“Intravascular lymphomatosis” (angioendotheliomatosis): Evidence for a T-cell origin in two cases

“Intravascular Lymphomatosis” (Angioendotheliomatosis): Evidence for a T-Cell Origin in Two Cases NORBERT SEPP, MD, GEROLD SCHULER, MD, NIKOLAUS ROMANI. PHD, DIETMAR GEISSLER MD, CLAUS GAllRINGER, MD, GUNTER BURG, MD, CLAUS R. BARTRAM, MD, AND PETER FRITSCH, MD Intravascular multifocal volving

lymphomatosis

intravascular

(IL)

is a rare and potentially

proliferative

disorder,

the skin and the central nervous

sidered an endothelial as an angiotropic

disorder,

lymphoma,

report immunocytochemical

fatal

most often

system. Originally

con-

IL has recently been reclassified most often of B-cell

and ultrastructural

patients with IL, both representing

origin.

findings

angiotropic

T-cell

lympho-

tissue was examined

blot analysis and monoclonal

T-cell receptor rearrangement

As an additional

sive serum factor was demonstrated leukopenia; Saunders

by Southern was

feature in one patient, a myelosuppresin peripheral

itor cell cultures as the cause of underlying lymphoma

We

in two

mas. In one patient, lesional found.

in-

blood progen-

chronic anemia and

this factor is thought to be a cytokine product of the cells. HUM PATHOL 21:1051-1058.

C

1990 by W.B.

Company.

Prolif’vrative angioendotheliomatosis (PA), originally described in 1959 by Pfleger and Tappeiner,‘.” is a rare disease entity characterized by multifocal proliferation of large pleomorphic cells within small blood vessels, most often of the skin and the central nervous system (CNS). As the term implies, PA was, until recently, interpreted as an unusual proliferative disorder of vascular endothelia on the basis of light and electron microscopic findings and factor VIII have been staining. I-“’ More than a dozen synonyms proposed in the past decades.” According to its clinical course, a rough distinction between a benign and malignant variant of PA has been generally made in the literature: the benign form is often held to be associated1 with bacterial endocarditis3.8,‘” and responsive to antibiotics and/or steroids; the malignant form is fatal within a few months after diagnosis with or without treatment,5.1:3 although rare cases of remission j.‘ollowing chemotherapy have been reported.7.‘4 In a recent series of reports, immunophenotyping studies of the intravascular proliferative cells led to entirely different views: strong expression of leu-

From the Departments of. Dermatology and Internal Medicine, University of Innsbruck, Austria; Department of Dermatology. University ot Wiirzburg. Wiirzburg, FRG: and Department of Pediatrics, University of Ulm, Ulm, FRG. Accepted for publication November 15. 1989. KC? wont: angiotropic lymphoma, intravascular lymphomatosic. gene re.xrrangement. progenitor cell cultures, immunohistochemistr\. Address correspondence and reprint requests to Norbert Srpp, MD, Department ot Dermatology, Anichstrasse 35. A-6020 Innsbruck, .%ustria. ID by W.H. Saunders Company. 0046-8 177/90/2 1lo-0009$5.00/0

kocyte-common antigen and negative reactions for factor VIII-related antigen, except for a few cells entrapped within platelet and fibrin thrombi, revealing their leukocyte origin. 15-18 Based on these observations, PA was tentatively reclassified as; “angiotropic lymphoma.“‘H Further evidence of its lymphomatous origin was presented by Otrakji et al, who demonstrated specific B-cell immunoglobin gene rearrangement in the tumor cells of one patient. l9 Classification difficulties persist, nevertheless, since the existence of a benign. reactive type of PA of genuinely endothelial origin has been put forward by Wick and Rocamora”’ on the basis of histologic, immunohistochemical, and clinical evidence. We report immunohistochemical and ultrastructural findings of two cases of intravascular lymphomatosis (IL). Both patients had angiotropic T-cell lymphomas; in one, monoclonal T-cell receptor gene rearrangement was demonstrated by Southern blot analysis. CASE No. 1 An 81-year-old woman presented extensively disseminated hemorrhagic

