Granuloma annulare in patients with malignantlymphoma: Clinicopathologic study of thirteennew casesSarah Kay Barksdale, MD,* Charles Perniciaro, MD,a Kevin C. Halling, MD,band John G. Strickler, MDb Rochester, Minnesota

Background: Reports of necrobiotic granulomas or granulomaannularein patients withma­lignant lymphoma are rare.Objective: Our intentwasto determineany uniqueclinical or histopathologic features in pa­tients with granuloma annulare and lymphoma.Methods: Wereviewed the medical recordsand biopsy material from 13patientswith gran­uloma annulareand lymphoma.Results:Threepatients had Hodgkin's disease and 10 had non-Hodgkin's lymphoma. Thegranulomaannulare lesions showed typicalhistopathologic features. However, the clinicalpattern wasfrequently atypical, withpainfullesions in unusuallocations includingthe palmsandsoles. Threepatients displayed granulomatous inflammation in noncutaneous sites, eitherwithin the malignant lymphoma or in uninvolved tissues, and all three had atypicalclinicalpresentations of granuloma annulare.Conclusion: Granuloma annularewithatypicalclinical presentations may beassociated withan underlying hematopoietic malignancy and may be part of a generalized granulomatousreaction to malignant lymphoma.(J AM ACAD DERMATOL 1994;31:42-8.)

Granulomatous inflammation associated withmalignant lymphoma is a well-characterized phe­nomenon. This association is best described forHodgkin's disease, in which epithelioid granulomasfrequently occur in the lymph nodes, spleen, bonemarrow, and liver.1-4 Granulomatous responseshavealso been described in association with non­Hodgkin's lymphoma (NHL).5-7 The biologic rela­tion between granulomatous inflammation and ma­lignancy is a matter of speculation. Granulomasmay represent a host response to tumor, as issuggested by reports that their presence confers amore favorable prognosiscompared with that of pa­tients with tumors of the same stage and type but

From the Departmentof Dermatology' and Division ofAnatomicPa­thology," Mayo ClinicandMayo Foundation.

Acceptedfor publication 000. 18, 1993.

Reprint requests: C. Perniciaro, MD, Mayo Clinicjacksonville, 4500San Pablo Rd., Jacksonville, FL 32224.

*Visiting clinician at the Department of Dermatology. Now with theLaboratoryofPathology, NationalCancerInstitute,National Insti­tutes of Health, Bethesda, Md.

Copyright® 1994by the American Academy of Dermatology, Inc.

0190-9622/94 $3.00+ 0 16/1/53753

42

without granulomas.v 4, 8 Alternatively, granuloma­tous inflammation in association with malignantlymphoma may be an incidental observation or anaberrant immunologic response in patients with adisordered immune system either resulting from orperhaps predisposing to lymphoma. Studies in whichgranulomatous inflammation did not confer an im­proved prognosis for malignant lymphoma supportthese two alternative views.9-11 In some cases theremay be a histologiccoexistence of two processes suchas malignant lymphoma and sarcoidosis, althoughthe assessment of such reports is difficultbecause thepresence of sarcoidosis is often not easy to veri­fy.12, 13 From a practical standpoint the recognitionof granulomatous inflammation in malignant lym­phoma is important because it can obscure the his­tologic interpretation of specimens for either diag­nosis or staging purposes.

Infrequently, cutaneous granulomatous lesionshave been reported in association with malignantlymphomas, both primary cutaneous lymphomasand types that almost never appear in the skin. Manyreported cases show sarcoid-type granulomatous in­flammation14-17; some of these present as granulo-

Journal of the American Academy of DermatologyVolume 31, Number 1

matous rosacea.l'' The unusual skin disorder gran­ulomatous slack skin disease has been associatedwith Hodgkin'sdiseaseand withT-celllymphoma. II

A granulomatous variant of mycosis fungoides alsoexists.B-1O Granulomatous panniculitis has been de­scribed in subcutaneous T-cell lymphomas andHodgkin's disease. 19-23 Extravascular necrotizinggranulomas-" and nonspecific necrobiotic granulo­mas25in patients with lymphoproliferative disordershave also been reported.

