Fibrin Deposits in Hodgkin's Disease

NANCY L. HARRIS, MD, ANN M. DVORAK, MD,JOANNE SMITH, and HAROLD F. DVORAK, MD

Fibrin deposits were observed in the involved lymphnodes and/or spleens of 15 patients with Hodgkin's dis-ease by specific immunofluorescence and by electronmicroscopy. Two basic patterns of fibrin depositionwere observed: 1) intercellular deposits, chiefly associ-ated with nonneoplastic-appearing lymphoid cells and2) deposits associated with the collagen fibers of youngconnective tissue. In addition, coarse fibrin depositswere observed in areas of necrosis, presumably a non-specific finding. Fibronectin was also observed in inter-cellular areas, but staining was less intense than for

INVOLVEMENT of the coagulation system in tumorgrowth and metastasis is suggested by several lines ofevidence. Clotting abnormalities are frequently ob-served in patients with malignant neoplasms.` Pro-coagulant activity has been found associated with anumber of human and animal tumors and tumor celllines,5-1" and fibrin deposits have been described inseveral spontaneously arising and transplantable tu-mors in man and animals.4'5s12-19 Furthermore, thegrowth and metastatic potential of some tumors maybe decreased by administration of anticoagulants orantibodies to fibrin in vivo.2218,19 Although all ofthese observations suggest a role for the clotting sys-tem in tumor biology, the pathogenesis and biologicsignificance of fibrin deposition in tumors have notbeen thoroughly investigated.

Recent experiments from our laboratory demon-strated that deposition of a fibrin gel was an earlyfeature in the growth of two transplantable guineapig bile duct carcinomas, line 1 and line 10, as solidtumors.5'16 The abundant fibrin gel enveloping line 1tumors was subsequently organized into a dense col-lagenous matrix, giving a fibrous appearance that re-sembled scirrhous human carcinomas. In contrast,line 10 tumors, about which a lesser amount of fibrinwas deposited, developed minimal fibrosis. Both ofthese animal tumors were also found to elaborate me-

From the Departments of Pathology, Massachusetts General Hospital,Boston, Massachusetts, Beth Israel Hospital and Harvard Medical School,and the Charles A. Dana Research Institute, Beth Israel Hospital,Boston, Massachusetts

fibrin. Fibrin deposits were also observed in 3 of6 casesof non-Hodgkin's lymphoma, indicating that the find-ing is not an exclusive feature ofHodgkin's disease. Thepathogenesis and possible significance of fibrin deposi-tion in Hodgkin's disease are related to earlier observa-tions of activation of the coagulation system in neo-plasia and cell-mediated immunity and to the possiblerole of fibrin, fibronectin, and their breakdown prod-ucts in angiogenesis and fibroplasia. (AmJ Pathol 1982,108:119-129)

diators in vitro which could account for depositionand modulation of a fibrin gel; ie, factors that ren-dered normal blood vessels leaky, that caused plasmato clot, and that activated plasminogen to the fibrino-lytic protease plasmin.5'6

In an attempt to relate these observations to humandisease, we recently examined a series of mammarycarcinomas by immunofluorescence and electron mi-croscopy. Substantial fibrin deposits were found atthe tumor-normal-tissue interface and, to a lesser ex-tent, about more centrally placed tumor nests and inthe collagen of the scirrhous tumor stroma.17 In thepresent study, we applied the same techniques to thestudy of lymph nodes and spleens involved by Hodg-kin's disease, a form of malignant lymphoma in whichextensive fibrosis is frequently a prominent feature.20We looked for fibronectin as well as fibrin becausefibronectin is frequently associated with fibrin andhas been implicated along with fibrin in wound heal-ing 21-23

Supported by NIH Grant CA 28471 and by TrainingGrant CA 09216.Accepted for publication March 5, 1982.Address reprint requests to Harold F. Dvorak, MD, De-

partment of Pathology, Beth Israel Hospital, Boston, MA02215.

