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Intravascular Lymphomatosis: A Study of 20 Cases in Thailand and a Review of the Literature
Original Contribution Intravascular Lymphomatosis: A Study of 20 Cases in Thailand and a Review of the Literature Sanya Sukpanichnant,1 Sanan Visuthisakchai2
Abstract Background: According to the World Health Organization classification (2001), intravascular large B-cell lymphoma (IVLBCL) is characterized by the presence of lymphoma cells only in the lumina of small vessels. It has not been proven whether IVLBCL is a specific clinicopathologic entity. Intravascular large B-cell lymphoma and other intravascular lymphomatoses (IVLs), including IVL with B-cell phenotype and extravascular growth (B-IVL) and IVL with T-cell phenotype (T-IVL), were compared in a series of cases diagnosed at a single institution and in cases reported in the literature. Patients and Methods: Twenty cases of IVL diagnosed among 1826 consecutive cases of non-Hodgkin’s lymphoma (NHL,1.1%) at Siriraj Hospital included 3 cases of IVLBCL, 14 cases of B-IVL, and 3 cases of T-IVL. In the literature, 102 cases of IVLBCL, 88 cases of B-IVL, and 18 cases of T-IVL were described in sufficient detail to be analyzed. Results: All 3 groups were quite similar in clinical manifestations and outcome. Contrary to the previous review of 79 cases of IVL in 1989, blood, marrow, and nodal involvement could be detected in approximately 30% of cases. Patients who received chemotherapy had better survival than patients without treatment— statistically significant in IVLBCL and B-IVL (P < 0.05). Cases with skin involvement had better survival than cases without skin involvement— statistically significantly in T-IVL (P < 0.05). Conclusion: These results indicate that IVLBCL is not different from B-IVL or T-IVL in a biologic sense, and IVL seems to be better terminology than IVLBCL because it includes the T-cell phenotype that constitutes approximately 9% of cases. Early diagnosis is very important because chemotherapy significantly prolongs survival.
Clinical Lymphoma & Myeloma, Vol. 6, No. 4 319-328, 2006 Key words: Angiotropic lymphoma, Extranodal lymphoma, Intravascular large B-cell lymphoma, Malignant angioendotheliomatosis, Neoplastic angioendotheliomatosis, non-Hodgkin’s lymphoma
Introduction Malignant angioendotheliomatosis (MAE) has been proven as a misnomer in that such cases are now considered to be mostly intravascular lymphomatosis (IVL) or angiotropic lymphoma.1-10 Since 1985, there have been > 260 cases of IVL reported, but there have been only 15 series that include * 5 cases;2,3,11-23 some of them provide limited clinical information. Intravascular large B-cell lymphoma (IVLBCL) is designated as a disease entity of non-Hodgkin’s lymphoma (NHL) in the recent World Health Organization (WHO) classification.24 However, the clinical manifestations in the WHO classification monograph are mainly based on the literature review in 1989 of 79 cases of IVL and MAE;25 this study is flawed in that approximately 40% of cases were not proven to be lymphoid 1Department
of Pathology 2Department of Medicine Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Submitted: ???; Revised: ???; Accepted: ??? Address for correspondence: Sanya Sukpanichnant, MD, Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Fax: 66-2-411-4260; e-mail: [email protected]
and some had extravascular growth,1,3,4,7,10,26-32 excluding them by the WHO definition as examples of IVLBCL. By the WHO definition, IVLBCL is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries;24 it is perceived that macroscopic deposits of tumor at presentation exclude IVLBCL by definition. The validity of this definition has not been proven. In this study, we performed a retrospective analysis of all IVL cases in our institution as well as an extensive literature review in order to determine whether IVLBCL is a specific disease entity based on the definition by the WHO classification (2001).
Patients and Methods This retrospective analysis of IVL at Siriraj Hospital was approved by the Ethics Committee on Research Involving Human Subjects, Faculty of Medicine Siriraj Hospital, Mahidol University (No. 107/2002). Cases diagnosed as IVL during the 9-year period between August 1, 1993, and July 31, 2002, were analyzed. All cases had histopathologic features of IVL,3,4,7,24 proven to be malignant lymphoma by immunoperoxidase studies as described previously33 using antibodies against
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Clinical Lymphoma & Myeloma January 2006 • 319
Intravascular Lymphomatosis CD45, CD20, and CD3. A B-cell phenotype (B-IVL) was established when the lymphoma cells were CD20+ but CD3–, whereas a T-cell phenotype (T-IVL) was established when the lymphoma cells were CD3+ but CD20–. Only intravascular malignancies that had been shown to be lymphoid phenotype were included. The clinical and pathologic information in each case was retrieved from the clinical records, surgical pathology reports, and autopsy reports (if performed). Histopathologic findings in each case were reviewed by one of the authors (SS). A literature review of IVL was performed by electronic search of the English literature until the closing date of February 1, 2003, under the key words “lymphomatosis,” “angiotropic,” or “angioendotheliomatosis.” Each paper was retrieved and thoroughly reviewed. The frequency of manifestations was determined only from the various case reports in which specific clinical or pathologic features were described; this meant that individual cases with incomplete data in some series were not included in the final analysis. Cases were then divided into those that strictly followed the definition of IVLBCL according to the WHO classification24 and those that did not. The latter included patients who had organ enlargement or a mass lesion at presentation, patients who had extravascular involvement without an established diagnosis of IVLBCL during life, or patients with T-cell phenotype. Cases that met the definition of IVLBCL for diagnosis based on tissue biopsy during life and did not have any organ enlargement at the time of diagnosis, but later developed extravascular involvement during the course of the disease, were still considered to be IVLBCL. Extravascular involvement or growth was characterized by demonstration of lymphoma cells outside the vascular lumina in * 1 histologic section of the tissue obtained for pathologic evaluation. We included cases with organomegaly at the time of diagnosis for analysis as B-IVL instead of IVLBCL, because it was not possible to confirm the clinical observation of organomegaly in these cases whether it was caused only by congestion and/or secondary changes to occlusion of the vasculature by lymphoma cells or by extravascular growth and proliferation by lymphoma cells. So any organomegaly at the time of diagnosis was regarded as clinical evidence against the WHO definition of IVLBCL,24 and this criterion was important in determining whether cases of patients who were alive or did not have autopsy were IVLBCL or B-IVL for analysis. For statistical analysis, the χ2 test was used to assess differences among groups of IVL in terms of clinical features and abnormal laboratory findings. Fisher’s exact test was used when * 1 of the expected counts in a 2 × 2 table were so small that the χ2 test could not be used. The log-rank test was used to assess differences in median survival after the onset of disease estimated by Kaplan-Meier method among different groups of patients with IVL.
Results Of the 1826 consecutive cases of classifiable NHL diagnosed at Siriraj Hospital during the 9-year period, 20 cases of IVL (1.1%) were diagnosed (19 in-house cases and 1 consultation
320 • Clinical Lymphoma & Myeloma January 2006
case, case 5). There were 8 men and 12 women (M-F ratio, 1:1.5). The mean age was 62 ± 12 years (range, 34-77 years). Bcell phenotype was much more common than T-cell phenotype (85% vs. 15%). Of the 20 cases, 3 cases were IVLBCL (cases 13), 14 cases were B-IVL (cases 4-17), and 3 cases were T-IVL (cases 18-20). A brief summary of each case is given in Tables 13. None of the IVLBCL cases had organomegaly or mass lesion at presentation, but 1 case had hepatomegaly and a subependymal nodule detected at relapse. Organomegaly or mass lesions were found in 12 cases of B-IVL (86%), and hepatosplenomegaly was found in 1 case of T-IVL (33%) at presentation. All but 1 case of B-IVL had abnormal liver function tests; however, clinical jaundice was observed in only 3 cases of B-IVL (21%) and 1 case of T-IVL (33%). In addition to anemia, thrombocytopenia was observed in 1 case of IVLBCL (33%), 10 cases of B-IVL (71%), and 2 cases of T-IVL (67%); but none had any bleeding disorder. Uncommon clinical presentation included dyspnea in 2 cases of B-IVL and 2 cases of T-IVL, jaundice in 3 cases of B-IVL and 1 case of T-IVL (with dyspnea and anuria), nasal mass in 1 case of B-IVL, and abdominal pain in 1 case of T-IVL. None of the 20 patients had a previous history of lymphoma or other malignancy. Lymphoma cells were demonstrated within the vascular lumina in all cases. Lymphoma cells were mostly centroblasts, and less commonly immunoblasts or pleomorphic large cells (Figures 1 and 2). They frequently distended small blood vessels and were occasionally enmeshed in fibrin thrombi with or without platelets. No significant cytologic difference was observed among the lymphoma cells in the 3 groups of IVL. Lymphoma cells were localized only within the vascular lumina in all histologic sections of tissue obtained for