The lesions of granuloma annulare (GA) aremostoften locatedon the dorsalsurfacesof the hands andfeet,26 Histologically, GA is characterizedby focaldegeneration of dermal collagensurroundedby aninfiltrate of mainly histiocytes with some lympho­cytes.The deposition of acidmucopolysaccharides isprominent in the majority of cases. In a series of 207cases-? several histologic subtypes of GA weredescribed, including infiltrative (71%), palisading(26%),and epithelioid patterns (3%).Unusualclini­copathologic forms exist,includingperforating, gen­eralized, and subcutaneous varieties.P The patho­genesis of GA is unknown, but immunologic studiesimplicatea cell-mediatedimmune response, and de­layed hypersensitivity skin tests can produce histo­pathologic lesions identical to those of GA,28

Only a fewcase reportshave described GA in pa­tients with malignant lymphoma.29-3 I In this reportwe describe 13 additional patients with GA andmalignant lymphoma. Our intent was to determineany unique features of these patients. In each casethe clinicalhistorywasobtained,the pathologic fea­tures were reviewed, and the treatment and fol­low-up information, when available, were deter­mined.

MATERIAL AND METHODS

All patients were seen and received diagnoses at theMayoClinicfrom 1976to 1992. Byusinga computerizeddatabase, 12,415 patients with a diagnosis of malignantlymphoma (Hodgkin'sdisease, NHL, mycosis fungoides,or Sezary syndrome) were cross-referenced with 1355patientswithGA. A subsetof 16 patientswithbothlym­phoma and GA was established. The medical records ofthese 16patientswerereviewed for pertinent clinical andpathologic data.

Histologic sections from the original skin biopsy spec­imensofGA lesions wereevaluated in all but onepatient(case 9). The diagnosis of GA was made on the basisofparaffin-embedded sections stainedwithhematoxylin andeosin. Specialstains for organisms (Fite and periodic ac­id-Schiff) and acid mucopolysaccharides (alcian blue)

Barksdale et al. 43

wereperformed inallcases. Thehistopathologic featuresweresubclassified according tocriteriadescribed by Urn­bert and Winkelmann.e? Three cases were eliminatedfrom the studywhen our review of the skin biopsy spec­imens disclosed histopathologic features inconsistent withGA. One biopsy specimen from an excluded patientshowed a palisading granuloma most consistent with acutaneous extravascular necrotizing granuloma." Theother two excluded patients had unusual epithelioidgranulomas that lacked mucin deposition, necrobiosis, orother features of GA. A final group of 13 patients wasdefined.

The diagnoses ofNHL were made with the standardcriteriaoftheworking formulation. Earlier cases that hadbeenclassified according to the Rappaport scheme werereclassified according to working formulation criteria.32

Thediagnosis ofHodgkin's disease wasmadebystandardhistologic criteria.P Diagnoses were madefrom formalin­fixed, paraffin-embedded sections stained withhematox­ylinandeosin. Weobtained andreviewed lymph nodebi­opsy specimens in 11 cases, and bone marrow biopsyspecimens were also reviewed in three of thesecases. Incase5 an absolute lymphocyte countof5400 cells/J.LI es­tablished the diagnosis of chronic lymphocytic leukemia(CLL) inconjunction witha lymph nodebiopsy specimenthat showed smalllymphocytic lymphoma. In case6 thediagnosis of CLL was based on a bonemarrow biopsyspecimen that displayed focal aggregates of smalllym­phoidcells and peripheral blood flow cytometry immu­nophenotyping, which confirmed a clonal B-cell popula­tion. In case 13 the diagnosis of Sezary syndrome wasbasedon a peripheral blood smearthat showed a leuko­cyte countof7300cellsI J.Ll, with33% circulating Sezarycells. An electron micrograph ofthebuffy coatconfirmedthe presence of Sezarycells.

In selected cases immunoperoxidase studies wereper­formed on paraffin-embedded sections by means of astandard streptavidin-biotin technique. The followingantibodies were used: L26 (CD20, Dako, Carpenteria,Calif.), UCHL-l (CD45RO, Dako), Ber-H2 (CD30,Dako), Leu-Ml (CDIS, Becton Dickinson, San Jose,Calif.), andleukocytecommon antigen (C045RB,Dako).Polyclonal CD3 (Dako) staining was performed on par­affin-embedded sections bya modification ofthestandardprocedure.l" A B-cell phenotype was inferred if the neo­plastic cells expressed CD20; a T-cell phenotype wasin­ferred if the cells expressed CD45RO or CD3. TheReed-Sternberg cells in Hodgkin's disease expressedCD15 and CD30.

RESULTS

Age and sex

Eight of the patientswerewomen and five weremen.Theyrangedin agefrom20to 75years(mean,60.9 years) at diagnosis of GA.