in Ocl.ober

1985

with

nodules of trunk, face (Fig l), and extremities, some of them necrotic or ulcerative. and most surrounded by livedo reticularis of the starburst pattern. Skin lesions had been present for 1.5 years. There was a history of arthralgias and drastic weight loss (25 kg) over the past 6 months, as well as decreased visual and hearing acuity. Physical examination revealed a subfebrile patient with no pathologic signs except for liver enlargement and a grade 316 systolic ejection murmur radiating to the apex. Laboratory findings included high blood sedimentation rate (49 mm/l hr), anemia (hemoglobin 10.5 gm/dL), low serum iron (9.5 mmol/L; normal, 10.3 mmol/L), leukopenia (3.1 to 3.9 X lO”/L), and relative peripheral lymphocytosis (73%). Serum vitamin B,, and folate levels were within normal limits. The CD4+ to CD8+ ratio was 4: 1. Direct and indirect Coombs’ tests were negative and antinuclear antibodies were absent. Serum immunoglobulin levels were normal. Cryoglobulins and cold agglutinins were found in low titers. Serum electrophoresis, coagulation profile, and C3 and C4 levels were within normal range. Immune complexes were present (range, 38 to 52 pg/mL). as detected by the Clq binding assay. Serum beta-2 microglobulin levels were 6 mg/L (normal, up to 2.4). Serum transaminases were slightly elevated. Urinalysis, electrolytes, urea, and creatinine were normal; creatinine clearance was reduced (38 mlimin). Urine neopterin excretion was ‘excessively elevated to 4,799 kmol/mol creatinine (normal. ~250). Virus

1051

HUMAN PATHOLOGY

Volume 21, No. 10 [October 1990)

FIGURE I. Disseminated hemorrhagic papules and plaques (patient no. 1).

FIGURE 2.

Elythema nodosum-like lesions [patient no. 2).

MATERIALS AND METHODS antibodies

(including

hepatitis

B, Epstein-Barr

virus, cvtomegalovirus, and human immunodeficiency virus) were negative. Electrocardiogram revealed coronary heart disease and atria1 flutter. Ultrasound examination of the live] suggested an intrahepatic hemang_ioma. Bone marrow preparations were normal; signs of CNS involvement were absent. Blood transfusions were given as symptomatic therapy for anemia; the patient was later discharged in an IIIIchanged condition and failed to attend further appointments. She died of heart failure 6 months later. No autopsy was performed.

Biopsy material from both patients was processed f’o~ routine histology and electron microscopy. and snap-f.roLen in liquid nitrogen for immunofluorescence, immunophenotyping, and Southern blot analysis (patient no. 2). For~immunofluorescence studies in patient no. 1, tlu-

CASE No. 2 A 75year-old woman presented in December 1986 with erythema nodosum-like nodules of 4 months’ duration on both thighs (Fig 2). The patient felt well except for arthralgias and fatigue; fever was absent. Physical examination yielded no abnormalities of liver, spleen, or peripheral lymph nodes. including complete blood Laboratory investigations, count, urinalysis, coagulation profile, and liver and renal function parameters, were all normal except for a slightly elevated blood sedimentation rate. Electrocardiogram, bone marrow, and ultrasound examination of the abdomen and computer tomogram of the brain revealed no abnormalities. Eight months later, the patient developed widespread cutaneous involvement, with some of the lesions becoming necrotic. Therapy with interferon-alpha (2 to 5 million units daily) resulted in size reduction and reduced inflammation of the nodules; none of them disappeared, however, and many new lesions arose (Fig 3). Interferon was thus withdrawn and polychemotherapy (cyclophosphamide, vincristine. and prednisolone) was initiated. Progression continued, however, and the patient died of heart failure shortly thereafter, 18 months after onset of the initial lesions. An autopsy was refused. 1052

FIGURE 3. Partly necrotic nodular lesions, livedo reticularis of starburst type (patient no. 2).

