Immunohistochemical and Cytogenetic Studies Indicate that Malignant Angioendotheliomatosis is a Primary Intravascular (Angiotropic) Lymphoma Arturo Molina, MD,*$ Charles Lombard, MD,t Timothy Donlon, PhD,$ Charles D. Bangs, BS,$ and Ronald F. Dorfman, MB, BCh, FRC Patht

The authors performed immunohistochemical and cytogenetic studies in a 73-year old man with malignant angioendotheliomatosis. The patient was referred for evaluation of fever of unknown origin, hepatic failure, and neurologic deterioration. Examination of a muscle biopsy revealed numerous, noncohesive atypical mononuclear cells within small vessels. These cells stained positively with a pan-leukocyte marker CD45(PD7/26/16) and with a B-cell marker L26 but negatively with Factor VIII-related antigen, an endothelial cell marker. Peripheral blood obtained before chemotherapy was cultured and analyzed by the G-band method. A new translocation and numerous chromosomal aberrations were identified. The major cell line karyotype was 53,XY,+X,+Sq?,-6,+i[6p),+7,-10, +11,-12, +12p-,+12p-,+18,+marl,+mar2,t(1;3)(p~2;p2l),3q+,8p+. This is the first cytogenetic study performed in a case of malignant angioendotheliomatosis. Our findings demonstrate that the neoplastic cells in this disorder circulate in the peripheral blood and provide further evidence that malignant angioendotheliomatosis is a diffuse intravascular neoplasm of lymphoid origin. Furthermore, the authors conclude that this malignant lymphoproliferative disorder should be reclassified as a primary intravascular (angiotropic) lymphoma. Cancer 66:474-479,1990.

HE TERM MALIGNANT angioendotheliomatosis refers T to a rare systemic clinicopathologic entity charac- terized by the development of unexplained fever, micro- vascular skin lesions, dementia, neurologic changes, and progressive multisystem failure. ' - I 2 A distinguishing his- topathologic feature of this disorder is the extensive in-

Presented in part at the 69th Annual Session of the American College

Prize winning entry in the Associates Clinical Vignette Competition. From the Departments of Medicine (Oncology)* and Pathology (Sur-

gical Pathology? and CytogeneticsS), Stanford University Medical Center, and the Department of Biological Sciences,§ Stanford University, Stan- ford, California.

Supported by the Robert Wood Johnson Foundation grant 14546 (Drs. Molina and Schimke) and the Public Health Service Research grant CA 09287 (Dr. Rosenberg).

The authors thank Dr. Saul A. Rosenberg and Dr. Sandra J. Horning for advice on management of the patient and Phil Veroza for assistance with photography.

Address for reprints: Arturo Molina, MD, Stanford University Medical Center, Oncology Day Care Center, H-0274, Stanford, CA 94305.

Accepted for publication October 24, 1989.

of Physicians, New York, New York, March 4, 1988.

travascular proliferation of atypical mononuclear cells seen within the lumens of venules, arterioles, capillaries, and small arteries. The disease has a predilection for small blood vessels in the skin and central nervous system, al- though the lymph nodes, kidneys, heart, lung, spleen, and endocrine organs also may be involved. Patients fre- quently develop numerous abnormalities, including hy- poalbuminemia, hyponatremia, hypochloremia, elevated erythrocyte sedimentation rate, abnormal liver and renal function test results, and positive serology for rheumatoid factor and antinuclear antibodies.' In many instances, the diagnosis is made after death.

This condition was first described in 1959 by Pleger and Tappeiner as angioendotheliomatosis proliferans sys- t e m i ~ a t a . ' ~ . ' ~ Subsequently, more than 15 synonyms have been used to describe this d i~orde r .~ Some controversy exists about the origin of the neoplastic cell in malignant angioendotheliomatosis. Earlier reports assumed that the disease originated from transformed vascular epithelium, thereby implicating an endothelial origin of the prolifer- ating intraluminal cell^.'^-'^ Others have suggested that

