James A. Strauchen

Body Cavity-Based Malignant Lymphoma Containing Kaposi Sarcoma-Associated Herpesvirus in an HIV-Negative Man with Previous Kaposi Sarcoma

Kaposi sarcoma-associated herpesvirus is a newly identified herpesvirus found in almost all cases of Kaposi sarcoma that are associated with the acquired immunodeficiency syndrome (AIDS). It is also found in classic Kaposi sarcoma, post-transplantation Kaposi sarcoma, and Kaposi sarcoma that occurs in areas endemic for the disease [1-8]. Kaposi sarcoma-associated herpesvirus has also been found in a small subset of AIDS-related lymphomas that are positive for the Epstein-Barr virus (EBV); these lymphomas are called body cavity-based lymphomas because they predominantly manifest as malignant effusions [9]. Recently, a body cavity-based lymphoma containing Kaposi sarcoma-associated herpesvirus was reported in a patient who was negative for the human immunodeficiency virus (HIV) and had no history of Kaposi sarcoma [10]. We describe an elderly, HIV-negative patient with a history of classic Kaposi sarcoma who developed a body cavity-based lymphoma that was shown to contain Kaposi sarcoma-associated herpesvirus. In contrast to what is usually seen with AIDS-related body cavity-based lymphomas, EBV infection was absent. Epidemiologic studies have suggested that Kaposi sarcoma is associated with the development of secondary lymphoproliferative disorders [11, 12]. The case we describe supports the premise that Kaposi sarcoma-associated herpesvirus has a role in the oncogenic transformation of EBV-negative lymphoid neoplasms. Further, the development of a malignant lymphoma positive for Kaposi sarcoma-associated herpesvirus in an HIV-negative patient suggests that this herpesvirus has an etiologic role in the development of secondary neoplasms in association with Kaposi sarcoma. Case Report A 94-year-old man was admitted to the Mount Sinai Hospital, New York, New York, for management of massive ascites. The patients medical history included resection of a stage II adenocarcinoma of the colon in 1981. Kaposi sarcoma of the right foot had been diagnosed in 1988 and treated with surgical excision. The patient denied having any risk factors for HIV infection, and he had not received any transfusions; the results of serum enzyme-linked immunosorbent assay (ELISA) for antibodies to HIV were negative. The Kaposi sarcoma did not recur. In 1989, the patient presented with pericardial tamponade. The results of pericardiocentesis were not diagnostic. A large left pleural effusion developed, and thoracentesis yielded bloody fluid that contained malignant lymphoma cells. Immunophenotypic studies done by flow cytometry showed a monoclonal B-cell phenotype (CD19-positive, CD20-positive, light chain). Computed tomography of the chest, abdomen, and pelvis showed no lymphadenopathy or masses, and the effusion was drained. The patient did well without receiving specific therapy until 1992, when the left pleural effusion recurred and responded to pleural drainage. Ten days before the patients final hospitalization in 1995, abdominal distention was noted and examination showed massive ascites. Ultrasonography and computed tomography of the abdomen confirmed the presence of massive ascites without intra-abdominal lymphadenopathy or masses. Chest radiography showed a small left pleural effusion. Abdominal paracentesis was done on admission to the hospital and yielded more than 1 L of fluid that contained malignant lymphoma cells (Figure 1). Fever and abdominal tenderness developed, exploratory laparotomy was done, and an ileal perforation was repaired. The patients postoperative course was characterized by recurrent fever, intra-abdominal abscess, respiratory failure, and seizures. Peripheral blood T-cell subsets showed marked decreases in the ratio of CD4 cells to CD8 cells (0.1) and in the absolute CD4 cell count (60 cells/mm3). The results of serum ELISA for antibodies to HIV and of polymerase chain reaction (PCR) for HIV RNA were negative. The patient died on the 70th day of hospitalization. Autopsy showed scattered foci of malignant lymphoma that involved the pleura, pericardium, and peritoneum. No recurrent Kaposi sarcoma was found. Figure 1. Cytospin preparation of ascitic fluid cells treated with Papanicolaou stain. Methods Cells from ascitic fluid were pelleted by centrifugation and stored frozen at 80C. Genomic DNA from cryopreserved cells was obtained by digestion with proteinase K, extraction with phenol-chloroform, and precipitation with ethanol [13]. Immunophenotypic studies were done on deparaffinized sections of pelleted ascitic fluid and on autopsy tissue by using the avidin-biotin immunoperoxidase technique [14]. The antibodies used were obtained from DAKO (Carpinteria, California) (CD45 [LCA], CD20 [L26], epithelial membrane antigen, HLA-DR, CD68 [KP-1], CD30 [KI-1], CD45RO [UCHL1], and light chains) and Becton-Dickinson (Mountain View, California) (anticytokeratin [CAM 5.2]). We did PCR amplifications on genomic DNA extracted from ascitic