Madeleine D. Kraus

Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease

PURPOSE The patterns of presentation, histologic pattern (nodular or diffuse), treatment, and long-term outcome were studied in patients with lymphocyte-predominant (LP) Hodgkins disease (HD) to determine whether these patients should be treated differently than patients with other subtypes of HD. PATIENTS AND METHODS Pathology was reviewed for 97 patients with an initial diagnosis of LPHD made between 1970 and 1993. Seventy-five patients had LPHD on review: 55 had nodular LPHD, 14 had diffuse LPHD, and six had LP histology without subclassification. There were 60 males (80%) and 15 females (20%). Sixty-six patients (88%), presented with clinical stage (CS) I or II disease. Seventy-one patients were treated at the Joint Center for Radiation Therapy (JCRT) and were considered for analysis of treatment outcome. Sixty-one of these 71 were treated with radiation (RT) alone; 17 received mantle RT alone, 27 mantle and paraaortic RT, and seven total-nodal irradiation (TNI). Ten patients with subdiaphragmatic HD received pelvic and paraaortic RT. Of the 10 remaining patients, four were treated with RT and chemotherapy (CT) and six were treated with CT alone. The median follow-up time was 10.8 years. RESULTS The 10-year actuarial freedom-from-first-relapse (FFR) and 10-year overall survival rates for the 71 patients with LPHD treated at the JCRT were 80% and 93%, respectively. The 10-year actuarial FFR by nodular (n = 51), diffuse (n = 14), and unspecified (n = 6) histologic pattern was 74%, 100%, and 60%, respectively. Overall, 14 of 71 patients have relapsed: nine of 61 with stage IA, IB, or IIA disease and five of 10 with stage IIB to IVB disease have relapsed. The median time to relapse was 53 months. Nine of 71 patients have died. Only one death has been from HD: five patients died of second cancers, two of cardiac disease, and one of alcoholic liver cirrhosis. Of seven patients with second malignancies, five died. None of the second malignancies were non-Hodgkins lymphoma (NHL). CONCLUSION Patients with LPHD have different patterns of presentation, sex and age distribution, and likelihood of occult abdominal disease than patients with nodular-sclerosing (NS) or mixed-cellularity (MC) disease. The median time to relapse for LP patients was later than reported for other histologic subtypes; however, there was no pattern of continuous late relapse. With pathologic staging and standard treatment, mortality from LPHD is low; nearly all deaths have been cardiac- or second tumor-related. This suggests that less aggressive treatment for LPHD might continue to yield excellent results, while perhaps lowering the long-term risk of complications.

The spleen as a diagnostic specimen

Few studies have examined the yield of the diagnostic splenectomy, and the relevance of these studies to the management of patients with unexplained splenomegaly or a splenic mass are limited by low number of cases, the use of selection criteria, and the lack of modern terminology and modern ancillary studies. The current study correlates clinical intent with preoperative clinical and radiologic studies and histologic findings in an assessment of the diagnostic yield of splenectomy.

Posttransplant Lymphoproliferative Disease in Children: Correlation of Histology to Clinical Behavior

Purpose To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. Patients and Methods We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. Results Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. Conclusions We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.

The spleen in the Wiskott-Aldrich syndrome : Histopathologic abnormalities of the white pulp correlate with the clinical phenotype of the disease

