Khalil Sheibani

Further Evidence That Malignant Angioendotheliomatosis Is an Angiotropic Large-Cell Lymphoma

Malignant angioendotheliomatosis is a rare, generally fatal disease characterized by a multifocal proliferation of neoplastic mononuclear cells within the lumens of small blood vessels. Although the disease primarily involves the vasculature of the skin and central nervous system, vascular involvement of other organs may occur and may produce a variety of clinical findings. Some early investigators concluded that malignant angioendotheliomatosis was a neoplasm of endothelial cells, but recently others have suggested that it is of hematopoietic origin. We have studied three patients with the disease and have characterized the immunophenotype of the neoplasm on cryostat-cut fresh-frozen tissues. A detailed antigenic phenotyping of neoplastic lymphoid cells showed that one patient had the immunophenotype T11+, Leu-1+, Leu-3+, Leu-2+, B1-, B2-, SIg-, LN1-, LN2-, the predominant phenotype for peripheral T-cell lymphoma; the others had T11-, Leu-1-, Leu-3-, Leu-2-, B1+, B2+, SIg+, LN1+, LN2+, consistent with a B-cell-derived lymphoma. On the basis of our results, we suggest that angiotropic (intravascular) large-cell lymphoma would be more appropriate than malignant angioendotheliomatosis as a name for this disease.

Leu-M1 antigen in human neoplasms. An immunohistologic study of 400 cases.

Several studies have shown that the Leu-Ml antigen, a monocyte/granulocyte-related marker, is consistently expressed by the neoplastic cells of patients with Hodgkins disease (HD). It has been suggested that reactivity of Reed-Sternberg cells with Leu-Ml can be used in support of a morphologic interpretation of HD, and that it is helpful in the differential diagnosis of HD from morphologically similar lesions. To evaluate the significance of the Leu-Ml positivity of Reed-Sternberg cells in the diagnosis of HD, we investigated the distribution of Leu-Ml antigen in a series of patients with HD, non- Hodgkins lymphomas, and nonhematopoietic neoplasms. We were able to demonstrate the presence of Leu-Ml antigen not only in the majority of patients with HD, but also in 12 of 18 (67%) peripheral T-cell lymphomas, as well as in a variety of nonhematopoietic neoplasms, which included 113 of 199 carcinomas, most of them (58%) adenocarcinomas. Only one of 34 sarcomas showed a focal positive reaction. Leu-Ml-related antigen was not detected in any of 18 mesotheliomas, 15 germ cell tumors, 13 melanomas, three schwannomas, or three astrocytomas. Our study indicates that Leu-Ml positivity has no value in supporting the diagnosis of HD in situations where the histologic diagnosis of HD is doubtful. However, since anti-Leu-Ml reacted positively in the majority of adenocarcinomas but was absent in mesotheliomas, melanomas, and most sarcomas, this antigen could serve as a new marker that may be helpful in situations in which carcinoma is a part of the differential diagnosis.

Ber-EP4 antibody as a discriminant in the differential diagnosis of malignant mesothelioma versus adenocarcinoma.

The pathologic diagnosis of malignant mesothelioma is often difficult, even with the benefit of special studies such as histochemistry, electron microscopy, and immunohistochemistry. Ber-EP4 is a newly characterized monoclonal antibody that reliably labels epithelial tissues but does not react with mesothelial cells. We evaluated Ber-EP4 on formalin-fixed, paraffin-embedded tissue sections from 115 malignant mesotheliomas and 83 adenocarcinomas. Although 72 cases (87%) of adenocarcinoma were positive for Ber-EP4, only one (1%) of the mesotheliomas was reactive. The only adenocarcinomas that did not stain were from the breast (eight of 25 cases nonreactive) and the kidney (all three cases nonreactive). The staining pattern in the positive adenocarcinomas was usually intense and membranous, but additional weak cytoplasmic staining was seen in many cases. The reactivity was diffuse in 59 cases and focal in 13 cases. The results of our study suggest that the Ber-EP4 antibody may have great use in the differential diagnosis of mesothelioma versus adenocarcinoma, particularly when only formalin-fixed tissue is available.

Signet-ring cell melanoma. A rare morphologic variant of malignant melanoma.

