susceptible. Although opportunistic infections are important causes of morbidity and mortality, noninfectious conditions frequently make substantial contributions to the disease course. Patients with HIV infection may be at increased risk for neoplastic disease. They do not, however, have an increased incidence of the most common tumors affecting the general population, such as breast, colon, and prostate carcinoma. Immunodeficiency results in increased susceptibility to malignant neoplasms, both by decreased immunologic response to abnormal cells and increased susceptibility to infection by viruses. All of the malignant neoplastic diseases that are Centers for Disease Control and Prevention (CDC) AIDS indicator conditions have been shown to have an association with a virus: Kaposi sarcoma (KS) with herpes hominis virus 8 (HHV.8), malignant lymphoma with Epstein-Barr virus (EBV), and cervical carcinoma with human papilloma virus (HPV). Patients with HIV infection also can develop reactive processes that are attributable to direct effects of HIV or immune system alterations. Such conditions include salivary gland cystic lymphoepithelial lesion, lymphadenopathy, lymphocytic interstitial pneumonitis, encephalopathy, enteropathy, nephropathy, hepatic conditions, dermatologic conditions and anemia. A n n D i a g n P a t h o l 1: 57-64, 1997. T h i s is a U S g o v e r n m e n t w o r k . T h e r e a r e no r e s t r i c t i o n s o n i t s use.

Index Words: AIDS, HIV, neoplasm, pathology, histology, complications surgical pathologists had an imortant part in the discovery of acquired immunodeficiency syndrome (AIDS). The histological diagnosis of Pneumocystis carinii pneumonia and Kaposi sarcoma (KS) in young homosexual men was a key factor in the recognition of the first AIDS cases in 1981. Pathologists' observations regarding AIDS-associated conditions provided the foundation for the Centers for disease Control (CDC) Surveillance Case Definition of AIDS. Patholo-

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From the Division of_AIDS and Emerging Infectious Diseases,Department of Infectious and Parasitic Disease Pathology,Armed ForcesInstitute of Pathology, Washington, DC. The opinions or assertionscontainedherein are theprivate views of the authors and are not to be construedca"o~dal or us reflecting the views of the United States Department of Army or the Department of Defense or the institutions with which the authors are affiliated. Address correspondenceto Ma~v K. Klassen, MD, 14th St and Alaska Av6 NW,, Washington, DC 20306-6000. This is a US government work. There are no restrictionson its use. 1092-9134/97/0101-0007500.00/0

gists continue to play substantive roles in the ongoing study of the pathogenesis of AIDS and in the care of patients with human immunodeficiency virus (HIV) infection. Surgical pathologists should understand the altered host response and should keep abreast of the changing spectrum of complications of HIV infection. Although persons infected with HIV show dysfunction in all components of immunity, cellular immunity is affected most markedly. Diminished number and function of CD4 helper cells are the basis for much of the immunodeficiency. Polyclonal B-cell activation and impaired antibody responses to soluble antigens are manifestations of impaired humoral immunity. The virusinfected macrophage is also intimately involved in clinical manifestations of H1V infection. Patients with HIV infection are at increased risk for not only opportunistic infections, but also neoplasms and reactive processes that may be attributed to immunodeficiency or the direct effects of HIV.

Annals of Diagnostic Pathology, Vol 1, No 1 (October), 1997: pp 57-64

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Klassen et al Malignant N e o p l a s m s