0002-9440/82/0709-0119$01.05 O American Association of Pathologists

119

120 HARRIS ET AL

Materials and Methods

Immunofluorescence

Fresh tissue blocks obtained at the time of lymphnode biopsy or splenectomy were quick-frozen andstored at - 70 C. Sections were cut in a cryostat, air-dried at room temperature, and washed in phosphate-buffered saline (PBS), pH 7.3. Sections were incubatedwith fluorescein isothiocyanate (FITC)-, or rhoda-mine-conjugated antiserum for 30 minutes in a moistchamber at room temperature, washed in PBS,mounted in Elvanol (E.I. du Pont de Nemours, Wil-mington, Del), and examined with a Zeiss fluores-cence microscope equipped with epiillumination. Insome experiments, sections were incubated with fluo-rescein-conjugated antiserum, washed in PBS, andstained with rhodamine-conjugated antibodies toprovide double labeling on a single slide.A number of different antiserums were studied.

Commercially prepared FITC-conjugated antibodiesto human fibrinogen were obtained from Cappel(Cochranville, Pa), Kallestad (Minneapolis, Minn),Hyland (Bannockburn, Ill), and Dako (AccurateChemical and Scientific Co, Hicksville, NY). Suchantibodies react with fibrinogen, fibrin, and, presum-ably, with certain of their degradation products; and,as in the past,21 we refer to this range of specificitiesby the collective term "anti-Fib." However, fibrincould usually be recognized as such by its fibrillar ap-pearance. In addition to reacting with Fib, the Cap-pel and Kallestad antiserums cross-reacted withhuman fibronectin, as demonstrated by staining of aWI-38 cell monolayer known to elaborate fibronec-tin.24 Antifibronectin reactivity was completely re-moved by absorption of antibody with sepharose-conjugated human fibronectin. The Dako antibodydid not stain WI-38 monolayers and was used withoutabsorption. We checked antibody specificity addition-ally by employing anti-fibrin antiserums that had beenabsorbed with sepharose-conjugated human fibrino-gen, so that they no longer stained a fibrin clot. Toeliminate the possibility of cross-reactivity with fibro-nectin and of binding of antibody to Fc receptors, anFITC-conjugated rabbit anti-guinea pig fibrinogenF(ab')2 antibody preparation was also used. This anti-body was shown to react with human as well as guineapig fibrinogen, and its method of preparation andspecificity have been previously reported.22

Sections were also stained with F(ab')2 fragmentsof FITC-conjugated rabbit anti-human fibronectin,prepared and tested as previously described,22 and

with commercially prepared FITC-conjugated goatanti-human IgM, IgG, fibronectin, C3, and albumin.

Electron Microscopy

Biopsy specimens taken for ultrastructural diagno-sis at the time of surgery were immediately cut into1-2-mm fragments in a pool of dilute Karnovsky'sfixative, held for 2 hours in this fixative at room tem-perature, and washed overnight in cold 0.1 M sodiumcacodylate buffer, pH 7.4.16 Tissue was postfixed for2 hours in 2% collidine-buffered osmium tetroxide at20 C, stained en bloc with uranyl acetate, dehydratedin a graded series of alcohols, and embedded in apropylene oxide-Epon sequence. Plastic 1-,u sectionswere cut, permanently stained with alkaline Giemsareagent, and studied by light microscopy. Represent-ative areas were thin-sectioned, stained on grids withlead citrate, and examined in a Philips 400 transmis-sion electron microscope.

Patient Material

Hodgkin's DiseaseLymph nodes from 12 patients with Hodgkin's dis-

ease, 11 untreated and 1 who had a relapse 10 yearsafter treatment, were studied by immunofluorescence.Splenic tumors obtained at staging laparotomy wereexamined in 5 patients. Two patients had both a lymphnode and splenic tumor available for study, making atotal of 17 specimens from 15 patients. Four tumorswere mixed cellular Hodgkin's disease, 10 nodularsclerosis, and one lymphocyte predominant type.Lymph nodes from 9 cases of Hodgkin's disease

were studied by electron microscopy, 8 of nodularsclerosis and 1 of mixed cellular type.

Non-Hodgkin's LymphomasTissue from 6 patients with non-Hodgkin's lymph-

omas was examined by immunofluorescence: 2 diffusehistiocytic lymphomas, 1 nodular histiocytic, 1 nodu-lar mixed, 1 nodular poorly differentiated lympho-cytic lymphoma, and 1 hairy-cell leukemia. Spleentissue was studied from the hairy-cell leukemia andlymph nodes in all other cases.

Normal or Reactive Tissues

Normal spleens from 4 patients were studied: unin-volved spleen from 3 patients with Hodgkin's diseaseand 1 spleen removed because of traumatic lacer-ation. Three hyperplastic lymph nodes were examined,all with nonspecific follicular and diffuse hyperplasia.