We recently received in consultation a lymph node involved by metastatic malignant melanoma with unusual and previously undescribed morphologic features. The neoplastic cells had a striking signet-ring appearance, similar to the signet-ring cells normally seen in mucinproducing adenocarcinoma and signet-ring cell lymphoma. Review of our consultation files of malignant melanomas revealed an additional case in which the neoplastic cells had a signet-ring cell appearance. Electron microscopic studies revealed that formation of signet-ring cells is caused by the presence of abundant vimentin filaments in the cytoplasm of neoplastic cells. Immunologic studies using a series of monoclonal and polyclonal antibodies, including S-100 protein, HMB-45, vimentin, cytokeratin, leukocyte common antigen, and Leu-M1, on both cases clearly established the diagnosis of this morphologically unusual variant of malignant melanoma for which we propose the term “signet-ring cell melanoma.”

Monocytoid B-cell lymphoma in patients with Sjögren's syndrome: A clinicopathologic study of 13 patients

A recent clinicopathologic study of a series of patients with monocytoid B-cell lymphoma (MBCL) indicated that there is a frequent association between MBCL and Sjögrens syndrome (SS) and raised the possibility of a relationship between these two disease entities. To further investigate the possible relationship of MBCL and SS, we studied pathologic and clinical characteristics of 13 patients with MBCL who had clinically documented SS. In all patients, the lymphoma had the characteristic morphologic features of MBCL, and immunologic and molecular hybridization studies confirmed the B-cell nature of the lymphoma. Twelve of the 13 patients were female, with a median age of 66 years at diagnosis. Eleven had localized disease and presented with either salivary gland or cervical lymph node enlargement; one patient presented with a breast mass, and another with generalized lymphadenopathy and hepatosplenomegaly. In five of 13 patients, the MBCL was associated with or progressed to large cell lymphoma. In two patients, there was bilateral involvement of the parotid gland; one had a synchronous high-grade lymphoma in both parotid glands. In two patients, bone marrow biopsies showed involvement by MBCL. Eleven patients are alive 2 to 55 months after the diagnosis of MBCL. One patient died with the disease 8 months after the initial diagnosis. Another patient died of an unrelated cause without evidence of disease 16 months after the diagnosis of MBCL. We conclude that there is a more than fortuitous association between MBCL and SS. This concept is consistent with previously reported observations of reactive monocytoid B cells in patients with benign lymphoepithelial lesions of salivary glands, which may result from selective homing of reactive monocytoid B lymphocytes to the benign lymphoepithelial lesions and their subsequent neoplastic transformation.

Monocytoid B lymphocytes: Their relation to the patterns of the acquired immunodeficiency syndrome (AIDS) and AIDS-related lymphadenopathy

It was shown recently that monocytoid cells express B-cell-restricted antigens and polyclonal surface immunoglobulins, and the term monocytoid B lymphocytes (MBL) has thus been offered as a more appropriate designation. Although most commonly seen in toxoplasmic lymphadenitis, MBL have been observed in a variety of reactive and neoplastic conditions involving lymph nodes. In the present study MBL were found in 17 of 22 lymph nodes from 20 patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related lymphadenopathy. In all 17 samples, the MBL were found in lymph nodes with florid reactive follicular hyperplasia, and they were geographically close to the hyperplastic lymphoid follicles. However, MBL were not detected in lymph nodes showing involuted follicles or lymphocyte depletion. The disappearance of MBL apparently parallels the progressive involution of secondary follicles. Leu-3+/Leu-2+ (T-helper/T-suppressor) ratios were studied in 14 lymph node cell suspension samples and ten peripheral blood samples. The lymph node Leu-3+/Leu-2+ ratios were significantly lower in AIDS-related lymphadenopathy than in non-AIDS-related reactive follicular hyperplasia (P less than 0.001); the peripheral blood ratios were decreased in nine of the ten cases. The diminished T-helper status in patients with AIDS and AIDS-related lymphadenopathy may be relevant to the immunopathogenesis of follicular involution and, indirectly, to the disappearance of MBL.

