K. Lennert

The Histopathology of Malignant Lymphoma

It has been possible to reinterpret non‐Hodgkins lymphomas by applying subtle histological, cytological, and cytochemical techniques and electron microscopy as well as by using modern immunological methods and immune chemical analyses. This has led to the differentiation of four main groups of low‐grade and three main groups of high‐grade malignant lymphomas. Most non‐Hodgkins lymphomas are derived from the B‐lymphocyte system. Only some of the lymphocytic, a small fraction of the lymphoblastic, and very few immunoblastic lymphomas originate from the T‐lymphocyte system. True reticulosarcomas are very rare and will have to be redefined.

Primary B-cell gastric lymphoma: A clinicopathological study of 145 patients

Resection specimens from 145 patients with primary B-cell gastric lymphoma at stage IE (n = 88) and at stage IIE (n = 57) were investigated. Histologically, low-grade malignant B-cell lymphomas arising from the mucosa-associated lymphoid tissue, including immunocytoma (n = 71), could be distinguished from high-grade malignant B-cell lymphomas with (n = 25) and without (n = 49) evidence of a low-grade component. The very rare low-grade B-cell lymphomas of centroblastic-centrocytic, centrocytic, and plasmacytic type were not considered. All patients had undergone primary gastric resection, and 65 received additional chemotherapy (n = 33), radiotherapy (n = 22), or both (n = 10). Actuarial overall survival rates calculated by the Kaplan-Meier life-table method were 76% after 5 years and 58% after 10 years. According to the Mantel test and a multivariate analysis using the Cox regression method, patients at stage IE had a significantly better survival probability than those at stage IIE (P less than 0.0001); 5-year survival rates were 87% and 61%, respectively. The survival probability for low-grade malignant lymphomas was significantly better than for tumors with secondary high-grade transformation (P less than 0.05) or for primary high-grade lymphomas (P less than 0.0001), whereas the two high-grade groups were not significantly different. Five-year survival rates were 91% for low-grade, 73% for secondary high-grade, and 56% for primary high-grade malignant lymphomas. Retrospectively, no significantly different survival rates were found between patients who had undergone gastric resection alone and patients who had received additional treatment. However, survival analyses showed that classification and grading according to the histopathological concept of mucosa-associated lymphoid tissue-derived gastric lymphomas into low-grade B-cell lymphomas of mucosa-associated lymphoid tissue type and high-grade B-cell lymphomas with or without evidence of a low-grade component has great prognostic relevance.

Primary lymphomas of the lung: morphological, immunohistochemical and clinical features

Sixty‐two cases of primary malignant lymphoma of the were investigated. Fifty‐eight lymphomas were of B‐ and two of T‐cell type. Two cases of high‐grade homa could not be further classified. The largest group (43 cases) consisted of low‐grade B‐cell lymphoma of the bronchus‐associated lymphoid tissue. These showed features similar to low‐grade B‐cell lymphomas of the mucosa‐associated lymphoid tissue of the stomach. The low‐grade lymphomas showed a peak occurrence in the sixth decade, the high‐grade lymphomas in venth decade. Males predominated slightly. Three‐quarters of the patients with low‐grade B‐cell lymphoma of the bronchus‐associated lymphoid tissue showed solitary or multiple sharply defined nodules of the lung. The prognosis of the B‐cell‐derived lung lymphomas without constitutional symptoms was relatively favourable, regardless of whether they were of low‐ or high‐grade malignancy, whereas patients with constitutional symptoms and the two patients with T‐cell lymphomas showed a bad prognosis. However, recurrences and metastases in the lung, stomach, lymph nodes and salivary glands were seen in about 46% of the cases of low‐grade B‐cell lymphoma of the bronchus‐associated lymphoid tissue.