Kaposi Sarcoma Kaposi sarcoma is the most common malignancy in HIV-infected persons, in whom it can be cutaneous or visceral. Among patients with HIV infection, KS is more common in homosexual males and residents of endemic geographic areas such as Africa. There is an association between KS and herpes hominis virus 8 (HHV-8). Nucleic acid sequences specific to HHV-8 are present in tissue samples of various forms of KS, including AIDSassociated, classic Mediterranean, endemic African, and transplant-associated. Tissues from different anatomic locations and other vascular tumors have been negative for HItV-8. Transmission electron microscopy has revealed hexagonal nucleocapsids and mature enveloped virions typical of herpesvirus in vasoformative spindle cells and mononuelear cellsd These findings support the hypothesis that HHV-8 is a causative agent of KS. Detection of HHV-8 may prove to be a useful tool for distinguishing KS from other forms of vascular proliferation .2 Cutaneous KS appears in three clinical and histopathological stages: patch, plaque, and nodular. 3 The patch stage is the least conspicuous and most difficult stage to recognize. The changes are usually confined to the reticular dermis. Vascular changes are often subtle such as proliferation of small, irregular vessels around normal vessels or adnexal structures. Ectatic, bloodfilled vessels are seen in many cases. The promontory sign, ie, protrusion of the vascular proliferation into the lumen of a vessel, may be present at this early stage. Irregular, branching vessels appear to dissect through the dermal collagen (Fig 1). The endothelial cells show

Figure 1, Patch stage of Kaposi sarcoma with small, irregular. branching vessels around normal vessels or adnexal structures that appear to dissect through the collagen of the reticular dermis.

Figure 2. Iron stain demonstrating extensive hemosiderin deposition in Kaposi sarcoma of the skin.

little atypia and mitotic figures are rare. Well-defined aggregates of spindle cells are not present at this stage. Hemosiderin deposition is usually present, although an iron stain may be necessary to detect it. Infiltration by lymphocytes and plasma cells may be present, especially around blood vessels; therefore, the differential diagnosis at this stage includes perivascular dermatitis. During the plaque stage, the spindle cell component and hemosiderin deposition become more prominent (Fig 2). The tumor fills the dermis and may extend into the subcutaneous tissue. Periodic acid-Schiff (PAS)-positive intracytoplasmic hyaline globules are most numerous in welldeveloped plaques and nodules. 4 They are not pathognomonic, because they are also present in a variety of neoplastic and inflammatory processes with vascular proliferation. Apoptotic endothelial cells are a useful characteristic of KS, especially in the plaque and nodular stages. The classic features of KS are present in the nodular stage. There are intersecting fascicles and sheets of spindle cells forming slit-like vascular spaces. There may be more mitotic figures and greater cytological atypia, but severe anaplasia is uncommon. The differential diagnosis includes other infectious and noninfectious forms of vascular proliferation. Infections to consider are bacillary angiomatosis, inflammatory pseudotumors, including vasoproliferation after acute toxoplasmosis, and spindle cell mycobacterial lesions. Special stains, such as Warthin-Starry forBartonella henselae and Ziehl-Neelsen for mycobacterium, are used to diagnose these other entities. Vascular neoplasms that mimic KS include targetoid hemosiderotic hemangioma, benign lymphangioendothelioma, cutaneous angiosarcoma, and spindle cell hemangioendothelioma. Other processes that show extravasation of erythrocytes and inflammation include pyogenic

Pathology of HIV Infections

granuloma, granulation tissue, and venous stasis dermatitis.

Malignant Lymphoma Malignant lymphoma is the second most common malignancy in HIV-infected patients) It differs from malignant lymphoma in the general population by being extranodal in a large percentage of cases and being more likely to involve the central nervous system (CNS), body cavities, and the mucosa-associated lymphoid tissue. 5 Up to 20% arise as primary CNS lymphomas. 6 Evidence of Epstein-Barr virus (EBV) is present in many cases. Up to 50% of AIDS patients with lymphoma have elevated EBV antibody titers. Immunohistochemical staining often shows the latent membrane protein of EBV in the malignant cells. Most cases have a high-grade B-lymphocyte phenotype. There are three predominant histological types: immunoblastic or plasmacytoid, large noncleaved and small noncleaved, or Burkitt's-like. Large cell anaplastic lymphomas that are Ki-1 (CD30)-positive have been reported] The diagnosis of CNS lymphoma presents a particular challenge, especially on a small brain biopsy specimen. Lymphoma usually presents as single or multifocal ring-enhancing lesions on computerized tomography. The differential diagnosis includes toxoplasmosis. Primary CNS lymphoma is located in the deep or periventricular regions and characteristically involves both gray and white matter. 8 Histologically, there is perivascular infiltration bylymphoid ceils (Fig 3). Immunohistochemical stains are sometimes helpful, although benign inflammatory infiltrates can be almost entirely B lymphocytes.

