Diffuse Large B-Cell Lymphoma Initially ... - Semantic Scholar

Hematopathology / DLBCL IN THE BONE MARROW

Diffuse Large B-Cell Lymphoma Initially Manifesting in the Bone Marrow Dai Kajiura, MD, Yoriko Yamashita, MD, PhD, and Naoyoshi Mori, MD, PhD Key Words: Diffuse large B-cell lymphoma; Bone marrow; Intravascular large B-cell lymphoma; Asian variant; Hemophagocytic syndrome; Immunohistochemistry DOI: 10.1309/2GW5W7KQBXF6LFAW

Abstract We histologically and immunohistochemically studied 37 cases of diffuse large B-cell lymphoma (DLBCL) initially manifesting in the bone marrow (BM). We also compared these cases with the Asian variant of intravascular large B-cell lymphoma (AIVL). Histologically, the neoplastic cells of the BM mostly had large and round nuclei and formed clusters. Immunohistochemically, all cases were positive for B-cell markers. Factor VIII staining revealed neoplastic cells within the sinusoids of BM in 8 cases; however, these cells accounted for fewer than 20% of the overall neoplastic cells. In several cases, the neoplastic cells infiltrated liver, spleen, kidneys, lungs, stomach, and adrenal glands with a mainly leukemic and infrequently intravascular pattern. Although our cases share some clinical features with AIVL, we consider DLBCL initially manifesting in the BM to be a unique entity because the neoplastic cells proliferate mainly in BM, with infrequent involvement of the sinusoids and occasional leukemic infiltration in various organs.

Secondary involvement of malignant lymphomas in bone marrow is relatively common.1 However, primary occurrence of lymphomas in bone marrow is quite rare, except in chronic lymphocytic leukemia or small cell lymphoma.2 Large cell lymphoma with primary bone marrow involvement is exceptional, although secondary involvement is sometimes observed.1,3-5 Murase et al6-8 reported the Asian variant of intravascular large B-cell lymphoma (AIVL) in which bone marrow involvement of large B lymphoma cells was frequently observed. They proposed criteria for AIVL, including clinical and laboratory criteria and histologic criteria. The former include cytopenia, hepatomegaly and/or splenomegaly, and absence of overt lymphadenopathy and tumor formation. The latter include erythrocyte hemophagocytosis, immunophenotypic evidence of neoplastic B cells, and pathologic findings of intravascular proliferation of lymphoma cells. We reviewed 37 cases of diffuse large B-cell lymphoma (DLBCL) primarily manifesting in bone marrow during the last several decades. In this article, we describe the clinical and histologic characteristics of such cases and compare them with AIVL described by Murase et al.6-8

Materials and Methods For histologic and immunohistochemical examination, tissue samples were fixed with 10% formaldehyde and embedded in paraffin. Then, 2- to 4-µm-thick sections were prepared and stained with H&E. The avidin-biotin-peroxidase complex method (Ultratech, Immunotech, Marseille, France) was used for antibody staining. Antibodies used included CD3, CD20 (L26), CD68 (KP1), CD79a (mb-1), IgG, IgA, IgM, κ, λ, and factor VIII (DAKO, Copenhagen, Denmark); 762 762

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Hematopathology / ORIGINAL ARTICLE

CD34 (Novocastra Laboratories, Newcastle upon Tyne, England); and CD5 (T cell Diagnostics, Cambridge, MA). We evaluated the degree of neoplastic cell infiltration in sinusoids of the bone marrow in 4 grades using factor VIII staining: grades 0, 1, 2, and 3 represent 0%, 0% to 10%, 10% to 20%, and more than 20% of the total neoplastic cells, respectively. We also examined hemophagocytosis using H&E-stained specimens of the bone marrow and CD68 staining, which is a marker of histiocytes. Mild, moderate, and severe degrees represent 1 to 3 cells, 4 to 6 cells, and more than 7 cells in 10 high-power fields, respectively.

