—  SPECIALTY CONFERENCE  —

Hematopathology

Case 2 - Intravascular Large B-cell Lymphoma

Marsha Kinney
University of Texas Health Sciences Center
San Antonio, Texas


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Clinical History:
This 63 year old male presented with progressive dyspnea over 4 months, dry cough, low-grade fever and chills, and 19 pound weight loss. Past medical history was significant for single vessel atherosclerotic cardiovascular disease, hyperlipidemia, hypertension, and peptic ulcer disease. Chest x-ray revealed a retrocardiac infiltrate. Patient had recent exposure to birds and puppies at a neighbor's house. Patient was treated with antibiotics for two weeks without response.

Patient was admitted to the hospital. CT examination revealed an alveolar infiltrate more pronounced in the bases than in the apices. There was no adenopathy by physical examination or CT. Pulmonary function tests revealed airflow obstruction. CBC was normal except for anemia (HCT = 30.3%). LDH was 1825 IU/L with a mildly elevated AST (124 IU/L) and a normal total billirubin and ALT. Haptoglobin was normal and reticulocyte count was 3.3%. Bronchoscopy with transbronchial biopsy of the right lower lobe was performed.


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Histology:
Sections of the transbronchial biopsy show small fragments of lung tissue. The alveolar capillaries are distended by large non-cleaved lymphocytes with folded, irregular nucleoli with dispersed chromatin and prominent nucleoli. Similar large, discohesive cells are present in small, dilated submucosal vessels. The bronchial epithelial cells are normal.

Immunophenotypic Studies:
Paraffin immunoperoxidase stains show the large lymphocytes are CD45+, CD20+, BCL-2+. Only a small number of scattered CD3+ T-cells are present. The tumor cells are negative for CD5, CD10, and CD43. There is a suggestion of weak kappa light chain expression in the cytoplasm of some of the large lymphocytes.

Diagnosis: Intravascular Large B-cell Lymphoma

Treatment and Follow-up:
Staging studies showed the marrow was negative by routine histology and flow cytometry. The patient received CHOP combination chemotherapy and was free of disease at last follow-up four years later.

This case was kindly contributed by Thomas S. Neuhauser, M.D., Major, USAF, Wilford Hall Medical Center, San Antonio, TX.

Discussion
Intravascular large cell lymphoma (IVL) (previously known as angiotropic lymphoma, malignant angioendotheliomatosis, intravascular lymphomatosis, and angioendotheliomatosis proliferans systemisata) is an unusual large cell lymphoma originally described in 1959 by Pfleger et al.38 In the early to mid 1980's several groups reported its lymphoid rather than endothelial origin.1,5,34,41 Non-cohesive large lymphocytes with somewhat irregular nuclei with dispersed chromatin and prominent nucleoli are present in the lumen of small vessels (arteries, veins, and predominantly capillaries) and may be surrounded by a meshwork of fibrin and platelets. Small foci of tumor outside of the vessel or previous lymphoma have been reported in small numbers of cases.53 Rare cases with small non-cleaved, non-Burkitt's morphology have been described .16 The tumor infiltrate is subtle and many cases have been diagnosed at post mortem examination.

Patients with IVL are older (average age 65, range 34-85 years; male to female ratio: 0.7 – 5.0)32.53 and present with generalized findings such as fever, weight loss, and malaise and signs and symptoms related to occlusion of small vessels in various organs, most frequently the central nervous system and skin. Autopsy shows disseminated disease with tumor in multiple organs, so the disease presentation can be protean. Skin lesions include tender erythematous nodules, tumors, teleangiectasia, cellulitis and lymphedema. Neurologic conditions include cerebral infarcts with secondary neurologic deficits, dementia, non-localizing defects, polyneuropathy and myopathy including myalgia and muscle weakness. CSF is only rarely involved. Lymph nodes are usually spared. The adrenal glands are another common disease site, and prostate enlargement, kidney disease with nephrotic syndrome, and lytic bone lesions have been described. IVL is only rarely associated with immunodeficiency and has been reported in three AIDs patients and one renal transplant patient.12,17,20,32

