Jonathan Ben-Ezra

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.

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.

Antigenic phenotype of the lymphocytic component of medullary carcinoma of the breast.

Medullary carcinoma of the breast, which is usually associated with a dense lymphocytic infiltrate, carries a better prognosis than do most other histologic subtypes of breast carcinoma. We studied cryostat‐cut fresh frozen sections from 12 patients with medullary carcinoma and, as controls, nine patients with infiltrating ductal carcinoma in order to determine and compare the antigenic phenotype of the lymphocytic components of these tumors. We used a large panel of monoclonal antibodies and polyclonal antisera for T‐cells (Leu‐1, Leu‐2a, Leu‐3a, Leu‐9, T‐3, T‐6, T‐10, T‐11, and TQ‐1), pre‐B and B‐cells (BA‐1, B‐1, B‐2, B‐4, and J5), NK cells (Leu‐7 and Leu‐11b), and cell activation associated antigens (T‐9, HLA‐Dr, and Tac). The most commonly encountered antigens on the lymphocytic components of both medullary carcinoma and infiltrating ductal carcinoma were: T‐3, T‐11, Leu‐1, Leu‐2a, Leu‐3a, and Leu‐9. There was little staining for NK—, pre‐B—, or B‐cell associated antigens in either type of carcinoma. However, the lymphocytes in the control cases tended to express HLA‐Dr and T‐10 more often than did the lymphocytes in the cases of medullary breast carcinoma. Our data indicate that: (1) the antigenic phenotypes of the lymphocytic infiltrates of medullary carcinoma and those of infiltrating ductal carcinoma of the breast are essentially similar; and (2) the lymphocytes in these carcinomas are composed predominantly of peripheral T‐lymphocytes. We therefore conclude that the favorable biologic behavior of medullary carcinoma of the breast cannot readily be explained by the immunophenotype of its lymphocytic component.

Breast conservation therapy : local tumor control in patients with pathologically clear margins who receive 5000 cGy breast irradiation without local boost

SummaryA retrospective study was performed to determine the value of pathological evaluation of inked primary tumor specimen margins in the local control of patients with stage I and II breast cancer. In 150 patients with 153 invasive breast cancers, treatment involved surgical resection of the primary tumor, pathological determination of tumor-free inked specimen margins, and 5000 cGy whole breast radiation therapy (RT) without tumor bed RT local boost. This approach yielded an actuarial five-year local control rate of 95%. The local control rate was 96% for T-1 cases and 93% for T-2 cases. The local control rate was 96% for patients with clear margins achieved at initial resection and 94% for patients with clear margins achieved at re-excision. Among patients with clear margins at re-excision, the local control rate was 97% for those with no residual cancer and 88% for those with residual cancer. Patients with surgical margins clear by 3 mm or less had a local control rate of 92% at five years. Local control rates appear to be comparable to other breast conservation approaches which routinely employ local RT boosts. In omitting the local RT boost in patients with clear margins, the overall RT course will be briefer and the cosmetic changes associated with high-dose, large volume local RT boosts can be avoided.

Nodular lymphocyte-predominant Hodgkin's disease: Study of immunoglobulin light chain protein and mRNA expression

The techniques of immunohistochemistry and in situ hybridization were applied to 10 formalin- or B5-fixed, paraffin-embedded cases of nodular lymphocyte-predominant Hodgkins disease to determine whether lymphohistiocytic (L&H) cells contain any detectable amount of immunoglobulin light chain protein or messenger RNA. None of the cases studied demonstrated any detectable amount of either kappa or lambda light chain mRNA within L&H cells or Reed-Sternberg cells despite positive labeling of plasma cells, immunoblasts, and germinal center cells. Polyclonal kappa light chain antibody studies showed positive staining of L&H cells in seven cases, including three costaining with polyclonal lambda light chain antibody. Monoclonal kappa and lambda light chain antibody studies, however, showed no staining of L&H cells despite positive staining of immunoblasts and plasma cells. It is suggested that L&H cells do not synthesize appreciable amounts of light chain immunoglobulin protein and are not closely related to reactive immunoblasts or germinal center cells.

Hashimoto's thyroiditis lacks detectable clonal immunoglobulin and T cell receptor gene rearrangements.

The development of B cell lymphoma, predominantly of the large-cell type, in patients with autoimmune diseases such as Hashimotos thyroiditis or Sjogrens syndrome is well known. In Sjogrens syndrome, it has been recently shown that the benign-appearing lymphocytic infiltrates of the lymphoepithelial lesions in the salivary glands have clonal rearrangements of immunoglobulin genes in their DNA, even in the absence of malignant lymphoma. To investigate whether a similar situation occurs in Hashimotos thyroiditis, we studied the thyroid glands from four patients with this disease. In all four cases, there was a benign-appearing lymphocytic infiltrate in the thyroid, with eosinophilic changes in the Hurthle cells. In immunologic studies, we determined that the lymphocytes were polyclonal in each case. We extracted DNA from the frozen tissue blocks of these four patients and analyzed it by molecular hybridization for the presence of clonal immunoglobulin (IgH, kappa, and lambda) and T cell receptor beta chain gene rearrangements, and detected none in any case. Therefore, we conclude that the lymphocytes in Hashimotos thyroiditis are immunologically and immunogenetically polyclonal proliferations of cells, and that the initial lesion of Hashimotos thyroiditis does not contain a detectable clone of cells that may eventually develop into malignant lymphoma.