pathologic examination in cases of IVLBCL, whereas * 1 microscopic focus of lymphoma cells outside the vascular lumina could be demonstrated in cases of B-IVL. Associated hemorrhagic foci and coagulative necrosis could be observed in the vicinity. Perivascular infiltration by small lymphocytes was sometimes noted. Table 2 shows the sites of intravascular and extravascular growth in the present series from Siriraj Hospital. Nearly all organs examined in these 3 groups showed infiltration by lymphoma. In the B-IVL group, * 1 organ showed extravascular growth; spleen, lymph nodes, bone marrow, and adrenal glands were among the common sites. Lymph node involvement was found in 7 of the 9 patients (78%) with lymph node tissue available for examination. In the T-IVL group, extravascular growth was found in 2 of 3 patients (67%). Lymphoma cells could be found in marrow aspirate smears in the only case of IVLBCL, 8 of 11 cases of B-IVL, and the only case of T-IVL with marrow involvement. Circulating lymphoma cells were not found in IVLBCL, but they were seen in 4 cases of B-IVL (cases 8, 9, 15, and 17) and in 2 cases of T-IVL (cases 19 and 20). As many as 22% of nucleated cells in the peripheral blood were lymphomatous in case 20. The literature search resulted in the retrieval of 297 of 334 full articles (89%); of these, only 266 cases of IVL were documented by immunophenotypic evidence that the neoplastic cells were lymphoid in nature.1-23,25,34-66 The mean
Sanya Sukpanichnant, Sanan Visuthisakchai Table 1 Case
1
Summary of 20 Cases of Intravascular Lymphomatosis at Siriraj Hospital
Age(Years)/ Sex; Clinical Presentation
Major Laboratory Abnormalities
76/F; FUO, weight loss, anemia Hb↓, LDH↑, abn LFT for 4-5 months
Enlargement or Mass Lesion Phenotype; Diagnostic Presentation Autopsy Tissue
Clinical Course (Survival Time)*
Specific Treatment
None
Liver, spleen
B; Autopsy
Steroids only; died of respiratory failure (5 months)
None
None
Not done
B; Breast
First relapse in CNS, 2nd relapse in skin, 3rd relapse as cauda equina syndrome; refused treatment; DOD (18.5 months)
COP; brain radiation at relapse
B; Marrow
Spontaneous clinical remission; refused treatment; liver, subependymal nodule, and respiratory failure at relapse; full recovery after treatment; lost to follow-up (9.3 months)
Chemotherapy at relapse
2
71/F; Skin rash over both breasts for 3 months
LDH↑, abn LFT
3
77/M; Fever for 10 days
Hb↓, plt↓, LDH↑, abn LFT
None
Lost to follow-up
4
69/F; FUO for 4 months
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
None
Liver, adrenals
B; Kidney, marrow
Died of acute renal failure (5 months)
None
5
34/F; Headache, left hemiparesis for 4 months
Hb↓, abn LFT, Cr↑
None
Liver, spleen, kidneys, adrenals
B; Autopsy
Transient response to steroids; died of multiorgan failure (5 months)
None
6
57/F; Fever, headache, diplopia for 3 weeks
Hb↓, WBC↑, plt↓, LDH↑, abn LFT, adrenal insufficiency, hypoglycemia
Right parasellar mass
Liver, spleen, kidneys, adrenals, para-aortic lymph nodes
B; Autopsy
Sudden dyspnea; died of multiorgan failure (5 weeks)
None
7
59/F; Exertional dyspnea for 3 months
Hb↓, WBC↑, plt↓, Cr↑
Right kidney mass, para-aortic lymph nodes
Liver, spleen, kidneys, adrenals, para-aortic lymph nodes
B; Autopsy
Died of respiratory failure (3.5 months)
None
8
69/M; FUO, mild jaundice for 8 months
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
Liver, spleen
Liver, spleen
B; Autopsy
Died of respiratory failure (8 months)
None
9
69/M; Jaundice, nausea, dizziness for 10 days
WBC↑, plt↓, LDH↑, abn LFT, adrenal insufficiency
Liver, spleen, adrenals
Adrenals, kidneys, retroperitoneal lymph nodes
B; Autopsy
Died of multiorgan failure (2 weeks)
None
10
58/M; FUO, anemia, jaundice for 1 month
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
Liver, spleen
Not done
B; Marrow, lung, liver†
Died of multiorgan failure (1 month)
None
11
54/M; FUO, anemia for 2 months
Hb↓, plt↓, LDH↑, abn LFT
Liver, spleen
Liver, spleen
B; Autopsy
Treated as MH; died of multiorgan failure (14 months)
CHOP, COP
12
56/M; Dizziness, fever, malaise for 1 week
Pancytopenia, LDH↑, abn LFT
Liver, spleen
Not done
B; Marrow, lung, liver, spleen†
Died of multiorgan failure (10 days)
None
13
72/F; Left nasal mass for 1 month
Hb↓, LDH↑, abn LFT
Left maxillary sinus, nasal
Not done
B; Nasal mass, marrow
Died of diarrhea with shock after CHOP (1.7 months)
CHOP
14
50/M; Headache, ptosis for 2 months
LDH↑, abn LFT, hypopituitarism
Liver, spleen
Not done
B; Paranasal sinus
Died of respiratory failure (2.5 months)
None
15
55/F; FUO for 2 months
Pancytopenia, LDH↑, abn LFT
Liver, spleen, uterus
Not done
B; Spleen, uterus
Treated as splenic NHL; DOD (12 months)
CHOP
16
65/F; FUO for 4 months
Hb↓, LDH↑, abn LFT
Spleen
Lost to follow-up
B; Spleen
Treated as splenic NHL; relapse; lost to follow-up (15.5 months)
CHOP
17
53/F; Fever, cough, dyspnea for 2 months
Hb↓, plt↓, LDH↑, abn LFT
Spleen, lymph nodes
Liver, spleen, lymph nodes, kidneys, adrenals
B; Autopsy
Died of respiratory failure (2.5 months)
None
18
48/F; Abdominal pain, fever for 3 days
LDH↑, abn LFT
None
–
T; Colon
Alive and well after colectomy (19.1 months)
None
19
76/M; Fever for 3 weeks; acute dyspnea
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
None
Liver, spleen, right kidney
T; Autopsy
Died of respiratory failure (3 weeks)
None
20
77/F; FUO, jaundice, dyspnea for 1 month; anuria
WBC↑, plt↓, LDH↑, abn LFT, Cr↑
Liver, spleen
Liver, spleen
T; Autopsy
Died of multiorgan failure (1 month)
None
Cases 1-3: typical intravascular large B-cell lymphoma; cases 4-17: other intravascular lymphomatosis of B-cell phenotype; and cases 18-20: intravascular lymphomatosis of T-cell phenotype. *Survival time after the onset of illness. †Postmortem biopsy. Abbreviations: abn LFT = abnormal liver function tests; CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone; CNS = central nervous system; COP = cyclophosphamide/vincristine/prednisone; Cr = serum creatinine; DOD = died of disease; FUO = fever of unknown origin; Hb = hemoglobin; LDH: serum lactate dehydrogenase; MH = malignant histiocytosis; plt = platelet count; WBC = white blood count
Clinical Lymphoma & Myeloma January 2006 • 321
Intravascular Lymphomatosis Table 2
Sites of Intravascular and Extravascular Growth in 20 Cases of Intravascular Lymphomatosis at Siriraj Hospital
Intravascular Growth Case Other Number Brain Thoracic Abdominal Adrenals Endocrine Genital Lymph Bone Organs Nodes Marrow Viscera Viscera Organs* +
1
+
+
+
+
+†
2
–
+§
Spleen, bone marrow
+
+
+
–
Brain, lungs, spleen, adrenals, female genital organs, lymph nodes
+
–
+
+
Adrenals
+
+
+
+
–
Spleen, kidneys, adrenals, lymph nodes
–
+
+
–
+§
Spleen, bone marrow
+
+‡
+
+§
Adrenals, lymph nodes
+
Liver, bone marrow
4
+
+
–
5
+
+
+
+
6
+
+
+
+
7
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
10 11
+
12
+
+
+‡
–
13 14
+
15
+
16
+ +
17
+
+ + +
+
+ +
+
+
18
–
+§ +
+
–
–
+
+
9
–
+
3
8
Extravascular Growth
19
+
+
+
+
+
20
–
+
+
–
–
+
+§
Spleen
+§
Lungs, spleen
+§
Nasal mass, bone marrow
+§
Spleen
+§
Spleen
–
Spleen and hilar lymph nodes
+
Liver, spleen, gastrointestinal tract, urinary bladder, lymph nodes
–
Transverse colon
+
–
–
–
+§
Liver, spleen, bone marrow
*Including pituitary gland, thyroid gland, and pancreas (endocrine part). †Only breast biopsy examined. ‡Prostate also involved. §Large lymphoma cells also found in bone marrow aspirate smears. Abbreviations: Blank = no tissue for examination; – = tumor not seen; + = tumor present
age of the patients was 63 ± 12 years (range, 13-90 years). There were 146 men and 120 women (M-F ratio, 1.2:1). Forty-six cases (17%) were Asian and the others were non-Asian, mainly from the United States and Europe. Among 218 cases with known phenotype, 91% were B-cell IVL and 9% were T-cell IVL. The frequencies of B-cell IVL and T-cell IVL in Asia were 86% and 14%, respectively, whereas those in North America and Europe were 93% and 7%, respectively. Only 208 cases could be classified specifically as IVLBCL (102 cases), B-IVL (88 cases), and T-IVL (18 cases). B-cell or T-cell phenotype was not proven in 48 cases, and information was inadequate for a definite grouping of IVL in 10 cases with known phenotype. In the IVLBCL group, the M-F ratio was 1.1:1; mean age, 65 ± 11 years (range, 35-90 years); and ethnicity, Asian in 12% of cases. In the B-IVL group, the M-F ratio was 1.1:1; mean age, 63 ± 13 years (range, 13-87 years); and ethnicity, Asian in 24% of cases. In the T-IVL group, the M-F ratio was 2:1; mean age, 56 ± 20 years (range, 17-84 years); and ethnicity, Asian in 33% of cases. Seven cases of IVLBCL (7%), 3 cases of B-IVL (3%), and 3 cases of T-IVL (17%) had a previous history of NHL, varying in each group from clinically indolent (approximately 30%-40%) to aggressive types (approximately 60%-70%) and ranging from
322 • Clinical Lymphoma & Myeloma January 2006
4 months to 6 years before the diagnosis of IVL. Two cases of IVLBCL (2%), 7 cases of B-IVL (8%), and 1 case of T-IVL (6%) were found to have simultaneous NHL at the time of autopsy, all clinically aggressive NHL but 1 gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in the patient with IVLBCL. Table 3 compares clinical features and abnormal laboratory findings among the 3 groups of IVL during the clinical course of the disease by analyzing information derived from the present series and the literature. No significant difference in clinical or laboratory findings was observed among the 3 groups of patients with IVL in the present series (P > 0.05). But, in the literature, significant differences between the IVLBCL group and the B-IVL group (P < 0.05) were observed in the frequency of skin lesions (53% vs. 31%), hemophagocytic syndrome (3% vs. 14%), enlarged adrenal glands (2% vs. 17%), and bone marrow involvement (13% vs. 44%). Significant differences between the IVLBCL group and the T-IVL group (P < 0.05) were observed in the frequency of fever (84% vs. 55%) and anemia (83% vs. 50%). Significant differences between the BIVL group and the T-IVL group (P < 0.05) were observed in the frequency of fever (87% vs. 55%), skin lesions (31% vs. 67%),