cells. To detect Kaposi sarcoma-associated herpesvirus, we used the primer set for KS330233, as described by Chang and colleagues [1]. The primers for EBV targeted the IR-1 [15] and EBER gene loci [16]. Primers and PCR conditions for cytomegalovirus and human herpesviruses 6 and 7 are described elsewhere [17, 18]. Kaposi sarcoma-associated herpesvirus analysis was done by Southern blot hybridization using the KS631Bam probe [1] on BamHI digests. Immunoglobulin gene rearrangement analysis was done using JH and JK probes on HindIII and EcoRI digests. The genomic organization of c-myc was investigated using an exon 3 probe [19]. Results The lymphoma cells in the ascitic fluid cell block and in the autopsy tissue showed a null cell immunophenotype with loss of B-cell antigens (CD45 focally positive, CD20-negative, CD45RO-negative, CD30-negative, HLA-DR-negative, CD68-negative, epithelial membrane antigen-positive, cytokeratin-negative, and immunoglobulin light chain-negative). The cells from the ascitic fluid were positive for Kaposi sarcoma-associated herpesvirus by PCR. They were negative for several other herpesviruses for which we tested, including EBV, cytomegalovirus, and human herpesviruses 6 and 7. High numbers of copies of Kaposi sarcoma-associated herpesvirus 5DNA sequences were present in the ascitic fluid cells (as determined by Southern blot hybridization) when compared with similar amounts of DNA from the BC-1 cell line, which has approximately 40 to 80 copies of viral genome per cell (Figure 2). The presence of c-myc rearrangement was tested using a probe representative of c-myc exon 3 that is known, on HindIII and EcoRI digestion, to detect most c-myc rearrangements in AIDS-related non-Hodgkin lymphoma [19]. No abnormally migrating band indicative of c-myc rearrangement was seen. Despite the lack of surface lineage markers on the ascitic fluid cells, analysis of the JH and JK loci with HindIII and EcoRI confirmed the presence of a clonal rearrangement showing that the malignant cells were clonal and of B-cell lineage. Figure 2. Southern blot of Kaposi sarcoma-associated herpesvirus in malignant ascitic cells. Discussion Kaposi sarcoma-associated herpesvirus DNA sequences were first detected in patients with Kaposi sarcoma and AIDS [1]. They have subsequently been identified in cases of Kaposi sarcoma not associated with HIV infection [2-8] and in some lymphoproliferative disorders, including AIDS-related body cavity-based lymphoma [9], multicentric Castleman disease in persons with and without HIV infection [20], and a recent case of body cavity-based lymphoma not associated with HIV infection [10]. We describe an HIV-negative patient with a history of classic Kaposi sarcoma who presented with a body cavity-based lymphoma, the cells of which contained many copies of Kaposi sarcoma-associated herpesvirus, as determined by Southern blot hybridization. Body cavity-based lymphoma is a distinct subtype of non-Hodgkin lymphoma that occurs predominantly in association with HIV infection and has distinctive clinical, immunophenotypic, and molecular genetic features [9]. Body cavity-based lymphoma presents predominantly as malignant effusions (liquid lymphomas) in the pleural, pericardial, and peritoneal cavities without significant mass or lymphadenopathy. Most body cavity-based lymphomas do not express surface B-cell antigens, but B-cell lineage is indicated by the presence of clonal immunoglobulin gene rearrangement [9]. For our patient, B-cell surface antigens were detected by flow cytometry on cells from the pleural effusion in 1989, but they were not detected by immunohistochemical tests on cells from ascitic fluid. B-cell lineage of the ascitic fluid cells was confirmed by the presence of clonal rearrangement of the immunoglobulin heavy- and light-chain genes. Our patient was HIV-negative on two serum ELISAs and one PCR analysis. He had no identifiable risk factors for HIV infection. The cause of his CD4 lymphopenia has not been established; his lymphocytes were studied only in the period after his bowel perforation, when the confounding factors of sepsis and stress were present. The indolent clinical course of the lymphoma and the prolonged response to drainage of the effusions without other specific therapy also distinguishes our patients lymphoma from that typically seen in patients with AIDS [9]. The presence of Kaposi sarcoma-associated herpesvirus in body cavity-based lymphoma suggests a possible pathogenic role for the virus in the development of this neoplasm [9]. Kaposi sarcoma-associated herpesvirus shows sequence homology to EBV and herpesvirus samiri, both of which can transform lymphocytes; infection with both of these viruses has also been associated with the development of malignant lymphoma. Kaposi sarcoma-associated herpesvirus in AIDS-related body cavity-based lymphomas has invariably been associated with the presence of EBV [9], which suggests that co-infection with these two viruses has a pathogenic role. In our patient and in the only previously repor

