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Macrophage-histiocytes in malignant lymphoma, small lymphocytic type (well-differentiated lymphocytic lymphoma).

The authors studied the occurrence of Ricinus communis agglutinin (RCA)-binding macrophage-histiocytes in paraffin-embedded tumor tissue of 38 patients with malignant lymphoma, small lymphocytic type, a tumor of low-grade malignancy. Thirty-one patients (82%) had an indolent clinical course and were free of disease for a minimum follow-up period of 24 months. However, seven patients (18%) died within 24 months of biopsy, and six of the seven patients died of rapid progression of their tumor despite intensive treatment. Histologically, the tumors of these six short-term survivors were indistinguishable from those of the long-term survivors. RCA staining of paraffin-embedded tumor tissue of the 38 cases revealed three groups of tumors: (1) tumors with numerous (greater than 10/high-power field [HPF]) stromal macrophage-histiocytes (4 patients); (2) tumors with a moderate number (4-9/HPF) of macrophage-histiocytes (5 patients); (3) tumors with rare or no (0-3/HPF) macrophage-histiocytes, or only thin, anuclear variants (29 patients). Each of the six short-term survivors had readily demonstrable RCA-binding macrophage-histiocytes in their tumor; these were numerous in four and moderate in two. In contrast, macrophage-histiocytes were either rare or absent, or were anuclear variants, in 29 of the 31 patients who had an indolent clinical course. These observations suggest that in small lymphocytic type malignant lymphoma there is a subgroup characterized by an increased number of stromal macrophage-histiocytes and aggressive behavior of the tumor. Tumors of this subgroup can be detected by RCA staining.

Aged↗

Histiocytic sarcomas and monoblastic leukemias. A clinical, histologic, and immunophenotypical study.

Eight histiocytic sarcomas, identified by examination of more than 2000 malignant lymphomas, are described. For comparison, tumor infiltrates from five monoblastic leukemias were also analyzed. The histiocytic sarcomas were all high-grade malignancies consisting of markedly pleomorphic large cells with many mitotic figures. At presentation, six of the patients had systemic symptoms (fever, fatigue, loss of weight), skin infiltrates, and lymphadenopathy. Despite aggressive chemotherapy, clinical remissions were short, and six patients died of disease .5-48 months (mean, 6.5 months) after diagnosis. The remaining two patients are alive and in partial or complete remission 7 and 12 months after diagnosis. Immunotypic examination showed that all the histiocytic sarcomas were positive for macrophage-related antigens and negative for antigens on B cells, T cells, myeloid cells, epithelial cells, and melanocytes. T-cell receptor and immunoglobulin genes were studied in three cases and were present in a germline configuration. One of the histiocytic sarcomas resembled Langerhans' cells in phenotype and morphology; it was classified as a Langerhans' cell sarcoma. The remaining histiocytic sarcomas did not express accessory cell-associated antigens, but more closely resembled "ordinary" tissue macrophages; they were positive for lysozyme and/or CD68, followed in frequency by CD11c, CD4, CD11b, CDw32, peanut agglutinin receptor, and CD13. Similar features were seen in the monoblastic leukemias. These conditions could only be distinguished from histiocytic sarcoma by clinical and morphologic, rather than immunophenotypic, criteria. Expression of oncoprotein p53 was studied in nine cases and was positive in six of six histiocytic sarcomas and one of three monoblastic leukemias. Rare malignancies show features consistent with the derivation from macrophages. Two entities may be distinguished: those that resemble antigen-presenting accessory cells and those that more closely resemble ordinary tissue macrophages. Recognition of these tumors is important clinically and requires assessment of clinical, morphologic, and immunophenotypic features, supplemented by analysis of T-cell receptor and immunoglobulin genes. Whether (or how) p53 gene mutations are implicated in their pathogenesis will be an important topic for future investigation.

Adolescent↗

Abnormalities of bone marrow simulating histiocytic medullary reticulosis in a patient with gastric carcinoma.