The Wiskott-Aldrich syndrome (WAS) is a X-linked hematologic disorder characterized by thrombocytopenia, eczema, and immunodeficiency of variable severity. Reported here are the results of a morphologic, morphometric, and immunophenotypic analysis of splenic lymphoid tissue in 12 WAS patients with documented molecular defect and with different disease severity. Spleens from 29 age-matched patients with different diseases were used as controls. Paraffin-embedded tissue (from all cases) and fresh-frozen samples (from 5 WAS patients and 4 control subjects) were used to study the different white pulp compartments by classic morphologic, immunophenotyping, and image analysis techniques. Data were statistically analyzed by both parametric and nonparametric tests. Spleens from WAS patients showed a significant depletion of the total white pulp (p = 0.0008), T cell (p < 0.05), and B cell (p = 0.0002) areas and marginal zone (MZ) thickness (p < 0.0001). Among WAS patients, a negative correlation was found between the score of severity of the disease and all variables considered (Spearmans rank correlation coefficient, r = -0.79, r = -0.73, r = -0.68, and r = -0.56, respectively). In conclusion, this study shows that in WAS a general depletion of the splenic white pulp occurs, supporting the evidence that WAS is characterized by a combined immune defect. The significant reduction of the MZ may explain the inability of WAS patients to mount a response to T-independent antigens.

Splenic pathology in myelodysplasia : A report of 13 cases with clinical correlation

Splenomegaly is uncommon in myelodysplasia (MDS) and, although cytopenias may be severe, therapeutic splenectomy is rarely performed. We report the histologic, histochemical, and immunophenotypic findings of nine cases of surgical splenectomy and four postmortem spleens from MDS patients. Four histologic patterns were identified: one dominated by erythrophagocytosis, one characterized by red pulp plasmacytosis, one with extramedullary hematopoiesis as the only salient finding, and one with marked red pulp expansion caused by a monocytic proliferation. Wright-Giemsa and histochemical stains were performed on touch preparations in three cases and played a critical role in the precise subclassification of one MDS patients hematologic disorder, which ultimately proved to be chronic myelomonocytic leukemia. Splenectomy led to sustained improvement of cytopenias in three cases, but did not eliminate transfusion dependence for the remaining patients. Three splenectomy cases exhibited clustered Leder-negative mononuclear elements: two of these patients experienced disease progression to refractory anemia with excess blasts in transformation or acute myelogenous leukemia during post-splenectomy follow-up, whereas none of the three splenectomy patients without clustered mononuclear elements did. We conclude that splenomegaly in MDS usually reflects the sequelae of dyspoiesis rather than evidence of a proliferative phase, that clustering of Leder-negative large cells may correlate with either a substantial monocytic component or, possibly, increased risk of disease progression, and that the spleen can provide diagnostic as well as prognostic information in MDS patients with splenomegaly.

Trisomy 3 in gastric lymphomas of extranodal marginal zone B-cell (mucosa-associated lymphoid tissue) origin demonstrated by FISH in intact paraffin tissue sections

Some reports have indicated that trisomy 3 represents a characteristic chromosomal abnormality found in lymphomas arising in mucosa-associated lymphoid tissues (MALT)/extranodal marginal zone B-cells (MZBC). Traditional cytogenetic analysis of metaphase preparations is cumbersome and not always possible, especially in those situations in which the diagnosis in not suspected before a biopsy. Our aim is to use a relatively simple method to evaluate trisomy 3 in paraffin-embedded, formalin-fixed tissue, using fluorescence in situ hybridization (FISH) on intact tissue sections. Formalin-fixed, paraffin-embedded archival tissues from 30 cases (27 lymphoma and 3 chronic gastritis cases) were hybridized with a chromosome 3 specific alpha-satellite probe (ONCOR, Gaithersburg, MD). Three of four cases of gastric MZBC/MALT lymphoma revealed trisomy 3. Ten cases of lymphoma of possible or probable MZBC origin were examined, and four revealed trisomy 3. Five of 13 non-MZBC lymphomas revealed trisomy 3. None of the chronic gastritis cases nor normal tonsil cases revealed trisomy 3. Our results, using a different methodological approach, confirm the findings of others that trisomy 3 is an abnormality found in a significant proportion of lymphomas of MZBC origin. Our approach also makes possible interphase cytogenetic analysis (by FISH) of routinely processed formalin-fixed, paraffin-embedded tissues, without the need to disaggregate cells. It thus may facilitate genetic analysis on specimens previously deemed unsuitable for such analysis, particularly when tissue quantity is limited.