INTRAVASCULAR LYMPHOMATOSIS (Sepp et al]

ichert Cltracut) were stained with lead citrate and examined with a goniometer-equipped Philips E.M 400 electron microscope operating at 80 kV.

olescein isothiocyanate (FIT(:) conjugated anti-I@, IgM. IgA. (23, and fibrin (Dakopatts, Glostrup, Denmark) in pllosphate-hufiereti saline-bovine serum albumin were uxed. For immunohistochemistrv of patient no. 2, an indirect immunoperoxidase technique was used as previously described.” Frozen tissue sections 4 km thick from patient no. 1 were stained with a series of monoclonal antibodies bt rhe avidin-biotin-peroxidase complex (ABC) immunoperosidase technique. Biotinylated anti-mouse antibody and avidin-biotin peroxidase complex were obtained from Vector Laboratorirs (Burlingame. CA); the chromogen subst rates 3-anlino-9-eth)I-carbazole and diaminobenzidine hvdrochloride were from Polyscience Inc. (Warrington. P.1) and Sigma (St Louis, MC)), respectively. The monoclonal antibodies and conventional antisera used, their specific immunore.ac-ti\,ities. and commercial sources are listed in ‘I able 1.

DNA Analysis (Patient No. 2) High molecular weight DNA was prepa.red from cryopreserved skin biopsies by standard techniques. A total of IO kg DNA was digested with appropriate restriction enzvmes (Boehringer, Mannheim, FRC;). eleccrophoresed on a’ 0.7% agarose gel. blotted, and hybridized as described previously.“’ To investigate imunoglobulin gene arrangement. BamHI and Hind111 digests were hrbridized to a l.Y-kb EcoRI (:k probe.‘:’ BamHI/HindII1 codigests toJH sequences,” and BamHI digested DN.A to a (1, probe.“’ For the detection of T-cell receptor gene rearrangements, EcoRI and HamHI digests were hybridized to TCRP sequencm- “’ and EcoRI digested samples to l.O-kb PstIi EcoRI Ty fragments.” Probes were kindly provided by Drs P. Leder and J. van Dongen. After hvbrldlzac ion, the filters were washed under stringent conditions and exposed to NAR-5 films (Kodak, Rochester. NY) using DuPont intensifying screens for 12 hours at - 70”<:.

Electron Microscopy FineI) minced skin specimens were fixed strength Karnovskv’s paraformaldehyde-glutaraldehyde

in

halI

fixative (5 hours nr room temperature) and rinsed three times in 0.1 mol/L cacodylated buffer, pH 7.4 at 4°C:. After postfixation it1 3% aqueous solution of 0~0, at 0°C: and en bloc staining with veronal acetate buffered uranvl acetate, rhe hpecimenh were dehy,drated in a graded series of alcohols and ernheddrd in Epon 812. LIltrathin sections (Re-

TABLE

1.

Monoclonal Pred(uninant

.Alltibod\

Progenitor Cell Cultures These

studies

out a progeniror

Antibody

were performed cell defect as the

Panel and Lectin Used

St ~I,,~C~:‘

immunor-eat-ti\,il~

( ‘SC no. I T “00 ((:D45) BMA 03’ (CD3) Leu 3a ((:l)‘ll Leu I ((:I:).?) OKT X ((:DXI OK-I Y ((X)71, Leu I? ((:l)lOi ‘1‘0 I5 (CIWI BA I (CD?4I IL. 2K (<:w’,) anti-HLA-DK I -- 1 anti-\‘III-R Ag ( -~! Leu I la l(.Dlli) Lru 41.5 ( ) Ki Ml ((321 1~I I’les eur,,partis Itwin C ase no. 2 LC:A ((X4.i) .I‘ I I (CDL’) OKT x (l.:DHr Leu 3a ((:I)11 Ki-I ((:D?iO) PC: (iii ti’il ( - 1 OKM 1 ((:DI lh1 IX11 I (<:D.i) anti-OK la1 ( I anti-II-2 !(;D25) 1.t.u 12 (i::Dl!)) L.eu I-1 (C‘D”“) I &.. iii Ml (CDllcl Ki M2 (<:I)141 Ki M5 ((:DW) anti-DRC: I - ) Ljlex europarur Iec-tin Techniques

uwd:

(- 1

Pan leukoc-vtc antigen Pan T-lwnphocyte antigen T helper-/inducer l’a~~-‘f cell marker T suppre\soric~ttrtoxjc Transferrin receptor Pan B cell marker Pan B cell marker Pan B cell marker Interleukirl-2 receptor HI.A-DR Endothelial cells ‘I‘ cells. NIC cells Monocvtes Monocvtes Endothelial cells

t- )

Leucoccw common antigen E-rosette receptor. T cells T ~uppressoric~totc)xic T helperiinducer Reed-Sternberg cells Proliferating cells Zlonocytes T-lymphocytes, some B-cell chronic lymphocvtic leukemia cells HLA-DR antigens IL-2 receptor Pan B cell marker Pan B cell marker Mononuclear cells Mononuclear cells Mononuclear cells Dendritic reticulum cells Endothelial cells

case no. I. AU<: (avidin-biotin-complex);

in patient no. 1 to rule cause of the underlying

case no. 2. AP.4AP

1053

Hbbritech (San L)ieg-0, (1~1) B&ring iVienna, Auslrla) Becton I)ickinson (Mountain \‘iew, akopatts ((~IosLI-up. I)wmark) Becton Dickirtson Dakopatts Becton Dickinson Becton Dickinscm Behring E-1’ Laboratot-ies (San Mateo. CA) Dakopatts (louher Immunolog\ Ortho Becton Dickinson Dakopatts Dakopatts Ortho Becton Dickinwn Ortho Dakopatts Becton Dickinson Becton Dickinson Behring Behring Behring Dakopatts E-Y Laboratories (alkaline

phosphatase-anti-alkaline

phosphatasel.

Volume 21, No, 10 [October 1990)

HUMAN PATHOLOGY

persistent granulocytopenia. A previously described microagar culture system for erythropoietic, granulopoietic. and megakaryopoietic progenitor cells was used.‘” Bone marrow and peripheral blood cells obtained from patient no. 1 were separated on a lymphoprep density gradient (D =

1,077) (Nygaard,

Oslo, Norway) and mononuclear

cells

(MNCs) were suspended in McCoy’s medium containing 20% human serum and 0.3% agar (Agar-Agar, Merck, Darmstadt, FRG). The agar was allowed to solidify at room temperature and was then overlayered with 0.25 mL of alpha medium (Gibco, Paisley, UK) containing either 2.4 I.U. sheep erythropoietin (Step III; Connaught Medical Research Laboratories, Willowdale, Ontario, Canada) plus phytohemagglutininlymphocyte-conditioned medium (PHA-LCM) 5% for the stimulation of erythropoietic progenitor cells or recombinant GM-CSF in a pretested optimal concentration of 200 ng/mL (Behring-Werke, Marburg, FRG) for granulopoiesis. Megakaryocytic colony growth was obtained by the addition of 20% pretested serum from a patient with severe aplastic anemia, containing a high concentration of Meg-CSF. The cultures were incubated for 12 days at 37°C in a fully humidified atmosphere containing 5% CO,, then fixed with glutaraldehyde (2.5%,), dried on a microscopic slide, stained according to the Pappenheim method, and screened for colony formation as described previously.g”

Screening for Humoral and Cell-Mediated Progenitor Cell Suppression GM-CSF-stimulated progenitor cell cultures were grown as described above. From day 0, the patient’s serum was added to the medium in concentrations ranging from 10% to 30%, and their growth measured at day 12. In another set of experiments, peripheral blood was depleted of T lymphocytes and monocytes by adherence to plastic or E-rosetting techniques, respectively, prior to setting up progenitor cell cultures.

