True histiocytic lymphoma

It is likely that a significant number of cases of THL will continue to be misdiagnosed unless appropriate cytochemical and immunologic markers are incorporated into the panel of studies performed at diagnosis. The clinical findings are nonspecific. With the possible exception of skin infiltration, the frequency of symptoms and signs appear to approximate those of intermediate grade lymphomas. Most commonly, it is the histopathological features that suggest the histiocytic nature of a malignant process, but these alone are not sufficient to secure the diagnosis. Thus, in the absence of a clearly defined lymphoid origin, it is the detection of specific histiocytic markers that establishes a lymphoma as THL. Only the recognition and careful study of additional cases will potentially enable clinical investigators to identify any unique characteristics and distinguish this disease from other lymphomas. For the present, it would appear that the treatment indicated for a patient with diffuse large cell lymphoma would also be appropriate for a comparable patient with THL. Although long-term disease-free survival in THL is possible, there are presently inadequate data to estimate curability.     

True Histiocytic Lymphoma: A Study of 12 Cases Based on Current Definition

True histiocytic lymphoma (THL), as it is currently defined, is a rare entity. We report 12 cases of THL seen at Stanford over the last ten years. By definition, the neoplastic cells in each case showed histological and immunological evidence of histiocytic differentiation. Seven females and five males ranged in age from 9 to 67 years. Sites of involvement included lymph node, soft tissue, bone, stomach, small intestine, mediastinum, kidney, breast and salivary gland. Lymph nodes showed diffuse architectural effacement and/or a paracortical pattern of involvement. The infiltrates involved other tissues in a diffuse pattern. Cytologically the cells were characterized by abundant eosinophilic cytoplasm and enlarged, indented eccentrically placed nuclei containing prominent nucleoli. In all cases the cytological features were sufficiently atypical to indicate a neoplastic infiltrate. Paraffin section immunophenotyping demonstrated reactivity of the atypical cells for CD15, 43, 45RO, 45RB, 68, lysozyme and/or S100. In frozen sections, the atypical cells demonstrated reactivity for CD4 (cytoplasmic), 11c, 14, 15, and/or 68. Genotypic studies were performed on 3 cases, one of which showed rearrangements of immunoglobulin heavy and light chain genes. Follow-up was available on eleven patients, six of whom died of disease 0.5 to 36 months following diagnosis.     

Diagnostic significance of histiocyte-related markers in malignant histiocytosis and true histiocytic lymphoma

Interrelationships of immunologic and enzymatic markers of histiocytes have been studied in malignant neoplasms of histiocytic/monocytic origin and in differential diagnostically relevant, large cell non-Hodgkin's lymphomas. Cryostat sections required for demonstrating cell surface antigens by monoclonal antibodies are inadequate for studying cellular detail, enzymatic maturation by alpha-naphthyl acetate esterase (ANAE), and demonstrating the classical cytoplasmic markers of histiocytes like lysozyme, alpha-1-antitrypsin (AT), and alpha-1-antichymotrypsin (ACT). These markers have been compared in gently fixed and vacuum paraffin-embedded material. The reactivity for monoclonal anti-human monocyte 1 (Mo 1) has also been preserved by this method. Malignant histiocytosis (MH) is characterized by a heterogeneous cell population. The mature, ANAE-positive cells with macrophage morphology usually show a diffuse cytoplasmic positivity for AT and ACT. Lysozyme is moderately positive to negative in these cells, but it is more efficient than these markers in revealing smaller cells resembling monocytes by focal positivity in the cytoplasm. The expression of Factor XIIIa (F-XIIIa) is connected with the phagocytic activation of histiocytic cells. F-XIIIa positive cells usually form a minority of the neoplastic population in MH, but the large cytophagocytic marcophages are invariably positive. Reactive macrophages in large cell non-Hodgkin's lymphomas are characterized by a coexpression of ANAE, AT, ACT, lysozyme, F-XIIIa and Mo 1. Typical cases of true histiocytic lymphoma (THL) are made up of a homogeneous population showing the above mature, phagocytizing phenotype. In MH, Mo 1 and ANAE recognize different subpopulations. The reciprocal relation of these markers is an abnormal phenotypic feature. The results presented in this article prove the diagnostic value of ANAE and lysozyme in confirming the histiocytic differentiation of malignant cells. Monoclonal anti-human monocyte 1 is useful for identifying the immature component in MH. Factor XIIIa can be considered a functional marker of mature phagocytic histiocytes and an aid in the diagnosis of THL.     