44 Barksdale et al.Journal of the American Academy of Dermatology

July 1994

Fig. 1. Granulomatous infiltrates in noncutaneous sites from patients with malignant lym­phomas. A, Case 2. Noncaseating granulomas in bone marrow. B, Case 4. Microgranulomasin lymph node involved with small lymphocytic lymphoma with plasmacytoid features. C,Case 11. Epithelioid granuloma in liver. (Hematoxylin-eosin stain; X205.)

Malignant lymphoma

The histopathologic features of the malignantlymphomas were diverse. Three patients had nodu­lar sclerosing Hodgkin's disease (cases 1,2, and 3).The majority of the patients had B-celllymphomasof various types. Three patients had small lympho­cytic lymphomas (or CLL) (cases 4, 5, and 6). Threepatients had follicular lymphomas (cases 7, 8, and9), and one of these (case 9) showed progression todiffuse disease. One patient (case 10) had a lym­phoma that is best classified according to the work­ing formulation as a diffuse, small cleaved cell lym­phoma, but it can also be considered as a lympho­cytic lymphoma of intermediate differentiation or

mantle cell lymphoma.P Patient 11 had a diffuselarge-cell lymphoma of B-cell phenotype (CD20­positive, CD45RO- and CD3-negative). The lym­phoma in case 12was a diffuse large-cell lymphomaby working formulation criteria, but it had morpho­logic and immunohistochemical features (CD30­positive; CD20-, CD45RO-, and CD3-negative) ofan anaplastic large-cell lymphoma, null cell type.One patient had Sezary syndrome (case 13).

Three patients had granulomatous inflammationin sites other than the skin (Fig. 1). In patient 2, a75-year-old man with Hodgkin's disease, noncaseat­ing granulomas were found in the bone marrow thatwas otherwise uninvolved with lymphoma (Fig. 1,

Journal of the American Academy of DermatologyVolume 31, Number I Barksdale et al. 45

Fig. 2. Case 5. Histopathologic features of GA. Cutaneous biopsy specimen from dorsumof hand shows palisading pattern of histiocytes around central area of necrobiotic collagenand mucin . (Hematoxylin-eosin stain ; X55.)

A ). In case 4 microgranulomas were observed in aleft supraclavicular lymph node that was involvedwith small lymphocytic lymphoma (Fig. 1, B). Incase 11 the lymphoma cells were admixed with ep­ithelioid histiocytes. A cervical lymph node biopsyspecimen showed confluent granulomatous lymph­adenitis without necrosis that was considered to beconsistent with sarcoidosis. An epithelioid histiocyteproliferation was also observed in the liver(Fig. 1,C)and spleen. In each of these three patients results oftissue cultures and special stains for bacteria, myco­bacteria, and fungi were negat ive.

Granuloma annulare

Seven patients had asymptomatic lesions of 4months'to 1.5 years' duration (cases 1,3,5,6,7,8,and 9). The onset of the skin lesions was from 5 yearsbefore to 27 years after the diagnosis of malignantlymphoma. In these asymptomatic cases lesionswere most frequently on the hands, arms, and legs,but a more generalized eruption was present in fourpatients (cases 1, 6, 7, and 9). ane patient hadlesions on the face (case 6). The clinical appearanceof these lesions was generally typical for GA.

Five patients had painful lesions of a few days' to2 years' duration (cases 4, 10, 11, 12, and 13). Theskin lesions appeared from 3 years before to 2 yearsafter the diagnosis of malignant lymphoma. In onepatient (case 13) the lesions were pruritic. The

lesions in these five patients were mainly on the ex­tremities, including the palms and sales; more gen­eralized lesions occurred in two patients (cases 12and 13). The clinical appearance in the painful caseswas described as erythematous nodules and papules;in two patients this resembled erythema nodosum.Patient 4 had macular erythema without nodules orpapules.

Four of the 13 patients had lesions on the palms,the soles, or the glabrous surfaces of the fingers. Inthree the lesions were painful (patients 11, 12, and13). In one patient with a localized eruption (case 2),the symptoms were not mentioned. These patientshad skin lesions 3 years to 4 months before the di­agnosis of lymphoma was made.

The three patients who had granulomatous in­flammation within thei r lymphoma or in distantnoncutaneous sites (cases 2, 4, and 11) all had atyp­ical clinical presentations of GA.

Histopathologic findings in skin biopsyspecimens

Twelve patients had a total of 19 skin biopsyspecimens that demonstrated typical histologic fea­tures of GA. Changes were limited to the dermis inall cases. The most common finding (noted in 15specimens from nine patients [cases 1through 6, and8, 12, and 13]) was an area of necrobiotic collagensurrounded by a palisading array ofhistiocytes (Fig.