Cyclin D1 as an aid in the diagnosis of mantle cell lymphoma in skin biopsies: A case report

Mantle cell lymphoma (MCL), an uncommon and aggressive form of non-Hodgkin lymphoma, typically involves lymph nodes. It usually only secondarily involves extranodal sites. We describe an unusual case of a MCL that presented and relapsed in the earlobes. Light microscopic findings were initially regarded as suggestive of small lymphocytic lymphoma, although subsequent analysis of fresh tissue by flow cytometry led to the diagnosis of MCL. Retrospective application of a broad panel of recently developed markers suitable for analysis of routinely processed tissue yielded results that also permitted a diagnosis of MCL. If these results had been available at the time of initial presentation, they would have obviated the need for rebiopsy. Greater awareness not only of the phenotypic criteria by which lymphomas are classified but of the lymphoma markers available for evaluation of routinely processed tissue should facilitate the accurate diagnosis of diseases like MCL and minimize the risk of misdiagnosis as an indolent disorder.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia: one disease or three?

In the 57 years since Jan Waldenström first described the clinical and laboratory manifestations of what we now refer to as Waldenström macroglobulinemia (WM),1 the essential parameters of this syndromic constellation of signs and symptoms have remained fairly constant. In contrast, our understanding of the defining features of the hybrid immunoproliferative/lymphoproliferative disorder that most often causes it (lymphoplasmacytic lymphoma [LPL]) remains less settled. The immunoproliferative qualities of LPL/WM usually include a substantial IgM paraprotein in the blood and at least a minor degree of plasmacytoid differentiation in lesional cells, while the lymphoproliferative qualities are reflected in the predominant lymphoid histologic features, lymphadenopathy, and splenomegaly. In the recently published World Health Organization (WHO) Classification,2 essential features of LPL/WM include elevated monoclonal serum IgM levels in the blood of a patient with a lymphoma composed of small cells and lacking in histologic or immunophenotypic features characteristic of another specific type of lymphoma—in other words, it remains a diagnosis of exclusion. Molecular analysis of lesional cells in LPL/WM documents that most have somatically mutated heavy chain loci.3-6 Although the cells have undergone antigen selection,5,6 they have failed to switch immunoglobulin class, suggesting that an initial transforming event occurred at a late stage of development, while the clone was proliferating in the setting of antigen-driven conditions. Specific hepatitis C virus–derived proteins have been postulated to provide the proliferative stimulus in type II cryoglobulinemia and in cryoglobulinemia-related non-Hodgkin lymphomas, including LPL,5,7 but clearly the precise role of hepatitis C virus in lymphomagenesis is far from clear. Other lines of investigation into the pathogenesis of LPL/WM have identified the t(9;14)(p13;q32) involving the PAX5 and IgH loci as a recurring karyotypic abnormality in up to 50% of the analyzed cases.8,9 This translocation quite likely leads to the deregulated expression of PAX5, a B-cell lineage-specific protein necessary for maturation beyond the pro-B-cell stage of maturation, whose over-expression leads to proliferation of a specific subset of splenic B cells.10 Changes in terminology and multiple meanings for a single term have made it difficult to follow the literature on LPL/WM. In the Kiel Classification,11 the term immunocytoma was applied to lymphomas with plasmacytic differentiation: the lymphoplasmacytoid subtype was distinguished from the lymphoplasmacytic subtype on the basis of its consistent CD5 expression, the presence of proliferation centers, and the tendency to manifest with limited paraproteinemia. According to the Revised European-American classification of lymphoid neoplasms (REAL) criteria, however, this CD5+, CD23+ lymphoplasmacytoid subtype of Lennert would correspond more closely to B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and in most cases would be regarded as B-cell CLL/SLL rather than LPL. Despite this, the Revised European-American classification of lymphoid neoplasms retained the term lymphoplasmacytoid lymphoma,12 a point of confusion until the more recent WHO Classification was published to clarify the point with a change to lymphoplasmacytic lymphoma.2 Lennert and Feller13 initially included but then discarded as “merely confusing” and “superfluous” the original third category of “polymorphic immunocytoma,” a category intended to identify cases with histologic features suggestive of an