Immunohistological Analysis of Human Lymphoma: Correlation of Histological and Immunological Categories

Publisher Summary The analysis of human tissue lymphoma biopsies by immunohistological techniques provides the opportunity for investigating whether previously established histological categories can be correlated with different patterns of antigen expression. The results reported in the chapter are gratifying in the context that many previously recognized lymphoma categories do indeed appear to represent immunologically distinct entities. In particular the concept, central to the Kiel classification, that many non-Hodgkins lymphomas, both diffuse and follicular, are derived from germinal center cells is confirmed in this study. Immunohistological analysis has also shed new light on the diffuse lymphomas. No clear-cut distinction can be drawn at present between the two major large cell categories found in the Kiel classification—centroblastic and immunoblastic. The nature of lymphomas expressing Ki-1 antigen and their relationship to Hodgkins disease requires to be elucidated. The results reported through this chapter indicate that while providing much new insight into human lymphoma, immunohistological studies also raise many new and fascinating questions.

Mast cells and mast cell neoplasia: a review*

MC are diffusely distributed throughout the connective tissue. Most of the conventional staining methods applied to tissue sections fail to visualize these cells. In Giemsa-stained sections, however, MC can be easily identified by the typical metachromasia of their lysosomal granules, which is due to the high affinity of MC granules to basic dyes, such as toluidine blue or thionin (Padawer 1959, Lison 1960). The cytoplasmic granules of MC show intense reactivity for naphtho1-AS-Dchloroacetate esterase (Leder 1964), with which even immature MC can be selectively stained . In tissue imprints and bone marrow smears, MC are easily discernible from blood basophils. Blood basophils contain many fewer granules and show a negative reaction for chloroacetate esterase. In sections from routinely fixed and embedded tissue, it is not possible to stain blood basophils, because their granules are water-soluble: the reason why most pathologists are less familiar with this particular type of granulocyte. The difference in water-solubility and preservation between the granules of M C and those of blood basophils appears, by itself, to be a good argument in favour

Bone marrow findings in systemic mastocytosis

The neoplastic proliferation of tissue mast cells constitutes a group of rare diseases that have localized and systemic variants. The cytologic (n = 7) and histologic (n = 38) findings in bone marrow from a total of 45 patients with systemic mastocytosis were evaluated. Three distinct histologic patterns of marrow involvement were distinguished. In 21 cases a patchy or focal infiltration pattern was encountered. Mast cell aggregates were located predominantly in peritrabecular and perivascular areas. The adjacent trabeculae were thickened. A dense network of reticulin fibers and foci of lymphocytes accompanied the mast cell infiltrates. Increased numbers of eosinophils frequently demarcated the mast cell infiltrates from the surrounding tissue. In the noninfiltrated marrow areas hematopoiesis and the distribution of fat cells appeared to be normal. This histologic pattern, designated type 1, was observed exclusively in patients showing primary involvement of the skin, indistinguishable from urticaria pigmentosa. In 14 additional cases peritrabecular and perivascular sheets of mast cells, with concomitant fibrosis and osteosclerosis, were also present. Unlike the findings in type 1, however, the noninfiltrated marrow areas showed marked reductions in fat cell content and markedly increased granulocytopoiesis or increased numbers of blast cells (infiltration pattern type 2). On the basis of the hematologic and clinical findings, chronic myeloid leukemia was diagnosed in six of these cases, myelomonocytic leukemia in three cases, and acute myeloid leukemia in two cases. The bone marrow of three patients was diffusely infiltrated by atypical mast cells, leading to marked hypoplasia of fat cells and blood cell precursors. These histologic features were identified as infiltration pattern type 3. The diagnosis of mast cell leukemia was confirmed in all three cases by the presence of numerous mast cells in the blood. The prognosis for patients with the type 1 marrow infiltration pattern and primary skin involvement was favorable (actuarial survival rate five years after diagnosis, 0.75). This variant was called benign systemic mastocytosis. Primary skin involvement did not occur in the patients with type 2 or 3 infiltration patterns. The prognosis for these patients was poor (actuarial survival five years after diagnosis, 0.17 for type 2 and 0.00 for type 3). These two forms were accordingly designated malignant systemic mastocytosis.