Posttransplantation plasmacytic proliferations related to Kaposi's sarcoma-associated herpesvirus

Kaposis sarcoma-associated herpesvirus (KSHV), which was originally detected in Kaposis sarcoma, also has been found in primary effusion lymphomas (PELs) and some cases of multicentric Castlemans disease. We describe two transplant recipients who developed Kaposis sarcoma and a spectrum of non-neoplastic lymphoproliferative disorders that show pronounced plasmacytic and plasmacytoid features. The first patient had recurrent pleural effusions and Castlemans disease-like changes in lymph nodes. The second patient had systemic lymphadenopathy and hepatosplenomegaly secondary to diffuse infiltration by polyclonal plasma cells and plasmacytoid B lymphocytes that clinically mimicked Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease. In both cases, KSHV DNA was detected by polymerase chain reaction and Southern blotting, and KSHV vIL-6 protein expression was identified in affected tissues by immunohistochemical localization. In contrast, no evidence of KSHV coinfection was detected in any of 31 EBV-related posttransplant lymphoproliferative disorders or 112 non-PEL lymphomas tested. The pathologic findings in these two patients were not representative of malignancy by morphologic, immunophenotypic, or molecular criteria. This study underscores the marked propensity for hematolymphoid proliferations associated with KSHV infections to show plasmacytic features. Additionally, this study describes use of an antibody reactive against KSHV vIL-6 that can readily detect a subpopulation of KSHV-infected hematopoietic cells.

Ten-year experience with primary ocular reticulum cell sarcoma (large cell non-Hodgkin's lymphoma)

Fourteen patients with intraocular reticulum cell sarcoma (non-Hodgkins large cell lymphoma) ranging in age from 27 to 77 are presented. All patients had evidence of vitritis with 50% showing intraretinal and/or subretinal lesions and 21% having anterior uveitis. Five of the patients developed central nervous system lesions and subsequently died. Primary radiation therapy to the eyes and CNS appears to prevent spread of the disease and improve longevity. Chemotherapy improved survival in one patient with CNS spread of disease.

Chemotherapy in the management of intraocular lymphoma.

Six patients with intraocular (vitreous) lymphomas were treated with high‐dose intravenous cytosine arabinoside (Ara‐C). Four patients were previously untreated, one patient had previously received ocular and central nervous system radiation therapy and relapsed, and one patient had previously received chemotherapy for systemic lymphoma. Five responses were observed: one complete and four partial. High‐dose Ara‐C is active in intraocular (vitreous) lymphoma, but complete response is uncommon. Adjunctive use of Ara‐C in combination with ocular irradiation may be a useful form of therapy in this uncommon lymphoma.

Hodgkin's disease in AIDS complex patients: Report of four cases and tissue immunologic marker studies

Hodgkins disease developed in four homosexual men with prodromal manifestations associated with the Acquired Immune Deficiency Syndrome (AIDS) (generalized lymphadenopathy in three and persistent diarrhea, fever, and weight loss in one). All had inversion of the peripheral blood helper‐to‐suppressor T‐cell ratio. The presentations with Hodgkins disease were atypical with advanced disease (Stage IIIB or IV) in three of four patients and marrow involvement at diagnosis in two. Response to therapy was poor. Immunopathologic studies on the Hodgkins disease tissue were performed in two patients. In contrast to Hodgkins disease in non‐AIDS risk patients, the Hodgkins disease tissue in these patients demonstrated severe depletion of helper T‐lymphocytes with a predominance of suppressor cells (tissue helper‐to‐suppressor cell ratio of 0.19 and 0.33, respectively, on immunoperoxidase‐stained preparations). In contrast, in five cases of Hodgkins disease from non‐AIDS risk individuals, the lymphocytes population consisted predominantly of helper T‐lymphocytes (median tissue helper‐to‐suppressor cell ratio 3.15, range 2.12–7.77). Homosexual men with AIDS risk factors are at risk for the development of Hodgkins disease. Hodgkins disease in these patients may be atypical with severe depletion of helper T‐lymphocytes and a predominance of suppressor cells. The lack of an appropriate T‐cell immunologic response may contribute to the poor prognosis observed in these patients.