Sanya Sukpanichnant, Sanan Visuthisakchai Table 3
Clinical and Laboratory Findings of Intravascular Large B-cell Lymphoma, Intravascular Lymphomatosis of B-cell and T-cell Phenotypes B-IVL
IVLBCL Clinical Laboratory Findings
T-IVL
Present Study (n = 3)
Literature (N = 102)
Present Study (n = 14)
Literature (N = 88)
Present Study (n = 3)
Literature (N = 18)
Fever
2/3 (67)
48/57 (84)
9/14 (64)
52/60 (87)
3/3 (100)
6/11 (55)
Neurologic Deficits
2/3 (67)
62/80 (78)
8/14 (57)
54/74 (73)
0/3 (0)
8/14 (57)
Skin Lesions
1/3 (33)
29/55 (53)
1/14 (7)
15/49 (31)
0/3 (0)
10/15 (67)
Anemia
2/3 (67)
44/53 (83)
12/14 (86)
43/56 (77)
1/3 (33)
7/14 (50)
Hemophagocytic Syndrome
0/3 (0)
3/102 (3)
3/13 (23)
12/88 (14)
1/3 (33)
1/18 (6)
Hypoxia
2/3 (67)
18/102 (18)
7/14 (50)
16/88 (18)
2/3 (67)
2/18 (11)
Enlarged Adrenals
0/1 (0)
2/102 (2)
5/8 (63)
15/88 (17)
0/3 (0)
0/18 (0)
Elevated LDH
3/3 (100)
27/29 (93)
12/12 (100)
42/43 (98)
3/3 (100)
3/3 (100)
Abnormal LFT
3/3 (100)
17/102 (17)
13/14 (93)
22/88 (25)
3/3 (100)
3/18 (17)
–
16/102 (16)
6/6 (100)
17/88 (19)
0/3 (0)
2/18 (11)
1/3 (33)
9/68 (13)
11/14 (79)
28/64 (44)
1/3 (33)
4/11 (36)
Abnormal Renal Functions Marrow Involvement
Numbers in parentheses are percentages. Abbreviations: LDH = serum lactate dehydrogenase; LFT = liver function tests
and anemia (77% vs. 50%). Thirty-five of 102 patients (34%) with IVLBCL were found to have extravascular involvement during their course after the diagnosis of IVLBCL. This high frequency of extravascular disease led us to determine the number of patients with IVLBCL who did not have extravascular disease in an autopsy population. To rule out treatment effects, only patients who did not receive specific treatment were included. We then compared clinical and laboratory findings in 3 groups: 20 autopsied cases of untreated IVLBCL without extravascular disease (IVLBCL group 1); 35 cases of IVLBCL with extravascular disease (IVLBCL group 2); and 88 cases of B-IVL. Significant differences between IVLBCL group 1 and the B-IVL group (P < 0.05) were observed in the frequency of neurologic deficits (100% vs. 73%) and marrow involvement (7% vs. 44%), but the only significant difference between IVLBCL group 2 and the B-IVL group (P < 0.05) was observed in the frequency of skin lesions (60% vs. 31%). The only significant difference between IVLBCL group 1 and group 2 (P < 0.05) was observed in the frequency of neurologic deficits (100% vs. 70%). The frequency of enlarged adrenal glands in IVLBCL group 1 was lower than that in the B-IVL group (0 vs. 17%), but it was not statistically significant (P = 0.06). The frequencies of enlarged adrenal glands and marrow involvement in IVLBCL group 2 were lower than those in B-IVL (6% vs. 17% for enlarged adrenal glands and 22% vs. 44% for marrow involvement), but they were not statistically significant (P = 0.14 and 0.07, respectively). Fever, anemia, hypoxia, and abnormal liver and renal function tests were similar among the 3 groups in term of frequency. Interestingly, all or nearly all organs examined at autopsy in these 3 groups, especially the brain, demonstrated microscopic involvement by lymphoma cells, with the exception of IVLBCL group 1, which did not have any evidence of extravascular growth.
Table 4 demonstrates the frequency of correct diagnosis during life among the 3 groups of patients with IVL. Diagnoses ranged from 33% to 67% in the present series and from 55% to 72% in the literature. The chance of “specific” treatment given to the 3 groups of patients with IVL was mostly lower than that of correct diagnosis during life, ranging from 0 to 67% in the present series and from 49% to 65% in the literature. In the present series, treatment consisted of chemotherapy. But, in the literature, treatment varied considerably among the 3 groups of IVL cases; 86%-100% of patients received combination chemotherapy, with 45%-62% of the regimens including the cyclophosphamide/doxorubicin/vincristine/prednisone combination and other anthracycline-based regimens. Other treatments included single-agent chemotherapy with or without radiation therapy or systemic psoralen plus ultraviolet A light, radiation therapy alone, combined chemotherapy and radiation therapy, and autologous bone marrow or peripheral blood stem cell transplantation. Survival time after the onset of disease was recorded in 72 cases of IVLBCL, 66 cases of B-IVL, and 17 cases of T-IVL. No significant difference in overall survival was observed among the 3 groups of patients with IVL (Table 4). However, patients with IVLBCL and B-IVL who received chemotherapy had significantly better survival than patients who received no treatment (P < 0.05). Better survival in patients with T-IVL who received chemotherapy was also observed, but it was not statistically significant (P = 0.28). Survival was also better in all 3 groups of IVL in patients with skin involvement than in patients without skin involvement, but it was statistically significant only in patients with T-IVL (P < 0.05). Despite the fact that the small number of patients in the present series precluded statistical analysis, the survival in all 3 groups of patients with IVL seemed to be comparable with that observed in the literature, because those who received chemotherapy or those with skin involvement had better survival.
Clinical Lymphoma & Myeloma January 2006 • 323
Intravascular Lymphomatosis Figure 1 Intravascular Lymphomatosis in the Breast A
Figure 2 Intravascular Lymphomatosis in the Colon A
B B
(A) Large lymphoma cells of centroblastic type within the vascular lumen (hematoxylin and eosin; original magnification ×400). (B) Distinct membrane staining with CD20, a B-cell marker. CD3 is negative (not shown). (Case No. 2)
Discussion In this series from Siriraj Hospital, IVL accounts for 1.1% of all cases of NHL, a percentage comparable with a report from Hong Kong (0.9% of 325 cases of NHL),67 but the frequency is much lower in series from Japan68 (0.1% of 3025 cases) and India69 (0% of 2773 cases). To our knowledge, the present series is the largest from a single institution. The most recent publication of an IVL study by the International Extranodal Lymphoma Study Group (IELSG) included 38 patients from 22 centers (21 centers in Europe and 1 center in Australia); only 8 centers had > 1 patient, and the largest number of patients from 1 center was only 6.70,71 In the present series, clinical manifestations are similar to those reported in the literature with regard to neurologic deficits and skin lesions; we also observe hepatosplenomegaly, progressive hypoxia, renal or adrenal insufficiency, spontaneous regression of clinical symptoms, temporary improvement by steroids, and localized disease. The distribution of B-cell phenotype and T-cell phenotype in the present series of IVL is 85% and 15%, respectively, percentages comparable with those from Asia (86% and 14%). Intravascular lymphomatosis with associated hemophagocytic syndrome (HS) has been called the Asian variant of IVL;18,34 there are 4 cases in the present series: 3 cases of B-cell phenotype and 1 case of T-cell phenotype. The literature review reveals 16 cases of IVL with associated HS that
324 • Clinical Lymphoma & Myeloma January 2006
C
(A) Admixture of centroblasts, immunoblasts, and large pleomorphic cells within the vascular lumen (hematoxylin and eosin; original magnification ×400). (B) Focal extravascular growth by centroblasts (hematoxylin and eosin; original magnification ×200). (C) Distinct membrane staining with CD3, a T-cell marker. CD20 is negative (not shown). (Case No. 18)
were phenotyped; 15 cases were B-cell IVL (13 Asian and 2 non-Asian), and 1 case was T-cell IVL (non-Asian).18,34-44 The significant differences between IVLBCL (105 patients, including 102 patients in the literature and 3 patients in the present series) and B-IVL (102 patients, including 88 patients
Sanya Sukpanichnant, Sanan Visuthisakchai Table 4
Clinical Aspects and Survival of Intravascular Large B-cell Lymphoma, Intravascular Lymphomatosis of B-cell and T-cell Phenotypes IVLBCL
Clinical Aspects
B-IVL
T-IVL
Present Study (n = 3)
Literature (N = 102)
Present Study (n = 14)
Literature (N = 88)
Present Study (n = 3)
Literature (N = 18)
Correct Diagnosis
2/3 (67)
71/102 (70)
5/14 (36)
48/88 (55)
1/3 (33)
13/18 (72)
Skin Involvement
1/3 (33)
29/55 (53)
1/14 (7)
15/49 (31)
0/3 (0)
10/15 (67)
Specific Treatment
2/3 (67)
48/92 (52)
4/14 (29)
43/87 (49)
0/3 (0)
11/17 (65)
12.2 (0.2 month-10.1 years)
3 (0.3 month-1.3 years)
8 (0.2 month-6.5 years)
9.3 Overall Survival, Months (Range) (5 months-1.5 years)
1 6 (0.7 month-1.6 years) (2.5 months-3.8 years)
Survival, Months (Range) Treatment No Treatment
13.9 (9.3 months-1.5 years) 5
23 (1 month-9.8 years)
13 18 (1.7 months-1.3 years) (0.5 month-6.5 years) 4 2.5 3 (0.2 month-10.1 years) (0.3 month-0.7 years) (0.2 month-2.4 years)
NA
8 (3 months-3.8 years)
1 (0.7 month-1.6 years)
3 (2.5 months-2 years)
NA
18 (2.5 months-3.8 years)
Survival, Months (Range) Skin Involvement No Skin Involvement
18.5
23 (3 months-10.1 years)
7.2 (5 months-0.8 year)
12 (0.8 month-5.3 years)
3.5
18 (1.2 months-2.9 years)
