Robert W. McKenna

Bilateral trephine bone marrow biopsies in lymphoma and other neoplastic diseases.

We have evaluated the usefulness of bilateral rather than unilateral posterior iliac spine trephine biopsies in searching for lymphoma and other neoplastic diseases in the bone marrow. Two hundred and eighty-two patients with these diseases were studied. Tumor was found on only one side in 22% of patients with non-Hodgkins malignant lymphoma, in 43% of patients with Hodgkins disease, and in 36% of patients with other neoplastic processes. Thus, the second biopsy yields an additional 11% to 22% of positive biopsies. We conclude that bilateral trephine bone marrow biopsies should be routinely performed when searching for tumor in the bone marrow.

Chronic lymphoproliterative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics

Four of 105 patients with chronic lymphocytic leukemia (CLL) manifested clinical, morphologic, ultrastructural and membrane surface marker characteristics that differed from those found in patients with typical CLL of demonstrated B-lymphocyte origin. These four patients presented with moderate increases in absolute lymphocyte counts, absolute neutropenia, polyclonal hypergammaglobulinemia and hepatosplenomegaly without lymphadenopathy. Two of them were unusually young, 19 and 25 years old, at the time of diagnosis. The proliferating lymphocytes carried receptors for sheep erythrocytes, a T-lymphocyte marker. In the three patients tested, the lymphocytes also carried Fc receptors. Ultrastructurally the lymphocytes contained cytoplasmic inclusion bodies consisting of parallel tubular arrays. The parallel tubular arrays corresponded to prominent cytoplasmic azurophilic granules on light microscopy. Parallel tubular arrays were found in less than 1 per cent of the lymphocytes in eight patients with typical B-lymphocyte CLL. The process in these four patients may be a distinctive chronic lymphoproliferative disorder originating in T lymphocytes with Fc receptors found in small numbers in the blood of normal persons.

Presence of simian virus 40 DNA sequences in human lymphomas

Simian virus 40 (SV40)--a potent oncogenic virus--has been associated previously with some types of human tumours, but not with lymphomas. We examined human tumours for the presence of specific SV40 DNA sequences by PCR and Southern blotting. Viral sequences were present in 29 (43%) of 68 non-Hodgkin lymphomas, and in three (9%) of 31 of Hodgkins lymphomas. Viral sequences were detected at low frequencies (about 5%) in 235 epithelial tumours of adult and paediatric origin, and were absent in 40 control tissues. Our data suggest that SV40 might be a cofactor in the pathogenesis of non-Hodgkin lymphomas.

Zinc-Induced Copper Deficiency A Report of Three Cases Initially Recognized on Bone Marrow Examination

Copper deficiency is a rare cause of sideroblastic anemia and neutropenia that often is not suspected clinically. The morphologic findings in bone marrow, while not pathognomonic, are sufficiently characteristic to suggest the diagnosis, leading to further testing to establish the correct diagnosis. Excess zinc ingestion is among the causes of copper deficiency. We present 3 cases of zinc-induced copper deficiency in which the diagnosis first was suggested on the basis of bone marrow examination. The first patient was a 47-year-old man with a debilitating peripheral neuropathy that had progressed during the previous 18 months, mild anemia, and severe neutropenia. The second was a 21-year-old man receiving zinc supplementation for acrodermatitis enteropathica in whom moderate normocytic anemia and neutropenia developed. The third patient was a 42-year-old man with anemia, severe neutropenia, and a peripheral neuropathy that had progressed during 8 months. The bone marrow findings in all cases suggested copper deficiency, which was confirmed by further laboratory testing and determined to be due to zinc excess. The morphologic features, clinical manifestations, differential diagnosis, and pathogenetic mechanisms are discussed.

Precursor B-cell lymphoblastic lymphoma: A study of nine cases lacking blood and bone marrow involvement and review of the literature

We describe 9 cases of precursor B-cell lymphoblastic lymphoma (LYL) without evidence of marrow or blood involvement. Four patients had superficial nodal disease, 2 cutaneous involvement, and 1 each ovarian, retroperitoneal, or tonsillar primary tumor. Six patients had limited disease; 3 patients were stage III. Immunophenotyping revealed a terminal deoxynucleotidyl transferase (TdT)-positive, immature B-cell population with variable expression of CD10, CD20, and CD45. All patients are in complete clinical remission (median follow-up, 14 months). A literature review yielded 105 patients with a diagnosis of precursor B-cell LYL based on less than 25% marrow involvement. Of these, 64% were younger than 18 years. Skin, lymph nodes, and bone were the most common sites of disease. Mediastinal involvement was uncommon. TdT, CD19, CD79a, CD10, and HLA-DR were the most frequently expressed antigens, while CD45 and CD20 were expressed in only two thirds of the cases. Cytogenetic analysis showed additional 21q material as a recurring karyotypic abnormality. At a median follow-up of 26 months, 74% of patients were alive; the median survival was 19 months for patients dying of disease. Comparison with precursor B-cell acute lymphoblastic leukemia showed several overlapping features, although distinct differences were identified.