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Hodgkin'sDisease Hodgkin's disease is relatively uncommon, accounting for only about 1% of malignancies in AIDS. It is not a CDC AIDS indicator condition. In this immunocomproraised population, Hodgkin's disease is a more aggressive neoplasm and tends to be at a higher stage with extranodal involvement at time of presentation. 9 HIVpositive patients usually present at stages III or IV, whereas HIV-negative patients generally present at stage I or II. In patients with AIDS, there is also a lower survival rate and an increased incidence of secondary lymphomas and opportunistic infections after treatment. EBV sequences can often be detected by polymerase chain reaction or in situ hybridization, suggesting that it plays a role in the pathogenesis. 1° Hodgkin's disease should be considered in the differential diagnosis of fever, especially when no opportunistic infection is present. Hodgkin's disease tends to involve the bone marrow relatively early in the course of the disease; therefore, bone marrow examination may be the initial source of the diagnosis, l~ The classical types of Hodgkin's disease, nodular sclerosis and mixed cellularity, are most frequent. The histological features are the same as those in HIV-seronegative persons. Classic ReedSternberg cells or lacunar variants are present.

Lung Carcinoma Lung carcinoma is not a CDC AIDS indicator condition. Although it is rare, the incidence may be increased compared with that in ttIV-seronegative persons of the same age. Immunodeficiency may modulate the expression ofbronchogenic carcinoma or may have a role in its causation. In a small series of lung carcinoma cases in H1V-positive patients, most tumors were high grade and presented at stage 11I or IV. Many of the patients were younger than 40 years old with low clusters &differentiation (CD) 4 counts. 12 Other series have shown similar findings. Is,14 Adenocarcinoma is more frequent than squamous cell carcinoma. There is a higher rate of postoperative morbidity and mortality among patients with low CD4 counts. 15 Transbronchial biopsy to rule out bronehogenic carcinoma may be useful in patients with focal lung lesions that persist despite therapy for opportunistic infections.

Cervical Carcinoma

Figure 3. Perivascular infiltrate of lymphoid cells in CNS lymphoid (H&E stain).

Moderate-to-severe cervical dysplasia and carcinoma in situ are CDC category B conditions; invasive cervical cancer is a category C AIDS indicator conditionJ 6 Cervical dysplasia and carcinoma, especially when related to human papilloma virus (HPV) infection, occur

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at higher rates in women who have sex at an early age or with multiple partners. The disease course is accelerated in women with AIDS. Expression of HPV and the development of cervical dysplasia or carcinoma in situ is correlated with decreased CD4 count in both HIVseronegative and HIV-seropositive women. 17,18HPV 16 and 18 are the types most often present in cervical carcinomas, but types 31, 33, 35, 39, 45, 51, and 52 are also associated with carcinoma. 1~ Cervical intraepithelial neoplasia and invasive carcinoma are cytologically and histologically identical to that found in the general population. Anal Carcinoma