2.5 10 1 (0.3 months-1.3 years) (1.4 months-6.5 years) (0.7 month-1.6 years)
5 (2.8 months-0.9 year)
Comparison of different types of intravascular lymphomatosis as to correct diagnosis during life, skin involvement, specific treatment, overall survival, survival with and without treatment, and survival in cases with and without skin involvement (median and range of survival time after the onset of disease) in the present series and in the literature. Numbers in parentheses are percentages unless otherwise indicated. Abbreviation: NA = not available
in the literature and 14 patients in the present series) are skin lesions (52% vs. 25%), HS (3% vs. 15%), enlarged adrenal glands (2% vs. 21%), and bone marrow involvement (14% vs. 50%), as demonstrated in Table 3. However, none of these significant differences exist when the setting is limited to the autopsied untreated population. In this particular setting, neurologic deficits appear to be the only significant difference between IVLBCL without extravascular disease and B-IVL (100% vs. 73%). Interestingly, this clinical feature of neurologic deficits is also the only significant difference between IVLBCL without extravascular disease and IVLBCL with extravascular disease (100% vs. 70%). The presence of lymphoma cells in all or nearly all organs examined at autopsy in these 3 groups, especially the brain, makes it difficult to explain why neurologic deficit is the only significant difference among these 3 groups. Because there are no clinicopathologic features that are significantly different between IVLBCL and B-IVL under various circumstances, and approximately one third of IVLBCL cases in the literature develop extravascular disease during the course of the disease, IVLBCL as a disease entity in the WHO classification24 is not different from B-IVL in a biologic sense. In addition, the WHO definition of IVLBCL as “a type of lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries” seems to be ideal because it is not possible to exclude any extravascular growth that is not grossly visible somewhere in the body even at the time of autopsy. Interestingly, approximately 10% each of IVLBCL and BIVL cases and 20% of T-IVL cases in the literature are previously diagnosed to have NHL * 4 months before the
diagnosis of IVL or have a simultaneous NHL at the time of the diagnosis of IVL. In most cases with available morphologic and immunophenotypic data of preceding or simultaneous NHL, the morphology and phenotype are similar to those of IVL; the same clonality has been demonstrated in 2 cases,10,22 but the available tissue and techniques cannot prove the clonality in 1 case report.45 The type of NHL in approximately 30%-40% of cases with preceding NHL is clinically indolent; morphologic progression to large-cell lymphoma at the time of IVL has been proposed,22,44,46 and in * 1 case, the same clonal immunoglobulin gene rearrangement has been demonstrated in indolent NHL and IVL.22 Regarding the results of immunophenotypic studies, IVL is heterogeneous. Approximately 10 of 28 cases (36%) are CD5+ and 6 of 6 cases (100%) are CD23–;12,19,22,39,42,47-49 these cases are distinguished from chronic lymphocytic leukemia or mantle cell lymphoma owing to their lack of CD23 and cyclin D1 expression.12,19,22 Another large subgroup, 14 of 21 cases (67%), shows CD5–/CD10– expression, similar to the phenotype of many diffuse large B-cell lymphomas.22,39,42,49 It is estimated that < 3% of IVL cases arise from low-grade lymphomas or unclassifiable lymphoid neoplasms.14,22,23,44,46 Aberrant adhesion molecules and cytogenetic abnormalities have been demonstrated in a small number of cases of IVL, similar to those previously reported in advanced NHL.11,21,34,50-54 Translocations involving myc, bcl-2, bcl-6, or immunoglobulin genes are not described. Only 4 of 38 cases (11%) of IVL have been associated with Epstein-Barr virus (EBV) by in situ hybridization for EBV-encoded RNA (EBER).15,18,22,42,44,45,55-58,62,63,67 In summary, the phenotype
Clinical Lymphoma & Myeloma January 2006 • 325
Intravascular Lymphomatosis of lymphoma cells in IVL is heterogeneous, and the relationship to a specific lymphocytic cell of origin has not been established. In our review of the literature, circulating lymphoma cells and bone marrow and lymph node involvement can be found in approximately 30% of IVL cases by light microscopy alone. Subtle involvement can undoubtedly be detected in a higher percentage by immunoperoxidase studies for CD20 and CD3 in histologic sections51,64,65 and by molecular genetic techniques looking for clonal rearrangements of the immunoglobulin heavy chain (IgH) gene or T-cell receptor gene.17,44,56,57 In the present series from Siriraj Hospital, circulating lymphoma cells are also detected in 30% of cases, but the higher percentage of cases with involvement of the bone marrow (65%; with the application of immunohistochemistry to detect lymphoma cells in 3 cases with negative marrow by conventional morphologic evaluation) and lymph node (75%). The recent publication of an IVL study by the IELSG demonstrates marrow involvement in 32% of 38 cases of IVL.70,71 Moreover, among these cases, 55% have systemic symptoms, 39% have skin lesions or central nervous system involvement, 34% have hepatosplenic involvement, 63% have anemia, 29% have thrombocytopenia, and 16% each have cardiopulmonary or renal involvement. In our review of 260 cases of IVL, 60% have systemic symptoms, 63% have central nervous system involvement, 24% have skin lesions, 32% have hepatosplenic involvement, 42% have anemia, 17% have thrombocytopenia, 16% have cardiopulmonary involvement, 15% have renal involvement, and 7% have hemophagocytic syndrome. Hence, most features are comparable between that series and our literature review. Therefore, IVL is not as mysterious as stated in earlier case reports, in which patients who did not have lymphadenopathy or hepatosplenomegaly and blood and marrow involvement were typically spared. Unfortunately, it is so difficult to publish an extensive literature review of > 260 cases of IVL, mostly case reports, because of a very long list of references, that most of the reports or even the WHO classification monograph uses the literature review by Domizio et al25 to shorten the reference list. That literature review published in 1989 included cases of IVL and MAE; approximately 40% of cases were not proven to be lymphoid in nature. The unusually low frequency of clinical features in that literature review included systemic symptoms (9%), hepatosplenomegaly (3%), hypoxemia, and renal failure (1% each). We hope that our extensive review of the literature will provide a better understanding of this rare type of NHL. We have also demonstrated that specific treatment, mostly combination chemotherapy, significantly prolongs survival in patients with IVL. This observation concurs with the recent study by the IELSG on anthracycline-based chemotherapy as primary treatment for IVL.70,71 The 5-year survival rate in treated cases of IVL is comparable to that in the high-risk group of NHL defined by the International Prognostic Index.72 Skin involvement is another good prognostic factor in IVL based on our extensive review and the recent IELSG study.70,71 The significance of specific treatments for the clinical outcome of IVL obviously emphasizes the importance of early diagnosis of this disease. Therefore, it is very important for physicians to
326 • Clinical Lymphoma & Myeloma January 2006
keep IVL in mind when patients present with clinical manifestations and laboratory abnormalities described in the literature review herein. In particular, physicians should consider random skin biopsy for diagnosis as suggested by Gill et al.66 Large lymphoma cells can be detected in bone marrow aspirate smears, but the diagnosis of IVL requires the demonstration of intravascular localization of lymphoma cells in histologic sections. The use of molecular genetic techniques for clonal rearrangements of the IgH gene or T-cell receptor genes in the peripheral blood mononuclear cells to screen for IVL has not been implemented clinically. But it is possible for such an approach to be used in the future for early detection of IVL.
Conclusion Intravascular lymphomatosis is rare and heterogeneous in nature. Although most of the cases are of B-cell phenotype, Tcell phenotype constitutes approximately 9% of cases. Contrary to the previous case reports and literature review, circulating lymphoma cells and bone marrow and lymph-node involvement in IVL can be detected in approximately 30% of cases. Early diagnosis is crucial to the successful clinical management of IVL, because specific treatment, especially anthracycline-based combination chemotherapy, significantly prolongs survival. Cases with skin involvement might have a better prognosis. Finally, IVLBCL as a disease entity in the WHO classification24 is in doubt, because approximately one third of the patients with IVLBCL have been shown to have extravascular disease during their clinical course. Intravascular lymphomatosis seems to be a better term than IVLBCL because it includes the T-cell phenotype. An international registry of IVL should be established to gather cases around the world for extensive studies in order to understand this very aggressive NHL.
Acknowledgements The authors thank Miss Saowalak Hunnangkul for statistical analysis, Dr Ake-Chittra Sukkul and Dr Supinda Petchjom for clinical information of 11 cases, Mr Chaiyuth Buawatana for photographic assistance, and Professor Dr Robert D. Collins at Vanderbilt University Medical Center for his comments.