AJP * July 1982

FIBRIN DEPOSITS IN HODGKIN'S DISEASE 121

Figure 1 - Hyperplastic lymph nodes with reactive germinal centers. A-Immunofluorescence staining with anti-Fib antibodies revealsfibrillar intercellular staining of varying intensity within a germinal center. (x 110) B - Routine H&E histologic study. Arrows indicate amor-phous intercellular eosinophilic material within the germinal center. (x 256) (With a photographic reduction of 3%)

Results

Immunofluorescence

Normal or Reactive Tissue

Fibrin staining of hyperplastic lymph nodes was

confined to the germinal centers of reactive follicles(Figure IA). Deposits were extracellular and con-

sisted of irregular masses of amorphous or fibrillarmaterial, distributed throughout the germinal center.They corresponded in distribution to amorphous,eosinophilic material visible in sections stained withhemotoxylin and eosin in the germinal centers of re-

active follicles (Figure 1B). Anti-Fib antibodies fromall sources stained this material; staining was elimi-nated by absorption with fibrinogen-sepharose beads.This material did not stain with antiserum to C3 or

albumin, and appeared distinct from the intercellularnetwork of material that stained with antiserum toimmunoglobulin (see below).The white pulp of a spleen removed for trauma

and the uninvolved spleens from Hodgkin's patientsstained in a manner identical to that of reactive lymphnodes, with fibrin deposited in reactive follicles. Thesplenic red pulp also exhibited patchy staining forfibrin with scattered flecks and granules along thesinuses; this staining was absorbed by fibrinogen-sepharose. Anti-Fib antibodies sometimes stainblood vessel linings in other organs as well. Largecytoplasmic inclusions present in some mononuclearcells of the red pulp stained brightly and nonspecifi-cally with all antiserums studied and were unaffectedby our absorptions.

Antibodies to human fibronectin stained normallymphoid tissue in a pattern analogous to that of areticulin stain, as previously described;25 the entireframework of lymph nodes and spleen, and the basallamina zone of small blood vessels were stained, giv-ing a clear demonstration of tissue architecture. Inaddition, fibrillar material in follicle centers whichstained for fibrin also reacted weakly with antibodyto fibronectin. Double staining of a normal spleen for

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122 HARRIS ET AL

Figure 2-Lymph nodes with Hodgkin's disease, nodular sclerosis type. Tumor nodules are surrounded by circumferential bands of fibrousconnective tissue. A-Immunofluorescence staining with anti-Fib antibodies reveals fibrillar and globular intercellular staining of the tu-mor nodule (left and center). Surrounding collagen (right) is also decorated with Fib staining. (x 180) B-Routine H&E histologic study ofan analogous area. Lighter staining portions of the central tumor area contain numerous Reed-Sternberg cells (arrows). (x 64) (With a photo-graphic reduction of 3%)

fibrin with FITC-conjugated anti-Fib antibody andrhodamine-conjugated anti-fibronectin antibodyconfirmed these observations.Antibody to immunoglobulins produced surface

staining of small lymphocytes in primary and secon-dary follicles of lymph nodes and spleen. In addition,an extracellular network of material in the reactivefollicles stained positively for immunoglobulin. Thisstaining was finely granular in character, had an over-lapping but not identical distribution to the fibrin de-posits, and did not appear to be the same material inmost cases.

Hodgkin's DiseaseFibrin deposition was seen in all 17 specimens of

Hodgkin's disease (15 cases) examined. All antiserumsto Fib produced two distinct staining patterns: be-tween cells and along collagen fibers. In addition,fibrin deposits were found in areas of tumor necrosis.

In cellular areas, a fine fibrillar staining pattern wasregularly observed around and between cells, aggre-gating focally into coarse, amorphous deposits simi-lar to those found in the centers of reactive lymphoidfollicles, but much more extensive (Figure 2; comparewith Figure 1). Regardless of histologic subtype, thefibrin deposits aggregated in a vaguely nodular pat-tern, corresponding to tumor nodules. Reed-Stern-berg cells were difficult to identify in immunofluores-cence preparations, but, in general, most of the fibrindeposition was related to lymphocytes, rather than toReed-Sternberg cells. Sections stained with hematox-ylin and eosin contained focal amorphous eosino-philic intercellular material that corresponded in dis-tribution to the material that reacted with anti-Fibantiserums (Figure 3).The second pattern of anti-Fib staining consisted

of fine, fibrillar deposits along collagen bundles incases of nodular sclerosis (Figure 2A). Finally, coarse-