Non-Hodgkin's lymphomas: an ultrastructural study correlating morphology with immunologic cell type.

Ultrastructural studies were performed on 40 B-cell and 14 T-cell lymphomas of non-Hodgkin's type (NHL). Most B-cell lymphomas were comprised of neoplastic cells with morphologic features compatible with a follicular center cell origin. Dendritic reticulum cells and their desmosome-associated processes, characteristic of germinal centers, were observed in all 11 cases of nodular poorly differentiated lymphocytic lymphoma and in one of two cases of nodular "histiocytic" lymphoma, but were not identified in the lymphomas with a diffuse growth pattern. Desmosomes were observed between dendritic reticulum cells and were not found between lymphoid cells. Large neoplastic cells comprising lymphomas of "histiocytic," mixed lymphocytic "histiocytic," and "undifferentiated" types were characterized ultrastructurally and immunologically as lymphoid cells. Malignant lymphomas of well and moderately well differentiated lymphocytic types (7 cases) revealed B-cell markers, and represented a distinct homogenous group of neoplasms, with electron microscopic features most closely resembling follicular cuff lymphocytes. T-cell malignancies included lymphoblastic lymphomas (3 cases), large cell ("histiocytic") lymphomas (4 cases), lymphoepithelioid cell ("Lennert's") lymphomas (2 cases), mycosis fungoides (3 cases) and diffuse poorly differentiated lymphocytic lymphomas (2 cases). A consistent finding in the T-cell proliferations was the presence of small and/or large lymphoid cells with extremely irregular and/or convoluted nuclei, which occurred in varying proportions and with variable degrees of nuclear complexity. The nuclear irregularity evident in the neoplastic T cells was distinguishable from that observed for lymphoid cells of B-cell lymphomas. In comparing the cytoplasmic features of the T- and B-cell neoplasms ultrastructurally, the only distinguishing feature was the presence of well developed granular endoplasmic reticulum with dilated cisternae, i.e., plasmacytoid features, predictive of a B cell origin.     

Malignant lymphoma of true histiocytic (monocyte/macrophage) origin

Since the advent of the newer classifications of non-Hodgkin's lymphoma and the realization that the majority of tumors classified as histiocytic under the Rappaport classification were in fact of lymphocytic origin, there have been remarkably few reports of true histiocytic (monocyte/macrophage) tumors and it has been suggested by some that such tumors should not be considered as a variety of malignant lymphoma. This article describes five patients with malignant lymphoma of neither B- or T-lymphocyte origin in whom the malignant cells could be characterised immunologically, cytochemically, and immunohistochemically as of true histiocytic derivation. The cases showed considerable morphologic diversity but there were shared characteristics at both light microscopic and ultrastructural levels. Positive immunohistochemical staining for alpha 1-antitrypsin was the single most useful criterion in classifying these tumors. Without the use of special techniques there were no clinical or pathologic features that reliably distinguished these cases from non-Hodgkin's lymphomas of lymphocytic derivation. Tumors of histiocytic origin are, therefore, inevitably being included among the non-Hodgkin's lymphomas and are most appropriately classified as such. Identification of histiocytic lymphomas should be encouraged so prognosis and optimum treatment can be established.     

Biology of the human malignant lymphomas. IV. Functional characterization of ten diffuse histiocytic lymphoma cell lines.