Results We studied 37 cases of DLBCL of the bone marrow at initial diagnosis. Clinical characteristics were obtained in 35

cases ❚Table 1❚. The median age of the patients was 67 years, with a range from 45 to 84 years. The patients comprised 17 men and 20 women. Initial symptoms included fever (24/37 [65%]), general fatigue (14/37 [38%]), anorexia (11/37 [30%]), weight loss (5/37 [14%]), and hepatosplenomegaly (25/37 [68%]). Hemophagocytic syndrome was observed clinically in 13 cases. Laboratory data indicated high lactate dehydrogenase levels in 34 cases. Clinical stages were IVB in 23 (66%), IVA in 3 (9%), IB in 6 (17%), and IA in 3 (9%). The mean survival was 14.9 months in the 35 patients with DLBCL of the bone marrow ❚Figure 1❚. Of 35 patients, 31 underwent chemotherapy; of these, 6 were alive at last followup. About 70% of the patients in our study died within 2 years despite chemotherapy. Neoplastic cells were found in the peripheral blood in 8 cases, comprising up to 34%. International prognostic indexes were high in 26 (74%), high

❚Table 1❚ Clinical Findings for Patients With Diffuse Large B-Cell Lymphoma of Bone Marrow at Initial Examination Case No./Sex/ Age (y)

PS

LDH

Lymphoma Cells in Peripheral Blood (%)

No, of Extranodal Lesions (Organ)

HPS

Stage

1/F/72 2/F/84 3/F/56 4/F/64 5/F/76 6/F/70 7/F/68 8/F/45 9/F/70 10/F/75 11/F/77 12/F/73 13/F/54 14/F/49 15/F/79 16/F/82

2 3 3 1 3 3 4 4 2 4 3 3 3 2 4 NA

High High High High High High High High High High High High High High High High

0 1 1 NA NA NA 0 NA NA 0 0 0 0 NA NA NA

2 (BM, Lv) 4 (BM, Lv, Sp, IpM) 2 (BM, Sp) 4 (BM, Lu, Lv, Sp) 3 (BM, Lv, Sp) 4 (BM, Lv, Sp, Kd) 3 (BM, Lu, Sp) 1 (BM) 1 (BM) 2 (BM, Sp) 3 (BM, Kd, St) 6 (BM, Lv, Sp, Lu, AG, Kd) 1 (BM) 1 (BM) 4 (BM, Lv, Sp, Kd) 1 (BM)

– + – – + + + – – – – – + – + –

IVB IVA IVB IVB IVB IVB IVB IB IB IVB IVB IVB IB IB IVB IB

17/F/59 18/M/81 19/M/54 20/M/55 21/M/69 22/M/54 23/M/66 24/M/63 25/M/67 26/M/74 27/M/66 28/M/74 29/M/51 30/F/63 31/F/61 32/M/66 33/M/58 34/M/67 35/M/70

4 3 2 0 2 1 2 2 3 3 3 1 1 3 4 3 2 4 0

High High High Normal High High High High High High High High High High High High High High High

NA 19 2 NA 0 0 0 NA NA 30 0 32 0 0 3 NA NA NA 34

6 (BM, Lv, Kd, AG, Br, Rt) 2 (BM, Sp) 6 (BM, Lv, Sp, Br, Lu, Kd) 1 (BM) 3 (BM, Lv, Sp) 1 (BM) 2 (BM, Lv) 3 (BM, Lv, Sp) 3 (BM, Lv, Sp) 2 (BM, Sp) 3 (BM, Lv, Sp) 1 (BM) 3 (BM, Lv, Sp) 3 (BM, Lv, Sp) 3 (BM, Lv, Sp) 3 (BM, Lv, Sp) 2 (BM, Sp) 4 (BM, Lv, Sp, St) 1 (BM)

+ + – – – – – – + + + – + – – – – + –

IVA IVB IVB IA IVB IB IVB IVB IVB IVB IVB IA IVB IVB IVB IVA IVB IVB IA

IPI High High High High High High High High intermediate High intermediate High High High High intermediate High intermediate High Low ~ high intermediate High High High Low High Low intermediate High High High High High Low High High High High High High Low intermediate

Clinical Course, mo* (Outcome) 35 (D) 13 (D) 26 (D) 12 d (D) 1 d (D) 1 d (D) 26 (D) 13 (D) 6 (D) 14 d (D) 9 (D) 2 (D) 37 (D) 14 (D) 1 (D) 10 d (D) 5 (D) 5 (D) 16 (D) 36 (D) 10 (D) 19 (D) 7 (D) 17 (D) 15 (D) 9 (D) 2 (D) 2 (D) 7 (D) 13 (AWOD) 107 (AWOD) 46 (AWOD) 7 (AWOD) 13 (AWOD) 1 (AWD)

AG, adrenal gland; AWD, alive with disease; AWOD, alive without disease; BM, bone marrow; Br, brain; D, died; HPS, hemophagocytic syndrome; IPI, International Prognostic Index; IpM, iliopsoas muscle; Kd, kidney; LDH, lactate dehydrogenase level; Lu, lung; Lv, liver; NA, not available; PS, performance status; Rt, retina; Sp, spleen; St, stomach; +, present; –, absent. * Unless otherwise indicated.