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Abstract Background: According to the World Health Organization classification (2001), intravascular large B-cell lymphoma (IVLBCL) is characterized by the presence of lymphoma cells only in the lumina of small vessels. It has not been proven whether IVLBCL is a specific clinicopathologic entity. Intravascular large B-cell lymphoma and other intravascular lymphomatoses (IVLs), including IVL with B-cell phenotype and extravascular growth (B-IVL) and IVL with T-cell phenotype (T-IVL), were compared in a series of cases diagnosed at a single institution and in cases reported in the literature. Patients and Methods: Twenty cases of IVL diagnosed among 1826 consecutive cases of non-Hodgkin’s lymphoma (NHL,1.1%) at Siriraj Hospital included 3 cases of IVLBCL, 14 cases of B-IVL, and 3 cases of T-IVL. In the literature, 102 cases of IVLBCL, 88 cases of B-IVL, and 18 cases of T-IVL were described in sufficient detail to be analyzed. Results: All 3 groups were quite similar in clinical manifestations and outcome. Contrary to the previous review of 79 cases of IVL in 1989, blood, marrow, and nodal involvement could be detected in approximately 30% of cases. Patients who received chemotherapy had better survival than patients without treatment— statistically significant in IVLBCL and B-IVL (P < 0.05). Cases with skin involvement had better survival than cases without skin involvement— statistically significantly in T-IVL (P < 0.05). Conclusion: These results indicate that IVLBCL is not different from B-IVL or T-IVL in a biologic sense, and IVL seems to be better terminology than IVLBCL because it includes the T-cell phenotype that constitutes approximately 9% of cases. Early diagnosis is very important because chemotherapy significantly prolongs survival.
Clinical Lymphoma & Myeloma, Vol. 6, No. 4 319-328, 2006 Key words: Angiotropic lymphoma, Extranodal lymphoma, Intravascular large B-cell lymphoma, Malignant angioendotheliomatosis, Neoplastic angioendotheliomatosis, non-Hodgkin’s lymphoma
Introduction Malignant angioendotheliomatosis (MAE) has been proven as a misnomer in that such cases are now considered to be mostly intravascular lymphomatosis (IVL) or angiotropic lymphoma.1-10 Since 1985, there have been > 260 cases of IVL reported, but there have been only 15 series that include * 5 cases;2,3,11-23 some of them provide limited clinical information. Intravascular large B-cell lymphoma (IVLBCL) is designated as a disease entity of non-Hodgkin’s lymphoma (NHL) in the recent World Health Organization (WHO) classification.24 However, the clinical manifestations in the WHO classification monograph are mainly based on the literature review in 1989 of 79 cases of IVL and MAE;25 this study is flawed in that approximately 40% of cases were not proven to be lymphoid 1Department
of Pathology 2Department of Medicine Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Submitted: ???; Revised: ???; Accepted: ??? Address for correspondence: Sanya Sukpanichnant, MD, Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Fax: 66-2-411-4260; e-mail: [email protected]
and some had extravascular growth,1,3,4,7,10,26-32 excluding them by the WHO definition as examples of IVLBCL. By the WHO definition, IVLBCL is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries;24 it is perceived that macroscopic deposits of tumor at presentation exclude IVLBCL by definition. The validity of this definition has not been proven. In this study, we performed a retrospective analysis of all IVL cases in our institution as well as an extensive literature review in order to determine whether IVLBCL is a specific disease entity based on the definition by the WHO classification (2001).
Patients and Methods This retrospective analysis of IVL at Siriraj Hospital was approved by the Ethics Committee on Research Involving Human Subjects, Faculty of Medicine Siriraj Hospital, Mahidol University (No. 107/2002). Cases diagnosed as IVL during the 9-year period between August 1, 1993, and July 31, 2002, were analyzed. All cases had histopathologic features of IVL,3,4,7,24 proven to be malignant lymphoma by immunoperoxidase studies as described previously33 using antibodies against
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Clinical Lymphoma & Myeloma January 2006 • 319
Intravascular Lymphomatosis CD45, CD20, and CD3. A B-cell phenotype (B-IVL) was established when the lymphoma cells were CD20+ but CD3–, whereas a T-cell phenotype (T-IVL) was established when the lymphoma cells were CD3+ but CD20–. Only intravascular malignancies that had been shown to be lymphoid phenotype were included. The clinical and pathologic information in each case was retrieved from the clinical records, surgical pathology reports, and autopsy reports (if performed). Histopathologic findings in each case were reviewed by one of the authors (SS). A literature review of IVL was performed by electronic search of the English literature until the closing date of February 1, 2003, under the key words “lymphomatosis,” “angiotropic,” or “angioendotheliomatosis.” Each paper was retrieved and thoroughly reviewed. The frequency of manifestations was determined only from the various case reports in which specific clinical or pathologic features were described; this meant that individual cases with incomplete data in some series were not included in the final analysis. Cases were then divided into those that strictly followed the definition of IVLBCL according to the WHO classification24 and those that did not. The latter included patients who had organ enlargement or a mass lesion at presentation, patients who had extravascular involvement without an established diagnosis of IVLBCL during life, or patients with T-cell phenotype. Cases that met the definition of IVLBCL for diagnosis based on tissue biopsy during life and did not have any organ enlargement at the time of diagnosis, but later developed extravascular involvement during the course of the disease, were still considered to be IVLBCL. Extravascular involvement or growth was characterized by demonstration of lymphoma cells outside the vascular lumina in * 1 histologic section of the tissue obtained for pathologic evaluation. We included cases with organomegaly at the time of diagnosis for analysis as B-IVL instead of IVLBCL, because it was not possible to confirm the clinical observation of organomegaly in these cases whether it was caused only by congestion and/or secondary changes to occlusion of the vasculature by lymphoma cells or by extravascular growth and proliferation by lymphoma cells. So any organomegaly at the time of diagnosis was regarded as clinical evidence against the WHO definition of IVLBCL,24 and this criterion was important in determining whether cases of patients who were alive or did not have autopsy were IVLBCL or B-IVL for analysis. For statistical analysis, the χ2 test was used to assess differences among groups of IVL in terms of clinical features and abnormal laboratory findings. Fisher’s exact test was used when * 1 of the expected counts in a 2 × 2 table were so small that the χ2 test could not be used. The log-rank test was used to assess differences in median survival after the onset of disease estimated by Kaplan-Meier method among different groups of patients with IVL.
Results Of the 1826 consecutive cases of classifiable NHL diagnosed at Siriraj Hospital during the 9-year period, 20 cases of IVL (1.1%) were diagnosed (19 in-house cases and 1 consultation
320 • Clinical Lymphoma & Myeloma January 2006
case, case 5). There were 8 men and 12 women (M-F ratio, 1:1.5). The mean age was 62 ± 12 years (range, 34-77 years). Bcell phenotype was much more common than T-cell phenotype (85% vs. 15%). Of the 20 cases, 3 cases were IVLBCL (cases 13), 14 cases were B-IVL (cases 4-17), and 3 cases were T-IVL (cases 18-20). A brief summary of each case is given in Tables 13. None of the IVLBCL cases had organomegaly or mass lesion at presentation, but 1 case had hepatomegaly and a subependymal nodule detected at relapse. Organomegaly or mass lesions were found in 12 cases of B-IVL (86%), and hepatosplenomegaly was found in 1 case of T-IVL (33%) at presentation. All but 1 case of B-IVL had abnormal liver function tests; however, clinical jaundice was observed in only 3 cases of B-IVL (21%) and 1 case of T-IVL (33%). In addition to anemia, thrombocytopenia was observed in 1 case of IVLBCL (33%), 10 cases of B-IVL (71%), and 2 cases of T-IVL (67%); but none had any bleeding disorder. Uncommon clinical presentation included dyspnea in 2 cases of B-IVL and 2 cases of T-IVL, jaundice in 3 cases of B-IVL and 1 case of T-IVL (with dyspnea and anuria), nasal mass in 1 case of B-IVL, and abdominal pain in 1 case of T-IVL. None of the 20 patients had a previous history of lymphoma or other malignancy. Lymphoma cells were demonstrated within the vascular lumina in all cases. Lymphoma cells were mostly centroblasts, and less commonly immunoblasts or pleomorphic large cells (Figures 1 and 2). They frequently distended small blood vessels and were occasionally enmeshed in fibrin thrombi with or without platelets. No significant cytologic difference was observed among the lymphoma cells in the 3 groups of IVL. Lymphoma cells were localized only within the vascular lumina in all histologic sections of tissue obtained for pathologic examination in cases of IVLBCL, whereas * 1 microscopic focus of lymphoma cells outside the vascular lumina could be demonstrated in cases of B-IVL. Associated hemorrhagic foci and coagulative necrosis could be observed in the vicinity. Perivascular infiltration by small lymphocytes was sometimes noted. Table 2 shows the sites of intravascular and extravascular growth in the present series from Siriraj Hospital. Nearly all organs examined in these 3 groups showed infiltration by lymphoma. In the B-IVL group, * 1 organ showed extravascular growth; spleen, lymph nodes, bone marrow, and adrenal glands were among the common sites. Lymph node involvement was found in 7 of the 9 patients (78%) with lymph node tissue available for examination. In the T-IVL group, extravascular growth was found in 2 of 3 patients (67%). Lymphoma cells could be found in marrow aspirate smears in the only case of IVLBCL, 8 of 11 cases of B-IVL, and the only case of T-IVL with marrow involvement. Circulating lymphoma cells were not found in IVLBCL, but they were seen in 4 cases of B-IVL (cases 8, 9, 15, and 17) and in 2 cases of T-IVL (cases 19 and 20). As many as 22% of nucleated cells in the peripheral blood were lymphomatous in case 20. The literature search resulted in the retrieval of 297 of 334 full articles (89%); of these, only 266 cases of IVL were documented by immunophenotypic evidence that the neoplastic cells were lymphoid in nature.1-23,25,34-66 The mean