Ten consecutive diffuse histiocytic lymphoma (DHL) cell lines established in our laboratory were studied for the presence of Epstein-Barr virus (EBV) genomes, lysozyme, nonspecific esterase and other cytochemical reactions, phagocytic activity, cytoplasmic immunoglobulin light and heavy chains, and surface receptors to sheep erythrocytes, complement, and the Fc fragment of immunoglobulin. In agreement with previous studies performed on biopsy specimens, our results indicate that the diffuse histiocytic lymphomas, as a histopathologic entity, represent a heterogeneous group of neoplasms, the majority of which are B-lymphocyte in origin. The cell lines appear to fall into three categories based on the following criteria: 1) presence of monoclonal cytoplasmic immunoglobulins (B-lymphocytic type, 6/10 cell lines); 2) presence of non-specific esterase, phagocytic activity, and/or lysozyme (histiocytic type, 2/10 cell lines); and 3) absence of all lymphoid and histiocytic cell characteristics (null cell type, 2/10 cell lines). Despite the fact that many of the lymphoma patients had positive serologies to EBV antigens, all of the DHL cell lines were negative for the presence of EBV genomes. Both of the two B-lymphocytic type and one of the two histiocytic type lines tested were susceptible to infection with EBV, as indicated by synthesis of early antigen and also, in a small proportion of the infected cells, of viral capsid antigen. These prototypic DHL cell lines may permit the development of new criteria for the differential diagnosis and treatment of this highly malignant and diverse group of lymphomas.     

Nodal B-Cell Lymphomas in Japan -- Particularly in Tohoku District --

There are different frequencies in the immunological phenotypesof malignant lymphomas in Tohoku and Kyushu districts of Japan.In the Tohoku district, the northern area of Honshu, B-celllymphomas are more preponderant than T-cell lymphomas. Thisis just the reverse on the islands of Kyushu and Shikoku. Histologicallydiffuse lymphoma of large cell type, formerly termed reticulumcell sarcoma or histiocytic lymphoma, was the most frequent(48%) among B-cell lymphomas. It is characteristic of B-celllymphoma that immunoglobulin is produced in either or both thecellular surface and cytoplasm. Cytoplasmic IgM in lymphomacells was mainly detected by an electron microscopic enzyme-labeledmethod. Cytoplasmic-Ig was present both in the nuclear membraneand endoplasmic reticulum. This technique is particularly usefulin medium-sized lymphoma cells because of the scanty cytoplasmicrim making light microscopic evaluation difficult. Histological transition from follicular to diffuse pattern ischaracterized by a change of cellular arrangement from labyrinth-likecellular connections in follicular lymphoma to more simple connectionsin diffuse lymphoma. The transition is also supported by thefact that a higher deoxyribonucleic acid content is observedin large cells than medium-sized cells in follicular lymphoma.The data also supports the hypothesis that a diffuse lymphomaevolved from follicular lymphoma mainly occurs in cases of largecell lymphomas.     

An investigation of Ki-1 positive large cell lymphoma with antibodies reactive with tissue macrophages

The diagnosis of true histiocytic lymphoma (THL) represents one of the most difficult and controversial areas of lymph node pathology. Recently, Stein et al. (1985) have demonstrated that a series of tumours presenting with morphological and immunocytochemical features, previously considered as being indicative of THL, share antigenic markers with Reed-Sternberg and mononuclear Hodgkin's cells and, therefore, may be derived from lymphocytes, rather than histiocytes. In this study we have re-investigated some of these cases with a panel of monoclonal antibodies variously reactive with macrophages. Although all cases contain a heavy infiltrate of reactive histiocytes the tumour populations are negative for histiocyte antigens.     

Surface glycoprotein patterns of normal and malignant human lymphoid cells. II. B cells, B blasts and Epstein-Barr virus (EBV)-positive and -negative B lymphoid cell lines.

Surface glycoproteins of normal human B lymphocytes, B blasts and various types of lymphoid cell lines were labelled by the galactose oxidase-tritiated sodium borohydride method. The labelled glycoproteins were separated by polyacryUmide slab gel electrophoresis in the presence of sodium dodecy! sulfate and visualized by modified autoradiography (fluorography). The battery of examined hematopoietic cell lines included Epstein-Barr virus (EBV) carrying lines of proven malignant origin (Burkitt's lymphoma) and presumed non-neoplastic origin (lymphoblastoid cell lines), and EBV-genome-negative lymphocytic lymphoma, histiocytic lymphoma, myeloma and myeloid leukemia lines. The presence of possible EBV-associated surface glycoproteins, detectable by the labelling method, was studied by use of two EBV-negative cell lines (BJAB and Ramos) and their EBV-converted sublines. The six Burkitt lymphoma and three lymphocytic lymphoma lines had all the basic surface glycoprotein pattern of resting B cells and, in addition to individually distinct bands, two characteristic pairs of glycoproteins sf apparent molecular weights of 87,000/85,000 and 71,000/69,OOO. These glycoproteins were not detected on the normal B celts, B blasts or non-neoplastic lymphoblastoid lines. Neither were they found on the other types of neoptastic line. No consistent difference in the surface glycoprotein patterns was detected between the EBV-genome-negative and EBV-con-verted BJAB and Ramos sublines. The glycoprotein pattern of the six lymphoblastoid lines resembled that of the B blasts. The histiocytic lymphoma, myeloma and leukemia lines all had distinct patterns. These results confirm that the Burkitt's lymphoma and the lymphoblastoid cell lines represent two biologically distinct EBV-carrying B lymphoid celts and that the galactose oxidase NaB[³H]₄ surface labelling technique can be used as a reliable molecular mapping method to distinguish between these two and other types of lymphoid cell lines.     

