Clonal proliferation of cyclin D1-positive mantle lymphocytes in an asymptomatic patient: an early-stage event in the development or an indolent form of a mantle cell lymphoma?

Mantle cell lymphoma (MCL) is a B-cell neoplasm with a relatively aggressive clinical course. There is a very small subgroup of patients who present with atypical lymphocytes in peripheral blood, with or without lymphocytosis, lymphadenopathy, or splenomegaly, and with an indolent clinical course. They frequently show mutated IgV(H) genes and CD5 negativity. We report an asymptomatic elderly patient who presented with a single submandibular lymphadenopathy. The biopsy showed immunophenotype and t(11;14)(q13;q32) consistent with MCL. The abnormal lymphoid population was also detected in peripheral blood and bone marrow. The patient has remained asymptomatic for 5 years without receiving any therapy. It is uncertain whether these cases represent an early-stage event in the development or an indolent form of MCL. The existence of such asymptomatic patients with an indolent clinical course should induce a strict clinical judgment in terms of therapeutic decisions.     

Gain of chromosome 3/3q in B-cell chronic lymphoproliferative disorder is associated with plasmacytoid differentiation with or without IgM overproduction

Trisomy 3 has been reported to be associated with marginal zone B-cell lymphoma. However, its occurrence and significance in other B-cell chronic lymphoproliferative disorders has not been fully defined. We report five cases of B-cell chronic lymphoproliferative disorders showing gain of chromosome 3 or 3q. The patients were elderly males who presented with splenomegaly with or without hepatomegaly and lymphadenopathy. The diagnoses included chronic lymphocytic leukemia (3 cases), prolymphocytic leukemia (1 case), and Waldenstrom macroglobulinemia (1 case). Distinctive feature in this group of patients was the plasmacytoid appearance of the leukemic lymphocytes, with an associated IgM hypergammaglobulinemia in three patients. The relationship between the gain of chromosome 3 and plasmacytoid differentiation in B-cell chronic lymphoproliferative disorders is discussed.     

Splenic lymphoma with villous lymphocytes

Splenic lymphoma with villous lymphocytes (SLVL) is a rare disorder that comprises less than 1% of lymphoid neoplasms. It is the leukemic counterpart of splenic marginal zone lymphoma (SMZL) and is characterized by splenomegaly, often with no lymphadenopathy, moderate lymphocytosis and villous lymphocytes on peripheral blood smear. Here, we report a case of SLVL in a 56-year-old male with very high leukocyte counts, massive splenomegaly and relatively few leukemic cells with subtle villous projections on the surface. This disorder is often confused with other chronic lymphoproliferative disorders, especially chronic lymphocytic leukemia (CLL) and hairy cell leukemia and should be differentiated from them. We are reporting this case to highlight the diagnostic pitfalls associated with this disorder.     

2 cases of Richter's syndrome]

Two cases of Richter's syndrome are reported (in a 62 and 64 years old man) consistent with the appearance of B cell lymphoma of high malignancy in the course of CLL (low malignancy B cell lymphoma). In one patient, after 8-, and in the other one--after 53 months since the diagnosis of CLL, there was rapid clinical deterioration with lymphadenopathy, hepato- splenomegaly, fever and progressive cachexia, anemia and thrombocytopenia and leukopenia, unrelated to treatment. Both patients died, 4 and 3 months respectively, since the appearance of these symptoms. In the first cases Richter's syndrome was diagnosed histopathologically from the autopsy material. In the liver, spleen, adrenals and bone marrow, in addition to the characteristic infiltrates of CLL (small lymphocytes) there were areas of large cell proliferation consistent with high malignancy lymphoma. In the other case, the infiltrates of large cell lymphoma were found in the gall bladder removed because of acute cholecystitis, and in the lymph node from the hepatic hilar area. Immunocytochemical studies performed on the biopsy material indicated that the neoplastic cells had markers of B lymphocytes and cytoplasmic IgM kappa, as lymphocytes of CLL. In patients with CLL, who display rapid clinical deterioration and general symptoms with cachexia, the possibility of Richter's syndrome should be considered, and appropriate morphological studies performed.     