Sanya Sukpanichnant, Sanan Visuthisakchai Table 1 Case
1
Summary of 20 Cases of Intravascular Lymphomatosis at Siriraj Hospital
Age(Years)/ Sex; Clinical Presentation
Major Laboratory Abnormalities
76/F; FUO, weight loss, anemia Hb↓, LDH↑, abn LFT for 4-5 months
Enlargement or Mass Lesion Phenotype; Diagnostic Presentation Autopsy Tissue
Clinical Course (Survival Time)*
Specific Treatment
None
Liver, spleen
B; Autopsy
Steroids only; died of respiratory failure (5 months)
None
None
Not done
B; Breast
First relapse in CNS, 2nd relapse in skin, 3rd relapse as cauda equina syndrome; refused treatment; DOD (18.5 months)
COP; brain radiation at relapse
B; Marrow
Spontaneous clinical remission; refused treatment; liver, subependymal nodule, and respiratory failure at relapse; full recovery after treatment; lost to follow-up (9.3 months)
Chemotherapy at relapse
2
71/F; Skin rash over both breasts for 3 months
LDH↑, abn LFT
3
77/M; Fever for 10 days
Hb↓, plt↓, LDH↑, abn LFT
None
Lost to follow-up
4
69/F; FUO for 4 months
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
None
Liver, adrenals
B; Kidney, marrow
Died of acute renal failure (5 months)
None
5
34/F; Headache, left hemiparesis for 4 months
Hb↓, abn LFT, Cr↑
None
Liver, spleen, kidneys, adrenals
B; Autopsy
Transient response to steroids; died of multiorgan failure (5 months)
None
6
57/F; Fever, headache, diplopia for 3 weeks
Hb↓, WBC↑, plt↓, LDH↑, abn LFT, adrenal insufficiency, hypoglycemia
Right parasellar mass
Liver, spleen, kidneys, adrenals, para-aortic lymph nodes
B; Autopsy
Sudden dyspnea; died of multiorgan failure (5 weeks)
None
7
59/F; Exertional dyspnea for 3 months
Hb↓, WBC↑, plt↓, Cr↑
Right kidney mass, para-aortic lymph nodes
Liver, spleen, kidneys, adrenals, para-aortic lymph nodes
B; Autopsy
Died of respiratory failure (3.5 months)
None
8
69/M; FUO, mild jaundice for 8 months
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
Liver, spleen
Liver, spleen
B; Autopsy
Died of respiratory failure (8 months)
None
9
69/M; Jaundice, nausea, dizziness for 10 days
WBC↑, plt↓, LDH↑, abn LFT, adrenal insufficiency
Liver, spleen, adrenals
Adrenals, kidneys, retroperitoneal lymph nodes
B; Autopsy
Died of multiorgan failure (2 weeks)
None
10
58/M; FUO, anemia, jaundice for 1 month
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
Liver, spleen
Not done
B; Marrow, lung, liver†
Died of multiorgan failure (1 month)
None
11
54/M; FUO, anemia for 2 months
Hb↓, plt↓, LDH↑, abn LFT
Liver, spleen
Liver, spleen
B; Autopsy
Treated as MH; died of multiorgan failure (14 months)
CHOP, COP
12
56/M; Dizziness, fever, malaise for 1 week
Pancytopenia, LDH↑, abn LFT
Liver, spleen
Not done
B; Marrow, lung, liver, spleen†
Died of multiorgan failure (10 days)
None
13
72/F; Left nasal mass for 1 month
Hb↓, LDH↑, abn LFT
Left maxillary sinus, nasal
Not done
B; Nasal mass, marrow
Died of diarrhea with shock after CHOP (1.7 months)
CHOP
14
50/M; Headache, ptosis for 2 months
LDH↑, abn LFT, hypopituitarism
Liver, spleen
Not done
B; Paranasal sinus
Died of respiratory failure (2.5 months)
None
15
55/F; FUO for 2 months
Pancytopenia, LDH↑, abn LFT
Liver, spleen, uterus
Not done
B; Spleen, uterus
Treated as splenic NHL; DOD (12 months)
CHOP
16
65/F; FUO for 4 months
Hb↓, LDH↑, abn LFT
Spleen
Lost to follow-up
B; Spleen
Treated as splenic NHL; relapse; lost to follow-up (15.5 months)
CHOP
17
53/F; Fever, cough, dyspnea for 2 months
Hb↓, plt↓, LDH↑, abn LFT
Spleen, lymph nodes
Liver, spleen, lymph nodes, kidneys, adrenals
B; Autopsy
Died of respiratory failure (2.5 months)
None
18
48/F; Abdominal pain, fever for 3 days
LDH↑, abn LFT
None
–
T; Colon
Alive and well after colectomy (19.1 months)
None
19
76/M; Fever for 3 weeks; acute dyspnea
Hb↓, plt↓, LDH↑, abn LFT, Cr↑
None
Liver, spleen, right kidney
T; Autopsy
Died of respiratory failure (3 weeks)
None
20
77/F; FUO, jaundice, dyspnea for 1 month; anuria
WBC↑, plt↓, LDH↑, abn LFT, Cr↑
Liver, spleen
Liver, spleen
T; Autopsy
Died of multiorgan failure (1 month)
None
Cases 1-3: typical intravascular large B-cell lymphoma; cases 4-17: other intravascular lymphomatosis of B-cell phenotype; and cases 18-20: intravascular lymphomatosis of T-cell phenotype. *Survival time after the onset of illness. †Postmortem biopsy. Abbreviations: abn LFT = abnormal liver function tests; CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone; CNS = central nervous system; COP = cyclophosphamide/vincristine/prednisone; Cr = serum creatinine; DOD = died of disease; FUO = fever of unknown origin; Hb = hemoglobin; LDH: serum lactate dehydrogenase; MH = malignant histiocytosis; plt = platelet count; WBC = white blood count
Clinical Lymphoma & Myeloma January 2006 • 321
Intravascular Lymphomatosis Table 2
Sites of Intravascular and Extravascular Growth in 20 Cases of Intravascular Lymphomatosis at Siriraj Hospital
Intravascular Growth Case Other Number Brain Thoracic Abdominal Adrenals Endocrine Genital Lymph Bone Organs Nodes Marrow Viscera Viscera Organs* +
1
+
+
+
+
+†
2
–
+§
Spleen, bone marrow
+
+
+
–
Brain, lungs, spleen, adrenals, female genital organs, lymph nodes
+
–
+
+
Adrenals
+
+
+
+
–
Spleen, kidneys, adrenals, lymph nodes
–
+
+
–
+§
Spleen, bone marrow
+
+‡
+
+§
Adrenals, lymph nodes
+
Liver, bone marrow
4
+
+
–
5
+
+
+
+
6
+
+
+
+
7
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
10 11
+
12
+
+
+‡
–
13 14
+
15
+
16
+ +
17
+
+ + +
+
+ +
+
+
18
–
+§ +
+
–
–
+
+
9
–
+
3
8
Extravascular Growth
19
+
+
+
+
+
20
–
+
+
–
–
+
+§
Spleen
+§
Lungs, spleen
+§
Nasal mass, bone marrow
+§
Spleen
+§
Spleen
–
Spleen and hilar lymph nodes
+
Liver, spleen, gastrointestinal tract, urinary bladder, lymph nodes
–
Transverse colon
+
–
–
–
+§
Liver, spleen, bone marrow
*Including pituitary gland, thyroid gland, and pancreas (endocrine part). †Only breast biopsy examined. ‡Prostate also involved. §Large lymphoma cells also found in bone marrow aspirate smears. Abbreviations: Blank = no tissue for examination; – = tumor not seen; + = tumor present
age of the patients was 63 ± 12 years (range, 13-90 years). There were 146 men and 120 women (M-F ratio, 1.2:1). Forty-six cases (17%) were Asian and the others were non-Asian, mainly from the United States and Europe. Among 218 cases with known phenotype, 91% were B-cell IVL and 9% were T-cell IVL. The frequencies of B-cell IVL and T-cell IVL in Asia were 86% and 14%, respectively, whereas those in North America and Europe were 93% and 7%, respectively. Only 208 cases could be classified specifically as IVLBCL (102 cases), B-IVL (88 cases), and T-IVL (18 cases). B-cell or T-cell phenotype was not proven in 48 cases, and information was inadequate for a definite grouping of IVL in 10 cases with known phenotype. In the IVLBCL group, the M-F ratio was 1.1:1; mean age, 65 ± 11 years (range, 35-90 years); and ethnicity, Asian in 12% of cases. In the B-IVL group, the M-F ratio was 1.1:1; mean age, 63 ± 13 years (range, 13-87 years); and ethnicity, Asian in 24% of cases. In the T-IVL group, the M-F ratio was 2:1; mean age, 56 ± 20 years (range, 17-84 years); and ethnicity, Asian in 33% of cases. Seven cases of IVLBCL (7%), 3 cases of B-IVL (3%), and 3 cases of T-IVL (17%) had a previous history of NHL, varying in each group from clinically indolent (approximately 30%-40%) to aggressive types (approximately 60%-70%) and ranging from
322 • Clinical Lymphoma & Myeloma January 2006
4 months to 6 years before the diagnosis of IVL. Two cases of IVLBCL (2%), 7 cases of B-IVL (8%), and 1 case of T-IVL (6%) were found to have simultaneous NHL at the time of autopsy, all clinically aggressive NHL but 1 gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in the patient with IVLBCL. Table 3 compares clinical features and abnormal laboratory findings among the 3 groups of IVL during the clinical course of the disease by analyzing information derived from the present series and the literature. No significant difference in clinical or laboratory findings was observed among the 3 groups of patients with IVL in the present series (P > 0.05). But, in the literature, significant differences between the IVLBCL group and the B-IVL group (P < 0.05) were observed in the frequency of skin lesions (53% vs. 31%), hemophagocytic syndrome (3% vs. 14%), enlarged adrenal glands (2% vs. 17%), and bone marrow involvement (13% vs. 44%). Significant differences between the IVLBCL group and the T-IVL group (P < 0.05) were observed in the frequency of fever (84% vs. 55%) and anemia (83% vs. 50%). Significant differences between the BIVL group and the T-IVL group (P < 0.05) were observed in the frequency of fever (87% vs. 55%), skin lesions (31% vs. 67%),