Variability in interpretation of immunohistologic findings in lymphoproliferative disorders by hematopathologists. A comprehensive statistical analysis of interobserver performance

Eight hematopathologists independently reviewed 56 consecutive cases of benign and malignant lymphoproliferative disorders (LPD) to determine: (1) the degree of interobserver agreement on the interpretation of immunologic findings on fresh‐frozen sections alone and on that of the immunologic findings in conjunction with corresponding hematoxylin and eosin (H & E)‐stained histologic sections; (2) whether prior knowledge of morphologic characteristics influences the interpretation of immunohistologic sections; (3) whether immunologic phenotype could be predicted reliably based solely on study of histologic sections; and (4) the significance of immunologic data as an aid in the interpretation of histologic sections. The study was carried out in three independent review sessions consisting of (1) review of immunohistologic sections only, (2) review of the same immunohistologic sections together with histologic sections, and (3) review of the histologic sections alone. A consensus diagnosis was defined as agreement of five or more pathologists on the final diagnosis and identification of the immunophenotype. When the authors compared the total number of major disagreements in the first review session with those in the second, the accuracy of the determination of immunophenotype in the second session was clearly superior (P < 0.05). Similarly, the total number of major disagreements in the second review session was significantly lower than that in the third review session (P < 0.001). When histologic diagnoses in the second session were compared with those in the third session, it became apparent that the immunologic data helped the pathologist to correct major misinterpretations in 14 cases (25%). This study is the first to demonstrate quantitatively that (1) knowledge of morphologic features influences and greatly enhances the accuracy of the interpretation of immunologic findings, (2) the immunophenotype of LPD cannot be predicted based on morphologic findings alone, and (3) immunologic findings improve the accuracy of interpretation of histologic findings in situations in which a diagnosis cannot be made from morphologic features only.

Origin of urinary epidermal growth factor in humans : excretion of endogenous EGF and infused [131I]-human EGF and kidney histochemistry

1. This study examined (i) whether blood‐infused epidermal growth factor (EGF) can pass into urine; (ii) whether infused labelled EGF behaves like endogenous plasma immunoreactive EGF; and (iii) which parts of the human nephron show morphological evidence of EGF synthesis?

Concurrent presence of two clonal populations in small lymphocytic lymphoma of the lung

In a patient with small lymphocytic proliferation (SLP) involving the right middle and right lower lobes of the lung, immunophenotypic studies showed that the neoplastic lymphoid cells in the right middle lobe expressed kappa light chains, whereas those in the right lower lobe expressed lambda light chains on their surface. Gene rearrangement studies with Southern-blot hybridization confirmed the disparate surface immunoglobulin expression, and showed that the SLPs in the two lobes were derived from separate clones. The findings indicate that even morphologically identical lymphomas in the same organ may be immunophenotypically and genotypically heterogeneous. Our findings demonstrate that immunologic and DNA gene rearrangement analyses may complement each other in the study of lymphomas. This case is unique in that it is the first reported case of the concurrent presence of two immunologically distinct clonal populations in an extranodal site.

The in-vitro response of CD2-positive acute myelogenous leukemia to proliferation and differentiation inducing agents☆

Acute mixed lineage leukemias (MLL) are a heterogeneous group of acute leukemias that express morphologic and/or immunophenotypic features of more than one hematopoietic cell line. The ontogenetic significance of this mixed lineage expression is unclear. We therefore studied the conviction of the lineage commitment in a group of MLL by examining the in-vitro response of five CD2+ (E-rosette receptor) acute myelogenous leukemia (AML) to a panel of proliferation and differentiation-inducing agents. Three of the five CD2+ AML were TdT-positive. Antigen receptor gene studies revealed no rearrangements at either the T beta or immunoglobulin heavy chain gene loci in any case. When blast-enriched cell populations were placed in short term suspension cultures with PHA, IL-2, PHA + IL-2, GM-CSF or TPA, three of the leukemias responded in a similar fashion while the remaining two cases showed no response. In the three MLL that responded to the in-vitro culture manipulations, features indicative of differentiation along the monocytic lineage pathway were observed. This differentiation was not pronounced in the presence of the phorbol ester TPA, and was manifested by loss of CD2 and CD7 expression, continued expression of myeloid antigens, and the development by the blasts of morphologic and cytochemical characteristics of monocytic cells. None of the five MLL showed any evidence of induced maturation along the T-lymphocyte line of differentiation with any of the agents used. rGM-CSF was the only exogenously added agent to induce proliferation; the proliferative response was slight and was seen in only one of the five leukemias. Therefore, the phenotypic expression of CD2 and CD7 in blasts from MLL is not indicative of irreversible commitment to T-lymphocyte development. The in-vitro loss of T-cell antigens in concert with the development of monocytic features in three of the five CD2+ AML in this study suggests the leukemic cells were preferentially committed to a non-lymphoid lineage differentiation pathway.