HPV also plays a role in the pathogenesis of anal condylomas and carcinoma. 2° HPV 6 and 11 are the most common types in condylomas. Anal condylomas and intraepithelial neoplasia occur more frequently in men and women who practice receptive anal intercourse. Although rates of dysplasia and carcinoma are increased in HIV-infected individuals with low CD4 counts, they are not CDC indicator conditions. The increased prevalence of anal squamous intraepithelial lesions among immunodeficient H1V-seropositive men may be the result ofa nonspecifie increase in productive HIV infection or HIV-induced immune alterations of HIV-related neoplasia. 21 These lesions appear as white-to-pink tumors, are slightly elevated-to-exophytic, and are on the external anus or within the anal canal. Anal-intraepithelial neoplasia occurs more frequently in slightly raised lesions than in papillary lesions. 22Like cervical carcinoma, anal carcinoma tends to arise in the transformation zone between squamous and columnar epithelium. Cytology may be a useful screening tool, but it may not be adequate for detecting anal-intraepithelial neoplasia9 Abnormal anal cytology should prompt anoscopic examination and biopsy of acetowhite areas.

proliferation of lymphocytes and salivary gland tissue within intraparotid lymph nodes (Fig 4A). 25 There are numerous dendritic cells and CD8 lymphocytes. The dendritic cells express HIV-1 major-core protein and HIV-1 RNA, indicating active replication of the virus. The presence of active HIV-1 replication suggests that HIV- 1 primarily induces the pathogenesis of the lymphoepithelial lesion.26 In patients with HIV infection who have characteristic radiographic findings, one can make the diagnosis of lymphoepithelial cyst by fine-needle aspiration-cytology. Computerized tomography shows multiple homogeneous cystic masses with peripheral enhancement. Often ce1~ical lymphadenopathy is also visible. Cytological preparations contain lymphocytes and benign epithelial ceils. The radiographic and cytological features of malignant tumors of the parotid gland (ie, KS and malignant lymphoma) are sufficiently distinctive that biopsy is

Reactive Processes

Lymphoepithelial Lesion The cystic lymphoepithelial lesion of salivary glands occurs in the absence of H1V infection,24 although less frequently. It occurs early in the course of the disease and is usually associated with cervical or generalized lymphadenopathy.25 Bilateral parotid involvement is more common than unilateral. This condition is benign; however, malignant transformation can occur, especially in patients with low CD4 counts. The lymphoepithelial cyst is the end product of

Figure 4. (A) Lymphoepithelial lesion of the parotid gland (H&E stain, 30x). (B) Lymphoepithelial cyst with simple cuboidal lining overlying lymphoid tissue (H&E stain, 150x).

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often not necessary.27 Histology- shows cysts lined by cuboidal and squamous epithelium surrounded by lymphoid tissue with germinal centers (Fig 4B).

Lymphadenopathy Lymphadenopathy is one of the earliest manifestations of H1V infection. Persistent generalized lymphadenopathy is a CDC categoryA indicator condition. ~6The clinical definition is palpable lymphadenopathy with lymph nodes greater than 1 cm in more than two extrainguinal sites for a duration longer than 3 months. Histologically, the features fall into three stages: follicular hyperplasia, follicular involution, and l?~'nphocyte depletion. %,29The histological patterns correlate to a certain extent with the clinical and immunologic status of the patient. None of the histological findings are specific for H1V infection,a° Follicular hyperplasia occurs early. There are large geographic follicles, follicle lysis, paracortical hyperplasia, focal hemorrhage, and preservation of tingible body macrophages. The mantle zone lymphocytes invade follicles or are moderately to markedly decreased. Monocytoid B lymphocyte hyperplasia and Warthin-Finkeldey-like multinucleated giant cells may be present. B lymphocytes and a small number of mature T lymphocytes comprise the germinal centers. Proliferation and activation orB lymphocytes correlate with hypergammaglobulinemia.3I During follicle lysis, there is a reduction in the number of CD4 lymphocytes and a relative increase in CD8 lymphocytes. During follicular involution, there is diffuse lymphoid hyperplasia and loss of germinal centers. The mantle zone becomes thin, and there is intrafollicular plasmacytosis and erythrophagocytosis. Often, there is vascular proliferation, suggesting Castleman's disease or KS. Fibrosis of capsule or subcapsular sinus begins. Lymph nodes in the lymphocyte depletion or atrophic stage are small and not often biopsied. Follicles are absent, and lyrnphocytes are depleted. Fibrosis becomes more marked. At this stage, patients are generally more immunodeficient; therefore, it is important to examine these lymph nodes for the presence of opportunistic infections and KS. In all stages, immunohistochemical staining shows HIV antigens in germinal centers, in follicular dendritic reticulum cells, in endothelial ceils of paracortical venules, and in sinus macrophages 32 (Fig 5).