Sanya Sukpanichnant, Sanan Visuthisakchai Table 3
Clinical and Laboratory Findings of Intravascular Large B-cell Lymphoma, Intravascular Lymphomatosis of B-cell and T-cell Phenotypes B-IVL
IVLBCL Clinical Laboratory Findings
T-IVL
Present Study (n = 3)
Literature (N = 102)
Present Study (n = 14)
Literature (N = 88)
Present Study (n = 3)
Literature (N = 18)
Fever
2/3 (67)
48/57 (84)
9/14 (64)
52/60 (87)
3/3 (100)
6/11 (55)
Neurologic Deficits
2/3 (67)
62/80 (78)
8/14 (57)
54/74 (73)
0/3 (0)
8/14 (57)
Skin Lesions
1/3 (33)
29/55 (53)
1/14 (7)
15/49 (31)
0/3 (0)
10/15 (67)
Anemia
2/3 (67)
44/53 (83)
12/14 (86)
43/56 (77)
1/3 (33)
7/14 (50)
Hemophagocytic Syndrome
0/3 (0)
3/102 (3)
3/13 (23)
12/88 (14)
1/3 (33)
1/18 (6)
Hypoxia
2/3 (67)
18/102 (18)
7/14 (50)
16/88 (18)
2/3 (67)
2/18 (11)
Enlarged Adrenals
0/1 (0)
2/102 (2)
5/8 (63)
15/88 (17)
0/3 (0)
0/18 (0)
Elevated LDH
3/3 (100)
27/29 (93)
12/12 (100)
42/43 (98)
3/3 (100)
3/3 (100)
Abnormal LFT
3/3 (100)
17/102 (17)
13/14 (93)
22/88 (25)
3/3 (100)
3/18 (17)
–
16/102 (16)
6/6 (100)
17/88 (19)
0/3 (0)
2/18 (11)
1/3 (33)
9/68 (13)
11/14 (79)
28/64 (44)
1/3 (33)
4/11 (36)
Abnormal Renal Functions Marrow Involvement
Numbers in parentheses are percentages. Abbreviations: LDH = serum lactate dehydrogenase; LFT = liver function tests
and anemia (77% vs. 50%). Thirty-five of 102 patients (34%) with IVLBCL were found to have extravascular involvement during their course after the diagnosis of IVLBCL. This high frequency of extravascular disease led us to determine the number of patients with IVLBCL who did not have extravascular disease in an autopsy population. To rule out treatment effects, only patients who did not receive specific treatment were included. We then compared clinical and laboratory findings in 3 groups: 20 autopsied cases of untreated IVLBCL without extravascular disease (IVLBCL group 1); 35 cases of IVLBCL with extravascular disease (IVLBCL group 2); and 88 cases of B-IVL. Significant differences between IVLBCL group 1 and the B-IVL group (P < 0.05) were observed in the frequency of neurologic deficits (100% vs. 73%) and marrow involvement (7% vs. 44%), but the only significant difference between IVLBCL group 2 and the B-IVL group (P < 0.05) was observed in the frequency of skin lesions (60% vs. 31%). The only significant difference between IVLBCL group 1 and group 2 (P < 0.05) was observed in the frequency of neurologic deficits (100% vs. 70%). The frequency of enlarged adrenal glands in IVLBCL group 1 was lower than that in the B-IVL group (0 vs. 17%), but it was not statistically significant (P = 0.06). The frequencies of enlarged adrenal glands and marrow involvement in IVLBCL group 2 were lower than those in B-IVL (6% vs. 17% for enlarged adrenal glands and 22% vs. 44% for marrow involvement), but they were not statistically significant (P = 0.14 and 0.07, respectively). Fever, anemia, hypoxia, and abnormal liver and renal function tests were similar among the 3 groups in term of frequency. Interestingly, all or nearly all organs examined at autopsy in these 3 groups, especially the brain, demonstrated microscopic involvement by lymphoma cells, with the exception of IVLBCL group 1, which did not have any evidence of extravascular growth.
Table 4 demonstrates the frequency of correct diagnosis during life among the 3 groups of patients with IVL. Diagnoses ranged from 33% to 67% in the present series and from 55% to 72% in the literature. The chance of “specific” treatment given to the 3 groups of patients with IVL was mostly lower than that of correct diagnosis during life, ranging from 0 to 67% in the present series and from 49% to 65% in the literature. In the present series, treatment consisted of chemotherapy. But, in the literature, treatment varied considerably among the 3 groups of IVL cases; 86%-100% of patients received combination chemotherapy, with 45%-62% of the regimens including the cyclophosphamide/doxorubicin/vincristine/prednisone combination and other anthracycline-based regimens. Other treatments included single-agent chemotherapy with or without radiation therapy or systemic psoralen plus ultraviolet A light, radiation therapy alone, combined chemotherapy and radiation therapy, and autologous bone marrow or peripheral blood stem cell transplantation. Survival time after the onset of disease was recorded in 72 cases of IVLBCL, 66 cases of B-IVL, and 17 cases of T-IVL. No significant difference in overall survival was observed among the 3 groups of patients with IVL (Table 4). However, patients with IVLBCL and B-IVL who received chemotherapy had significantly better survival than patients who received no treatment (P < 0.05). Better survival in patients with T-IVL who received chemotherapy was also observed, but it was not statistically significant (P = 0.28). Survival was also better in all 3 groups of IVL in patients with skin involvement than in patients without skin involvement, but it was statistically significant only in patients with T-IVL (P < 0.05). Despite the fact that the small number of patients in the present series precluded statistical analysis, the survival in all 3 groups of patients with IVL seemed to be comparable with that observed in the literature, because those who received chemotherapy or those with skin involvement had better survival.
Clinical Lymphoma & Myeloma January 2006 • 323
Intravascular Lymphomatosis Figure 1 Intravascular Lymphomatosis in the Breast A
Figure 2 Intravascular Lymphomatosis in the Colon A
B B
(A) Large lymphoma cells of centroblastic type within the vascular lumen (hematoxylin and eosin; original magnification ×400). (B) Distinct membrane staining with CD20, a B-cell marker. CD3 is negative (not shown). (Case No. 2)
Discussion In this series from Siriraj Hospital, IVL accounts for 1.1% of all cases of NHL, a percentage comparable with a report from Hong Kong (0.9% of 325 cases of NHL),67 but the frequency is much lower in series from Japan68 (0.1% of 3025 cases) and India69 (0% of 2773 cases). To our knowledge, the present series is the largest from a single institution. The most recent publication of an IVL study by the International Extranodal Lymphoma Study Group (IELSG) included 38 patients from 22 centers (21 centers in Europe and 1 center in Australia); only 8 centers had > 1 patient, and the largest number of patients from 1 center was only 6.70,71 In the present series, clinical manifestations are similar to those reported in the literature with regard to neurologic deficits and skin lesions; we also observe hepatosplenomegaly, progressive hypoxia, renal or adrenal insufficiency, spontaneous regression of clinical symptoms, temporary improvement by steroids, and localized disease. The distribution of B-cell phenotype and T-cell phenotype in the present series of IVL is 85% and 15%, respectively, percentages comparable with those from Asia (86% and 14%). Intravascular lymphomatosis with associated hemophagocytic syndrome (HS) has been called the Asian variant of IVL;18,34 there are 4 cases in the present series: 3 cases of B-cell phenotype and 1 case of T-cell phenotype. The literature review reveals 16 cases of IVL with associated HS that
324 • Clinical Lymphoma & Myeloma January 2006
C
(A) Admixture of centroblasts, immunoblasts, and large pleomorphic cells within the vascular lumen (hematoxylin and eosin; original magnification ×400). (B) Focal extravascular growth by centroblasts (hematoxylin and eosin; original magnification ×200). (C) Distinct membrane staining with CD3, a T-cell marker. CD20 is negative (not shown). (Case No. 18)
were phenotyped; 15 cases were B-cell IVL (13 Asian and 2 non-Asian), and 1 case was T-cell IVL (non-Asian).18,34-44 The significant differences between IVLBCL (105 patients, including 102 patients in the literature and 3 patients in the present series) and B-IVL (102 patients, including 88 patients
Sanya Sukpanichnant, Sanan Visuthisakchai Table 4
Clinical Aspects and Survival of Intravascular Large B-cell Lymphoma, Intravascular Lymphomatosis of B-cell and T-cell Phenotypes IVLBCL
Clinical Aspects
B-IVL
T-IVL
Present Study (n = 3)
Literature (N = 102)
Present Study (n = 14)
Literature (N = 88)
Present Study (n = 3)
Literature (N = 18)
Correct Diagnosis
2/3 (67)
71/102 (70)
5/14 (36)
48/88 (55)
1/3 (33)
13/18 (72)
Skin Involvement
1/3 (33)
29/55 (53)
1/14 (7)
15/49 (31)
0/3 (0)
10/15 (67)
Specific Treatment
2/3 (67)
48/92 (52)
4/14 (29)
43/87 (49)
0/3 (0)
11/17 (65)
12.2 (0.2 month-10.1 years)
3 (0.3 month-1.3 years)
8 (0.2 month-6.5 years)
9.3 Overall Survival, Months (Range) (5 months-1.5 years)
1 6 (0.7 month-1.6 years) (2.5 months-3.8 years)
Survival, Months (Range) Treatment No Treatment
13.9 (9.3 months-1.5 years) 5
23 (1 month-9.8 years)
13 18 (1.7 months-1.3 years) (0.5 month-6.5 years) 4 2.5 3 (0.2 month-10.1 years) (0.3 month-0.7 years) (0.2 month-2.4 years)
NA
8 (3 months-3.8 years)
1 (0.7 month-1.6 years)
3 (2.5 months-2 years)
NA
18 (2.5 months-3.8 years)
Survival, Months (Range) Skin Involvement No Skin Involvement
18.5
23 (3 months-10.1 years)
7.2 (5 months-0.8 year)
12 (0.8 month-5.3 years)
3.5
18 (1.2 months-2.9 years)
2.5 10 1 (0.3 months-1.3 years) (1.4 months-6.5 years) (0.7 month-1.6 years)
5 (2.8 months-0.9 year)