AJP * July 1982

FIBRIN DEPOSITS IN HODGKIN'S DISEASE 123

ly granular foci of anti-Fib staining were seen in areasof tumor necrosis, independent of the two stainingpatterns just described.Tumors in the spleen stained similarly to those in

lymph nodes (Figure 4); it was possible to recognizeinvolved areas of spleen at low magnification by thebright, coarse, fibrillar staining for fibrin betweencells or along collagen bundles. All anti-Fib stainingof both involved lymph nodes and spleen was removedby absorption of antiserum with fibrinogen-sepharose.Antibody to fibronectin produced a reticulin and

vascular basement membrane pattern of staining sim-ilar to that seen in reactive lymphoid tissues. Somebut not all of the intercellular fibrillar material thatstained with antibody to fibrin also stained for fibro-nectin; however, the amorphous deposits generallydid not stain or stained much more weakly for fibro-nectin than for fibrin. No intracellular staining wasseen with anti-fibronectin in contrast to results re-ported by others.26 In general, there was less stainingfor fibronectin, but considerably more staining forfibrin, in Hodgkin's-disease-involved areas of spleenor lymph nodes than in normal or reactive lymphoidtissues.

Staining with antiserum to albumin and C3 wasnegative except for a small amount of albumin stain-ing in areas of necrosis. Antiserums to immunoglob-ulins stained the surfaces of some small lymphocytes,particularly in residual follicles. In 1 case with mas-sive amorphous anti-Fib reactive deposits, there wasweak staining of the same material with anti-immu-noglobulin.One case differed from the usual pattern. This was

a spleen extensively involved by a highly inflammatorynodular sclerosing tumor with large areas of necrosis.In addition to the usual fibrillar and amorphous in-tercellular deposits, there was in this tumor a strikingringlike pattern of fibrin deposition at the border be-tween tumor and uninvolved red pulp (Figure 5).Large amorphous fibrin deposits were also present inthe extensive areas of necrosis in this case.

Non-Hodgkin's LymphomasThree of the 6 non-Hodgkin's lymphomas we ex-

amined contained extracellular material that stainedwith antiserums to Fib. All 3 were large-cell lym-phomas: 2 diffuse and 1 nodular histiocytic lym-phoma. Staining took the form of fine intercellularfibrils and scattered coarse deposits. In the nodularlymphoma, the fibrin deposits were confined to thecenters of the nodules. In 1 case with extensive

Figure 3-Routine histologic study of a lymph node involved withHodgkin's disease, nodular sclerosis type, illustrating prominentamorphous eosinophilic intercellular material that corresponds indistribution to the material reacting with the anti-Fib stain in Fig-gures 2 and 4. The arrow indicates an atypical cell. Eosinophilic ma-terial envelopes lymphocytes but not the atypical mononuclear cell.V, vessels. (x400)

sclerosis, there was also bright staining along col-lagen bands. The other 3 cases had either no definitestaining for fibrin or only a few fine intercellularflecks or fibrils.

Fibrin Deposition in Hodgkin's Disease asObserved by Transmission Electron Microscopy

Fibrin was recognized by its characteristic appear-ance and periodicity in 5 of the 9 cases of Hodgkin'sdisease studied (a total of 16 thin sections). In view ofthe small sample taken and its random nature, thisincidence is remarkable and would undoubtedly havebeen substantially higher had more sections beentaken on the 4 putatively negative cases. The distribu-tion of fibrin observed by electron microscopy wasidentical to that described above by immunofluores-cence. In cellular areas, extensive deposits of fibrin

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Figure4-Higher magnification of an involved area from the spleen of a patient with the nodular sclerosis form of Hodgkin'sdisease. A-Immunofluorescence staining with anti-Fib presents a fibrillar pattern. B-The same field, photographed with phase-contrast optics, illustrates the intercellular localization of the fibrillar material. (x 575)

Figure 5-Spleen from an atypical case of nodular sclerosing Hodgkin's disease. A-Immunofluorescence staining with anti-Fib anti-bodies of central, uninvolved splenic red pulp (RP) surrounded by a prominent rim of brightly staining Fib and, more centripetally, by extensivetumor (HD) with prominent intercellular Fib deposits (x 110). B-Similar field with routine histology. Arrows indicate a prominent rim de-marcating the central red pulp (RP) from the more peripheral tumor (HD). This rim corresponded to the rim of Fib seen by immunofluorescenceand included numerous palisading histiocytes. (x 100)

I

IV.i

Q

FIBRIN DEPOSITS IN HODGKIN'S DISEASE 125

a.