474

No. 3 PRIMARY INTRAVASCULAR (ANGIOTROPIC) LYMPHOMA - Mofina et al. 47 5

the malignant cells are disseminated carcinomas of unknown primary origin.26 More recently, immunophe- notypingi -7- I 2,2728 and Southern blot a n a l y s i ~ ~ ~ . ~ ~ have been used to demonstrate that the intravascular cells in tissues involved by malignant angioendotheliomatosis are derived from lymphoid cells. Monoclonal populations of both B-cell or T-cell lineage have been reported. In that regard, some investigators have used the terms angi- otropic lymphoma and intravascular lymphomatosis to describe this malignant lymphoproliferative pro-

Using immunohistochemical staining to study a muscle biopsy specimen from a patient with malignant angioen- dotheliomatosis, we have identified atypical intravascular cells that show evidence of hematolymphoid differentia- tion. In addition, cytogenetic analysis of peripheral blood mononuclear cells revealed the presence of circulating malignant cells with karyotype abnormalities similar to those seen in some lymphomas and leukemias. On the basis of our observations and those of other investigators, we propose that this disease be reclassified as a primary intravascular (angiotropic) lymphoma. Moreover, this disorder should be considered in the differential diagnosis of prolonged fever of unknown origin. Use of newer im- munologic, cytogenetic and molecular techniques may facilitate the earlier diagnosis and treatment of this un- usual lymphoid neoplasm.

cess. 1,4,7- 12

Case Report

In April 1989, a 76-year-old man was admitted to Stanford University Hospital for diagnostic and therapeutic evaluai icn of prolonged fever of unknown origin. Four months before this hospitalization he developed profound personality changes, progressive malaise, low grade fevers, and an atypical skin erup- tion. During the following 2 months he also developed an ele- vated erythrocyte sedimentation rate (ESR) to over 100 mm/ hour and abnormal liver function tests (alkaline phosphatase of 788 U/1, SGOT of 337 U/1, and SGPT of 539 U/l). Serologic tests for Hepatitis A and B, cytomegalovirus, and Epstein Barr virus were negative or without evidence of acute infection. Liver biopsy showed only mild fatty change and was nondiagnostic. Bone marrow biopsy was without evidence of involvement by lymphoma or leukemia. Computerized tomography of the ab- domen and chest did not show organomegaly or lymphadenop- athy. Other studies, including nuclear bone scan, serum protein electrophoresis (SPEP), rheumatoid factor, and cryoglobulins were interpreted as normal. Extensive infectious disease evalu- ation was repeatedly negative. Temporal artery biopsy did not reveal evidence of arteritis or other inflammatory process. Em- piric treatment with prednisone 60 mg per day for presumed polymyalgia rheumatica resulted in resolution of rash and tran- sient symptomatic improvement.

As steroids were being tapered off, he developed right lower extremity weakness. Computerized tomography of the head, ce- rebral angiogram, and lumbar puncture were all nondiagnostic.

Electromyography showed mild focal muscle denervation. A muscle biopsy at another hospital did not reveal evidence of vasculitis or myositis. Total hemolytic complement (CH,,) was 1.0 mg/dl (normal, 64 to 192 mg/dl). Repeat SPEP and urine protein electrophoresis showed slight increase of IgA with normal IgG and IgM but no evidence of monoclonal gammopathy.

Because of progressive deterioration he was transferred to our hospital. On admission, he was an obtunded elderly man who was unable to follow commands. His exam was remarkable for profound anasarca. He had no hepatosplenomegaly or suspicious peripheral lymphadenopathy. His leukocyte count was 20,900 with 78% mature granulocytes, 11% band forms, and 9% lym- phocytes. Hemoglobin was 10.3 gm and hematocrit was 31.7. The platelet count was 522,000. Total protein was 4.5 g/dl (nor- mal, 6 to 8 g/dl), albumin was 1.7 g/dl (normal, 3.5 to 5.5 g/dl). Calcium (uncorrected) was 8.1 mg/dl. Liver function tests showed an alkaline phosphatase of 288 U/l, and transaminases were in the normal range. Renal function was normal. Repeat lumbar puncture showed normal chemistries and no evidence of infection or malignant cells.

Re-examination and immunohistochemical study of the muscle biopsy performed at the refemng hospital led to the diagnosis of angiotropic lymphoma/malignant angioendo- theliomatosis (Fig. 1). He was treated with combination che- motherapy consisting of doxorubicin (Adriamycin, Adria Lab- oratories, Columbus, OH), vincristine, cyclophosphamide, and high-dose corticosteroids. Despite transient improvement of his mental status after chemotherapy, his condition deteriorated rapidly and he died 2 weeks later. Consent for a postmortem examination was not obtained.