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100

Survival Rate (%)

90 80 70 60 50 40 30 20 10 0 0

20

40

60

80

100

120

Observation Period (mo)

❚Figure 1❚ Survival of 35 patients with diffuse large B-cell lymphoma of bone marrow at initial examination. About 70% of the patients died within 2 years despite chemotherapy.

or high to low intermediate in 5 (14%), low intermediate in 2 (6%), and low in 2 (6%). The clinical and laboratory criteria for AIVL were fulfilled by 18 cases, and, of these, 5 additionally fulfilled the histologic criteria. H&E staining revealed bone marrow that was hypercellular in 12 (32%) of 37 cases, normocellular in 17 (46%), and hypocellular in 8 (22%). The neoplastic cells typically had a large and round nucleus ❚Image 1A❚, but cleaved nuclei were observed in 4 cases. Of these, large atypical lymphoid cells were present in clusters in 28 (76%) of 37 cases, whereas scattered cells were observed in 9 (24%). Immunohistochemical studies ❚Table 2❚ indicated that all cases were positive for CD20 (L26) ❚Image 1B❚. All cases but 1 were CD79a+. Immunohistochemical staining using factor VIII revealed that

A

B

C

D

❚Image 1❚ A, Bone marrow biopsy specimen. The neoplastic cells have large and round nuclei (H&E, ×400). B, CD20 staining of a bone marrow biopsy specimen. The neoplastic cells are CD20+ and formed clusters in the extrasinusoidal space (×200). C, Factor VIII staining of a bone marrow biopsy specimen. The neoplastic cells are present in the sinusoid, but neoplastic cells in larger numbers proliferate in the extrasinusoidal space (×400). D, CD5 staining of a bone marrow biopsy specimen. The neoplastic cells are CD5+ (×200). 764 764




neoplastic cells were present in the sinusoids in 8 cases ❚Image 1C❚; of these, 7 were grade 1, 1 was grade 2, and none were grade 3. Of the 37 cases studied immunohistochemically, 10 were CD5+ ❚Image 1D❚. Hemophagocytosis was found in 33 (89%) of 37 cases overall ❚Image 1E❚, to a severe degree in 4 (11%), a moderate degree in 13 (35%), and a slight degree in 16 (43%). All cases were CD68+, a marker for active hemophagocytosis ❚Image 1F❚. Autopsy was performed in 7 cases, but 1 (case 8) was regional autopsy including brain and kidneys, and neoplastic lesions were not observed ❚Table 3❚. In addition, the stomach was biopsied in 2 cases, the liver in 1, and the kidney in 1. Of the cases in which biopsy or autopsy was performed,

involvement of the liver was observed in 6, the spleen in 5, the lungs in 3, the kidneys in 5, the stomach in 2, and the adrenals in 1. Of the 6 cases in which liver involvement was observed, neoplastic cells were mainly found in the portal areas in 5 cases ❚Image 1G❚; in 1 case, infiltration was found predominantly in the sinusoids. Five of the affected spleens exhibited diffuse infiltration. The neoplastic cells mainly infiltrated in the red pulp, forming variously sized clusters, accompanied by congestion and occasional necrosis, with almost total effacement of the white pulp. In lungs, neoplastic cells were observed in the vessels in 2 cases and in the interstitial tissue in 1 case. Of the 2 cases in which the stomach mucosa was

E

F

G

H

E, Bone marrow biopsy specimen. Hemophagocytosis is observed in the bone marrow (arrows) (H&E, ×400). F, CD68 staining of a bone marrow biopsy specimen. Erythrophagocytosis by CD68+ histiocytes is observed (arrows) (×400). G, Autopsy specimen of liver. The neoplastic cells predominantly infiltrate in the portal area, and a part of them invade in the sinusoids (H&E, ×100). H, Autopsy specimen of kidney. The neoplastic cells are present mainly in the blood vessels and glomerulus (H&E, ×100).

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❚Table 2❚ Results of Histologic and Immunohistochemical Analysis of Bone Marrow* Case No.

