Douglas S. Harrington

Malignant lymphoma in the X-linked lymphoproliferative syndrome†

Male patients with the X‐linked lymphoproliferative syndrome (XLP) have an inherited immune deficiency to Epstein‐Barr virus (EBV) infection that results in fatal infectious mononucleosis (IM), acquired hypogammaglobulinemia‐ or agammaglobulinemia, virus‐associated hemophagocytic syndrome, and non‐Hodgkins malignant lymphoma (ML). A clinicopathologic analysis of 17 patients with XLP who developed ML was performed. The median age of the patients at the time of diagnosis was 4.0 years (range, 2–19 years). The median overall survival was 12 months (range, 1–216 months). Eight patients had maternally related male relatives with ML. Other phenotypes of XLP were documented in male relatives of the remaining nine patients. Common presenting symptoms were fever, nausea, vomiting, and abdominal pain. Nine patients had “B” symptoms. All ML occurred at extranodal sites. The intestines, most commonly ileocecal, were involved in 76.5% of the cases. Thirteen patients had localized disease (Stages I and II) and four patients had advanced disease (Stages III and IV). A diffuse histologic pattern of growth was observed in all cases. The distribution of histologic subtypes included small noncleaved (41.2%), large noncleaved (17.6%), immunoblastic (17.6%), small cleaved or mixed cell (11.8%), and unclassifiable (5.9%) ML. Surgical resection, radiation therapy, and chemotherapy resulted in disease‐free survivals of up to 192 months in eight patients (median 114 months; range, 12–192 months). Eight of 17 patients (47%) are still alive. A median survival of only 6.0 months (range, 1–12 months) was observed in the nine patients who died. No residual ML was found at autopsy. The small noncleaved subtype had an adverse prognosis (seven of nine deaths versus one of eight survivors; P < 0.05). Bacterial infection was the major cause of death (seven of nine patients). Characteristics that distinguish ML in XLP from other ML include a maternal family history of XLP, early age of onset, acquired hypogammaglobulinemia, post‐EBV infection, and ileocecal involvement.

Interstitial Cystitis: Bladder Mucosa Lymphocyte Immunophenotyping and Peripheral Blood Flow Cytometry Analysis

Interstitial cystitis is a chronic bladder disorder of unknown etiology that primarily afflicts women and is characterized by urgency and pain. Although immune mechanisms have been implicated in the disease process, little is known about the local or peripheral blood immune responses. Cryostat sections of snap-frozen bladder biopsies obtained by transurethral resection from 43 patients (24 with classical and 9 with nonulcerative or early interstitial cystitis, and 10 controls) were analyzed using a panel of monoclonal antibodies with an avidin-biotin immunoperoxidase technique to characterize the local immune response of bladder mucosa. Simultaneously obtained heparinized peripheral blood (10 cc) was analyzed by flow cytometry in 24 patients (9 with classical and 5 with nonulcerative early interstitial cystitis, and 10 controls) using the same panel of antibodies. The control group biopsies (median age 44 years, range 27 to 52 years) had no ulcers, few lymphoid cells (predominately T-helper cells), rare T cell nodules and no B cells. The nonulcer group (median age 39 years, range 29 to 44 years) had rare mucosal ruptures but no ulcers, slightly increased lymphoid cells (predominately T-helper), occasional T cell aggregates, no B cell nodules and rare plasma cells. No statistically significant difference between control and nonulcerative interstitial cystitis patients was identified. In contrast, the classical interstitial cystitis group (median age 68 years, range 47 to 73 years) had ulcers, intense inflammation with focal sheets of plasma cells, aggregates of T cells, B cell nodules including germinal centers, a decreased or normal helper-to-suppressor cell ratio and suppressor cytotoxic cells in germinal centers. Flow cytometry analysis of peripheral blood lymphocyte subsets showed normal patterns in controls, increased numbers of secretory Ig positive B cells and activated lymphocytes in the nonulcerative group, and increased numbers of secretory Ig positive B cells with mildly abnormal kappa-to-lambda ratios and activated lymphocytes in the classical group. We conclude that an immune mechanism has at least a partial role in the pathophysiology of interstitial cystitis. A parallel between interstitial cystitis and inflammatory bowel disease is evident. Further studies are indicated.

Lymphomatoid papulosis and progression to T cell lymphoma: an immunophenotypic and genotypic analysis

A 37-year-old white man had untreated lymphomatoid papulosis for 12 years before a submandibular T cell immunoblastic lymphoma developed. A genetic abnormality, composed of extra chromosomal material attached to the short arm of chromosome 9, was detected in the lymphoma tissue but not in the skin. The lymphomatoid papulosis skin lesions did not manifest clonal T cell receptor gene rearrangements, but the submandibular lymphoma tissue was clonal and of T cell lineage. The patients lymphoma responded well to combination chemotherapy, but the lymphomatoid papulosis remains active.

Malignant lymphoma in Nebraska and Guangzhou, China: A comparative study

Two hundred thirty-four consecutive cases of malignant lymphoma (192 non-Hodgkins lymphomas and 42 Hodgkins disease) from Guangzhou, China, and 589 cases (498 non-Hodgkins lymphomas and 91 Hodgkins disease) from the University of Nebraska Lymphoma Registry were examined in a retrospective histopathologic analysis and the results compared to those of the National Cancer Institute (NCI) Working Formulation Summary. Aggressive non-Hodgkins lymphoma was excessive in Guangzhou (82.3 per cent; P less than 0.001) and Nebraska (80.3 per cent; P less than 0.001) when compared with the NCI data (54.2 per cent). The small noncleaved cell, lymphoblastic, and diffuse mixed-cell subtypes were more frequent in China (15.6 per cent each; P less than 0.001), whereas the small lymphocytic, follicular large cell, and immunoblastic subtypes predominated in Nebraska (8 per cent, 8.4 per cent, and 21.8 per cent, respectively; P less than 0.001). The overall median age of onset for non-Hodgkins lymphoma was 42.0 years in Guangzhou and 63.5 years in Nebraska. Hodgkins disease represented 18 per cent of the malignant lymphomas in Guangzhou and 15 per cent in Nebraska. The mixed-cellularity type was most common in Guangzhou (52 per cent; P less than 0.001) and the nodular-sclerosing type in Nebraska (56 per cent; P less than 0.010). The low median age and excess of certain aggressive subtypes of non-Hodgkins disease in Guangzhou suggest a possible viral etiology, whereas the excess of certain subtypes of non-Hodgkins lymphoma in Nebraska may be related to intense agricultural activity.

Immunophenotypic and genotypic characterization of lymphomatoid papulosis

BACKGROUND Lymphomatoid papulosis (LyP) is a chronic dermatosis that histologically resembles malignant lymphoma. Thus far, only a few cases of LyP have been characterized in detail with regard to immunophenotype, genotype, and karyotype. OBJECTIVE Our purpose was to study seven patients with LyP and compare the results to those reported in the literature. METHODS Skin biopsy specimens were analyzed by frozen section immunohistochemical and molecular biologic techniques. Cytogenetic analysis was also performed in three cases. RESULTS The atypical lymphoid cells consisted of activated helper T cells; four of the seven patients had lesions with a detectable clonal T-cell population. A peripheral T-cell lymphoma developed in one patient before the emergence of a genotypically different LyP T-cell clone. Cytogenetic studies were abnormal in one case of LyP and normal in another, whereas the karyotype of the lymphoma was abnormal. CONCLUSION LyP is a preneoplastic proliferation of activated helper T cells, which is often clonal and may regress and expand with the development of new LyP clones or lymphoma.