Comparison of different types of intravascular lymphomatosis as to correct diagnosis during life, skin involvement, specific treatment, overall survival, survival with and without treatment, and survival in cases with and without skin involvement (median and range of survival time after the onset of disease) in the present series and in the literature. Numbers in parentheses are percentages unless otherwise indicated. Abbreviation: NA = not available
in the literature and 14 patients in the present series) are skin lesions (52% vs. 25%), HS (3% vs. 15%), enlarged adrenal glands (2% vs. 21%), and bone marrow involvement (14% vs. 50%), as demonstrated in Table 3. However, none of these significant differences exist when the setting is limited to the autopsied untreated population. In this particular setting, neurologic deficits appear to be the only significant difference between IVLBCL without extravascular disease and B-IVL (100% vs. 73%). Interestingly, this clinical feature of neurologic deficits is also the only significant difference between IVLBCL without extravascular disease and IVLBCL with extravascular disease (100% vs. 70%). The presence of lymphoma cells in all or nearly all organs examined at autopsy in these 3 groups, especially the brain, makes it difficult to explain why neurologic deficit is the only significant difference among these 3 groups. Because there are no clinicopathologic features that are significantly different between IVLBCL and B-IVL under various circumstances, and approximately one third of IVLBCL cases in the literature develop extravascular disease during the course of the disease, IVLBCL as a disease entity in the WHO classification24 is not different from B-IVL in a biologic sense. In addition, the WHO definition of IVLBCL as “a type of lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries” seems to be ideal because it is not possible to exclude any extravascular growth that is not grossly visible somewhere in the body even at the time of autopsy. Interestingly, approximately 10% each of IVLBCL and BIVL cases and 20% of T-IVL cases in the literature are previously diagnosed to have NHL * 4 months before the
diagnosis of IVL or have a simultaneous NHL at the time of the diagnosis of IVL. In most cases with available morphologic and immunophenotypic data of preceding or simultaneous NHL, the morphology and phenotype are similar to those of IVL; the same clonality has been demonstrated in 2 cases,10,22 but the available tissue and techniques cannot prove the clonality in 1 case report.45 The type of NHL in approximately 30%-40% of cases with preceding NHL is clinically indolent; morphologic progression to large-cell lymphoma at the time of IVL has been proposed,22,44,46 and in * 1 case, the same clonal immunoglobulin gene rearrangement has been demonstrated in indolent NHL and IVL.22 Regarding the results of immunophenotypic studies, IVL is heterogeneous. Approximately 10 of 28 cases (36%) are CD5+ and 6 of 6 cases (100%) are CD23–;12,19,22,39,42,47-49 these cases are distinguished from chronic lymphocytic leukemia or mantle cell lymphoma owing to their lack of CD23 and cyclin D1 expression.12,19,22 Another large subgroup, 14 of 21 cases (67%), shows CD5–/CD10– expression, similar to the phenotype of many diffuse large B-cell lymphomas.22,39,42,49 It is estimated that < 3% of IVL cases arise from low-grade lymphomas or unclassifiable lymphoid neoplasms.14,22,23,44,46 Aberrant adhesion molecules and cytogenetic abnormalities have been demonstrated in a small number of cases of IVL, similar to those previously reported in advanced NHL.11,21,34,50-54 Translocations involving myc, bcl-2, bcl-6, or immunoglobulin genes are not described. Only 4 of 38 cases (11%) of IVL have been associated with Epstein-Barr virus (EBV) by in situ hybridization for EBV-encoded RNA (EBER).15,18,22,42,44,45,55-58,62,63,67 In summary, the phenotype
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Intravascular Lymphomatosis of lymphoma cells in IVL is heterogeneous, and the relationship to a specific lymphocytic cell of origin has not been established. In our review of the literature, circulating lymphoma cells and bone marrow and lymph node involvement can be found in approximately 30% of IVL cases by light microscopy alone. Subtle involvement can undoubtedly be detected in a higher percentage by immunoperoxidase studies for CD20 and CD3 in histologic sections51,64,65 and by molecular genetic techniques looking for clonal rearrangements of the immunoglobulin heavy chain (IgH) gene or T-cell receptor gene.17,44,56,57 In the present series from Siriraj Hospital, circulating lymphoma cells are also detected in 30% of cases, but the higher percentage of cases with involvement of the bone marrow (65%; with the application of immunohistochemistry to detect lymphoma cells in 3 cases with negative marrow by conventional morphologic evaluation) and lymph node (75%). The recent publication of an IVL study by the IELSG demonstrates marrow involvement in 32% of 38 cases of IVL.70,71 Moreover, among these cases, 55% have systemic symptoms, 39% have skin lesions or central nervous system involvement, 34% have hepatosplenic involvement, 63% have anemia, 29% have thrombocytopenia, and 16% each have cardiopulmonary or renal involvement. In our review of 260 cases of IVL, 60% have systemic symptoms, 63% have central nervous system involvement, 24% have skin lesions, 32% have hepatosplenic involvement, 42% have anemia, 17% have thrombocytopenia, 16% have cardiopulmonary involvement, 15% have renal involvement, and 7% have hemophagocytic syndrome. Hence, most features are comparable between that series and our literature review. Therefore, IVL is not as mysterious as stated in earlier case reports, in which patients who did not have lymphadenopathy or hepatosplenomegaly and blood and marrow involvement were typically spared. Unfortunately, it is so difficult to publish an extensive literature review of > 260 cases of IVL, mostly case reports, because of a very long list of references, that most of the reports or even the WHO classification monograph uses the literature review by Domizio et al25 to shorten the reference list. That literature review published in 1989 included cases of IVL and MAE; approximately 40% of cases were not proven to be lymphoid in nature. The unusually low frequency of clinical features in that literature review included systemic symptoms (9%), hepatosplenomegaly (3%), hypoxemia, and renal failure (1% each). We hope that our extensive review of the literature will provide a better understanding of this rare type of NHL. We have also demonstrated that specific treatment, mostly combination chemotherapy, significantly prolongs survival in patients with IVL. This observation concurs with the recent study by the IELSG on anthracycline-based chemotherapy as primary treatment for IVL.70,71 The 5-year survival rate in treated cases of IVL is comparable to that in the high-risk group of NHL defined by the International Prognostic Index.72 Skin involvement is another good prognostic factor in IVL based on our extensive review and the recent IELSG study.70,71 The significance of specific treatments for the clinical outcome of IVL obviously emphasizes the importance of early diagnosis of this disease. Therefore, it is very important for physicians to
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keep IVL in mind when patients present with clinical manifestations and laboratory abnormalities described in the literature review herein. In particular, physicians should consider random skin biopsy for diagnosis as suggested by Gill et al.66 Large lymphoma cells can be detected in bone marrow aspirate smears, but the diagnosis of IVL requires the demonstration of intravascular localization of lymphoma cells in histologic sections. The use of molecular genetic techniques for clonal rearrangements of the IgH gene or T-cell receptor genes in the peripheral blood mononuclear cells to screen for IVL has not been implemented clinically. But it is possible for such an approach to be used in the future for early detection of IVL.
Conclusion Intravascular lymphomatosis is rare and heterogeneous in nature. Although most of the cases are of B-cell phenotype, Tcell phenotype constitutes approximately 9% of cases. Contrary to the previous case reports and literature review, circulating lymphoma cells and bone marrow and lymph-node involvement in IVL can be detected in approximately 30% of cases. Early diagnosis is crucial to the successful clinical management of IVL, because specific treatment, especially anthracycline-based combination chemotherapy, significantly prolongs survival. Cases with skin involvement might have a better prognosis. Finally, IVLBCL as a disease entity in the WHO classification24 is in doubt, because approximately one third of the patients with IVLBCL have been shown to have extravascular disease during their clinical course. Intravascular lymphomatosis seems to be a better term than IVLBCL because it includes the T-cell phenotype. An international registry of IVL should be established to gather cases around the world for extensive studies in order to understand this very aggressive NHL.
Acknowledgements The authors thank Miss Saowalak Hunnangkul for statistical analysis, Dr Ake-Chittra Sukkul and Dr Supinda Petchjom for clinical information of 11 cases, Mr Chaiyuth Buawatana for photographic assistance, and Professor Dr Robert D. Collins at Vanderbilt University Medical Center for his comments.
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