CD20 (L26)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

+ 3+ + + 3+ 2+ 2+ + + + + 2+ 2+ + 2+ 2+ + 3+ 3+ + + + 2+ 2+ + 2+ 3+ 2+ 3+ 3+ 3+ 2+ 3+ 2+ 3+ 3+ +

CD79a (mb-1) + 2+ + 2+ 2+ 2+ 3+ 2+ + + + + 2+ 2+ 2+ 2+ + 3+ 3+ 3+ + + 2+ 2+ – 3+ 3+ 3+ 3+ 3+ 2+ 2+ 2+ 2+ 2+ 3+ +

CD68 (KP-1)

CD5

+ 2+ 2+ 3+ + 2+ + 2+ 2+ 3+ 2+ + 2+ 2+ 2+ 2+ 2+ + 2+ + + 3+ + + + 2+ + 2+ 2+ + 2+ 3+ 2+ 2+ + + 2+

Factor VIII (Findings of Intrasinusoidal Involvement)

– – – + – ND – – – + – – + – + + + – + – – + – – – + – – + – – – – – – – –

Grading of Intrasinusoidal Involvement

Hemophagocytosis

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 0 1 0 0 0 0 1 0 0 1 0 0 1 1 0 1 0 0 0 0

+ 2+ + + + 2+ – + – 3+ 2+ 2+ 2+ 2+ + + + + 2+ 2+ 2+ – 2+ 2+ + 3+ 3+ + + + + 2+ + 3+ – + 2+

– – – – – ND – – – – – – – – – + + – + – – – – + – – + – – + + – + – – – –

ND, not done. * Scoring or grading was as follows: for CD20, CD79a, and CD5 (overall neoplastic cells positive): 3+, >80%; 2+, 30%-80%; +, 5%-30%; –, 20%; hemophagocytosis (cells in 10 high-power fields): 3+, >7; 2+, 4-6; +, 1-3; –, none.

❚Table 3❚ Infiltration Sites and Pattern of Lymphoma Cells in Autopsy Specimens Case No. Bone Marrow 6

Liver

Spleen

Cluster formation Massive cluster formation Cluster formation

Portal area infiltration Portal area infiltration Sinusoidal infiltration

Diffuse infiltration Diffuse infiltration Diffuse infiltration

16

Cluster formation

Portal area infiltration

Diffuse infiltration

17 27

Not involved Massive cluster formation

Not involved Portal area and sinusoidal infiltration

Not involved Diffuse infiltration

7 12

Brain

Lung

Adrenal Gland

Kidney

ND

Not involved

Not involved

Interstitial infiltration

ND

Mild intravascular infiltration Intravascular infiltration

Not involved

Not involved

Intravascular infiltration

Intravascular infiltration and small amount of glomerular infiltration Interstitial infiltration and small amount of glomerular infiltration

ND

Perivascular and parenchymal infiltration ND Not involved

Interstitial infiltration

Not involved

Not involved Not involved

Not involved Not involved

Not involved Interstitial infiltration

ND, not done.

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infiltrated, gland destruction was seen in one case and cluster formation observed in the other. In kidneys, neoplastic cells were found in the interstitial tissue in 2 cases, in the glomerular capillaries in another 2, and in both in 1 case ❚Image 1H❚. In the adrenal gland, neoplastic cells were observed in the sinusoids in 1 case.

Discussion Intravascular lymphomatosis was first described as angioendotheliomatosis proliferans systemisata by Pfleger and Tappeiner9 in 1959. Subsequently, various reports10-17 have indicated that this neoplasm originated not from endothelial cells but from lymphocytes. Some reports10,11,14,18 indicated that surface immunoglobulin was demonstrated on the neoplastic cells. Although most reports10,11,13,14,17-19 indicated a B-lymphocytic origin for the neoplastic cells, some suggested that they arose from T lymphocytes.13,20-25 This rare disease is characterized by multifocal, intravascular proliferation of large pleomorphic cells within small vessels of most organs, with a predilection for the skin and central nervous system. Clinically, patients with intravascular lymphomatosis have focal neurologic signs and a progressive decline in mental status, frequently resulting in circulatory disturbances, followed by death in a few months.15,21,22 In our study, the mean survival was 14.9 months in the 35 patients with DLBCL of the bone marrow. This result was not so different from a past report.5 Conlan et al1 reported that the presence of large cell lymphoma of bone marrow predicted a short survival. There have been reports indicating that the deficiency or absence of adhesion molecules might contribute to the inability of lymphoma cells to extravasate and invade primary tissues.16,26 Murase et al6-8 reported AIVL. According to their report, patients had high fever, anemia, thrombocytopenia, hepatosplenomegaly, hemophagocytosis, bone marrow invasion, respiratory disturbances, and disseminated intravascular coagulopathy but usually lacked lymphadenopathy, mass formation, neurologic abnormalities, and skin lesions. Histologic analysis revealed large lymphoid cells infiltrated into vessels and/or sinusoids of the liver, marrow, lung, kidney, and other organs. Hemophagocytic syndrome is frequently seen in T-/natural killer (NK)-cell lymphomas.27,28 This syndrome is due to the cytokinemia produced by neoplastic T/NK cells. However, the mechanism underlying the hemophagocytic syndrome of diffuse large cell lymphoma of the bone marrow remains totally unknown.6-8,29-34 Secondary involvement of lymphoma in the bone marrow is rarely accompanied by hemophagocytic syndrome. It is quite remarkable that the hemophagocytic syndrome is relatively specific for DLBCL