Angiomatosis with angiokeratoma-like features in children : A light microscopic and immunophenotypic examination of four cases

We have identified three patients with an initial clinical or biopsy diagnosis of angiokeratoma, all of whom were found to have a more extensive vascular lesion within the surgical excision. A fourth patient with identical histologic findings had no specified clinical diagnosis and his first procedure was excisional. The patients ranged in age from 7 to 16 years, and the lesions were located on the buttock, thigh, calf, and foot. Macroscopic appearances included mildly keratotic pink-red or blue-grey macules (three cases) and pink macules with focal ulceration (one case). In three of the four cases, a shave biopsy diagnosis of angiokeratoma had been made, and the extensive and deeply infiltrative nature of the vascular proliferation was recognized only at subsequent resection, at which point angiomatosis was diagnosed. In the fourth case. excisional biopsy was attempted at presentation, and the superficial morphology was angiokeratoma-like, but the vascular proliferation was present in the deep subcutaneous fat. CD31 and CD34 reactivity was present in the superficial and deep vessels in all cases, and lesional vessels were rimmed by a bland population of smooth muscle actin positive pericytes, findings that differentiate these cases from angiokeratoma, which has previously been reported to be CD34 negative. We conclude that the dilated vascular spaces that typify angiokeratoma may also be seen overlying a deep vasoformative process that is not amenable to resection, and suggest that caution should be exercised in evaluating small biopsies with angiokeratoma-like appearance.

Relationship of Bcl-2 expression with apoptosis and proliferation in colonic graft versus host disease

Graft versus host disease (GVHD) occurs in up to 75% of patients who have had an allogeneic bone marrow transplant (BMT). However, the pathophysiology of this disorder, including the mechanisms responsible for enhanced apoptosis, are poorly understood. Bcl-2 is a cellular protein known to inhibit apoptosis in a variety of human tissues. Therefore, the aim of this study was to evaluate the expression of Bcl-2 in colonic GVHD and to determine its relationship to cell proliferation and apoptosis in this disease. Routinely processed colonic mucosal biopsy specimens from 47 allogeneic BMT patients with diarrhea were evaluated histologically for the grade of GVHD (0-4) and for the degree of apoptosis (apoptosis index). Immunohistochemical staining for Bcl-2 and MIB-1, a cell proliferation marker, was performed, and the results were correlated with the histological findings and with each other. Normal-appearing colonic mucosal biopsy specimens from 10 age-matched patients with noncolonic diarrhea served as controls. Also evaluated were 13 colonic biopsy specimens from 13 patients with chronic ulcerative colitis (three inactive, four mild chronic-active, six moderately severe chronic active) to test the specificity of our findings. When compared with controls, a slight trend toward increased Bcl-2 expression was noted in patients with high-grade GVHD (grade 3 or 4) (P=.09). However, Bcl-2 expression did not correlate with the degree of apoptosis in these patients. In contrast, the degree of Bcl-2 staining correlated positively with the crypt proliferative rate (P=.04). Furthermore, crypt proliferation was significantly higher in the GVHD patients in comparison with controls (MIB-1 index, 27.7+/-17.1 v 15.6+/-11.4, =.02), and increased progressively with each successively higher grade of GVHD, and with the degree of apoptosis. Similar to GVHD, Bcl-2 expression was increased in biopsy specimens of CUC patients with higher grades of active injury and epithelial regeneration. This immunohistochemical study does not provide support for Bcl-2 in the pathogenesis of GVHD-induced apoptosis in the colon, but instead, indicates that this protein may play a nonspecific role in the generalized response to cellular injury in GVHD.