Broad Morphologic Spectrum Research Articles

Large B-cell lymphomas: variants and entities

Large B-cell neoplasms represent one of the most frequent groups of non-Hodgkin-lymphomas (30-40%). They are characterized by an aggressive clinical course. These lymphomas may evolve either de novo or secondary during the course of a less aggressive lymphoma. In addition to primary nodal, a primary extranodal manifestation is rather common. The neoplastic cells, even within one given case, show a broad morphological spectrum. Several findings of the last two decades have revealed that the large B-cell lymphomas represent an inhomogeneous group. This fact has been taken into account by the new WHO classification of malignant lymphomas. There are two groups identified, that of the variants and that of the subtypes. The various variants (centroblastic, immunoblastic, anaplastic, T-cell/histiocyte-rich) correspond to lymphomas without reproducible discriminating criteria lacking characteristic clinical, immuno-phenotypical and genetic findings. In contrast, the primary mediastinal, the intravascular, the primary effusion and primary central nervous system lymphomas represent distinct disease entities. A number of recently described large cell lymphoma types, i.e. plasma-blastic, ALK-positive and primary gastric, are included in the classification, their designation as distinct entities is still under discussion.

Die vielen Gesichter des anaplastischen großzelligen Lymphoms

Fifteen years after their first description by one of the authors (HS) anaplastic large cell lymphoma (ALC-lymphoma, ALCL) now represents a generally accepted group of large cell lymphomas. Essential defining features comprise of a proliferation of large lymphoid cells with strong expression of the cytokine receptor CD30 and a characteristic growth pattern. Using molecular and clinical criteria three entities of ALC-lymphoma have been identified: primary systemic anaplastic lymphoma kinase (ALK)-positive ALC-lymphoma, primary systemic ALK-negative ALC-lymphoma and primary cutaneous ALC-lymphoma. The ALK expression in the primary systemic ALC-lymphoma entity is caused by chromosomal translocations, most commonly t(2;5), and can nowadays be reliably detected by immuno-histology. ALK-positive ALC-lymphoma predominantly affects young male patients and if treated with chemotherapy has a favourable prognosis. They show a broad morphological spectrum, with the "common type", the small cell variant and the lymphohistiocytic variant being most commonly observed. The knowledge of the existence of these variants is essential in establishing the correct diagnosis. ALK-negative ALC-lymphomas occur in older patients, equally affecting both genders and have an unfavorable prognosis. The morphology and the immuno-phenotype of primary cutaneous ALC-lymphoma shows an overlap with that of lymphomatoid papulosis. Both diseases have an excellent prognosis and secondary systemic dissemination is only rarely observed. The ALC-lymphomas described above derive from T cells and are generally accepted as biological entities. In contrast, large B-cell-lymphomas with anaplastic morphology are now believed not to represent an own entity but a morphologic variant of diffuse large B-cell lymphoma. Malignant lymphomas with morphological features of both Hodgkin- and ALC-lymphoma have formerly been classified as ALCL Hodgkin-like. Recent immuno-histological analysis of these cases however suggests that ALCL Hodgkin-like does not represent an own lymphoma entity. Most of these cases are likely to be examples of tumor cell rich classical Hodgkin lymphoma, while a minority of these cases appear to fall either into the category of ALK-positive or ALK-negative ALC-lymphoma.

Phenotypic plasticity and prognostic factors in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is an intriguing entity with a broad morphologic spectrum that overlaps features found in other benign and malignant mesenchymal tumors. This phenotypic plasticity should be known to avoid erroneous diagnosis. The identification of older age, larger tumor size, proximal tumor location, and metastatic disease as independent adverse predictors of survival is useful in achieving optimal treatment and follow-up in high-risk patients.

Mantle cell lymphoma in leukemic phase: characterization of its broad cytologic spectrum with emphasis on the importance of distinction from other chronic lymphoproliferative disorders.