RESULTS Light Microscopy In HE sections of skin biopsies of both patients, dermal and subcutaneous capillaries and postcapil-

lary venules (Fig 4) were partially or completely occluded) by fibrinous thrombi and clusters of atypical cells. These cells were slightly eosinophilic and had hyperchromatic pleomorphic nuclei, occasionally in syncytial aggregation (Fig 5, right). There were moderate perivascular inflammatory infiltrates, some containing clusters of atypical cells similar to those described above. lmmunohistochemistry In case no. 1, intravascular cells were strongly positive for the leucocyte common antigen (CD45), the pan-T cell marker (CD3), and antibodies against CD5, CD4, and CD8, suggesting T-cell origin. Staining of transferrin receptors (CD71) and class II antigens (HLA-DR) was also positive. B-cell markers (CD24, CD19, CD22) were negative, as were FITCconjugated antibodies against IgA, IgM, C3, and IgG. Interestingly, a few cells stained with antibodies against IL-2 receptor (CD25) and monocyte markers (Leu-M5, CD1 lc). Only the vascular endothelia were reactive with factor VIII-related antigen and Ulex europaeus agglutinin; the intravascular cells were negative. The results were similar for case no. 2. The intravascular cells were strongly positive for the leucocyte-common antigen (CD45) (Fig 5, left), OKlal (HLA-DR), and T-cell markers (CD4, CD2); B-cell markers (CD19, CD22) were negative. Antibodies against CD8, CD30, and Ki67 stained only a few cells. Again, many intravascular cells expressed monocyte markers (CD14, CD68, CD1 1). Only a few cells were positive with antibodies against the IL-2 receptor antigen (CD25) and dendritic reticulum cells (DRCs). Factor VIII-related antigen was positive only in the endothelial cells and a few scattered cells within the clusters of intravascular atypical cells.

FIGURE 4. Dermal capillaries and postcapillary venules distended and partially occluded by clusters of intravascular cells (patient no. 2) (HE; magnification x 135)

INTRAVASCULAR LYMPHOMATOSIS (Sepp et al]

FIGURE 5. [Right) Atypical lymphoid intravascular cells with large nuclei [HE; magnification X 340) (Left) Positive ieucoqte common antigen staining of intravascular cells (patient no. 2) (Immunoperoxidase, APAPP; magnification x 800)

Electronmicroscopy In specimens of both patients, dermal vessels were occluded by fibrinous material, aggregates of large cells of lymphoid appearance (Fig 6), and atypical, often bizarrely folded, nuclei (Fig 6, inset). ‘They

FIGURE 6. tow power elec tronmicrograph showing a dermal blood vessel occluded by ellectron dense intravascular tumor cells unconnected to the endothelial lining, cellular debris and fibrinous material (magnification x 4,000) Inset: Bizarrely nucleated tumor cells (magnification x 6,600) [patient no. 11

were not continuous with endothelial tained no Weibel-Palade-bodies.

cells and

con-

Southern Blot Analysis (Patient no. 2) Southern blot analysis of a lesional skin sample revealed a monoclonal T-cell receptor 13 chain rear-

HUMAN PATHOLOGY

rangement (Fig 7), whereas TCR and immunoglobulin heavy and showed germline configurations. Progenitor

Cell Studies

Volume 21, No. 10 (October 1990)

TABLE 2. Megakaryocytic, Granulocytic, and Erythrocytic Colony Formation By Bone Marrow and Peripheral Blood Cells in Patient No. 1

A chain sequences light chain genes

Normal Controls (n = 5)

(Patient no. I) Patient

Patient no. 1 clearly had normal numbers of committed bone marrow and blood cell-derived progenitor cells (Table 2), suggesting the absence of primary progenitor cell defects. Addition of the patient’s serum to the culture medium resulted in drastic reduction of progenitor cell growth (Table 2), whereas no difference was observed in cultures previously depleted of T lymphocytes and monocytes.