Immunohistochemistry

The tissue obtained from a muscle biopsy was formalin fixed, paraffin embedded, and examined on routine his- ioiagic stains. Numerous, noncohesive atypical neoplastic cells were seen within small vessels. These tumor cells had large nuclei with coarse chromatin, prominent nucleoli, and scant eosinophilic cytoplasm. Immunoperoxidase studies were performed on 3-5 pm sections of the paraffin- embedded tissue. The intravascular cells stained negatively with two antikeratin markers, AEl and CAM 5.2, and with an antibody directed against Factor VIII-related an- tigen, an endothelial cell marker (Fig. 1A) but showed cytoplasmic membrane reactivity with CD45 (PD7/26/ I6), thus indicating expression of leukocyte common an- tigen (Fig. 1 B). Furthermore they reacted strongly with a B-cell marker L26 (Fig. 1C) but failed to stain with two T-cell markers, L60 and UCHLI. These studies provided strong support for a B-lineage lymphoma.

Cytogenetic Analysis

Peripheral blood obtained before chemotherapy was cultured without mitogenic stimulation, harvested by routine methods, and analyzed by the G-band method.29 Ten metaphases were analyzed, representing two related

476 CANCER August I 1990 Vol. 66

that showed a third marker chromosome (mar3) that is in part derived from the short arm of the missing extra X. The cell line karyotypes are described by the Inter- national System for Human Cytogenetic Nomenclature3' as follows:

1. Major cell line karyotype: 53,XY,+X,+5q?- -6,+i(6p),+7,- lo,+ 1 1 ,-12,+ 12p-,+ 12p-,+ 18,+marl,- +mar2,t( 1;3)(~22;p21),3q+,8p+ (Fig. 2).

2. Minor cell line karyotype: 5 3 ,XY,+ 5 ,-6, +i( 6p), + 7 ,- - 10,- 12,+ 12p-,+ 12p-,+ 18,+marl, +mar2, +mar3,t( 1 ;3) (p22;p2 1),-3q+,8p+.

Discussion

The various clinical and pathologic features of malig- nant angioendotheliomatosis have been described in the medical l i t e r a t ~ r e . ' - ~ ~ ~ . ~ Most patients present with fever of unknown origin and nonspecific cutaneous and neu- rologic manifestations. Alteration of mental status, de- mentia, and disturbances of vision and speech frequently develop in these patients. Some patients have focal neu- rologic signs and symptoms suggestive of transient isch- emic attacks or stroke. However, neuroradiologic studies and cerebrospinal fluid analyses are usually nondiagnostic. Firm subcutaneous nodules or masses may develop, sometimes, in association with prominent telangiectasia or ulceration. In the past, these cutaneous lesions have been confused with mycosis fungoides, sarcoidosis, vas- cular neoplasms, or cutaneous involvement by lymphoma or l e~kemia .~

FIGS. 1 A- IC. Angiotropic lymphoma/malignant angioendothelio- matosis. (A) Intravascular malignant cells fail to show specific staining for Factor VIII-related antigen but (B) stain with CD45 (PD7/26/16), indicating expression of leukocytecommon antigen. (C) In addition these cells stain strongly with a B-lineage marker L26. The presence of a cell with large vesicular nuclei containing prominent nucleoli consistent with a large cell lymphoma is shown in the inset (X640).

clones. Eight cells showed 53 chromosomes, and two cells showed 52 chromosomes because of apparent random artifactual loss of one autosome. All cells showed the fol- lowing abnormalities: trisomies of nos. 5, 7, 12, and 18, monosomy 10, a translocation between the short arms of no. 1 and no. 3, extra unidentified materials on a no. 3 long arm and a no. 8 short arm, an isochromosome for the no. 6 short arm with concurrent loss of a no. 6 long arm, identical rearrangement or deletion of the short arms of two no. 12s, and two unidentifiable marker chromo- somes (marl and mar2). The major cell line, found in eight cells, showed, in addition, an extra X chromosome and an unidentifiable rearrangement of one no. 5 long arm. The minor cell line was present in two cells that did not show the rearrangement of no. 5 or the extra X but FIG. 2. Representative karyotype of the major cell line.