Mantle cell lymphoma is a mature, virgin B-cell neoplasm characterized immunologically by a panB+, CD5+, CD23-, cyclin D1+ phenotype and genetically by t(11;14)(q13;q32) with overexpression of the cyclin D1 (bcl-1) gene. It usually presents as advanced stage disease, involving lymph nodes, spleen, bone marrow, and extranodal sites, particularly the gastrointestinal tract. However, frank leukemic presentation with high white cell counts is uncommon and can be difficult to distinguish from other chronic lymphoproliferative disorders. The aim of this study was to characterize the morphologic spectrum of leukemic mantle cell lymphoma. During the period July 1994 through October 1998, 14 patients with mantle cell lymphoma in leukemic phase were diagnosed at the Department of Pathology, Queen Elizabeth Hospital, Hong Kong. The diagnosis of mantle cell lymphoma was based on histologic and immunocytochemical findings and was confirmed by cyclin D1 immunoreactivity in all cases. The clinical records and laboratory results were reviewed. Peripheral blood smears, bone marrow, and other tissue biopsies were examined, with particular attention to the cytologic features of the leukemic mantle cells. Mantle cell lymphoma in leukemic phase showed a very aggressive clinical course. Eight patients died at a mean of 13 months, and only 1 patient was disease free. Morphologically, the leukemic mantle cells exhibited a broad morphologic spectrum, with several cytologic patterns identified: 1) mixed small and medium-sized cells, 2) predominantly medium-sized cells, 3) predominantly large cells, and 4) giant cells. Despite variations in the size and nuclear shape, the leukemic mantle cells could usually be recognized by the nuclear irregularity and clefting, moderately dense but evenly distributed chromatin, small nucleoli, and scant cytoplasm. Recognition of the characteristic cytologic features of leukemic mantle cells can help to distinguish them from other chronic lymphoproliferative disorders. In contrast to the latter, the clinical course is aggressive and response to conventional chemotherapy is poor.

Hobnail hemangioma ("targetoid hemosiderotic hemangioma"): clinicopathologic and immunohistochemical analysis of 62 cases.

Hobnail hemangioma, also known as "targetoid hemosiderotic hemangioma", represents a distinctive, benign vascular tumor, characterized histologically by a biphasic growth pattern of dilated vascular structures in the superficial dermis lined by prominent hobnail endothelial cells, and collagen dissecting, rather narrow neoplastic vessels in deeper parts of the lesion. We analyzed the clinicopathologic and immunohistochemical features in a series of 62 cases. Patient age range was 6-72 years (median: 32 years); 34 patients were male and 25 female. Clinically, a broad variation of diagnoses ranging from hemangioma to dermal melanocytic nevus and fibrous histiocytoma was suggested. Nineteen tumors arose in the lower and 13 in the upper extremities, 12 on the back, 8 in the buttock and hip region, and one case on the chest wall. Follow-up information on 35 patients (range from 1 to 4 years; mean: 1.5 years) revealed no local recurrence nor systemic metastasis. All neoplasms were located in the dermis and showed a broad morphologic spectrum in dependence of the age of the lesions. In addition to lesions resembling cavernous lymphangioma or lymphangioma circumscriptum, neoplasms were seen with morphologic features reminiscent to retiform hemangioendothelioma, progressive lymphangioma and so-called Dabska's tumor. Immunohistochemistry performed in 28 cases showed positive staining of tumor cells for CD31 in all cases tested, whereas only 3 out of 28 cases stained completely positive for CD34. In addition 4 out of 8 cases stained positively for vascular endothelial growth factor receptor-3 (VEGFR-3). Neoplastic endothelial cells were surrounded by actin-positive pericytes in only 7 out of 27 cases tested. Hobnail hemangioma occurs more frequently in male patients and arises commonly in the extremities and the trunk. Histologic and immunohistochemcial features suggest a lymphatic line of differentiation for this distinctive vascular neoplasm.

Mediastinal B-cell lymphoma: A study of its histomorphologic spectrum based on 109 cases

Mediastinal B-cell lymphoma (MBL) is a distinct variant of aggressive non-Hodgkin's lymphoma with characteristic clinical and biological features but less well-defined histomorphology. We reevaluated 124 biopsy specimens from 109 MBL patients of an Italian/French/German retrospective clinical study. MBL was primarily diagnosed on clinical and histological grounds in conjunction with the detection of CD20 expression by immunohistology. Cytologically, MBL features limited intralesional but considerable interindividual cytological diversity, ranging from medium-sized to very large, atypical cells. Sclerosis and necrosis are restricted to extrathymic and extranodal sites of involvement, predominantly the lung, as is angioinvasion, which predominantly affects larger vessels. The medium-sized and the large cell variants resemble marginal zone lymphoma variants, whereas the very large cell variant of MBL has not so far been found to have any extramediastinal counterpart. We conclude that MBL displays a broad morphological spectrum covering more than is implied by the term “diffuse large cell lymphoma.” Because statistical analysis of cytological and histological criteria failed to correlate with prognosis in this comprehensive group of patients, we think it inadvisable further to subclassify MBL.