Colony Number/

I x IO5 MNC Bone Marrow CFU-E BFU-E CFU-GM CFU-Meg

1162 90 + 44 * 14 +-

11 7 3 :i

DISCUSSION

Colony Number/ 5 x lo4 - MO-T*

Colony Number/ 1 x 10” MNC

180 64 74 25

140 65 70 46

_t 2 2 5

9 2 7 4

Patlent CFU-GM/ 5 x IO” MN’C

IL is a multisystem disease characterized by either exclusively or predominantly intravascular accumulations of lymphoid tumor cells, most often of small blood vessels. Clinical features and laboratory data reflect the type and extent of organ involvement; skin and the CNS are most frequently affected, whereas lymph nodes, liver, spleen, and bone marrow are usually spared. The cutaneous manifestations are variable and not diagnostic.* The most common findings are partially hemorrhagic and ulcerative nodular or plaquelike firm dermal inflammatory infiltrates, adherent to the underlying tissue. Teleangiectasia may be prominent. Predileciton sites are trunk and extremities, although lesions may occur anythere. The clinical differential diagnosis ranges from erythema nodosum” to mycosis fungoides, panniculitis,’ granulomatous vasculitis, sarcoidosis, and Kaposi’s sarcoma. Initial signs are most often central nervous system disturbances (85%):‘“*27 progressive dementia (55% of cases); vision impairment; transient episodes of aphasia, numbness, weakness, seizures, hemipare-

a b

c 23

kb

b”

FIGURE 7. Southern blot analysis of BamHl digested DN4.s (10 kg) obtained from a skin lesion of patient no. 2 (a] as well as control fibroblast and placenta samples. The TCRp probe detects a 23.Kb germline fragment, Arrow points to the rearranged fragment.

1056

15 + 3 Peripheral Addition 19% “0% SO% Peripheral depleted cells and

blood of patient’s

2 -c -c 2

75 35 35 28

Normal Control CFU-GM/ 5 x IO’ MNC 4x 2 30

serum 521 3 + 2 CI+ 1

blood ot patient of mononuclear T cells (-MO-T)

CF;I_(;M/ 2.5 X IOi cells* I5 % 7

Values represent the mean (*SD) of the absolute number of bone marrow and peripheral blood early and late erythropoietic (BFU-E, CFU-E). granulopoietic (CFU-GM), and megakaryopoietic (CFU-Meg) colonies. All experiments were performed in triplicate. Abbreviations: Mo-T. monocyte and T-lymphocyte depleted bone marrow and peripheral blood progenitor cultures. * Only half the number of bone marrow low density cells were used to compensate for the enrichment of progenitor cells in the target cell population.

sis; and sensory loss. I 5 Electroencephalography and computed tomography may show significant brain abnormalities; in contrast, cerebral angiograms are usually normal. Systemic signs include fever, malaise, weight loss, myalgia, and arthralgia. Common laboratory abnormalities include mild anemia, elevated erythrocyte sedimentation rate. very high serum lactate dehydrogenase levels, and elevated cerebrospinal liquor protein.” The key histopathologic feature is the intravascular accumulation of large tumor cells with pleomorphic nuclei, which distend and occlude the vascular lumina and are often associated with fibrinous thrombi. Extravascular accumulation of tumor cells is occasionally observed. Patients generally respond poorly to radiation or chemotherapy, although successful treatment with chemotherapeutic agents has been reported.‘*‘” The overall mortality rate is over 80%, and the average survival time is 13 months, according to a review of the 40 cases previously reported in the literature.” Obviously, IL represents a very unusual type of lymphoproliferative disease in which many aspects are as yet poorly understood; eg, site of origin, type(s) of lymphoid cells involved (heterogeneity of the disease). and the mechanisms that mediate the exclusive affinity of the lymphoma cells to certain types of

INTRAVASCULAR LYMPHOMATOSIS (Sepp et al)