No. 3 PRIMARY INTRAVASCULAR (ANGIOTROPIC) LYMPHOMA * Molina et al. 477

Since its first description in 1959, the histogenesis of malignant angioendotheliomatosis has remained a subject of controversy among pathologist^.^,'^,'^ A prominent histologic feature has been the intravascular proliferation of large pleomorphic tumor cells in small blood vessels, most notably in the skin and central nervous system, al- though involvement of most organ systems has been re- ported. In the 15 patients reported by Wick and col- leagues,' disease involving the alimentary tract, heart, kidney, liver, lung, and genitourinary tract was docu- mented in more than one half the patients. Occlusion of blood vessels occurs to varying degrees, and transluminal involvement is seen in some cases. Benign forms of this condition have been reported in association with bacterial end~cardi t is~ ' -~~ and are distinguished on the basis of their clinical and histopathologic features.

Most of the evidence in favor of an endothelial origin of intravascular cells in malignant angioendotheliomatosis is based on histologic observations that show tumor cells attached to the endothelial lining of affected blood ves- s e l ~ . ' ~ - ' ~ However, several researchers have stained in- volved tissues with an antibody directed against Factor VIII-related antigen, an endothelial cell marker,34 and

is proposed by Bhawan3 that artifactual intraluminal in- folding may resemble intravascular cells and account for the few cases that appear to stain positively for Factor- VIII related antigen.

In 1982, there were two reports of known malignant lymphoma with coexisting features of malignant an- gioendotheliomatosis.3s~36 Using light microscopy, elec- tron microscopy, and immunohistochemical studies, Bhawan and colleagues were the first to demonstrate that the neoplastic intraluminal cells are of lymphoid origin.2 Subsequently, their findings were confirmed by various groups. 1-4.7- 12 Moreover, the majority of cases studied with immunophenotyping are monoclonal lymphoprolifera- tions of B-cell lineage, although at least one case of ma- lignant angioendotheliomatosis with T-cell markers has been documented.'

A recent study by Otrakji and colleagues reported Southern blot hybridization analysis performed on de- oxyribonucleic acid (DNA) extracted from adrenal tissue obtained at autopsy from a patient with malignant an- gioendotheliomatosis; they detected a specific B-cell im- munoglobulin gene r ea~~angemen t ,~~ thereby providing the first genotypic evidence for the monoclonal lymphoid origin of this disease. In their study, the neoplastic cells also reacted positively with anti-kappa light chain anti- body on cryostat cut fresh-frozen sections.

The patient reported in this study presented with the common clinical and pathologic features of malignant angioendotheliomatosis: older age, fever of unknown or- igin, mental status changes, focal neurologic deficits, and

have found no reactivity in the majority of case^.',^^^-'^ It

cutaneous lesions. Subsequently, the patient developed fulminant multisystem failure, anasarca, and dementia. His condition eluded diagnosis until the malignant intra- vascular cells were identified upon reexamination of the referred muscle biopsy specimen. Typically, the diagnosis of malignant angioendotheliomatosis is made on skin and brain biopsy specimens or at postmortem examination. Unfortunately, the patient was moribund at the time he was transferred to Stanford University Hospital. Despite aggressive supportive interventions, the patient's condition deteriorated further, and he died 2 weeks after treatment with combination chemotherapy.

The immunohistochemical findings presented here confirm that the cell of origin in malignant angioendothe- liomatosis is of hematolymphoid lineage. The intravas- cular neoplastic cells stained positively with CD45 (PD7/ 26/ 16), a common leukocyte antigen detectable in paraf- fin-embedded tissue, but did not react with factor VIII- related antigen, a marker of endothelial differentiation. Moreover, they showed strong membrane reactivity with a B-cell marker, L26, but not with two T-cell markers, L60 and UCHLI, thus providing strong support for a B- lineage lymphoma. In addition, the intravascular cells did not stain with AEl and CAM 5.2, antibodies specific for keratin expression.

