Russell K. Brynes

Human immunodeficiency virus‐related lymphoma. Prognostic factors predictive of survival

In an attempt to determine factors predictive of survival in patients seropositive for human immunodeficiency virus (HIV) with acquired immune deficiency syndrome (AIDS)‐related lymphoma, the authors studied 60 such patients, all of whom were treated with curative intent. Eleven patients presented with lymphoma primary to the brain (P‐CNS); the remaining 49 had systemic AIDS‐related lymphoma. Patients with P‐CNS lymphoma had more severe underlying HIV‐related disease than did patients with systemic lymphoma as evidenced by a higher incidence of AIDS before the diagnosis of lymphoma (73% versus 37%; P = 0.04), and lower median number of CD‐4–positive lymphocytes in peripheral blood at diagnosis of lymphoma (30/dl versus 189/dl; P = 0.005). Median survival of such patients was 2.5 months versus 6.0 months for patients with systemic lymphoma (P = 0.04). Forty patients with systemic AIDS‐related lymphoma have died; three factors were strongly associated with shorter survival: (1) Karnofsky performance status (KPS) of less than 70% (multivariate relative survival risk [RSR] = 3.1); (2) history of AIDS before the diagnosis of lymphoma (multivariate RSR = 3.0 for opportunistic infection plus Kaposis sarcoma); and (3) bone marrow involvement (RSR = 3.1)). All three factors (KPS of less than 70%, prior AIDS diagnosis, and marrow involvement) were associated with early demise attributed to AIDS, whereas death attributed to lymphoma per se was associated with only two factors (KPS of less than 70% and marrow involvement). In the absence of all three risk factors, a “good prognosis” group of 17 patients was defined, with a median survival of 11.3 months; the median survival of the remaining patients (“poor prognosis”) was 4.0 months (P = 0.0002). Attainment of complete response to therapy (CR) was strongly related to prolonged survival in the patients in the good prognosis group (17.8 months in patients with CR versus 5.0 months in those with less than CR); however, such meaningful prolongation of survival was not seen in patients with poor prognosis who attained CR (6.3 months versus 3.4 months). The patients with poor prognosis may be unable to tolerate the insult of multiagent chemotherapy, experiencing low CR rates (25%) and death caused by lymphoma and AIDS. However, patients in either prognostic category who attained CR remained at risk for dying of AIDS while the lymphoma was in remission. Thus, it is apparent that meaningful prolongation of survival in the patient with AIDS‐related lymphoma will require not only effective antineoplastic intervention, but also control of the underlying HIV infection. In addition, future therapeutic trials should stratify patients based upon the prognostic factors defined here in an attempt to clarify the results obtained. 68:2466‐2472, 1991.

extramedullary myeloid cell tumors: an immunohistochemical and morphologic study of 28 cases

In an attempt to correlate the morphologic and immunophenotypic findings in extramedullary myeloid cell tumors (EMT), we studied 28 cases with a large panel of antibodies using paraffin section immunohistochemistry. A previous or concurrent diagnosis of acute myelogenous leukemia or chronic myelogenous leukemia was made in 25 cases. Six EMT were morphologically classified as well differentiated (WD-EMT), 17 as poorly differentiated (PD-EMT), and five as blastic EMT. The WD-EMT were easily recognized morphologically and displayed a relatively mature myeloid phenotype, with elastase, CD15, and CD68 positivity in all cases. On the other hand, the five blastic-EMT displayed no morphologic evidence of myeloid derivation, were completely negative for CD 15, and were weakly positive for elastase in only one case. The PD-EMT, with a morphologic appearance that resembles large cell non-Hodgkins lymphoma, variably expressed CD 15 and elastase. CD68 and lysozyme were present in the majority of PD-EMT, with some variability, but were negative in most blastic-EMT. CD45 (LCA) was detected in 75% of all EMT and CD34 was positive in 36%; neither antigen was significantly associated with a specific morphology. CD30 reactivity was not evident in any case, but slight positive staining was seen with CD20 (L26) in one WD-EMT. CD43 (Leu 22) was the only antibody that was positive in 100% of cases; staining was always intense and widespread. Antimyeloperoxidase (MPO) was positive in all cases but two, both with a blastic morphology. We conclude that (a) an immunohis-tochemical panel including CD20, CD43, CD68, and MPO can successfully identify the vast majority (96%) of EMT in paraffin sections, and (b) there is an association between morphology and phenotype in these lesions.

Azidothymidine Associated with Bone Marrow Failure in the Acquired Immunodeficiency Syndrome (AIDS)

Four patients with the acquired immunodeficiency syndrome, and a history of Pneumocystis carinii pneumonia developed severe pancytopenia (hemoglobin, less than 85 g/L; granulocytes, less than or equal to 0.5 X 10(9)/L; platelets, less than or equal to 30 X 10(9)/L) 12 to 17 weeks after the initiation of azidothymidine (AZT) therapy. The bone marrow was markedly hypocellular in three patients and moderately hypocellular in the fourth. Partial bone marrow recovery was documented within 4 to 5 weeks in three patients, but no marrow recovery has yet occurred in one patient during the more than 6 months since AZT treatment was discontinued. Azidothymidine should be used cautiously, with close monitoring of blood values.