In the proper clinical setting, phagocytosis by bone marrow histiocytes of erythrocytes, granulocytes, and platelets (panphagocytosis) is generally accepted as the morphologic hallmark of histiocytic medullary reticulosis. A patient with clinical manifestations that suggested histiocytic medullary reticulosis was found also to have histiocytic panphagocytosis in the bone marrow. Biopsy of the liver, however, revealed metastatic adenocarcinoma. In addition, postmortem examination demonstrated a gastric adenocarcinoma with massive hepatic involvement and absence of lymphadenopathy, splenomegaly, or evidence of generalized histiocytic proliferation. Therefore, histiocytic panphagocytosis is probably not specific for histiocytic medullary reticulosis, and may be a nonspecific feature of a variety of diseases.

Bone Marrow↗

Peanut agglutinin: a new marker for tissue histiocytes.

The histiocyte (macrophage) is a unique cellular constituent of the immune system which is involved in immune and non-immune cellular reactions, as well as in the genesis of a variety of benign and malignant neoplasms. The ability to distinguish histiocytes from similar appearing cells morphologically, is often difficult, yet may be of considerable practical and theoretical importance. The present study describes a new marker for histiocytes, applicable to routinely processed tissues. An immunoperoxidase procedure to detect binding of peanut agglutinin (PNA) was applied to 58 specimens consisting of lymph nodes, extranodal lymphoid tissues, neoplasms and reactive histiocytic lesions. Results were compared with a currently accepted histiocytic marker--cytoplasmic muramidase. Of the 58 tissues, 51 showed PNA binding to morphologically recognizable histiocytes, whereas muramidase was detected in only 44. PNA binding- appeared at least as sensitive and specific as muramidase, as a marker for histiocytes, and offers the advantage that it does not bind to cells of the granulocytic series.

Cytoplasm↗

Malignant fibrous histiocytoma. Proliferative compartment and heterogeneity of "histiocytic" cells.

To elucidate the precise origin and characteristics of the proliferating cells in malignant fibrous histiocytoma (MFH), the authors analyzed 33 MFH tumors, using immunohistochemical techniques with a panel of 12 antibodies. All three types of MFH cells (spindle cells, polygonal cells, and bizarre giant cells) stained positively for mesenchymal antigens (FU3 and vimentin) but did not stain for macrophage/histiocyte markers (HAM 56 and CD68). Therefore, the MFH cells may not represent true histiocytes, although they may be mesenchymal-derived cells behaving as "facultative histiocytes" with superficial resemblance to actual histiocytes. Normal histiocytes in the stroma tested positive for macrophage/histiocyte antigens; the most common cells were HAM 56-positive cells constituting 30-80% of nonneoplastic stromal cells, followed by those positive for CD68 (10-50%), Mac 387 (less than 2%), and S-100 protein (less than 1%). Our results indicate the presence of heterogeneity of "histiocytic" cells in MFH. Proliferating-cell nuclear antigen (PCNA) was expressed not only in the spindle and polygonal MFH cells but also in the bizarre giant cells. These findings suggest that all three types of MFH cells participate in the proliferative compartment of MFH. Uneven PCNA staining of the irregular nuclear segments of the bizarre giant cells may result in abnormal DNA synthesis, possibly contributing to the marked diversity of nuclear morphology in MFH. Touton-type and osteoclast-like giant cells did not stain for PCNA but stained positively for histiocytic markers. Therefore, these giant cells may lack proliferative activity and probably result from normal histiocytes fusing together.

Adult↗

Cytological characters, transformation, and ontogenesis of dermal histiocytes and fibroblasts of rats.

Cell morphology of histiocytes and fibroblasts was observed light- and electron microscopically in the subcutaneous connective tissue of unstimulated adult rats. Striking ultrastructural differences between them were noted in the cell surface characters, extent and development of endoplasmic reticula, especially of rough-surfaced ones, and volumes of lysosomal components. Rosetting assays revealed that histiocytes were positive for EA- and EAC-rosette formation and capable of engaging in immunophagocytosis. However, fibroblasts were negative for both rosettings. In the experiments of vital staining with lithium carmine, Fesin phagocytosis, carrageenin granuloma formation, in vivo culture by intraperitoneal implantation of diffusion chambers, and subculture, cytological changes of histiocytes or macrophages and fibroblasts, as well as their transformation, were investigated. Although fibroblasts often simulated histiocytes under certain stimulated conditions, no transformation of fibroblasts into histiocytes was confirmed. Ontogenetically, histiocytes already existed in the subepidermal mesenchyme of rat fetuses before differentiation of undifferentiated mesenchymal cells into fibroblasts and showed no relationship to the fibroblasts. Ultrastructural cell morphology and cultural characteristics of the fetal histiocytes were presented and their possible origin was discussed briefly.