This is the first report describing the use of cytogenetic analysis to detect circulating neoplastic cells in the pe- ripheral blood of a patient with malignant angioendothe- liomatosis; the malignant cells were not recognized on manual or automated leukocyte differential examinations performed on the numerous hemograms obtained throughout the course of his illness. Cytogenetic analysis revealed two related abnormal clones with a hyperdiploid karyotype and several chromosomal abnormalities com- monly seen in malignant lymphoproliferative disorders (trisomy 7, trisomy 12, trisomy 18, and functional deletion of the long arm (4) of chromosome 6 because of formation of an isochromosome for the no. 6 short arm) as well as a novel translocation involving the short arms (p) of chro- mosomes no. 1 and no. 3.

Additional cytogenetic studies of malignant angioen- dotheliomatosis are needed to determine whether specific numerical or structural chromosome aberrations exist in this disorder. Although trisomy 12 (+12) is seen in 20% to 40% of cytogenetically abnormal cases of low grade lymphoproliferative disorders such as chronic lympho- cytic leukemia/small lymphocytic lymphoma 37-39 and lymphocytic lymphoma of intermediate differentiation?' this chromosomal abnormality also has been found in multiple myel0ma,4'.~~ Hodgkin's disease,43 follicular lymphoma^,^^^^^-^^ diff use lymphoma^,^^,^^,^^ large cell immunoblastic l y m p h ~ m a , ~ ~ , ~ ~ - ~ ' and high grade small noncleaved cell lymphoma.s2 In the low grade lymphoid malignancies, trisomy 12 can seen as the sole cytogenetic

47 8 CANCER August I 1990 Vol. 66

abnormality, whereas in the more aggressive lymphomas it tends to occur as part of a more complex karyotype. At least two cases of of high grade immunoblastic lymphoma, however, have presented with + 12 as the only cytogenetic

Deletions of the long arm of chromosome 6 (6q-) ap- pear in 5% to 15% of acute lymphoblastic leukemia and various non-Hodgkin’s lymphomas with other clonal chromosomal abn~rmalities.~~ Although this abnormality seems to be a marker for lymphoid malignancies and is almost never found in nonlymphatic hematologic neo- plasms, there is no specific association with any particular histologic subtype. The exact chromosomal break points can be variable but are localized to 6q 15 and 6q2 1 in the majority of cases. Barletta and colleagues recently found no rearrangement of c-myb, a cellular oncogene mapped to 6q2 1-24, in six patients with hematolymphoid malig- nancies and 6s- but found significantly increased c-myb messenger RNA levels in these patients.54 Their findings suggest that c-myb alterations may be involved in the pathogenesis of malignancies bearing the 6q- abnormality.

Trisomy 7 (+7) can be seen as a secondary abnormality in 5% to 15% of non-Hodgkin’s lymphomas. It is usually present as part of a complex karyotype involving cytogenetic abnormalities specific for a particular histo- logic subtype.38~39~44-48~50~51 In non-Hodgkin’s lymphomas bearing the t( 14; 18)(q32;q2 1 ), the presence of an extra chromosome 7 is associated with a diffuse histologic pat- tern compared to the follicular pattern seen in the absence of trisomy 7.55 Furthermore, +7 has also been reported in some solid tumors, such as malignant melanoma and bladder cancer.56 Trisomy 18 (+18) also occurs in 10% to 15% of all non-Hodgkin’s lymphomas as a secondary abnormality of uncertain ~ignificance.~’ Interestingly, in the study by Armitage et ~ l . , ~ ~ additional copies of chro- mosome 18 and deletion of a portion of the long arm of chromosome 6 were seen in 22% and 17% of lymphomas with t( 14; 18)(q32;q2 I) , respectively, but these secondary abnormalities did not correlate with histologic subtype or treatment outcome.

In summary, the cytogenetic and immunohistochem- ical studies presented here demonstrate that malignant angioendotheliomatosis is an unusual hematolymphoid neoplasm that originates in the intravascular compart- ments. Despite the usual evaluation undertaken for fever of unknown origin, our patient’s condition eluded diag- nosis for more than 4 months because the circulating ma- lignant cells were not identified on routine examination of the peripheral smear or on the initial examination of the muscle biopsy specimen. It has been proposed that this malignant lymphoproliferative disease should be re- classified as a primary intravascular (angiotropic) lym- phoma as this term more accurately describes the clinical,

histologic, and biologic features seen in this disorder. Use of newer diagnostic methods such as karyotyping, im- munophenotyping, and genotyping may lead to earlier diagnosis and treatment of this aggressive form of lym- phoma.

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