Laparoscopic Antrectomy for the Treatment of Type I Gastric Carcinoid Tumors

BACKGROUNDnWhile the optimal treatment for type I gastric carcinoid tumors remains controversial, there is evidence to suggest that in multifocal disease, antrectomy may not only control local disease but also may lead to enterochromaffin-like cell (ECL) hyperplasia regression compared to medical and endoscopic treatments.nnnMATERIALS AND METHODSnA single institution retrospective review of eight consecutive patients with multifocal type I gastric carcinoid tumor patients with no evidence of metastatic disease was performed from 2005 to 2006. All of these patients underwent laparoscopic antrectomy with Billroth II reconstruction. Patients preoperative gastrin, chromogranin A levels, and biopsy and surgical specimen slides were compared with postoperative laboratory and biopsy slides. Pathology slides were reanalyzed by a blinded pathologist from our institution for evidence of tumor and ECL hyperplasia regression.nnnRESULTSnAll patients tolerated the procedure well with no reoperations or mortalities. Six of eight patient complained of mild reflux which was treated medically. One of eight had a mild wound infection which resolved with a course of cephalexin. Gastrin levels significantly decreased (98.9%) in all patients (P = 0.001). Furthermore, chromogranin A levels also significantly decreased (81.4%). Eight of eight patients showed no evidence of carcinoid tumor after surgery at mean biopsy follow-up of 17 mo (range 2-35 mo), however there was ECL hyperplasia after resection. Four of eight patients (50%) showed regression of ECL hyperplasia on postop biopsy, while the remaining four of eight showed no evidence of regression.nnnCONCLUSIONSnThis is the largest case series to investigate the surgical, clinical, and histologic outcomes of laparoscopic antrectomy in type I gastric carcinoid. Our data suggest that laparoscopic antrectomy is a safe and minimally invasive approach to treat nonmetastatic type I gastric carcinoid. All patients had no evidence of gross or microscopic disease at follow-up biopsy and almost half had regression of ECL hyperplasia at follow-up suggesting that antrectomy may be sufficient to prevent tumor recurrence. However, continued regular endoscopic surveillance and medical follow-up of patients with ECL hyperplasia are recommended.

Primary intracerebral Rosai-Dorfman disease : a case report

A 45-year-old woman presented with an isolated, contrast-enhancing brain lesion in white matter of the right frontal lobe, preoperatively thought to be either a primary brain neoplasm or metastasis. The lesion was demonstrated by histology and immunohistochemistry to be Rosai–Dorfman disease. Central nervous system (CNS) manifestations of this disease are rare. There have been 27 cases of intracranial involvement reported previously. All of them have been dural-based, where the disease clinically and radiologically resembles meningioma. To our knowledge, this is the first case of an isolated intraparenchymal CNS lesion without dural attachment, where the clinical and radiological features resembled an intraparenchymal glial neoplasm, lymphoma or metastatic tumor.

Spindle cell reaction to nontuberculous mycobacteriosis in AIDS mimicking a spindle cell neoplasm. Evidence for dual histiocytic and fibroblast-like characteristics of spindle cells.

We report 5 patients with AIDS who had an unusual spindle cell proliferation in the lymph nodes and skin caused by nontuberculous mycobacteriosis. The spindle cell proliferation in these tissues may mimic a spindle cell neoplasm and pose a diagnostic problem if an infectious aetiology is not suspected. The fibroblast-like spindle cells contained numerous acid fast bacilli. They were strongly positive for antibody markers of monocyte/macrophage and leukocyte derivation: Leu M3, Mo-9, T-200, and HLA-DR, and variably positive for alpha-1 anti-chymotrypsin and lysozyme. Ultrastructurally these spindle cells were predominantly fibroblast-like with poorly developed features of macrophages. These results reveal the dual macrophage and fibroblastic character of the spindle cells and probably imply a functional differentiation rather than a histogenetic one.

Hodgkin disease in patients 60 years of age or older. Histologic and clinical features of advanced‐stage disease

Background. This article reviews the salient pathologic and clinical features of 171 patients with Stage III‐IV disease who were 60 years of age or older who were treated on four Hodgkin disease (HD) protocols from 1969 to 1988.

The changing face of post-transplant lymphoproliferative disease in the era of molecular EBV monitoring.

Kerkar N, Morotti RA, Madan RP, Shneider B, Herold BC, Dugan C, Miloh T, Karabicak I, Strauchen JA, Emre S. The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring.u2028Pediatr Transplantation 2010: 14:504–511.