Establishment and characterization of a human histiocytic lymphoma cell line (U-937).

A human hematopoietic cell line (U-937) with exceptional characteristics was derived from a patient with generalized histiocytic lymphoma. The morphology of the cell line was identical to that of the tumor cells in the pleural effusion from which the line was derived. Since Epstein-Barr virus (EBV) carrying diploid lymphoblastoid cell lines unrelated to the tumor population often become established in vitro from non-Burkitt lymphoma explants, several parameters were studied to discriminate the U-937 from such lines: morphology in vitro, growth characteristics, cytochemistry, surface receptor pattern, Ig production, lysozyme production, beta2-microglobulin production, presence of EBV genome and karyotype. In all these respects U-937 differed from prototype lymphoblastoid cell lines. The histiocytic origin of the cell line was shown by its capacity for lysozyme production and the strong esterase activity (naphtol AS-D acetate esterase inhibited by NaF) of the cells. It is therefore concluded that the U-937 is a neoplastic, histiocytic cell line.     

皮肤真性组织细胞性淋巴瘤的诊断与误诊分析

目的 探讨右大腿皮肤组织细胞性恶性淋巴瘤的诊断、误诊原因及预防对策。方法 对1例皮肤组织细胞性淋巴瘤的标本，采用10％的福尔马林固定，石蜡切片，HE、网状纤维染色及多种免疫组化染色，光镜观察、会诊及病理读片会讨论。结果 临床因早期表现为局部单发肿块，皮肤改变不明显而误诊为皮肤纤维瘤，病理则因组织学上既象淋巴瘤样细胞弥漫分布又有瘤细胞互相粘着不松散而似癌细胞巢，且瘤细胞核大，核仁明显又似恶性黑色素瘤，凭皿切片难以诊断，免疫组化及会诊结果为皮肤组织细胞性恶性淋巴瘤。结论 原发于皮肤的组织细胞性恶性淋巴瘤非常少见。组织学上注意与蕈样霉菌病、美克耳细胞癌、恶性黑色素瘤、恶性组织细胞增生症等鉴别。免疫组化不支持上述病变时要想到本病的可能。误诊的主要原因是早期临床表现不具有特征性，肿瘤发病部位及类型罕见，临床及病理对此类型淋巴瘤认识不深，未能及时进行免疫组化检查。     

滤泡细胞性淋巴瘤转化为c-MYC重排的“双击”或“三击”B细胞淋巴瘤3例及文献复习

  目的   本文旨在对“双击”B细胞淋巴瘤（double-hit B-cell lymphoma,DHL）和“三击”B细胞淋巴瘤（triple-hit B-cell lymphoma,THL）的诊断及治疗分析,以期提高对该类淋巴瘤的认识,为其诊治提供临床经验。   方法   对2011年1月至2012年12月本院收治的3例滤泡细胞性淋巴瘤（follicular lymphoma,FL）转化的“双击”或“三击”B细胞淋巴瘤病例进行分析,3例患者均经免疫组织化学、荧光染色体原位杂交（fluorescence in situ hybridization,FISH）检测诊断明确。   结果   1例“三击”患者3个月后死亡,2例经R-CHOP,R-ESHAP等方案化疗仍未达到完全缓解。   结论   “双击”淋巴恶性程度高,多伴有中枢神经系统、骨髓等髓外病变,病程呈侵袭性,部分病例由滤泡细胞淋巴瘤转化而来,对化疗不敏感,患者预后差,FISH检测是诊断该病的重要手段,目前尚无标准治疗方案。      

Nodular lymphocytic lymphoma eventuating into diffuse histiocytic lymphoma: immunoperoxidase demonstration of monoclonality.