Lymphocytic InterstitialPneumonitis Lymphocytic interstitial pneumonitis (LIP) is almost exclusively a pediatric condition and a CDC category B indicator condition in children younger than age 13.33

Figure 5, Lymph node showing positive immunohistochemical staining for H~V-1 p24. antigen in a germinal center (300×),

Patients present with fever, cough, dyspnea, and bilateral diffuse reticulonodular or nodular infiltrates that may be more predominant in the lower lobes. EBV DNA is present in 80% of lung biopsy specimens. 34 Increased levels of anti-EBV IgG-secreting cells and CD8 lymphocytes are present in the infiltrate. Bronchoscopic biopsy is the most useful method for diagnosing LIP.35 Lymphocytes, plasma cells (some of which contain Russell bodies), plasmacytoid lymphocytes, and immunoblasts diffusely infiltrate the alveolar septa and peribronchial and perivascular tissue. Although there is no vasculitis or granulomas, there may be granuloma-like collections of pale mononuclear cells or focal nodular aggregates of lymphoid cells with germinal center formation. The lymphocytes may be atypical and invasive of bronchioles. The differential diagnosis includes malignant lymphoma and infection. Patients with LIP may have similar benign lymphoid infiltrates in kidney, liver, nasopharynx, or bone marrow.36

Encephalopathy AIDS dementia complex is directly caused by infection of the brain by H1V. It becomes a CDC category C AIDS indicator condition after 1 month's duration. 1G There are two histological patterns: leukoencephalopathy and encephalitis.37 H1V leukoencephalopathy is diffuse, noninflammatory, and degenerative. HIV encephalitis is multifocal and inflammatory. H1V leukoencephalopathy manifests itself early in the course of H IV infection before severe immunodeficiency. HIV encephalitis appears at more advanced stages of AIDS.

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Both HIV encephalitis and H1V leukoencephalopathy are characterized histologicallyby the presence of multinucleated giant cells and involve the cortex and white matter. In HIV encephalitis, there are microglial nodules composed of tight aggregates of microglia, astrocytes, and macrophages. Characteristic multinucleated giant cells and demyelination are present in only 50% of brain biopsies from patients with AIDS-related dementiaY, s9 Measurement of CNS viral burden is a more sensitive and earlier indicator of dementia. The differential diagnosis includes progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy also results in focal neurological deficits and demyelination. Histologically, there are oligodendroglial cells with hyperchromatic, enlarged nuclei and enlarged bizarre astrocytes.

Enteropathy In addition to opportunistic infections of the gastrointestinal tract, patients with H1V infection are prone to developing noninfectious inflammatory conditions. Diarrhea and other gastrointestinal symptoms often occur in the absence of any identifiable pathogen. 4°,41Inflammatory conditions are divided into two categories: those that are H/V-related and those that are unrelated, such as neutropenic enterocolitis and regional enteritis-like enteropathy.42 H/V-related nonhealing ulcers can occur at any site in the gastrointestinal tract, especially the oropharynx, esophagus, and anus. Patients with symptoms of malabsorption show histological abnormalities of the small intestinal mucosa. These abnormalities are believed to be caused by HIV directly and include nonspecific acute or chronic inflammation, apoptosis or maturational defect in enterocytes, and mild villous flattening.4S,44

Nephropathy HIV-associated nephropathy, which is more common in injection drug users, usually presents as a constellation of nephrotic syndrome, focal segmental glomerulosclerosis, and rapidly progressive renal failure.45 Patients with AIDS may also develop various types of immune complex glomerulonephropathy and renal lesions related to infection of the kidney by HIV, tumor invasion, nephrocalcinosis, and fluid and electrolyte disturbances. The histological pattern of HIV-associated nephropathy is focal and segmental glomerulosclerosis.46 There may be distinctive global collapse of the glomerular tuft (Fig 6). There is tubular dilatation with hyaline casts progressing to tubular atrophy and interstitial fibrosis.