Antigenic phenotype of Langerhans cell histiocytosis: An immunohistochemical study demonstrating the value of LN-2, LN-3, and Vimentin

In order to determine the antigenic phenotype of the proliferating cells in Langerhans cell histiocytosis (LCH), we studied 15 such examples by using formalin- and B5-fixed, paraffin-embedded tissues. We used a panel of antibodies that are known to react with lymphocyte- and histiocyte-associated antigens. These included LN-1, LN-2, and LN-3 monoclonal antibodies (MoAbs), MoAbs to leukocyte common antigen (LCA), Leu-M1 antigen, vimentin, and epithelial membrane antigen (EMA), as well as polyclonal antibodies to lysozyme and S100 protein. The antigens encountered most frequently in LCH cells were S100 protein (93% of cases), vimentin (86%), and those detected by LN-2 (80%) and LN-3 (82%). Lysozyme was detected focally in two cases and diffusely in one case. The LCH cells were negative for LN-1, LCA, Leu-M1, and EMA. There was only one specimen in which S100 protein was not demonstrated; in this case, LN-3, vimentin, and T6 on frozen section were positive. The phenotype of LCH cells is similar to that of Langerhans cells and interdigitating histiocytes. Our results demonstrate the value of using a panel of antibodies, including anti-vimentin MoAb, LN-2, and LN-3 for the immunophenotypic diagnosis of LCH in addition to an antibody to S100 protein.

A novel biotinylated probe specific for hyaluronate. Its diagnostic value in diffuse malignant mesothelioma.

Diffuse malignant mesotheliomas are known to secrete a large amount of hyaluronate, whereas adenocarcinomas produce predominantly neutral mucins. In the present study, we assessed the diagnostic usefulness of a new, highly specific and sensitive hyaluronate binding probe to discriminate between mesotheliomas and adenocarcinomas. We studied 33 mesotheliomas and 37 adenocarcinomas in order to establish specific diagnostic criteria for using the hyaluronate binding probe. Of the adenocarcinomas, only three showed significant positive staining for hyaluronate (8%). By contrast, all the mesotheliomas exhibited positive staining for hyaluronate. Furthermore, the staining reaction was classed as moderate or greater in 26 mesotheliomas (79%), thus suggesting the utility of this probe in the differential diagnosis of malignant mesothelioma versus adenocarcinoma. We conclude that strong cytoplasmic or membranous staining for hyaluronate is highly predictive of malignant mesothelioma. The hyaluronate binding probe should therefore be considered an important adjunct to be used in combination with electron microscopy and immunohistochemistry in the histologic diagnosis of diffuse malignant mesothelioma.

Angiotropic large cell lymphoma of the prostate gland: An immunohistochemical study

Malignant angioendotheliomatosis (MAE) is a rare disorder characterized by the intravascular proliferation of neoplastic mononuclear cells. Until recently, the cell of origin was uncertain; some investigators reported MAE to be lymphomatous in nature, while others claimed it to be of endothelial derivation. In the present unusual case, MAE was an incidental findings in the prostate of a patient with prostatic adenocarcinoma; it is shown to be a lymphoma of B-cell origin.

Acute nonlymphocytic leukemia in patients receiving chemotherapy for nonmalignant diseases

The occurrence of acute leukemia in patients receiving chemotherapeutic agents for malignant disease has been well established. Recent reports have suggested that chemotherapeutic drugs used to treat inflammatory conditions may have an oncogenic potential. From 1969 to 1977, 11 patients with a variety of collagen-vascular diseases who developed acute nonlymphocytic leukemia were seen at the Cleveland Clinic. Rheumatoid arthritis was the most common underlying disease, in addition to giant cell arteritis, polyarteritis nodosa, chronic glomerulonephritis, and scleroderma. All patients were treated with alkylating agents, and 10 of the 11 received multiple cytotoxic agents. According to the French-American-British classification there were six examples of M4 (myelomonocytic leukemia), with single examples of M1 (myeloblastic leukemia without maturation), M2 (myeloblastic leukemia with maturation), M5a (monocytic leukemia, poorly differentiated), M5b (monocytic leukemia, differentiated), and M6 (erythroleukemia). Cytogenetic studies were abnormal in five patients studied, showing varying degrees of aneuploidy. All patients died, and the mean duration of time from the diagnosis of leukemia to death was four and one-half months, with only one complete remission.