Histiocytic necrotizing lymphadenitis without granulocytic infiltration.

Twenty-seven cases of an unusual necrotizing lymphadenitis previously described only in Japan are reported as occurring in West Germany (23 cases), Iran (1 case), Italy (1 case), Korea (1 case) and Spain (1 case). The lesion frequently develops in the cervical lymph nodes of young women. It is characterized by infiltration of the cortex and/or paracortex by large collections of proliferating histiocytes and is devoid of granulocytes. Complete or, more often, incomplete necrosis of lymphoid tissue is seen in all cases. In cases with incomplete necrosis, the histiocytes are interspersed with pyknotic cells and nuclear debris. Based on the histological findings, the term “histiocytic necrotizing lymphadenitis without granulocytic infiltration” is proposed. Lesions to be considered in a differential diagnosis are malignant histiocytic neoplasms and necrotizing lymphadenitis with granulocytic infiltration, which is seen in lupus erythematosus and bacterial infections. The aetiology of histiocytic necrotizing lymphadenitis without granulocytic infiltration is still unclear. Some clinical and histological features indicate the possibility of an underlying viral infection.

Development of malignant lymphoma in myoepithelial sialadenitis (Sjögren's syndrome)

Forty-five cases of myoepithelial sialadenitis (MESA) were investigated histologically, immunologically, and clinically. Two patients with clinical evidence of Sjögrens syndrome were also included in the study, though salivary gland biopsies showing MESA were not available. A total of 16 patients had Sjögrens syndrome or another type of autoimmune disease. In 42 cases of MESA, so-called proliferation areas composed of immunoblasts and lymphoplasmacytoid cells were found. The proliferation areas were small and circumscribed in 16 cases, and extensive and confluent in 26 cases. All the confluent proliferation areas analyzed with the immunoperoxidase (PAP) method showed a monotypic immunoglobulin pattern (predominantly IgM/κ). Extrasalivary malignant lymphoma with the same histologic and immunohistologic features as the confluent proliferation areas was found in 14 patients. Thus, this type of MESA is called “manifest malignant lymphoma”. The tumor was classified as LP immunocytoma in 23 patients, and as LP immunocytoma transforming into immunoblastic lymphoma in three patients. One patient developed nodal B-immunoblastic lymphoma. The term “early lymphoma” is suggested for MESA with circumscribed proliferation areas showing a monotypic immunoglobulin pattern (usually IgM/κ), because extrasalivary malignant lymphoma developed later in four of the patients with this type of MESA. The two patients with only clinical evidence of Sjögrens syndrome also showed extrasalivary malignant lymphoma (LP immunocytoma in one case and immunoblastic lymphoma in the other). There is a close histogenetic relation between MESA with or without autoimmune disease and certain malignant non-Hodgkins lymphomas of B type, namely, LP immunocytoma and B-immunoblastic lymphoma. The interval between the appearance of salivary gland enlargement and the diagnosis of malignant lymphoma varied from 1.5 to 12 years. Generalization of malignant lymphoma led to death in 11 cases.