Kikuchi-Fujimoto disease mimicking malignant lymphoma

Histiocytic necrotizing lymphadenitis is a rare, benign entity described independently both by Kikuchi and Fujimoto et al. This disease, which has a broad morphologic spectrum, can readily be mistaken for malignant lym-phoma. Our report on the morphologic features in 10 selected cases of this disease highlights those features that mimicked lymphoma and those that helped us to make an accurate diagnosis. The distinctive features were (a) pathologic areas, which are pale and do not occupy the entire lymph node; (b) preserved sinuses in the uninvolved areas; (c) prominent mottling by histiocytes or transformed lymphoid cells in the nonpathologic areas; (d) frequent absence of overt necrosis; (e) presence of benign histiocytes with moderate to marked nuclear irregularities and scanty to moderate cytoplasm that resembled cleaved cells; (f) variable amounts of nuclear debris, usually extracellular; (g) presence of so-called plasmacytoid T cells at the periphery of or immediately outside the pathologic areas; (h) moderate numbers of mitotic figures and transformed lymphoid cells of medium and large size (immunoblasts); and (i) absence of inflammatory and granulomatous reaction. Because overt necrosis is often absent and histiocytes resemble cleaved cells, we support the suggestion that this entity should be called “Kikuchi-Fujimoto disease” rather than “histiocytic necrotizing lymphadenitis.”

Inflammatory meningeal masses of unexplained origin. An ultrastructural and immunological study.

Two patients with inflammatory meningeal masses were studied. Lesions in both patients showed varying proportions of meningothelial and inflammatory components. The non-neoplastic nature of the inflammation was confirmed in one case by lymphocyte surface marker study, which showed T and B cells in one to four ratio, and by immunohistochemistry, which revealed polyclonal plasma cells. The abundant histiocytes contained muramidase and often enclosed intact lymphocytes or plasma cells within their cytoplasm, i.e., emperipolesis. Their surfaces bore slender interdigitating pseudopodia, intercellular junctions, and subplasmalemmal linear densities. The derivation of these histiocytes is uncertain: mononuclear phagocytes, meningothelial cells, and multipotential meningeal cells are all possible progenitors. A comparison with eleven similar reported cases reveals a tendency for inflammatory meningeal masses to occur in the young, as well as a predilection for posterior fossa involvement. They resemble the extranodal lesions of sinus histiocytosis with massive lymphadenopathy, as well as plasma cell granulomas or inflammatory pseudotumors of lung and other tissues. However, it is possible that these lesions represent a variant of meningioma in which an unusual immunological response has been evoked.

Immunohistochemical expression of cyclin D1, E2F-1, and Ki-67 in benign and malignant thyroid lesions.

Cyclin D1 and E2F‐1 proteins are essential for the regulation of the G1/S transition through the cell cycle. Cyclin D1, a product of the bcl‐1 gene, phosphorylates the retinoblastoma protein, releasing E2F‐1, which in turn activates genes involved in DNA synthesis. Expression patterns of E2F‐1 protein in thyroid proliferations have not been reported. This study used monoclonal antibodies for cyclin D1 and E2F‐1 proteins to immunostain sections of normal thyroid, hyperplastic (cellular) nodules, follicular adenomas, follicular carcinomas, and papillary carcinomas. The proliferation rate was examined using an antibody specific for the Ki‐67 antigen. Fluorescence in situ hybridization (FISH) methods and chromosome 11‐specific probes were also employed to determine chromosome copy number and to assess for evidence of amplification at the 11q13 locus in papillary and follicular carcinomas with cyclin D1 overexpression. Concurrent overexpression of Ki‐67, cyclin D1, and E2F‐1 was found in the majority of benign and malignant thyroid lesions, compared with normal thyroid tissue. Cyclin D1 up‐regulation was not due to extra copies of chromosome 11, or bcl‐1 gene amplification. Malignant tumours showed the highest expression for all three markers, particularly papillary carcinomas. E2F‐1 was detected at the same or slightly lower levels than cyclin D1. It was only found when cyclin D1 was overexpressed. Because cyclin D1 normally activates E2F‐1, up‐regulation of cyclin D1 may lead to E2F‐1 overexpression in benign and malignant thyroid lesions. Copyright

Percutaneous needle biopsy in the diagnosis and classification of lymphoma

Results of percutaneous needle biopsies were evaluated retrospectively in 58 patients in whom a diagnosis of lymphoma was suspected. The biopsy specimen was diagnostic in 94% of the 36 patients with lymphoma, 20 of whom had recurrent disease and 16 of whom had newly diagnosed lymphoma. Sufficient tissue was obtained in 94% of these positive biopsy specimens to allow histologic subtyping of the lymphoma. Immunohistochemical studies performed on seven of the biopsy specimens allowed immunologic subclassi‐fication into B‐cell and T‐cell types of lymphoma. Our results suggest that the percutaneous needle biopsy is a useful and reliable tool in the diagnosis and classification of lymphoma.