Effect of various forms of metastatic lymph node involvement on prognosis of squamous epithelial carcinomas of the upper aerodigestive tract

Based on a new histo-morphological rating scheme, we assessed the impact on patient prognosis of lymph node metastasis of squamous cell carcinoma (SCC) in the head/neck area. Special attention was given to possible capsular rupture. In a retrospective study, 111 patients with squamous cell carcinoma of the head and neck with concomitant cervical lymph node metastases were evaluated to determine the importance of lymph node capsular rupture on the occurrence of disseminated disease, loco-regional recurrence as well as survival rate. To cover the broad morphological spectrum of cervical metastatic disease, a newly developed scheme (differentiating seven different histo-morphological types of lymph node metastasis) was applied. On the basis of this scheme, every single metastatic lymph node received a score from one to seven. These single scores were then added to obtain a total score for every individual patient. These total scores were then divided into four groups. Synthesis of histo-morphological pattern of metastasis in combination with the number of metastatic lymph nodes showed highest concordance/significance in respect of disseminated disease (p = 0.0029), local recurrence (p = 0.0008) and regional lymph node metastasis (p = 0.0000) as well as survival rate (p = 0.0000). The newly introduced histological scheme seems to provide more accuiate and detailed information on the prognosis of SCC in the head and neck area.

A Histologic Spectrum

Fibrous dysplasia (FD) and cemento-ossifying fibroma (COF) are benign fibro-osseous lesions that are generally considered to be separate entities, distinguished by histologic and radiographic features. In our experience, some lesions lack the classic clinical, radiographic, or pathologic features of FD or COF and rather have overlapping features of both entities. Consequently, these cases are frequently diagnosed nonspecifically as fibro-osseous lesions. We examined 56 gnathic and extragnathic fibro-osseous lesions of bone morphologically, clinically, and radiographically to determine whether they can be reliably distinguished and whether their distinction has any clinical or prognostic significance. The lesions exhibited a broad morphologic spectrum of patterns ranging from pure FD (24 cases) to pure COF (10 cases). Twenty-two lesions contained a mixture of both patterns; 11 lesions with a predominant FD pattern contained calcified spherules histologically indistinguishable from those characteristically seen in COF. The remaining 11 lesions contained areas of typical FD adjacent to areas of COF. The lesions examined also demonstrated considerable radiographic overlap, and FD could not be reliably distinguished from COF. The recurrence rate was low for all lesions regardless of the histologic pattern. Because of histologic and radiographic overlap and similar low recurrence rate of FD and COF, we consider them to be related lesions, and COF is probably an opposing end of a morphologic spectrum of FD.

CD5-Expressing B-Cell Non-Hodgkin's Lymphomas With bcl-1 Gene Rearrangement Have a Relatively Homogeneous Immunophenotype and Are Associated With an Overall Poor Prognosis

Mantle cell lymphomas (MCLs) are typically CD5-expressing B-cell non-Hodgkin's lymphomas (NHLs) that frequently harbor the chromosomal translocation t(11;14) or bcl-1 gene rearrangements. Insufficient data are available on the biologic features and clinical behavior of rigorously characterized MCL. As these NHLs have been reported to exhibit various histologic and cytologic expressions, and in order to avoid using somewhat arbitrary and subjective morphologic definitions, we chose to study cases of MCL selected on more objective grounds. Specifically, 15 samples (from 14 patients) of CD5-expressing B-cell NHLs with detectable bcl-1 gene rearrangement were included. Overall, these patients had relatively uniform clinical manifestations. Most were older men (mean age, 67 years) who presented with lymphadenopathy, high-stage disease, and bone marrow involvement. All but two patients relapsed, demonstrated residual tumor, or had disease progression after an initial response to various therapies. Nine patients have died; these patients had a median survival of only 19 months. All cases could be classified within the broad morphologic spectrum previously described for MCL, and no predominant histologic subtype was observed. However, cases could be segregated into two major groups according to tissue architecture: one with a purely diffuse pattern and the other with at least a focal nodular component. Patients with purely diffuse tumors had a lower survival rate (0%) than those with tumors having a nodular component (62% survival rate). In contrast to the morphologic variability, these NHL exhibited a rather homogeneous immunophenotypic pattern. All cases demonstrated intense CD20 expression, with typically intense IgM and light chain expression, and relatively weak IgD expression. In no case was CD10 detected on the neoplastic cells. DNA content analysis showed aneuploidy only in three instances, and two groups of cases could be arbitrarily defined on the basis of their S-phase fraction. A relationship between a purely diffuse growth pattern and a high S-phase fraction (greater than 5%) was observed. As expected from this association, patients with tumors having high S-phase fractions fared worse (14% survival rate) than those patients with tumors showing lower S-phase fractions (57% survival rate). Thirteen NHLs from 12 patients had amplifiable bcl-1 gene rearrangements at the major translocation cluster (MTC). The bcl-1 breakpoints aggregated within a 63-bp region of the MTC, and the amplified tumor DNA from each patient had unique N-nucleotide junctional sequences and Ig joining region breakpoint sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Kikuchiʼs Lymphadenitis