Ol~~

Figure 6-Electron micrograph of a lymph node involved by Hodgkin's disease, nodular sclerosis type. Note the prominent intercellular mesh-work of fibrin (dark fibrillar material) between well-preserved small and medium lymphocytes. Some lymphocytes (L) appear to be compressed,constricted, or indented at points of contact with fibrin. (x 7000) (With a photographic reduction of 4%)

were present between inflammatory cells (Figure 6).Fibrin appeared as multiple dense, irregularly orientedstrands closely associated with the surfaces of indi-vidual small and medium lymphocytes, without evi-dence of associated cell injury or tissue necrosis. Inmany instances, fibrin deposits apparently encased,constricted, and deeply invaginated individual lym-phocytes, leading to cytoplasmic and nuclear irregu-larities (Figures 6 and 7). However, fibrin depositsalways remained extracellular; phagocytosis of fibrinwas not observed. Fibrin was not observed adjacentto classical Reed-Sternberg cells; however, somelarge mononuclear cells, corresponding to atypical ormononuclear Reed-Sternberg cells, were envelopedin fibrin deposits.

Fibrin deposits were also associated with both long-spaced (Figure 8) and normal collagen. Fibrin wasparticularly abundant in areas of newly formed col-

lagen where active fibroblasts and myofibroblastswere numerous. Fibrin became progressively lessabundant as collagen fibrils became denser and moremature.

Platelets were not observed in association with anyof the extravascular fibrin deposits here described.

DiscussionIn the present study we observed substantial fibrin

deposits in all 15 cases of Hodgkin's disease studiedby immunofluorescence and in 5 of 9 cases sampledby transmission electron microscopy. With both tech-niques, two patterns of fibrin deposition emerged: 1)intercellular deposits in cellular areas, chiefly associ-ated with nonneoplastic-appearing lymphoid cells,and 2) linear deposits along collagen bundles in areasof sclerosis. In addition, coarse fibrin deposits were

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126 HARRIS ET AL

Figure 7-Higher-magnification electron micrograph of a lymphocyte (L) with associated fibrin deposits from a case similar to that illustratedin Figure 6. Fibrin is closely applied to the cell's plasma membrane. In one focus (arrow) fibrin resides within a deep invagination into the cyto-plasm, though remaining extracellular. (x 14,000) (With a photographic reduction of 4%)

observed in areas of necrosis, presumably a nonspe-

cific finding. Intercellular fibrin deposition was alsoobserved in 3 of 6 cases of non-Hodgkin's lympho-ma; the number of such cases examined was inade-quate to permit any generalization about fibrin depo-sition in relation to histologic type, although all 3positive cases were of the large-cell type.

Previous studies of malignant lymphomas have notspecifically addressed the issue of fibrin deposition.Electron-microscopic studies have focussed largelyon the atypical cells.2729 Two ultrastructural studieswere directed at the extracellular matrix of Hodgkin'sdisease;30-3' both described typical collagen, finely

granular extracellular material, and various types offilaments, and one,3' myofibroblasts in cases of nod-ular sclerosis. Stiller and Katenkamp noted long-spaced collagen and vascular basement membranereduplication in Hodgkin's disease.30 Hiramoto etal'3 described fibrin by immunofluorescence in 2 casesof Hodgkin's disease and in 2 of 3 "lympho-sarcomas." Amorphous extracellular material hasbeen described in non-Hodgkin's lymphomas.32'33Although the nature of the material was not deter-mined by the authors, we interpret the electronmicrographs from 2 reported cases33 to representfibrin.