in the bone marrow at diagnosis. Western cases showing such features have been also reported.31,32,35,36 In the present study, we examined 37 cases of DLBCL of the bone marrow at initial diagnosis. Some cases were accompanied by hemophagocytic syndrome. In addition, large numbers of hemophagocytic histiocytes were observed in bone marrow specimens, as highlighted by CD68 immunostaining. The neoplastic cells in these cases typically had large and round nuclei, with a cleaved nucleus in a small number of cases. These neoplastic cells proliferated diffusely or formed clusters in the bone marrow constituent cells. Only 8 cases had a sinusoidal involvement of bone marrow, in which fewer than 20% of the overall neoplastic cells were in the sinusoids. Autopsy was performed in 7 cases. Of these, 5 cases had lymphomatous involvement of various organs, including liver (5 cases), spleen (5 cases), adrenals (1 case), lungs (3 cases), and kidneys (4 cases). Of the cases in which the neoplastic cells were found in the liver at autopsy, infiltration in the portal areas was predominant in 4, whereas sinusoidal involvement was predominant in 1 (case 12). These findings indicated that although predominant infiltration of neoplastic cells in the vessels was observed in 1 case, in other cases, infiltration of neoplastic cells in various organs was usually not limited to the blood vessels, but also extended to the tissues themselves. In this respect, the infiltration pattern seems more leukemic than intravascular. Wong et al4 reported 14 cases of large cell lymphoma with initial manifestation in the bone marrow, of which 4 exhibited a B-cell phenotype, 3 a T-cell phenotype, and 1 a non-T non-B phenotype. Most patients had “swinging” fever and peripheral blood cytopenia. Reactive hemophagocytic syndrome was a common finding, causing significant morbidity and mortality. In some patients, involvement was apparently restricted to the bone marrow. The 4 cases in their report with a B-cell phenotype were mostly consistent with our current cases. Their report and ours suggest that diffuse large cell lymphoma in the bone marrow at initial diagnosis exists and that it shows quite unusual clinical features: in most of the involved sites other than bone marrow, the infiltration pattern was leukemic rather than intravascular. There was a report of large cell lymphoma cases showing a leukemic picture at diagnosis.37 Morice et al37 reported 2 cases of DLBCL with splenic and bone marrow involvement. They indicated that although there was prominent, but not exclusive, intravascular/intrasinusoidal lymphomatous marrow infiltration, this pattern of infiltration could not be called intravascular lymphomatosis because in these cases, diffuse infiltration of the neoplastic cells in splenic red pulp and lymph nodes was observed. Therefore, they concluded that intrasinusoidal infiltration of large cell lymphoma in bone marrow might be seen distinct from intravascular lymphomatosis. Am J Clin Pathol 2007;127:762-769



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This large B-cell lymphoma of the bone marrow is reported mostly in Asian countries, including Japan,4,6-8,29,38,39 with only a few reported Western cases.31,32,35,37,40 This difference in incidence is converse to that seen for chronic lymphocytic leukemia, which is relatively uncommon in Japan and other Asian countries compared with Western countries.41 This can be compared with the fact that the incidence of low-grade lymphoma in Western countries is relatively high compared with Asian countries, whereas the incidence of large cell lymphoma in Asian countries is higher than in Western countries.42-44 There have been several reports of CD5 expression in the cases of DLBCL in the bone marrow or AIVL.21,33,40,45,46 Khalidi et al45 reported CD5 antigen expression in 5 cases of intravascular lymphomatosis and suggested that these cases were related to or represented unusual histologic forms of transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma or mantle cell lymphoma. In our series, 10 cases were CD5+, suggesting de novo large cell transformation of chronic lymphocytic leukemia or small cell lymphoma in the bone marrow. We consider DLBCL of bone marrow at initial diagnosis to be a distinct entity in which the neoplastic cells proliferate mainly in the bone marrow, with infrequent involvement of the sinusoids and leukemic infiltration in a variety of organs, including liver and spleen. From the Department of Pathology of Biological Response, Nagoya University Graduate School of Medicine, Nagoya, Japan. Address reprint requests to Dr Kajiura: Dept of Pathology of Biological Response, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550, Japan.

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