blood vessels (capillaries, postcapillary venules) and prohibit the colonization of the organs most commonly colonized by lymphomas: lymph nodes, spleen, and bone marrow. ‘The majority of the few cases of IL previously subjected to phenotyping represented B-cell lymphomas. Ij’.L’8-3I Recently, Otrakji et al’!’ demonstrated clonal rearrangement of the immunoglobulin heavy chain by !iouthern blot analysis in a case of’ “malignant” IL. ‘I‘he clinical, histologic, ultrastructural, and imunohistochemical findings of the two patients reported justify the diagnosis of an intravascular T-cell lymphoma: expression of monocyte markers may be encountered in neoplastic T cells and thus does not militate against this interpretation. T-cell origin is further demonstrated by the monoclonal rearrangement of TCRP sequences in patient no. 2. This latter tinding also proves that a large proportion of the cells in question are derived from the same precursor cell and suggest their neoplastic nature. Definite proof, howe\:er , should be based on the investigation of multiple lesions at different stages of the disease. Patient no. I exhibited an additional interesting feature, ie, leukopenia and anemia. Progenitor cell studies showed the absence of primary growth defects, but revealed the presence of a humoral suppressive factor. which may be attributed to the lymphoma cells. Pre\,ious studies have clearly shown that transformed ‘I‘ cells may still be capable of producing inhibitors of hemopoietic progenitor cell growth, such as irlterttron-y or Iymphotoxin.:“’ In the case presented, inhibitory factors may have been produced by the lymphoma cells, along with other cytokines, which ma) also have caused the fever that so often accompanies IL. What makes neoplastic lymphocytes stay within blood ves:jels in intravascular, angiotropic Iymphomas? Obviously, the mechanisms regulating normal 1ymphocyl.e traffic between the intravascular space and tissues are impaired. It has recently been shown that both B and T lymphocytes are capable of binding to high endothelial-like venules in lymphoid organs;:‘:’ high endothelial like venules in the synovia of patients with rheumatoid arthritis have recently byen show11 to interact with lymphocytes via a novel t)pe of homing receptor.:“’ It is temptmg to speculate that in IL. B- or T-cell adhesion molecules to dermal and central nervous system capillaries and venules may be disturbecl, leading to either abnormal adherence and/or the inability to bind to the endothelial cells and migrate through the vessel wall. REFERENCES

4. Fulling KH, Gersell DJ: Neoplastic angioendotheliomatosis: Histologic. immunohistochemical, and ultrastructural findings in twocases. Cancer 51:1107-1118, 1983 5. Kauh proliferating X06. 1980

I’C. McFarland JP, Carnabuci GC, et al: hialignant angioendotheliomatosis. iZrch Dermatol 1I6:803-

6. Kitagawa gioendotheliosis. findings in three

M, Matsubara 0. Song S-Y. et al: Neoplastic anlmmunohistochemical and elec,tlon microscopic cases. Cancer 56: 1134 I 143, lW5

7. Lim HM:. Anderson HM: Angioendotheliomatosis associated with histiocytic lymphoma. Response to svstemic chemotherapv. ,J Amer Acad Dermatol 13:903-908. 1985

8. Martin S. Pitcher D. Tschen J? et al: Reactive angioendotheliomatosis. J Amer Acad Dermatol 2: 117- 123. 1980 9. Petit0 CK. Gottlieb GJ, Dougherty JH. et al: Neoplastic angioendotheliosis: Vltrastructural stud\ and review of literature. .4nn Neural 3:393-399, 1978 IO. Scott PWB. Silvers DN. Helweg EB: Proliferating tlotheliomatosis. .4rch Pathol 99:32:3-326, 1975

I 1. Bhawan

1: Xngioendotheliomatosis An angiotropic ne’hplasm of lvmphoid Path 4: 1x-v.* 19x7

ata:

angioen-

prolilerans systemisorigin. Semi; Diagn

12. Eisert J: Skin manifestations o! subacute bacterial endocarditis. Cash report of subacute bacterial endocarditis mimicking Tappciner’s .mgioendotheliomatosis. Cutis “.~I:394-4~w. 19x0 13. Braverman Ihl. Lerner AB: Diffuse malignant proliferation of vascular endothelium. A possible new clinical and pathologic entity. .4rch Dermatol X4:22-30. 1961 13. Keahey IX, Guerry D. Tuthill RJ. et al. Malignant allgioendotheliomatosis proliferans tr-eated with rloxorubicin. .4rch Der-mat01 11X:51?-514, 1982 1.5. Beal MF, Fisher MC: Neural Sci 53:359-375. 1982