Figure 6. Kidney section showing global collapse of the glomerular tuft (H&E stain, 300x).

In some cases, there is a nonspecific interstitial infiltrate oflymphocytes and plasma cells. There are no characteristic vascular lesions. On electron microscopy, there is wrinkling and thickening of glomerular basement membrane, and tubuloreticular inclusions may be present within endothelial cells.

Hepatic Conditions Patients with HIV are prone to hepatic abnormalities caused by antiretroviral therapy, HIV infection, and opportunistic infections. 47Hepatomegaly, steatosis, hepatitis, and hyperbilirubinemia are rare side effects of zidovudine (AZT) treatment. 4a,49Patients with late stage AIDS and wasting syndrome, which is a CDC category C AIDS indicator condition,16 may have marked hepatic steatosis. Sclerosing cholangitis should be considered in the differential diagnosis of an HIV-positive patient with jaundice. The cause is unknown, but possible agents include cytomegalovirus, Crvptosporidiumparvum,and other opportunistic pathogens, imaging studies of the biliary system are often helpful.5°

Dermatologic Conditions During acute HIV infection, patients may develop an urticarial exanthem characterized by a perivascular lymphocytic infiltrate with no epidermal change, spongiosis, vacuolar alteration, or epidermal necrosis. 51,52 Patients with HIV infection may develop a severe pruritus that has been called AIDS-related dermatitis or papular eruption. 5~ It has features similar to atopic dermatitis and other psoriasiform disorders. The excoriations caused by scratching may become secondarily infected. Patients with HIV are also at increased risk of

Pathology of HIV Infections developing other i m m u n e - m e d i a t e d a n d noninfectious dermatologic conditions. T h e most c o m m o n are xerosis, pruritus, psoriasis, seborrheic dermatitis, pruritic papular eruptions, a n d P L E V A (pityriasis lichenoides et varioliformis acuta).54,55 Because of the altered i m m u n e response, c o m m o n c u t a n e o u s eruptions often look dramaticallyworse in i m m u n o c o m p r o m i s e d persons. T h e r e m a y be u n u s u a l histological p a t t e r n s that are difficult to classify.

Anemia Patients with H I V infection are subject to cy-topenia of various etiologies. These include involvement of the b o n e m a r r o w by opportunistic infections or neoplasms a n d effects of antiretroviral therapy. A n e m i a occurs in 70% to 80% of H/V-infected patients. Usually it is n o r m o c h r o m i c normocytic a n e m i a . Infections comm o n l y associated with cytopenia include Mycobacterium avium complex a n d parvovirus B19. a6 H1V plays a direct role in hematosuppression. 57 Bone m a r r o w biopsy features that suggest H1V infection are hypercellularity, increased megakatTocytes , morphologically altered megakaryocytes, increased reticulin, mild plasmacytosis, a n d reactive lymphoid aggregates (Fig 7).5a Conclusions Diagnostic a n a t o m i c pathologists should be familiar with the histology" of the noninfectious conditions to which patients with H I V infection are susceptible. C o m pared with persons without HITV infection, they have increased susceptibility to c e r t a i n m a l i g n a n t n e o p l a s m s a n d reactive processes. T h e y are m o r e likely to have m o r e t h a n one disease in a particular tissue. T h e y can, of course, also develop the s a m e diseases that persons

Figure 7. Bone marrow showing hypercellularity, increased megakaryocytes, mild plasmacytosis, and reactive lymphoid aggregates.