AJP * July 1982

4 3-

.h's

db

Vol. 108 * No. 1

~ ~~.0 .M !0

Mr-amp, liv-, i ,;. k'il

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it .1-.... .4 .,%. 'n

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Figure 8-Electron micrograph of an area of collagen formation in a lymph node with Hodgkin's disease, nodular sclerosis type. A fibroblast(F) lies adjacent to a collection of wide-spaced collagen decorated with focal dense deposits of fibrin (arrows). (x 13,000) (With a photographicreduction of 4%)

Our findings in Hodgkin's disease have features incommon with guinea pig carcinoma and of humanbreast cancer. 61" These include substantial fibrin de-posits, association of fibrin with new collagen deposi-tion, and gradual disappearance of fibrin with col-lagen maturation. However, the intercellular patternof fibrin deposition in Hodgkin's disease differedfrom that seen in carcinomas, in that, with the excep-tion of one case, fibrin was present throughout the in-volved tissue, rather than being concentrated at thetumor-normal-tissue interface. It may be argued thatthe concept of a tumor-normal-tissue interface is notapplicable to Hodgkin's disease because the "tumor"contains a large number of presumably reactive lym-phocytes intimately admixed with Reed-Sternberg

cells and atypical mononuclear cells. The fibrin de-posits observed in cellular areas were predominantlyassociated with the surfaces of lymphocytes, ratherthan with Reed-Sternberg cells, although atypicalmononuclear cells sometimes had closely associatedfibrin.

Fibrin deposition in tumors presumably resultsfrom extravasation of plasma fibrinogen and its co-agulation in situ. The mechanisms by which this oc-curs are not known, but two possibilities have beenproposed: 1) that the tumor cells produce factorswhich cause fibrinogen extravasation and clotting;and/or 2) that fibrin deposition is part of an immu-nologic reaction to the tumor. In favor of the formerhypothesis is the fact that line 1 and line 10 guinea pig

127

128 HARRIS ET AL AJP * July 1982

bile duct carcinomas, and many other experimentaltumors, secrete both in vivo and in vitro a solublevascular permeability factor and shed procoagulantactivity; acting together, these factors can accountfor both fibrinogen extravasation and coagulation.5'6On the other hand, fibrin may be deposited in certainimmunologic reactions. Fibrin deposition is a promi-nent feature of classic delayed hypersensitivity reac-tions, being responsible for the induration that ischaracteristic of these lesions.2"'34 Recent studieshave Shown that macrophages activated by lympho-cytes, but apparently not lymphocytes themselves,develop substantial increases in cell-associated pro-coagulant activity that may account for these depos-its.34 Fibrin is also deposited in antibody-mediated le-sions such as the Arthus reaction and in manyvasculitides.34

In the case of Hodgkin's disease, the pathogenesisof fibrin deposition has not been investigated. Al-though occasionally observed in association withmononuclear Reed-Sternberg cells, fibrin was pri-marily associated with the surfaces of lymphocytes,cells not so far reported to initiate clotting. There-fore, if tumor-cell-secreted mediators were respon-sible for the fibrin deposits observed, we must assumethat conditions for fibrin deposition were suboptimalon the presumed tumor (Reed-Sternberg) cells, thatthe mediators secreted became effective only afterdiffusing away from such cells, or that Reed-Stern-berg cells, like many other tumor cells, secrete plas-minogen activators that generate plasmin and lyseany cell-associated fibrin that forms.

The intercellular pattern of fibrin deposition seenin Hodgkin's disease is also unlike that observed indelayed hypersensitivity reactions, where cellularareas are spared and fibrin is confined to the intervas-cular space between dermal collagen bundles. It isalso unlike that observed in antigen-antibody com-plex reactions where fibrin deposits are associatedprimarily with blood vessels. The pattern of fibrindeposition in Hodgkin's disease most closely resem-bles that seen in reactive lymphoid follicles. How-ever, fibrin deposition in reactive follicles, thoughreported,35 has not been widely appreciated, and itsmechanism is unknown.

Fibrin deposits may have a significant role in tu-mor growth and metastasis. In guinea pig hepatocar-cinomas and in human breast carcinomas, fibrin formsa barrier that apparently isolates tumor clumps fromsurrounding host inflammatory cells. If fibrin func-tions as a "cocoon" in Hodgkin's disease, it does soby isolating individual lymphocytes, not the Reed-Sternberg cells presumed to represent the malignantelement. Alternatively, both fibrin and fibronectin

have been implicated in angiogenesis and fibroplasia,the principle events of wound healing.16'17'2236 Al-though the mechanisms involved are poorly under-stood, it is known that soluble degradation productsof both proteins have a range of relevant biologic ac-tivities.36-38 The new vessel formation that is regular-ly observed in Hodgkin's disease and many other tu-mors may, therefore, be in part secondary to deposi-tion of fibrin and/or fibronectin or to their subse-quent degradation. The intimate association here ob-served between fibrin and fibronectin deposits andnew collagen argues in favor of such a relationship.

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