Seventy-five cases of Kikuchi's lymphadenitis, a self-limiting pseudomalignant condition, were reviewed to determine the spectrum of histologic findings. There were 55 females and 20 males; ages ranged from 9 to 57 years (mean, 25.5). Most patients presented with cervical lymphadenopathy (68 cases). Associated clinical findings were fever (20/52) and leukopenia (15/33). Serum antinuclear antibodies were negative in 15 patients among 16 tested. Among 32 patients with follow-up information, 31 remained well, including one who developed recurrence after 2 years. One patient died of fatal myocardial disease during the active disease. Histologically, the lymph nodes showed paracortical hyperplasia, often associated with a starry-sky appearance resulting from interspersed histiocytes and immunoblasts. The consistent finding was the presence of variable-sized discrete or confluent nodules in the paracortex composed of the following: (a) karyorrhectic and eosinophilic granular debris; (b) histiocytes, many of which were phagocytic and possessed distinctive peripherally placed crescentic nuclei and voluminous cytoplasm containing eosinophilic or karyorrhectic debris (for which we propose the designation crescentic histiocytes), mixed with nonphagocytic histiocytes having twisted or reniform nuclei which were often centrally placed; (c) plasmacytoid monocytes, which were medium-sized cells with eccentrically placed round nuclei and amphophilic cytoplasm; and (d) variable numbers of immunoblasts, which sometimes showed atypia such as irregular nuclear foldings and coarse chromatin. Neutrophils were absent or very sparse. In some nodules, coagulative necrosis was present in the center (45 cases). Foamy histiocytes were found in 23 cases, and they predominated in 11. Small clusters of plasmacytoid monocytes were noted in the paracortex in 40 cases. Perinodal inflammation was a common finding, and perinodal involvement by the karyorrhectic process occurred in 15 cases. In addition, we found a number of previously unreported features. Signet-ring histiocytes with clear or homogeneous lightly amphophilic cytoplasm and nuclei compressed into thin crescents, found in seven cases, could mimic signet-ring cell adenocarcinoma. In three cases, some germinal centers were involved by the karyorrhectic process. Foci of lymphocyte-depleted fibrovascular organization were present in eight cases, probably representing the resolving phase of the karyorrhectic process. Despite the broad morphologic spectrum, the intermingling of the distinctive crescentic histiocytes, karyorrhectic debris, and plasmacytoid monocytes in the form of nodules, together with the paucity of neutrophils, are the consistent findings that should permit a confident histologic diagnosis of Kikuchi's lymphadenitis.

Hypertrophic Cardiomyopathy in Athletes.

In brief Hypertrophic cardiomyopathy brief (HCM) accounts for a large proportion of sudden deaths in young athletes. HCM is a complex disease with a broad clinical and morphologic spectrum. Most patients with HCM have impaired diastolic filling of the left ventricle, and about 25% have left ventricular outflow tract obstruction. Cardiac symptoms and/or signs are often present, and the condition is most effectively identified with echocardiography. Propranolol or verapamil relieves symptoms in many patients; surgery may benefit patients who have outflow obstruction associated with symptoms that persist after pharmacologic therapy. Patients with HCM should not engage in organized competitive sports or particularly strenuous exercise, although moderate recreational exercise is likely to be acceptable for such individuals.