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without H I V infection get. Alterations in the i m m u n e response a n d direct effects of H1V infection m a y result in u n u s u a l histological presentations. References 1. OrensteinJM, Alkan S, Blauvelt A, et al: Visualization of human herpesvirus t3qpe 8 in Kaposi's sarcoma by light and transmission electron microscopy.AIDS 1997;1l:F35-F45 2. Maiorana A, Luppi M, Barozzi P, et al: Detection of human herpes virus type 8 DNA sequences as avaluahle aid in the differential diagnosis of Kaposi's sarcoma. Mod Pathol 1997;10:182-187 3. Chor PJ, Santa Cruz DJ: Kaposi's sarcoma. A clinicopathologic review-anddifferential diagnosis.J Cutan Pathol 1992;19:6-20 4. Fukunaga M, Silverberg SG: Hyaline globules in Kaposi's sarcoma: A light microscopic and immunohistochemical study. Mod Pathol 1991;4:187-190 5. IGaplanLD: HIV-associatedlymphoma.AIDS Clin Rev 1993-1994; 145-166 6. Knowles DM: Etiology and pathogenesis of AIDS-related ltonHodgkin's lymphoma. Hematol Oncol Clin NAm I996;t0:I08I-1109 7. Rush WL, Andriko J, Przygodzki R, et al: Primary pulmonary anaplastic large cell lymphoma (ALCL):A clinicopathologicstudy of 6 cases. USCAPAnnualMeetingAbstracts 1996;951 (abstr) 8. Dina TS: Primary central nervous system lyTnphoma versus toxoplasmosis in AIDS. Radiology 1991;179:823-828 9. Gerold M, Adler R: Hodgkin's disease as an indicator of AIDS. Med Hypotheses 1995;45:76-82 10. Boyle M-J,Vasak E, Tschuctmigg M, et al: Subtypes of EpsteinBarr virus (EBV') in Hodgkin's disease: Association between B-type EBV and immunocompromise. Blood 1903;81:468-474 11. Karcher DS: Clinically unsuspected Hodgkin disease presenting initially in the bone marrow of patients infected with the human immunodeficiencyvirus. Cancer 1993;71:1235-1238 12. Clark DP, Nelson AM, Frankel SS, et al: Lung carcinomas in HIV-infected patients. Presented at the Third Conference on Retroviruses and Opportunistic Infections, Washington, DC, January 28February 1, 1996;(abstr) 13. Tenholder MF, Jackson HI): Bronchogenic carcinoma in patients seropositivefor human immunodeficiency'Arus.Chest 1993;104: 1049-1053 14. Rosenthal E, GarNer G, Peyrade F, et al: Bronchial carcinoma in 3 HIV-irdected patients. Int ConfAIDS 1992;8:129 15. Thurer RJ, Jacobs JP, Holland FW 2nd, et al: Surgical treatment of lung cancer in patients with human immunodeficiencyvirus. Ann Thorae Surg 1995;60:599-602 16. Centers for Disease Control and Prevention (CDC). 1993 revised classification system for H1V infection and expanded surveillance case definition for AIDS among adolescents and adults. Morb Mortat Wkly Rep 1992;41:i - 19 17. Fuller C, Kissinger P, Abdalian S, et al: Association of rapid CD4 cell loss on expression of human papilloma virus and progression of squamous intraepithelial lesions among H1V-irdected adolescent women. HIV Infect Women Corff 1995;$59 18. Gemignani M, X~aimanM, Fruchter RG, et al: CD4 lymphocytes in women with invasive and preinvasive cervical neoplasia. Gynecol Oneol 1995;59:364-369 19. Howley PM: Papillomavirinae: The viruses and their replication, in Fields BN, Knipe DM, HowleyPM, et al (eds). Virology,3rd ed. Philadelphia, PA, Lippincott-Raven, I996, pp 2045-2076 20. Palefsky JM: Anal human papillomavirus infection and anal

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