The patient described here had a nodular, poorly differentiated lymphocytic lymphoma associated with a serum monoclonal protein, IgG lambda. Following a three year period of radiation-induced clinical remission she developed generalized diffuse histiocytic lymphoma. Direct immunoperoxidase staining of the tissue sections demonstrated that the neoplastic cells of each biopsy only contained IgG lambda immunoglobulin, identical to the serum monoclonal protein. This is presumptive evidence that these two histopathologically distinctive malignant lymphomas, occurring consecutively in the same patient, were responsible for the synthesis and secretion of the same serum M component. This strongly suggests that both lymphoid neoplasms arose from the same malignant clone. The results 1) confirm the light microscopic observation that nodular lymphocytic lymphoma may progress to diffuse histiocytic lymphoma and 2) offer further evidence that histiocytic lymphomas arising in patients with previous B cell malignancies are most probably related to the original B cell proliferation and do not represent the emergence of a second, separate malignant clone.     

Multilaminar endoplasmic reticulum and abnormal mitosis in Hodgkin tumor cells.

A multilaminar alteration of endoplasmic reticulum (ER) has been observed in tumor cells of eight patients with Hodgkin's disease and a patient with histiocytic lymphoma. These multilaminar structures are more numerous in dividing cells and thus appear to arise primarily during mitosis. The stacked membranes in the multilaminar structures possibly result from abnormal sticking of organelle membranes, as evidenced in this study of adherence of ER to other elements of ER, nuclear envelope, mitochondria, or lipid droplets. Multilaminar ER was identified in all mitotic tumor cells, a rare mitotic plasma cell, and numerous interphase Hodgkin cells. The paucity of multilaminar ER in normal mitotic cells and its virtual absence for normal interphase cells suggest that this structure represents a pathological alteration in tumor cells from patients with Hodgkin's disease and histiocytic lymphoma. The multilaminar defect of ER is associated with other atypical features of ER in Hodgkin tumor cells, including the excessive length and curving of ER profiles, the collapse of the ER cisternae, and the overall sparsity of this organelle. Other abnormalities observed in mitotic Hodgkin tumor cells include the presence of disorganized microtubules, large cytoplasmic vacuoles, and abnormally clumped chromosomal material and the persistence throughout mitosis of bodies suggestive of nucleoli and of the nuclear bodies of interphase cells.     

Primary lymphoma of the breast: ultrastructural study of two cases.

Two cases of primary non-Hodgkin's lymphomas of the breast were studied with light and electron microscopy. By light microscopy, according to Rappaport's classification, one was a poorly differentiated lymphocytic lymphoma, the other a diffuse histiocytic lymphoma. However, the ultrastructural features of the latter were more consistent with transformed lymphocytes. The differential diagnosis with medullary and poorly differentiated carcinomas of the breast is discussed. The first case had rapid dissemination as did most of the cases reported in the literature.     

Leukemic High Grade B Cell Lymphoma is Associated With MYC Translocation,Double Hit/Triple Hit Status,Transformation, and CNS Disease Risk: The Mayo Clinic Experience

Introduction: Leukemic involvement in high grade B cell lymphoma (L-HGBL) is rare and has been sparsely described in the literature. We report our experience in a large single institution multicenter academic setting. Materials and Methods: Medical records of patients with HGBL who received care at Mayo Clinic between 2003 and 2020 were reviewed. L-HGBL was confirmed by peripheral blood smear and flow cytometry with corroboration from tissue and bone marrow biopsy findings. Results: Twenty patients met inclusion criteria. All patients had significant bone marrow involvement by HGBL. Leukemic involvement presented in 11 of 20 (55%) in the de novo and 9 of 20 (45%) in the relapsed setting. Seven of 20 patients had DLBCL, NOS, 6 of 20 had transformation (t-DLBCL), 3 of 20 had transformed double/triple hit lymphoma (t-DHL/THL), 2 of 20 had double hit lymphoma (DHL), and 2 of 20 had HGBL with intermediate features between DLBCL and Burkitt lymphoma. Nine of 15 patients had MYC translocation. Based on Hans criteria, 11 of 20 had germinal center B-cell (GCB) cell of origin (COO) and 9/20 had non-GCB COO. Five of 11 de novo patients experienced CNS relapse/progression. All de novo patients received anthracycline-based chemoimmunotherapy. Eighteen of 20 patients died of progressive disease. Median overall survival was significantly better in the de novo compared to relapsed group (8.9 months vs. 2.8 months, P = .01). COO, MYC status, DHL/THL status, HGBL subtype, or treatment group did not demonstrate a significant effect on overall survival. Conclusion: L-HGBL carries a poor prognosis and is associated with MYC translocation, DHL/THL status, transformation, and high CNS risk. Novel therapeutic approaches are needed for L-HGBL.     