Over 200 cases of IVL have been reported27 but primary or predominant pulmonary involvement, as seen in this case, has been described only in about 20 cases.8,14,16,18,23,27,29,37,45,47,54 Chief complaints include dyspnea, cough, and fever. Chest x-ray and CT scan show reticular or reticulonodular densities suggesting interstitial lung disease. Pulmonary function tests reveal decreased diffusion capacity due to vascular obstruction by malignant cells. Patients can develop pulmonary hypertension and right heart failure and pulmonary angiitis.8,14,45 Transbronchial biopsy is diagnostic.47

Patients also present with FUO, anemia, thrombocytopenia, and less often leukopenia, autoimmune hemolytic anemia, and diffuse intravascular coagulation. A bone marrow sample may be the first tissue obtained for diagnosis.13 Marrow involvement is reported in 10%-15% of cases.49,51 The low detection rate may be due to lack of immunostaining in many cases. A small number of histologically and immunophenotypically negative marrows have shown 100% involvement when sensitive PCR studies have been performed.10 Lymphoma cells are generally present in small groups or single file in sinuses, but in some cases tumor cells markedly distend the sinuses. Despite the intravascular location, peripheral blood involvement has been reported only in a small number of cases; tumor cells vary from rare to up to 12% of the white blood cells.13 Clumps of tumor cells have been reported in peripheral blood smears made from the needle point after routine venipuncture.6

An Asian variant of IVL has been described (average age 66 years, males 62%) that is characterized by a hemophagocytic syndrome, pancytopenia, hepatosplenomegaly, and rare mass formation.35,36,42 In addition, marrow invasion, fever and hyperbilirubinemia and elevated levels of LDH were significantly more often present than in typical IVL. Neurologic abnormalities and skin lesions were significantly less frequent with tumor cells more often infiltrating vessels and/or sinusoids of the liver, marrow, lung, kidney and other organs. A small number of cases have been reported in the West supporting the concept of a specific variant.11

In up to one-third of IVL cases, there is a history of antecedent lymphoma (reviewed in reference 53) such as follicular lymphoma, MALT-type lymphoma, and cases of large cell lymphoma including primary cutaneous large cell lymphoma of the leg.14,18,22 It has been suggested IVL may represent an unusual transformation of low grade lymphoma; clonality studies to determine if the two lymphomas are related are limited.53

IVL is rarely reported co-existing with vascular lesions--hemangiomas in the skin40 and within the lesions of Kaposi's sarcoma in an AIDS patient 20.

Immunophenotype:
In a review of 82 cases reported by Ko et al., 199727 and 86 cases by Estalilla et al.13 85%-91% were B-cell and 9%-15% were T-cell. One T-cell case was CD30+ and had the morphology of anaplastic large cell lymphoma.27 Most (89-100%) cases express BCL-2 and 0-20% express CD43; there is variability in the expression of CD5 and CD10 with 50%- 60% being CD5-CD10- and approximately 20%-50% expressing either CD5 or CD10 on paraffin embedded tissue.26,39,53 Aprpoximately 20%-25% express BCL-6.53 Co-expression of CD5 and BCL-6 and of CD5 and CD10 has been reported in a small number of cases.53 The immunophenotype of variant Asian cases with hemophagocytosis may have more frequent CD5 expression (29%-67%) as compared to IVL in the West 36,42; no clinical differences were observed between CD5+ and CD5- cases in a Japanese study.42 Overall, the immunophenotypic findings in all cases of IVL demonstrate heterogeneity in the cell of origin. Although the presence of CD5 suggests transformation from CLL/SLL or mantle cell lymphoma in some of the cases, CD23 and cyclin D1 havebeen negative in small number of cases tested.26,53 Rare cases with expression of histiocyte antigens44 or co-expression of myeloperoxidase and CD20 have been reported 7.