Animals↗

Involution of lymph node histiocytes in AIDS.

Lymph nodes of human immunodeficiency virus (HIV)-infected patients were studied histologically and immunohistochemically to elucidate the pattern of involution of various histiocytes in AIDS. Specimens consisted of one node with hyperplasia, five with atrophy, and three with severe atrophy. Antibodies such as L25, ID1, My4, 12, anti-Leu 3a, KiM4, OKT6 and anti-S100 protein were used for identification of the histocytes. Another antibody, VAK5, was used to demonstrate HIV antigen. T-zone histiocytes were mildly decreased in the hyperplastic node, but considerably decreased in the atrophic nodes. My4+ sinus histiocytes were unchanged in number and enlarged in the hyperplastic node, but not decreased in the atrophic nodes. Follicular dendritic cells (FDCs), defined by KiM4, were mostly depleted in the atrophic nodes. The T4 antigen was detected in some of the sinus histiocytes of the atrophic nodes. T6-positive cells were not found in any of the nodes. HIV antigen was detected only in FDCs. It is therefore suggested that various histiocytes respond differently to HIV, and that T-zone histiocytes and sinus histiocytes persist up to the late stage of AIDS.

Acquired Immunodeficiency Syndrome↗

[The diagnosis and differential diagnosis of histiocytic necrotizing lymphadenitis. A study of histology, immunohistochemistry and electron microscopy].

OBJECTIVE: To study the diagnosis and differential diagnosis of histiocytic necrotizing lymphadenitis (Kikuchi disease, KD). METHODS: Histologic analysis and immunohistochemical study (EnVision method) was carried out in 46 cases of KD, 5 cases of nonspecific lymphadenitis (NLD), 5 cases of non-Hodgkin's lymphoma (NHL), 5 cases of Hodgkin's lymphoma (HD), 5 cases of cat-scratch disease (CSD) and 5 cases of tuberculous lymphadenitis (TBL). Electron microscopy was also performed in 6 cases of KD and 2 cases of NHL. RESULTS: Three histologic (proliferative, necrotizing and xanthomatous) patterns were noted in KD. In any of these patterns, there were some basic histologic findings: a wedge-shaped pale area at the edge of the lymph node or paracortical nodules associated with an increase in apoptotic cells or karyorrhectic debris, crescentic histiocytes, proliferative mononuclear histiocytes and absence of or very scanty neutrophils. Immunohistochemical study demonstrated focal occurrence of histiocytes expressing both CD68 and MPO. Electron microscopy confirmed the presence of apoptotic bodies, proliferative mononuclear histiocytes, crescentic histiocytes and dispersed T cells in the lesional areas. CONCLUSIONS: In general, there should not be much difficulty in differentiating KD from other types of lymphadenopathy. Sometimes, problems arise mainly because of the diversity of KD histology. Correct diagnosis can be made if one pays attention to the described characteristic morphology, peculiar immunophenotype of the histiocytes and possibly ultrastructural features.

Adolescent↗

[Thr role of histiocytes in the cytodiagnosis of endometrial adenocarcinoma].

The Authors point out the importance of histiocytes in Papanicolaou smears. Histiocytes are associated with endometrial carcinoma on tissue sections and may be seen on cervicovaginal smears as well. Smears obtained from 120 women, with clinical signs of endometrial diseases, were evaluated to determine the correlation between the presence of histiocytes in the cervicovaginal smears and endometrial adenocarcinoma. Histiocytes were quantified as minimal [less than 5 per high-power field (hpf)], moderate (5-10 hpf) or heavy (greater than 10/hpf). The histiocytes were found in smears from 80 women. Five adenocarcinomas, 9 hyperplasias were detected in 20 patients with moderate or heavy smears. The Authors conclude that the presence of histiocytes among postmenopausal women who have cervicovaginal smears should not be ignored. The data indicate that, in the absence of endometrial cells, histiocytes on cervicovaginal smears of postmenopausal women are associated with more elevated relative risk for endometrial carcinoma.

Adenocarcinoma↗

Histiocytes and the detection of endometrial adenocarcinoma.