Primary gastrointestinal lymphomas: a classification of 66 cases.

Using routine histology, resin embedded sections and immunohistochemical techniques on formalin-fixed, paraffin processed tissue, 66 cases of primary gastrointestinal lymphoma have been classified. This study necessitated the development of reliable criteria to separate lymphomas of true histiocytic origin from those of lymphocytic origin. Among the morphologic properties of malignant histiocytes were complex pleomorphic nuclei, abundant well delineated cytoplasm and phagocytosis. These cells were shown to contain all major immunoglobulin chains, C3, lysozyme and in some cases alpha 1 antitrypsin. Malignant lymphomas derived from histiocytes could be divided into two groups: malignant histiocytosis of the intestine (MHI), a recently described diffuse pleomorphic lymphoma associated with villous atrophy of the small intestine, and histiocytic lymphoma (HL) which forms solid tumor masses in a similar manner to lymphocyte derived tumors. Immunohistochemical studies of lymphocyte derived tumors were negative apart from one case with plasmacytoid differentiation. Of the 66 cases, 50% were of histiocytic origin (33% MHI, 17% HL) and 41% of lymphocyte origin, there was one case of Hodgkin's disease and five cases were unclassified. The role of the histiocyte in gastrointestinal mucosa deserves further study.     

Histiocytic lymphoma with sclerosis arising from a nodular lymphoma with a special stromal reaction.

Histiocytic lymphoma with sclerosis was found together with a small nodular lymphoma in a cervical lymph node biopsy from a 48-year-old man. Since the cellular origin of this entity is unclear and its ultrastructure has not been described before, we processed formalin-fixed samples for electron microscopy, which revealed three cell types: small lymphocytes with cleaved nuclei, large lymphocytes with vesticular noncleaved nuclei, and mesenchymal stromal cells occasionally bearing desmosomes or hemidesmosomes. In addition, there was an increase of the intercellular connective tissue, which consisted of a mixture of normal and fibrous long spacing collagen fibers. The results indicate that histiocytic lymphoma with sclerosis can evolve from a nodular lymphoma, and that diagnostic information can be obtained by electron microscopy of tissue samples previously fixed in formalin.     

Primary intracranial histiocytic lymphoma with Langerhans' granules. A light microscopic and ultrastructural study

An intracranial tumor classified as a histiocytic lymphoma was studied with light and electron microscopic examination and immunocytochemical methods. The characteristics of the malignant mononuclear phagocyte cells are described. The presence of some cells containing Langerhans' granules suggests differentiation towards a specialized cell of the mononuclear phagocyte system: the Langerhans' cell.     

Coexistence of leukemic reticuloendotheliosis and histiocytic lymphoma: a case report.

A 65-year-old woman had pancytopenia, splenomegaly, and an inaspirable bone marrow. Diagnostic evaluation demonstrated that she had both leukemic reticuloendotheliosis (LRE), or hairy cell leukemia, and an additional lympho-reticular neoplasm, most likely a "histiocytic" lymphoma. The diagnosis of LRE was based on the histopathology of spleen tissue and of a bone marrow biopsy specimen. The diagnosis of diffuse "histiocytic" lymphoma was based on the histopathology of a splenic hilar and a mesenteric lymph node, tumor nodules in the kidney and spleen, and tissue from a mass obstructing a ureter. This is the first well-documented association of a second lympho-reticular neoplasm with LRE. Even relatively gently treatment of the "histiocytic" lymphoma resulted in fatal pancytopenia, illustrating the restricitons on therapy imposed by the marrow impairment due to the LRE.