Acute promyelocytic leukaemia: a study of 39 cases with identification of a hyperbasophilic microgranular variant

Thirty‐nine cases of acute promyelocytic leukaemia (APL) were divided into two morphological subgroups, typical hypergranular APL (31 cases) and microgranular APL (eight cases, 21%). The leukaemic cells in the microgranular APL cases were characterized by striking nuclear folding or lobulation; granulation was present in most of these cells but was less abundant and finer than in typical APL. In three microgranular APL cases a distinctive small leukaemic promyelocyte with unusual nuclear lobulation and deeply basophilic cytoplasm containing few or no visable granules was the predominant leukaemic cell. This small hyperbasophilic promyelocyte was also present as a minor population of cells in the other five microgranular APL cases and in 28 of the 31 typical APL cases. Ultrastructurally the most abundant promyelocytes in microgranular APL had smaller and usually fewer granules than in typical APL; other characteristic ultrastructural features of APL were found with equal frequency. The median blood leucocyte count was significantly higher in microgranular APL, 83·0 × 109/1, than in typical APL, 1 · 8 × 109/1 (P < 0 · 01). The median duration of complete remission (CR) for microgranular APL, 6 · 5 months, was shorter than the 21 + month median CR for typical APL. The morphological characteristics of microgranular APL may mimic those of myelomonocytic leukaemia; however, the presence of cells with multiple Auer rods, large inclusions of Auer‐like material and the small hyperbasophilic promyelocytes are important distinguishing features. In equivocal cases cytochemistry, electron microscopy and cytogenetic studies may verify the diagnosis.

Systemic mastocytosis. Extracutaneous manifestations.

The clinical, radiologic, ultrastructural, and histopathologic findings in 14 patients with systemic mastocytosis were evaluated. Seven patients had evidence of urticaria pigmentosa (UP) and seven patients presented with no recognizable cutaneous lesions. There were no major clinical differences between patients with or without UP except for splenomegaly, which was present in one/ seven patients with UP and five/seven patients without UP and the median age, 44 in patients with UP, and 75 in patients without UP. Bone marrow involvement was present in 13/ 13 specimens studied. Involvement was both focal and diffuse. The focal involvement occurred frequently in a perivascular and paratrabecular location. The diffuse involvement resembled myelofibrosis. Involved lymph nodes exhibited prominent sinusoidal and paracortical infiltration by mast cells. Splenic involvement was characterized by fibrosis occurring both focally and diffusely. The focal splenic involvement was perivascular and involved both the red and white pulp in a nonpreferential manner. Liver specimens showed prominent portal fibrosis. The morphology of the mast cells in the different lesions varied considerably; some were typical, others were spindle-shaped, and some resembled histocytes. The mast cells reacted positively with toluidine blue and chloroacetate esterase. Six patients had radiologic changes: three were osteoblastic, two osteolytic, and one osteoblastic and osteolytic. Two patients developed a poorly differentiated lymphoreticular tumor and one a myeloproliferative disorder after the diagnosis of mastocytosis.

Therapy-related leukemia: a panmyelosis.

Fifteen patients developed acute nonlymphocytic leukemia (ANLL) 31 to 182 months following chemotherapy and/or radiotherapy for various malignancies and one non‐neoplastic disorder. The ANLL was commonly heralded by a brief preleukemic phase consisting of cytopenias and a variety of morphologic abnormalities. At diagnosis of ANLL, all of the patients had a panmyelosis with variation in the predominant abnormal cell line. Neutrophilic and erythroid abnormalities were most striking in 12 of the patients, megakaryocytic abnormalities predominated in 2 and monocytic abnormalities in 1. Pancytopenia, marked anisopoikilocytosis, normoblastemia, large hypogranular platelets, hypogranular neutrophils, pseudo‐Pelger‐Huet nuclei, low myeloblast counts and basophilia were the most common abnormalities in the blood. Bone marrows were hypercellular with increased myeloblasts and basophils, abnormal neutrophil precursors, occasional monocytoid blasts, dyserythropoiesis with PAS positive erythroblasts, ring sideroblasts and micromegakaryocytes. All of the 7 patients who had bone marrow chromosome studies exhibited major chromosomal abnormalities. Response to anti‐leukemic therapy was poor. The morphologic and clinical findings of these 15 patients appear to define a clinical‐pathologic entity.

The accelerated phase of Chediak‐Higashi syndrome. An expression of the virus‐associated hemophagocytic syndrome?

The clinical and pathologic findings of four patients with Chediak‐Higashi syndrome in the accelerated phase were studied in order to clarify the nature of this enigmatic process. Fever, lymphadenopathy, hepatosplenomegaly, and cytopenias were present in every patient. All cases demonstrated extensive parenchymal infiltrates in many organs composed of benign‐appearing histiocytes manifesting hemophagocytosis accompanied by lymphocytes and plasma cells. Studies in one patient suggested a viral etiology with the findings of a low blood lymphocyte OKT4 to OKT8 ratio, acquired loss of lymphocyte response to mitogens, the presence of Epstein‐Barr virus genome in the mononuclear cells of lymph node, blood, and bone marrow, and possible clinical responses to acyclovir. It is concluded that the accelerated phase of Chediak‐Higashi syndrome may be the clinicopathologic expression of the virus‐associated hemophagocytic syndrome.

ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature

We report detailed clinical and pathologic features of four cases of anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL), a rare entity with only 29 currently reported cases. This study is the third largest of all reported series. Biopsies from four adult patients aged 41, 49, 53, and 71 years (three lymph nodes and one nasopharyngeal mass) exhibited immunoblastic/plasmablastic morphology. By immunohistochemistry and/or flow cytometry, they expressed cytoplasmic ALK-1, CD138, VS38 (3/3), monoclonal cytoplasmic light chain, CD45, EMA, CD4, and CD57 (2/3), and were negative for CD3, CD30, CD56, and TIA-1. Two showed variable CD79a expression, and one had rare CD20(+) cells. Two of three cases exhibited rare CD43(+) reactivity. One case showed scattered cytokeratin(+) cells, which could possibly lead to a misdiagnosis of carcinoma. After CHOP and radiotherapy, two stage I patients were free of disease at 58 and 36 months, whereas a stage IV patient was dead of disease at 22 months.