Histiocytes have long been recognized as part of the milieu of endometrial carcinoma in gynecologic smears. In an effort to determine whether a quantitative assessment of histiocytes, especially in the absence of endometrial cells, could increase the effectiveness of the cervicovaginal smear for diagnosis of endometrial carcinoma, smears obtained prior to a tissue diagnosis of endometrial adenocarcinoma were evaluated from 44 postmenopausal women. Smears from 97 age-matched patients in the same clinic were also evaluated and used as a control group for the endometrial carcinoma patients. All smears were evaluated for the presence of histiocytes and for the presence of benign or malignant endometrial cells, with the histiocytes quantitated as minimal (less than 5 per high-power field [HPF]), moderate (5 to 10/HPF) or heavy (greater than 10/HPF). Sensitivity and specificity were calculated to assess the role of histiocytes in the presence and in the absence of endometrial cells using cytologic findings. Our data indicate that the presence of moderate or heavy numbers of histiocytes on cervicovaginal smears of postmenopausal women increased the cytologic sensitivity from 61% to 82% when considered a marker of disease along with endometrial cells. These results suggest that attention to the presence of histiocytes on cervicovaginal smears may increase the utility of cytology for the diagnosis of endometrial lesions and may be a useful guideline for the cancer-related gynecologic examination.

Adenocarcinoma↗

[Histiocytic cytophagic panniculitis].

A HISTOPATHOLOGICAL DIAGNOSIS: Histiocytic cytophagic panniculitis is the specific skin finding in the reactive hemophagocytic syndrome. It is a feverish nodular eruption which accompanies the other clinical and biological features of the reactive hemophagocytic syndrome. Histopathologic changes are diagnostic and consist in a lobular panniculitis characterized by the presence of a histiocytic infiltration of the fat. Histiocytes are benign in appearance and show variable degree of phagocytosis. INFECTION AND IMMUNE ANOMALIES: In more than 50% of the cases, the disease is triggered by an infection (mainly a viral infection from the herpes-virus family) in a patient with altered immune function (immunodeficiency, autoimmune disease, hematological disease). Search for subcutaneous T-cell lymphoma is mandatory, but is a diagnostic challenge. Such lymphomas are associated with histologic features of histiocytic cytophagic panniculitis. PATHOPHYSIOLOGY: Histiocytes in the histiocytic cytophagic panniculitis are activated by an abnormal cytokine secretion (interferon gamma, granulocyte/macrophage colony stimulating factor, phagocytosis inducing factor, ...) from neoplastic or reactive T cells. CLINICAL TRIALS: Untreated, the course of the disease is usually lethal. Etiologic treatment should be provided whenever possible. Symptomatic treatment consists in transfusion and corticosteroid therapy. Etoposide, and sometimes cyclosporin, have been reported to be efficient. Some authors recommend that histiocytic cytophagic panniculitis should always be treated with a CHOP-like polychemotherapy. More recently, good results were obtained with high dose intravenous immunoglobulin and this treatment therefore deserves further evaluation.

Diagnosis, Differential↗

Postarthroplasty histiocytic lymphadenopathy in gynecologic oncology patients. A benign reactive process that clinically may be mistaken for cancer.

BACKGROUND: A distinctive histiocytosis occurs in the regional draining lymph nodes after large joint replacements, resulting in lymphadenopathy that may mimic cancer both grossly and microscopically. Postarthroplasty histiocytic lymphadenopathy has most often been observed in males during surgery for prostate cancer. METHODS: The authors present three examples of postarthroplasty histiocytic lymphadenopathy that occurred in gynecologic oncology patients. We studied the clinical, histologic, and immunohistochemical features of all three cases and the ultrastructure of one of them. RESULTS: Most involved lymph nodes were enlarged, but histiocytosis was also seen in normal sized lymph nodes. Microscopically, histiocytes with abundant granular cytoplasm were present in the lymph node parenchyma, and, to a lesser extent, in the sinuses. Normal lymph node architecture was variably effaced and the histiocytic infiltrate extended focally into the perinodal tissue. Small, black metal particles were present in the histiocytes in every case. Birefringent polyethylene particles were a prominent finding in all three cases as confirmed by positive modified oil red O staining, and, in one case, by electron microscopy. The histiocytes were strongly immunoreactive for CD68, but immunostains for S100 protein, MAC 387, and cytokeratin were negative. CONCLUSIONS: Enlargement of the lymph nodes in cancer patients who have had large joint replacements may be due to a benign histiocytosis rather than to metastatic cancer. The histologic features of the lymphadenopathy are distinctive and recognizable in routine histologic preparations. Polyethylene wear particles shed from joint prostheses are the most common substances in the histiocytes and are the most likely cause of the histiocytosis.