Cyclin D1 overexpression in Spitz nevi: an immunohistochemical study.

The morphologic distinction between Spitz nevus and malignant melanoma can be difficult. Because cyclin D1 has been reported to be overexpressed in malignant melanomas, but not in common acquired nevi, we hypothesized that cyclin D1 might be a useful marker to distinguish Spitz nevi from malignant melanoma. Thus, we assessed for cyclin D1 expression in 11 Spitz nevi (10 compound and 1 intradermal) and 9 malignant melanomas (4 Clark stages I-III and 5 Clark stages IV-V) using an immunohistochemical method and routinely fixed and processed tissues. The cyclin D1 results were arbitrarily divided into three groups: 0% to 10%, >10% to 25%, and >25%. We confirmed the observations reported previously by others that cyclin D1 is expressed in malignant melanomas but not in common acquired nevi. Unexpectedly, a relatively high number of cyclin D1-positive cells (i.e., >10%) was also found in all cases of Spitz nevus. However, unlike malignant melanoma, the cyclin D1 positivity in Spitz nevi was present in a zonal pattern. In other words, the number of cyclin D1-positive cells decreased as the lesion extended more deeply, with the number of positive cells in the reticular dermis being less than that in the papillary dermis. Fluorescence in situ hybridization methods were used to assess amplification of 11q13, the locus harboring the cyclin D1 gene, in four cases of Spitz nevus; all were disomic. Using the antibody MIB-1, we compared cyclin D1 expression to the proliferation rate in Spitz nevi. Despite the high cyclin D1 positivity, all Spitz nevi had a relatively low number of MIB-1-positive cells (mean=3.2%), which was significantly lower than that of malignant melanomas (mean=15.3%) (p < 0.001). Thus, unlike malignant melanoma, there appears to be a dissociation between cyclin D1 overexpression and cell proliferation in Spitz nevi.

Monocytoid B-cell lymphomas: An assessment of diagnostic criteria and a perspective on histogenesis

To determine which morphologic criteria are most useful in distinguishing reactive from malignant monocytoid B cells (MBCs), we compared 16 monoclonal cases (11 nodal, five extranodal) of monocytoid B-cell lymphoma (MBCL) with 12 cases of various reactive diseases in which MBCs were polyclonal. The results of our study showed that in MBCL the MBC component was the predominant architectural finding and that there was confluence of MBCs in all but one case. In contrast, the MBC component did not predominate in the reactive group (P less than .000001) and focal confluence was seen in only one case. A cytologic comparison showed that in MBCL areas there were more large transformed (prominent nucleolated) MBCs (P = .003), a higher mitotic rate (P = .03), and more nuclear irregularities (P = .007) than were present in the reactive group. In addition, evolution to an aggressive histologic type was found in four cases of MBCL. Our results also revealed concomitant multiple, monoclonal, morphologically distinct populations in other compartments (follicular center cells in seven, mantle cells in five, small lymphocytes in five, and plasma cells in 11). These unique findings can be reconciled by postulating (1) that the simultaneous presence of these diverse cytologic types represents morphologic expressions of a B cell whose population is in different phases of its cell cycle and/or its evolution or (2) that the histogenesis of MBCL is possibly from a nodal pluripotent B-stem cell that can differentiate directly into these various cytologic types.

Indeterminate Cell Tumor A Rare Dendritic Neoplasm

Indeterminate cell tumor (ICT) is a rare neoplastic dendritic cell disorder that has been poorly defined due to its rarity and poorly understood histogenesis and pathogenesis. It is characterized by a proliferation of dendritic cells, which mimic Langerhans cells immunophenotypically (positive for CD1a and S-100 protein), but lack Birbeck granules characteristic of Langerhans cells. The clinical, morphologic, immunophenotypic, and ultrastructural features of 5 ICT cases are reported in an attempt to further define ICT and to examine the postulated relationship between indeterminate cells and Langerhans cells. Four of 5 patients were females, and 4 of 5 were older than 68 years. Three of 5 patients had cutaneous lesions, whereas 2 presented with cervical lymph node involvement. Two patients had a possible association with lymphoma: first patient had a history of progressive follicular lymphoma that led to patients demise and the second patient had unexplained systemic lymphadenopathy and died 1 week after the biopsy. All 5 ICT cases expressed CD1a and S-100 protein, but lacked Langerin expression and Birbeck granules ultrastructurally. Interestingly, a t(14;18) was detected by fluorescence in situ hybridization in the ICT cells of the patient with previous follicular lymphoma and a monoclonal κ light chain gene rearrangement was detected by polymerase chain reaction in the patient with systemic lymphadenopathy. In both cases, there was no morphologic or immunophenotypic evidence of a concurrent B-cell lymphoma. In conclusion, ICT is a rare neoplasm that can occur de novo or in association with a B-cell lymphoma, possibly as a result of B-cell dedifferentiation caused by relatively unknown mechanisms. Finally, Langerin immunostaining may be used as a surrogate marker for the ultrastructural demonstration of Birbeck granules, the absence of which represents a strong diagnostic criterion for ICT.