Kikuchi-Fujimoto Disease Mimicking Malignant Lymphoma

Histiocytic necrotizing lymphadenitis is a rare, benign entity described independently both by Kikuchi and Fujimoto et al. This disease, which has a broad morphologic spectrum, can readily be mistaken for malignant lymphoma. Our report on the morphologic features in 10 selected cases of this disease highlights those features that mimicked lymphoma and those that helped us to make an accurate diagnosis. The distinctive features were (a) pathologic areas, which are pale and do not occupy the entire lymph node; (b) preserved sinuses in the uninvolved areas; (c) prominent mottling by histiocytes or transformed lymphoid cells in the nonpathologic areas; (d) frequent absence of overt necrosis; (e) presence of benign histiocytes with moderate to marked nuclear irregularities and scanty to moderate cytoplasm that resembled cleaved cells; (f) variable amounts of nuclear debris, usually extracellular; (g) presence of so-called plasmacytoid T cells at the periphery of or immediately outside the pathologic areas; (h) moderate numbers of mitotic figures and transformed lymphoid cells of medium and large size (immunoblasts); and (i) absence of inflammatory and granulomatous reaction. Because overt necrosis is often absent and histiocytes resemble cleaved cells, we support the suggestion that this entity should be called "Kikuchi-Fujimoto disease" rather than "histiocytic necrotizing lymphadenitis."

Unusual distribution of left ventricular hypertrophy in obstructive hypertrophic cardiomyopathy: Localized posterobasal free wall thickening in two patients

Two patients with hypertrophic cardiomyopathy and a previously unreported distribution of left ventricular hypertrophy are described. Each patient showed substantial wall thickening that was confined to the posterobasal segment of the left ventricular free wall, as well as evidence of dynamic subaortic obstruction. This observation emphasizes the fact that hypertrophic cardiomyopathy is characterized by a broad morphologic spectrum. Furthermore, it demonstrates a unique circumstance in which left ventricular outflow tract obstruction may occur in the absence of anterior and basal septal hypertrophy.

Cutaneous lymphoma—A spectrum

In recent years evidence has been accumulating that mycosis fungoides and Sezary syndrome come under the ‘umbrella’ of cutaneous lymphoma. Cutaneous lymphoma cells are ‘T’ lymphocytes which have a tendency to localize in the skin and T cell regions of lymphoid tissue, and usually spare the bone marrow. Between 29/12/78 and 13/3/79 4 cases of cutaneous lymphoma presented to the Haematology-Oncology Unit in our hospital. They comprise a broad clinical and morphologic spectrum. Case 1 A 73-yr-old man with a 10 yr history of phenytoin treated petit mal epilepsy presented with a 6 mth history of a worsening maculopapular rash on legs, thighs, lower abdomen and back, and generalized lymphadenopathy and hepatosplenomegaly. Blood picture was Hb 12.2%, platelets 147,000/ml, W.C.C. 236,000/ml (96% lymphocytes). Skin biopsy revealed histological features of mycosis fungoides and marrow biopsy revealed diffuse involvement by the lymphoma. Cytogenetic analysis of the blood was grossly abnormal. This patient is currently responding very well to weekly courses of cyclophosphamide/vincristine/leucapheresis. Case 2 A 70-yr-old woman presented with a severe exfoliative dermatitis thought to be due to indomethacin. It was associated with generalized lymphadenopathy and hepatomegaly. Blood picture revealed Hb 4.5%, platelets 140,000/ml, and W.C.C. 61,000 (lymphocytes 9%, abnormal monocytes 10%, lymphoid blasts 14%). Skin biopsy-revealed histological features of mycosis fungoides, and in bone marrow aspirate lymphoid blasts comprising 50%, of nucleated cells. Seven per cent of cells were atypical monocytes with cleaved nuclei. Cytogenetic analysis of the marrow was abnormal. The patient has responded well to intermittent chemotherapy with prednisolone, cyclophosphamide and vincristine but therapy has been complicated by intercurrent problems. Case 3 A 55-yr-old man with progressive bilateral deafness, difficulty in speaking and dysphagia over 4 mth. At presentation he had generalized lymphadenopathy with very large tonsils and hepatosplenomegaly. He also complained of severe pruritus and developed a morbilliform rash on back, buttocks and anterior chest. Blood picture was Hb 15.1%, platelets 302.000/ml, W.C.C. 19,500/ml (12% monocytes—smear was otherwise normal). There was diffuse hyperglobulinaemia. Lymph node and bone marrow biopsy revealed a diffuse poorly differentiated lymphocytic (small cell non-cleaved) T cell lymphoma. Skin biopsy revealed features of mycosis fungoides. The patient has responded dramatically to intermittent COP therapy. Case 4 A 66-yr-old woman presented with progressive long standing skin lesions over L. scapula, upper anterior chest, right back and thighs. There was no lymphadenopathy or hepatosplenomegaly. Blood picture and bone marrow were normal. Biopsy of one of these lesions revealed deep skin infiltration by mononuclear cells which were characterized by regular non-convoluted nuclei. T-cell disease was diagnosed on skin and blood specimens. There was improvement with 150 rads TBI.