Aged↗

Malignant "histiocytic" lymphoma in childhood.

Forty-one cases of childhood "histiocytic" lymphoma were studied morphologically and immunologically to determine whether this tumor type is composed of true histiocytic cells. Lysozyme and alpha-1-antichymotrypsin were used as markers for histiocytes, and cytoplasmic immunoglobulins were used as markers for B cells. Both indirect immunofluorescence and immunoperoxidase methods were used for functional characterization of tumor cells. Eight different subgroups were identified in the series, and only one case was proved to be true histiocytic lymphoma. When survival was evaluated for different subgroups, excluding convoluted lymphocytic, unclassified, and true histiocytic lymphomas, mixed follicular cell lymphoma had the most favorable prognosis; six of seven patients survived for at least one year. Immunoblastic lymphoma, by contrast, had an unfavorable prognosis; none of four patients were alive one year after diagnosis. The difference is statistically significant (P < 0.05) by chi-square analysis. Other groups of lymphoma (large cleaved, large noncleaved, and small noncleaved) had an intermediae prognosis (three of five, six of nine, and five of nine patients surviving at one year). Our results indicate that "histiocytic" lymphoma is a morphologically heterogeneous group of neoplasms, mostly not related to true histiocytes, and that morphologic subclassification may be useful in predicting prognosis.

Child↗

Histiocytic lymphoma of the abdomen: radiographic spectrum.

Abdominal manifestations of histiocytic lymphoma were reviewed in 112 patients who had at least a 2-year follow-up period or had died. In 70% abdominal histiocytic lymphoma was found and in 29% histiocytic lymphoma was initially limited to the abdomen. Localized abdominal histiocytic lymphoma presented as (1) intrinsic disease of the stomach, (2) pancreatic/peripancreatic masses, (3) high aortic lymphadenopathy, (4) mesenteric masses associated with small bowel infiltration, and (5) intrinsic ileocolic masses. When all patients with abdominal histiocytic lymphoma are considered, computed tomography was positive in 87%, lymphography in 86%, upper gastrointestinal barium examination in 50%, excretory urography in 38%, and barium enema in 25%. The extent of abdominal histiocytic lymphoma was more accurately assessed with computed tomography than any other radiologic examination including lymphography. Computed tomography seems to be the radiologic examination of choice in the staging of abdominal histiocytic lymphoma; the other examinations should be used when specific symptoms are present or when the computed tomographic findings are equivocal.

Abdominal Neoplasms↗

Malignant histiocytosis: a reassessment of cases formerly classified as histiocytic neoplasms and review of the literature.

Malignant histiocytosis (MH) and true histiocytic lymphoma (THL) are hematopoietic malignancies of the mononuclear phagocytic system distinguished from each other by clinical presentation and presumed cell of origin. THL present as a localized mass derived from the fixed tissue histiocyte which may or may not disseminate. MH originates from the circulating monocyte or tissue macrophage and is characterized by a syndrome of systemic symptoms, pancytopenia, adenopathy, hepatosplenomegaly, and wasting. The distinction between MH and THL is at times arbitrary and overlap exists between these syndromes. The clinicopathologic studies that defined these entities were performed prior to the development of immunophenotyping and other molecular techniques currently used to ensure proper classification of hematopoietic malignancies. Nine patients from the University of Minnesota originally diagnosed with MH were retrospectively analyzed using a panel of antibodies reactive against T cell, B cell, and myelomonocytic antigens. Only one patient was reclassified as a possible histiocytic malignancy after reevaluation. Similar immunophenotyping studies have also shown cases previously diagnosed as MH or THL express lymphoid antigens, and would now be classified as Ki-1 positive anaplastic large cell lymphoma (ALCL) or some other hematopoietic neoplasm. These results indicate true histiocytic neoplasms are extremely rare, and previous concepts concerning clinical presentation and therapeutic outcome of the entities are inaccurate. In this paper we summarize the results of multiple retrospective analyses of cases previously diagnosed as MH or THL, including our experience at University of Minnesota, to illustrate the overall rarity of these entities. The current literature on malignant histiocytic disorders is reviewed, and the clinical presentation of patients determined to have histiocytic malignancies using contemporary analytical techniques is discussed.