Lymphogranulomatosen mit konstant hohem Epitheloidzellgehalt

Among fifty cases of lymphogranulomatosis (Hodgkins disease) having a constantly high content of epithelioid cells, it was possible to separate a particular form characterized by massive infiltrations of focally aggregated epithelioid cells. This form showed peculiar features concerning morphology, incidence and clinical manifestations. Typical Hodgkin cells and Sternberg giant cells were often absent, although it was always possible to find some atypical variants of these cells. Plasmocytes were often abundant. Fibrosis, even after treatment, did not appear. Transition into sarcoma was seen only once. This disease was found most frequently among middle-aged and older pople, without predilection of any sex. In the cases we studied the involvement of cervical lymph nodes was as common as that of the axillary and inguinal lymph nodes combined. Notable was the relatively frequent involvement of the tonsils. In addition to the typical constitutional symptoms of Hodgkins disease, allergic cutaneous manifestations were observed in some patients. In several cases strongly positive titres for toxoplasmosis were present although an infection by toxoplasma could not be verified. As to prognosis, we could not find significant differences from the average survival time in classical lymphogranulomatosis. The most important factor for evaluating prognosis seems to be the clinical stage at the time of first treatment. We propose calling this morphologic variant of Hodgkins disease (with small foci of epithelioid cells in rather regular arrangement) “epithelioid cell lymphogranulomatosis”, thereby separating it from lymphogranulomatosis with large areas of numerous epithelioid cells (“epitheloidzellreiche Lymphogranulomatose” = lymphogranulomatosis rich in epithelioid cells). The latter type shows neither important morphologic nor clinical differences from classical lymphogranulomatosis without pronounced epithelioid cell reaction. Unter 50 Fällen von Lymphogranulomatose (Lgr.) mit konstant hohem Epitheloidzellgehalt ließ sich eine Sonderform der Lgr. abgrenzen, die sich durch eine massive kleinherdige Epitheloidzellinfiltration auszeichnet. Sie ist durch weitere Besonderheiten in Morphologie, Vorkommen, Lokalisation und Klinik charakterisiert: Typische Hodgkin-Zellen und Sternbergsche Riesenzellen fehlen meist, dagegen finden sich immer atypische Hodgkin-und Sternberg-Zellen. Plasmazellen sind oft besonders reichlich vorhanden. Eine Vernarbung (Sklerosierung) tritt auch nach Behandlung nicht auf. Übergang in Sarkom wurde einmal beobachtet. Mittlere und höhere Altersgruppen sind bevorzugt, beide Geschlechter scheinen gleich häufig befallen zu werden. Halslymphknoten kommen in unserem Untersuchungsgut ebenso häufig vor wie axilläre und inguinale Lymphknoten zusammen. Besonders bemerkenswert ist das relativ häufige Befallensein der Tonsillen. Klinisch fallen neben den typischen Allgemeinerscheinungen der Lgr. nicht selten allergische Hautreaktionen auf. Auch fanden wir mehrere Fälle mit stark positiven Toxoplasmose-Reaktionen, ohne daß eine Toxoplasmose eindeutig verifiziert werden konnte. Demgegenüber ist in der Prognose kein sicherer Unterschied zum Durchschnitt der klassischen Lgr. festzustellen. Die Prognose scheint vielmehr im wesentlichen vom Stadium abzuhängen, in dem die Therapie begonnen wird. Wir schlagen vor, die morphologische Variante der Lgr. als epitheloidzellige Lgr. zu bezeichnen, und grenzen sie von einer epitheloidzellreichen Lgr. mit großflächigem Infiltrationstyp der Epitheloidzellen ab. Diese epitheloidzellreiche Lgr. zeigt in ihrem morphologischen, klinischen und sonstigen Verhalten keine charakteristischen Unterschiede von der klassischen Lgr. ohne stärkere Epitheloidzellbeteiligung.

Immunohistology and aetiology of histiocytic necrotizing lymphadenitis. Report of three instructive cases

Three cases of histiocytic necrotizing lymphadenitis are reported. Two patients came from Vietnam and the third from Greece. In all cases there was infection with Yersinia enterocolitica of serogroup 9 or 3. Cervical lymph nodes were examined. Histologically, the characteristic necrosis developed in large foci of so‐called T‐associated plasma cells. Immunological analysis showed that these cells have characteristic markers of helper/inducer T cells, but do not express sheep erythrocyte receptors. The T‐associated plasma cells perished by pyknosis and were then phagocytosed and digested by macrophages, which were present in large numbers. The necrotic areas were exclusively located in hyperplastic T regions. The B‐cell system did not play a role in the reaction. T‐associated plasma cells have been renamed ‘plasmacytoid T cells’ because they contain abundant rough endo‐plasmic reticulum (‘plasmacytoid’) and show immunological features of T cells. It appears likely that plasmacytoid T cells are the counterparts of plasma cells of the B‐cell system that secrete lymphokines instead of immunoglobulin.