Small lymphocytic lymphomas with predominant splenomegaly: a comparison of immunophenotypes with cases of predominant lymphadenopathy.

In this study, we compared small lymphocytic lymphomas with predominant lymphadenopathy with those with predominant splenomegaly and found differences in morphology and immunophenotype as well as clinical features. Cases with lymphadenopathy were characterized by widespread disease, CLL type morphology with proliferation centers, and a CD5, CD11c, CD23, CD43 positive, CD45Ro negative immunophenotype. Cases with predominant splenomegaly had more localized disease, a mantle zone pattern or a diffuse growth pattern without proliferation centers, and a CD5, CD11c, CD23, CD43 negative, and sometimes CD45Ro positive immunophenotype. CD45Ro (UCHL1) positivity and alkaline phosphatase staining were associated with a mantle zone growth pattern. Comparison with other small lymphocytic lymphoma subtypes indicated that each has its own specific immunophenotype.     

Mantle cell lymphoma, blastoid variant, diagnosed on the basis of cytomorphology and flow cytometric immunophenotyping of the lymph node aspirate and peripheral blood

Mantle cell lymphoma, blastoid variant (B-MCL), is a very rare type of non-Hodgkin's lymphoma exhibiting an aggressive clinical course. We describe a case of B-MCL showing generalized lymphadenopathy and leukemic conversion in a 62-yr-old man. The case was diagnosed and subclassified as B-MCL on the basis of cyto-morphology and immunophenotype. Microscopic examination of the peripheral blood (PB) showed a spectrum of cells ranging from small mature lymphocytes to medium- and large-sized lymphocytes with blast-like chromatin and prominent nucleoli. The lymphoma cells were monoclonal B cells with moderately intense surface IgM. They were CD5 positive, cyclin D1 positive, CD10 negative, and CD23 negative. The flow cytometric immunophenotyping and DNA ploidy analysis of the PB and material obtained by aspiration cytology supported the diagnosis of B-MCL. These findings underline the utility of aspiration cytology in diagnosing B-MCL when cytomorphologic examination is combined with flow cytometric analysis of immuno-phenotype and demonstration of proliferation markers.     

Large-cell lymphoma presenting with hepatic sinusoidal infiltration

We describe a case of large-cell lymphoma of B-cell phenotype with clinicopathologic features resembling malignant histiocytosis. The clinical presentation was characterized by fever, anemia, thrombocytopenia, coagulopathy, and elevated liver enzyme levels. These features and the finding of a predominantly sinusoidal infiltrate of neoplastic cells on liver biopsy raised the suspicion of malignant histiocytosis. The patient subsequently developed supraclavicular lymphadenopathy, which proved to be due to a diffuse large-cell lymphoma. Immunophenotypic studies performed on the lymph node and the original liver biopsy specimen established the B-cell nature of neoplastic cells at both sites. This case highlights a rare pattern of hepatic involvement by large-cell lymphoma, and contrasts the latter with other hematologic disorders associated with hepatic sinusoidal infiltrates.     

Case report: mantle cell lymphoma, prolymphocytoid variant, with leukostasis syndrome.

A 76-year-old man presented with leukostasis syndrome, including oculodynia, blurred vision, and visual field defects, due to mantle cell lymphoma, prolymphocytoid variant, with marked leukocytosis, 1227 x 10(9)/l. He had splenomegaly but no lymphadenopathy or hepatomegaly. The tumor cells were CD5+, CD19+, CD20+, FMC-7+, and kappa light chain restricted. Immunohistochemistry showed expression of p53 and of cyclin D1. Fluorescent in situ hybridization demonstrated t(11;14) with translocation between CYCLIN D1 and the immunoglobulin heavy-chain genes. The patient received leukapheresis and aggressive chemotherapy, but the leukocyte count remained above 100 x 10(9)/l. The patient's condition rapidly deteriorated with lymphomatous infiltration of his lungs and soft tissues, and he expired 6 months after diagnosis. While it is known that mantle cell lymphoma may have a leukemic phase, the degree of leukocytosis in this case exceeds that previously reported in the literature and resulted in a clinical syndrome of leukostasis.     