Molecular, cytogenetic, and pathogenetic features:
Molecular analysis of the immunoglobulin heavy chain gene variable region using direct sequence analysis of the complementary-determining region 2 (CDR2) and framework region 3 (FR3) has shown that 5/6 cases of IVL originated in post-germinal center B-cells based on the presence of somatic mutation in VH genes; three of the IVL with hypermutated genes were CD5+ providing further evidence against a mantle cell origin of IVL, as mantle cell lymphoma develops in pre-germinal center B-cells in the majority of cases.24 BCL-2 rearrangments have been negative in the small number of cases tested even though CD10 or BCL-6 expression has been reported in 44% of IVL.10,43,53

Cytogenetic data is limited. Review of cytogenetic studies in 6 cases found an accumulation of structural aberrations in chromosomes 1, 6, and 18, especially 1p (67% of cases) and trisomy 18 (67% of cases).48 A translocation, t(1;3)(p22;p21), has also been reported.33

There is little support for a viral etiology in IVL. EBV is only rarely detected in IVL by EBER in-situ hybridization.25,53 The small number of EBV+ cases have been reported in patients from the Far East.2,25 Two cases had a T-cell phenotype and the third case was a B-cell IVL in a patient with AIDs and Kaposi's sarcoma.2,20

It has been postulated that the peculiar intravascular growth pattern of IVL may be due to abnormal homing receptors on the tumor cells or endothelial preventing tumor cells from migrating into the tissue, but a well-defined concept has not emerged. Alterations the CD11a/CD18 complex (LFA-1), which mediates cell-to-cell adhesion on lymphocytes and binds to ICAM-1 (CD54) on endothelial cells, and lack of CD29 (beta-1 integrin subunit) and CD54 on tumor cells, have been described.21,25,39 CD44 expression appears normal.15,39

Treatment and Prognosis:
Early studies have shown a high mortality (>80%) with survivals ranging from 2-48 months.19 More recent studies report a good response to chemotherapy.4,52 It appears that IVL has a relatively good prognosis when diagnosed early and treated with multiagent chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) and in a small number of patients with stem cell transplant.28,47,52

Differential Diagnosis:
Vascular invasion is common in many tumors but disseminated intravascular anaplastic neoplasms with occult primary tumors are rare. The differential diagnosis includes metatstatic tumor (carcinoma, melanoma) and vascular tumors including reactive angioendotheliomatosis and angiosarcoma. Carcinoma and melanoma are exluded with immunophenotyping and the lack of keratin and S-100 and HMB-45 expression, respectively.

Benign reactive angioendotheliomatosis is a rare disorder occurring in the setting of a hypersensitivity reaction or systemic infection, most commonly bacterial endocarditis, or with cryoglobulinemia.30 Clinically patients have multiple erythematous nodules and indurated plaques on the trunk, limbs, face or ear lobes. Ulceration and blister formation, though uncommon, may occur. Lesions consist of endothelial and myoepithelial cell proliferations and stain with factor VIII-related antigen, Ulex europaeus and antibodies against smooth muscle cells (desmin, muscle specific actin).

Cases of intravascular disseminated angiosarcoma are rare.31 Tumor cells are irregular with slightly spindled morphology and hyperchromatic nuclei with scant cytoplasm. Occasional intravascular papillary structures can be seen. Tumor cells show variable expression of factor VIII antigen, CD31, CD34, and Ulex europaeus.

To make a diagnosis of intravascular lymphoma with a T-cell phenotype, other T cell lymphomas have to be excluded. Anaplastic large cell lymphoma (ALCL) can occur at extranodal sites and have vascular involvement;27 a diffuse growth of tumor cells is usually present in ALCL and markers such as CD30, EMA, and ALK-1 should be expressed. Some cases of hepatosplenic T-cell lymphoma show intravascular growth outside the liver, spleen and marrow and should be considered in the diagnosis of T-cell IVL. Correlation with clinical history (prominent liver and spleen involvement), TIA-1 expression, and the presence of isochromosome (7q) would favor hepatosplenic lymphoma.46,50

IVL in the lung resembles an inflammatory interstitial pneumonia. The tumor cells can be somewhat inconspicuous in a background of mild interstitial inflammation and proliferation of type II alveolar pneumocytes. Recognition of large intravascular lymphocytes and staining for CD20 lead to the appropriate diagnosis.

Finally, pathologists should be aware that intravascular menstrual endometrium can rarely be seen in hysterectomy specimens and mimic IVL.3 Histologically there is a variable mixture of small spindled stromal cells and large cuboidal epithelial cells that mark with vimentin in the former and low molecular weight cytokeratin and EMA in the latter.

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