Neoplastic

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16. Bhawaan.J. Wolff SM, Ucci AA. et al: Mali:~nant l~mphoma and malignant angioendotheliomatosis: One disease. Cancer 5.5: 570-576 . 1’18.5 17. Sheiham K. Battifora H. Winberg (ID. et al: Further e\idence that “malignant angioendotheliomatosis” is an angiotropic large-cell lymphoma. N Engl J Med 314:943-Y%+ 1986

18. Wrotnowski LT. Mills SE. Cooper PH: hla.ltgnant angioendotheliomatosis: An angiotropic lynphoma? .4mer ,J (Iin Pathol x:~:2+-24x, 19x.5 19. Otrakji C;L. \‘oigt M’. Amador .4. et al: Mahgnant angioendotheliomatoslsa true Iy,mphoma: .4 case ot intravascular malignant Ivmphomatosis studted by Southern blot hvbridization analvG. H;w PAT.HOI 19:475-478. 1988 20. Wick MK. Rocamora A: Reactive and malignant endotheliomatosis”: .4 discriminant clinicopathological <:utan Pathol 15:260-27 1, 3988

“angiostudy. ,J

2 1. CordelI JL, Balini B. Erber WN, et al: Immunocnzymatic labeling of monoclonal antibodies using immune complexes of. alkaline phosphatase (.4PAAP complexes). ,J Histochetn 32:219-229. 19x4 22. Raghavachar A. Bartram CK. Ganser A. t’t al: Acute undifferentiated leukemia: implications for cellular origin and clonalit! suggested b\ analysis of surface markers and immunoglobulin gene rearrangement. Blood 68:658-662. 1986 23. Bakhshi A. Minowada J, Arnold A, c’t al Lymphoid blast ct-ises of chronic myelogenous leukemia represent stages in the development of B-cell precursors. N Engl .J Med 309:826-839. 11186 24. Tahahashi N, Nahai S. Honjo munoglobulin p gene and comparison .4cids Res X:5983-5991. 1980

1. Pflegel- L. I‘appeiner ,J: Zur Kenntnis der svstemisierten Elldotheliomatose der cutanen Blutgefipe (Reticuloendotheliose?). Hautavt 111:359-363, 1959 2. ‘Tapprinel ,J, Pfleger L: Angioendotheliomatosls proliferans svstemis.dta. Ein klinisch und pathohistologisch neues Krankheitsbild. Hautarzt 14:67-70, 1963 3. Fievez M. Fiwez <:, Hustin J: Proliferating sytematizetl ;rngioendotheIiorrlatosis. Arch Dermatol 1W&:320-321. 1971

T: (:lonmg of human imwith mouse p gene. Nucl

25. Dongen van JJM, Quertermous T. Bat-tram CR. et al: The T cell receptor CD3 complex during earl, 7‘ cell differentiation: Analysis of immature T cell acute lymphoblastic leukemias (TALL) at DNA, RN.4 and cell membrane level. ,J Immunol 138: 1260-1269, 19x7

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HUMAN PATHOLOGY

Volume 21, No. 10 (October 1990)

26. Geissler D, Lu L, Bruno E, et al: The influence of T lymphocyte subsets and humoral factors on colony formation by human bone marrow and blood megakaryocyte progenitor cells in vitro. J Immunol 137:2508-2513, 1986 27. Wick MR, Banks PM, McDonald TJ: Angioendotheliomatosis of the nose with fatal systemic dissemination. Cancer 48:2510-2517, 1981 28. Willemze R, Kruyswijk MRJ, de Bruin CD, et al: Angiotropic (intravascular) large cell lymphoma of the skin previously classified as malignant angioendotheliomatosis. Brit J Dermatol 116393-399, 1987 29. Wick MR, Mills SE, Scheithauer BW, et al: Reassessment of malignant “angioendotheliomatosis”. Am J Surg Path01 10: 112. 123, 1986 30. D’Agati V. Sablay LB, Knowles DM. et al: Angiotropic large cell lymphoma (intravascular malignant lymphomatosis) of

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