Expression of cytotoxic molecule TIA-1 in malignant lymphomas mimicking fulminant hepatitis

Involvement of malignant lymphoma in the liver inducing fuiminant hepatic failure has rarely been reported. There fore, a close association between some lymphoma types with severe liver damage and the mechanism underlying the liver damage is intriguing. Three malignant lymphoma cases, which were clinically diagnosed as fulminant hepatitis, were collected from the autopsy records of Kawasaki Medical School (Kurashiki, Japan). All three cases were characterized by the presence of hepatosplenomegaly without superficial lymph node swelling, high elevation of transaminase and lactate dehydrogenase (LDH; especially LDH-2), and a quite aggressive clinical course. Immuno-histochemlcally, the tumor cells in all three cases were positive for T cell intracellular antlgen VIA-l), which is a cytolytic protein in cytotoxic T and natural klller (NK) cells. The lymphomas were CD8⁺ perlpheral T cell lymphoma (case l), CD56⁺ T/NK cell lymphoma (case 2), and T cell lymphoma in a patient with mosquito hypersensitivity (case 3). Epstein-Barr virus infection was demonstrated on the tumor cells of cases 2 and 3 using an in situ hybridization method and those cases showed high titers of serum interferon-γ and Fas. Frequent apoptosis of liver cells, where the lymphoma cells had infiltrated, was revealed by a terminal deoxyribosyl transferase-mediated deoxyuridine nick end-labeling (TUNEL) method. The findings in this study suggest that fulminant hepatic injury is closely associated with cytotoxic molecule TIA-1 expression of the lymphoma cells and that some specific mechanism may be involved In liver damage.     

From the archives of MD Anderson Cancer Center: Untreated leukemic non-nodal mantle cell lymphoma with relapse as pleomorphic variant mantle cell lymphoma 21 years later

Leukemic, non-nodal mantle cell lymphoma (MCL) is a distinct, rare, indolent variant of mantle cell lymphoma, but can relapse aggressively. It can present with lymphocytosis with chronic lymphocytic leukemia (CLL)-like morphologic and immunophenotypic features as was initially considered in the index case. However, at time of splenectomy, two years later cyclin D1 overexpression was shown and the disease was realized to be leukemic non-nodal MCL. The patient was followed for 21 years, without therapy, before he developed clinically aggressive MCL with lymphadenopathy. Lymph node biopsy showed MCL, pleomorphic variant. We review the literature and discuss the features of leukemic non-nodal MCL as well as the potential pitfalls in diagnosis. Furthermore, we are not aware of another cases reported with a 21 year interval from initial diagnosis of leukemic non-nodal MCL to aggressive MCL.     

Chronic hepatitis: a problem for the pathologist

The accepted histological categories of chronic hepatitis are chronic persistent hepatitis (CPH) and chronic active or aggressive hepatitis (CAH). A third form, chronic lobular hepatitis (CLH), encompasses those cases in which the lesion is predominantly within the lobules and in which portal and periportal inflammation are mild, CLH has many synonyms. International agreement on a reproducible and rational nomenclature of chronic hepatitis is still far from complete. CPH is characterized by portal inflammation. Histological definition is simple, but there are diagnostic pitfalls. The category may need subdivision on the basis of immunological studies. CAH should be regarded as a complex rather than a single disease, and it is important to specify the aetiology and pathological components in each instance. The concept of CAH must be altered to incorporate the lesion bridging hepatic necrosis (BHN). Piecemeal necrosis, accompanied by inflammatory infiltration, is considered to be the most important of the various pathogenetic factors in CAH, but BHN probably plays a significant part in accelerating the development of cirrhosis. An excessive portal and periportal inflammatory reaction with or without BHN, in a liver biopsy taken during the course of an acute hepatitis, helps to predict a possible chronic course.     