Histiocytic Disorders, Malignant↗

Visceral leishmaniasis: II. Histiocyte ultrastructure in bone marrow associated with low level of parasitaemia and mimicking malignant histiocytosis.

The ultrastructural features of histiocytes in the bone marrow (BM) were studied in a febrile, splenomegalic and pancytopenic Sudanese patient who was diagnosed by one of us as visceral leishmaniasis (VL) associated with low level of parasitaemia and mimicking malignant histiocytosis (MH). Serial thick (STS) and ultrathin (SUT) sections showed that the BM was hypercellular and markedly infiltrated by large histiocytes with prominent phagocytosis. A thorough examination of various ST and UT section revealed only a single, typical Leishman-Donovan body. At transmission electron microscopy (TEM) level, two principal types of histiocytic cells were identified: Type I, subdivided into two subtypes, were actively phagocytic histiocytes (PH) with large digestive vacuoles and primary lysosomes; type II were nonphagocytic histiocytes (nPH) with primary lysosomes only. The rate of PH to nPH ws 7:2 in plastic STS. The interaction between the PH and ingested cells is described. Both types of cell were morphologically similar to previously described malignant histiocytic cells. However, this study showed a better characterization of PH during VL.

Adult↗

T-zone histiocytes in adenocarcinoma of the lung in relation to postoperative prognosis.

Infiltration of T-zone histiocytes (Langerhans' cells and their precursors) and macrophages was investigated by immunohistochemical methods with the use of anti-S100 protein and anti-lysozyme antibodies in 40 Stage Ia cases of adenocarcinoma of the lung. Varying population densities of S100+ T-zone histiocytes were demonstrated in 31 (77.5%) of 40 adenocarcinomas; however, lysozyme+ macrophages were found in almost equal quantities in all cases of adenocarcinoma. The distribution of T-zone histiocytes was clearly different from that of macrophages. Namely, the former was mainly interspersed among the tumor cells, whereas macrophages were found in the stroma and around necrotic foci. The prognosis of Stage Ia adenocarcinoma cases was related to the density of T-zone histiocytes in tumor tissues. Patients with marked infiltration of T-zone histiocytes survived longer than those without or with only slight infiltration (P less than 0.05). Such relationship was not observed with regard to macrophages. This indicates that T-zone histiocytes infiltrating within the tumor and regional lymph nodes may play a role in host defense mechanisms against tumor in the early stage of adenocarcinoma of the lung.

Adenocarcinoma↗

Histiocytic aggregates in benign nodular goiters mimicking cytologic features of papillary thyroid carcinoma (PTC).

Macrophages/histiocytes are commonly seen in fine-needle aspiration biopsy (FNAB) specimens of thyroid nodules with varying degrees of cystic change. In some cases the histiocytic component of a cystic thyroid nodule can occur as large tissue fragments with marked nuclear atypia, including elongated nuclei with chromatin clearing, nuclear grooves, and membrane thickening. These nuclear changes mimic cytologic features of papillary thyroid carcinoma (PTC), thus leading to diagnostic difficulty in interpretation of FNAB specimens of benign cystic thyroid nodules. We evaluated ethanol-fixed Papanicolaou-stained smears of 273 cases of FNAB thyroid specimens from goitrous nodules with cystic change. Twenty cases were selected due to the presence of large aggregates of histiocytic cells with the above-mentioned nuclear atypia. An immunostain for histiocytic cells using CD68 was performed on alcohol-fixed slides. Histiocytic cells in tissue fragments with nuclear atypia mimicking PTC nuclei showed strong cytoplasmic staining for CD68; thyroid follicular cells stained negative for CD68. We conclude that histiocytic cells in cystic goitrous nodules can show nuclear features, which appear similar to PTC nuclei. Immunostaining for CD68 may be of value in differentiating between benign cystic thyroid nodules with histiocytic aggregates that mimic cytologic features of papillary carcinoma, and PTC with cystic change.

Adult↗