Morphology and immunology of circulating cells in leukaemic phase of follicular lymphoma.

Ten patients with follicular lymphoma presented with a high white cell count (45-220 x 10(9)/l) which resembled chronic lymphocytic leukaemia (CCL): all had pronounced splenomegaly and, except one, generalised lymphadenopathy. The blood lymphocytes were small with scanty cytoplasm, densely condensed nuclear chromatin, and deep clefts originating in sharp angles from the nuclear surface. CLL cells are larger, have more cytoplasm, a different pattern of chromatin condensation, and may have shallow nuclear indentations or foldings rather than clefts. The circulating follicular lymphoma cells had moderate to strong membrane immunoglobulins (SmIg), low mouse (M)-rosettes, strong reactivity with the monoclonal antibody FMC7, and occasional expression of the CD5-antigen; at least one third of cells in each case were positive with anti-cALLa (J5,CD10). Half the cases were referred as B-CLL but none had the typical B-CLL immunophenotype: weak SmIg, M-rosettes of greater than 50%, CD5 positive, FMC7 and J5 negative. The diagnosis of follicular lymphoma was confirmed by lymph node biopsy in seven of the 10 cases. The overall response to treatment was poor and five patients died within three years of diagnosis. This aggressive form of follicular lymphoma needs to be distinguished from B-CLL as different management is required.     

Testicular metastasis of primary cecal carcinoid tumor

Testicular carcinoids are rare and the majority are of primary testicular origin. Testicular carcinoids can also be secondary from extra-testicular primary tumors, but the incidence is even less common. The case described here is a patient who initially had an infiltrating cecal carcinoid with hepatic metastasis. Following surgery, he was managed with octreotide and had close monitoring of the levels of serum serotonin and its urinary metabolite. He experienced a fairly indolent clinical course and 5 years after excision of the primary cecal carcinoid, his hepatic lesion has virtually been unchanged. However, he developed a secondary testicular metastasis. He has otherwise remained well, without evidence of metastases elsewhere on imaging studies.     

Großzellige B-Zell-Lymphome Varianten und Entitäten

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.     

Subcutaneous panniculitis-like T-cell lymphoma in a patient with long-term remission with standard chemotherapy

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a very rare postthymic T-cell non-Hodgkin's lymphoma with poor prognosis. There is not a standard treatment for this disease. Here we describe the first case of SPTL with unusual periorbital involvement, pancytopenia, hepatic dysfunction and coagulopathy, which was successfully treated with a chemotherapy regimen of cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine) and prednisone (CHOP). Our case demonstrates that although the natural history of SPTL is aggressive, patients may respond effectively to combination chemotherapy. Early recognition of the classic subcutaneous lesions and its associated systemic signs, such as unusual periorbital involvement, liver dysfunction and hemophagocytic syndrome, is very important in managing this aggressive lymphoma. Immunohistochemical and genetic studies are helpful in confirming the diagnosis. Early initiation of aggressive chemotherapy is recommended for better clinical outcome.     

Malignant lymphoma with primary presentation in the spleen. A study of 20 patients

We describe 20 adult patients with malignant lymphoma with primary presentation in the spleen. The most common presenting symptoms were fever, malaise, and weight loss. Physical examination revealed prominent splenomegaly without palpable lymphadenopathy. Small lymphocytic lymphoma was the most frequent histologic type (11/20), followed by large cell lymphoma and mixed cell lymphoma (3/20 each). Bone marrow involvement was found in ten of 17 patients. At laparotomy, lymph node involvement, usually retroperitoneal, was found in six of 13 patients. There was liver involvement in seven of 15 patients. Follow-up has been relatively short, with an average of 24 months (range, one to 48 months). Four patients died as a result of progressive disease, one died of sepsis after splenectomy, and one died two years after diagnosis of a stroke. The prognosis in primary splenic lymphoma appears to be similar to that in nodal lymphoma.     

Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma

B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (DLBCL/BL) is a new lymphoma entity which is recognized in the current World Health Organization (WHO) classification (2008). We report a case of a primary central nervous system lymphoma (PCNSL) with findings consistent with DLBCL/BL. It is characterized by a very aggressive clinical course, and a widespread multifocal involvement of the CNS. Our case shows that a DLBCL/BL can manifest in the CNS alone without any systemic involvement.     

Lymph node disease with lymphocytic abnormal chromatin clumping in a myelodysplastic/myeloproliferative syndrome.

A case of abnormal chromatin clumping (ACC) which arose during the course of a myelodysplastic/myeloproliferative syndrome is described in a 61 year old woman who died of haemorrhage 43 months after diagnosis. Mature granulocytes exhibited the same nuclear abnormality described in other patients reported. Unusually, she presented with advanced splenomegaly and lymphadenopathy. This case was the third example of ACC in lymphocytes, the first with clinically confirmed lymphadenopathy. Diagnosis of this subset can be based on: older age; short duration of symptoms; no specific karyotypic damage; non-rearranged bcr; proliferative growth pattern in vitro; numerous circulating myelocytes; profound thrombocytopenia.     

An Epstein–Barr virus-positive diffuse large B-cell lymphoma presenting as multi-organ failure: A catastrophic lymphomatosis with fulminant visceral organ dissemination resulting in a precipitous death in a 59-year-old female with no identifiable etiology for immunodeficiency

Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is an aggressive B-cell neoplasm related to age-associated impaired immunity. We report such a case in a 59-year-old woman with a catastrophic disease course. The patient initially presented with fever, fatigue, malaise and weakness over one-week period. Despite empirical treatment with antibiotics and antiviral agents, she subsequently developed multi-organ failure and coagulopathy. Radiographic imaging revealed hepatomegaly, splenomegaly, pleural effusion, and ascites. Her complete blood cell count showed marked leukocytosis, anemia and thrombocytopenia. Morphologic examination of blood smear demonstrated many abnormal plasmacytoid lymphocytes, and flow cytometric analysis detected an intermediate-large mature B-cell population (69%) without detectable surface immunoglobulin. High copy numbers of EBV genome were detected in the blood by PCR. A diagnosis of EBV+ DLBCL, leukemic phase, was made. Despite aggressive treatment and supportive care, the patient succumbed to multi-organ failure one week after initial presentation. Autopsy demonstrated EBV+ DLBCL infiltration in all the organs examined. This case describes an unusual presentation of EBV+ DLBCL and highlights the necessity of pertinent ancillary tests to avoid delay in the diagnosis and treatment.     

A new form of alpha-chain disease with generalized lymph node involvement

An autopsy case of alpha-chain disease (ACD) clinically manifesting generalized lymph node swelling, slight splenomegaly and long-standing ichthyosiform skin eruptions, was reported. Autopsy revealed systemic superficial and profound lymph node swelling and slight splenomegaly, but little or no tumorous lesion in any part of the alimentary tract or pulmonary tissue. The histologic picture of the lymph nodes showed a diffuse monomorphic plasmocytic lymphoma, and there was tumor cell infiltration in the spleen and bone marrow. Immunohistochemistry demonstrated that the tumor cells contained IgA devoid of light chains, i.e. ACD protein. Immunoelectron microscopy revealed that this abnormal immunoglobulin was localized in the rough endoplasmic reticulum and perinuclear space. Persistent chronic inflammation with infiltration mainly of helper-inducer T cells were found in the skin and dermatopathic lymphadenopathy was confirmed in the lymph node biopsies. From these peculiar clinicopathological features, this case is considered to be a previously unknown form of ACD.