46 Barksdale et al.Journal of the American Academy of Dermatology

July 1994

Table I. Clinical and histologic features of patients with GA and lymphoma

Temporal relationCase Age Symptoms to malignant lymphoma Malignant Follow-up/AgeNo. Sex (yr)* Site ofGA olGA diagnosis lymphoma subtype (yr)

1 F 60 Arms and legs Asymptomatic 27 yr after NSHD Alive/622t M 75 Palms, fingers, Not stated 4 mo before NSHD Dead/76

soles offeet3 M 20 Dorsum of Asymptomatic 3Y2 yr after NSHD Alive/20

hand4t M 75 Fingers Painful erythema 1 yr before SL/CLL Alive/775 M 68 Dorsum of Asymptomatic 5 yr before SLjCLL Alivej75

hand6t F 68 Knees, face, Asymptomatic 3 mo after SL/CLL Alive/70

arms, legs,trunk

7 F 64 Chest, trunk, Asymptomatic 11 rna before Follicular SC Dead/65arms,thighs

8 M 66 Forearm, Asymptomatic 8 yr after Follicular mixed Deadj69helix

9 F 59 Arms, legs, Asymptomatic 11 yr after Follicular LC Alive/66back

lOt F 52 Arms and legs Painful, warm 2 yr after Diffuse SC Alive/56llt F 66 Fingertips Painful 3 yr before Diffuse LC Dead/71l2t F 73 Fingers, Painful 1 yr before Diffuse LC Dead/75

palms,sales, arms,legs, backof head

l3t F 46 Back, flank, Painful, pruritic 2 yr before Sezarysyndrome Dead/50legs, arms,palms

14* F 60 Dorsa of Painful 3 yr after NSHDhands

15* M 25 Neck, hands, Asymptomatic 6 yr after NSHDarms

l6§ M 40 Trunk, limbs Not stated 7 yr after HD (seminoma)1711 M 59 Face, scalp, Not stated 5 yr after Mycosis fungoides

trunk

HD, Hodgkin'sdiseasenot further subclassified; LC, largecell;NSHD, nodularsclerosing Hodgkin'sdisease; SC, smallcleaved; SL, smalilympho-cytic lymphoma.*Age at diagnosis of GA.tAtypical clinical presentation of GA.:j:Datafrom Schwartz et aU'§Data from Harman.P'IlData from Garde et al.29

2). Within the areas of necrobiosis was increased with abundant mucin. Special stains for organismsdeposition of acid mucopolysaccharides, as demon- werenegative in all cases.The clinical and histologicstrated by positivestainingwith alcian blue. An in- features are summarized in Table 1.filtrating pattern with histiocytes and focal necrobi-

DISCUSSIONosis was seen in patients 7 and 12. A second biopsyspecimen from patient 6 showed an epithelioidpat- Previous reports have suggested that cutaneoustern with prominent acid mucopolysaccharide dep- epithelioid granulomas may be the first manifesta-osition. The final biopsy specimen (case 11) dis- tion of an underlying malignant lymphoma IS, 18 andplayed a mixed infiltrating and epithelioid pattern that granulomatous inflammation may be admixed

Journal of the AmericanAcademyof DermatologyVolume 31, Number 1

with lymphoid malignancies of the skin, obscuringtheir true nature.v 22, 23 However, the occurrence inthe same patient of malignant lymphoma and GAhas been reported infrequently.

The clinicopathologic features of the previouslyreported cases of GA in patients with malignantlymphoma are summarized in Table I (cases 14 to17).29-31 Three occurred in patients withHodgkin'sdisease without cutaneous involvement. In thesethree patients GA developed 3 to 7 years after thediagnosis ofand therapyfor Hodgkin's disease. Thefourth caseoccurredin a patient withmycosis fun­goides after a 2-year course of chemotherapy andradiation.j? In this last patient,a GA pattern devel­oped within the patient's mycosis fungoides lesion.

Wedescribed 13additional patients withGAandmalignant lymphoma. Our data cannot be used toextrapolate more than a coincidental relation be­tweenGA and lymphoma because only a verysmallnumberof cases withboth diagnoses were retrievedfrom the database of a referral center with manypatients with these diseases. However, wedid noteseveral interesting features within this series. As inthe previously reported cases, the histopathologicfeatures of the GA lesions were typical. However,the clinical featuresofGA wereatypical inmanyofthese patients. Painful lesions or lesions in unusuallocations (or both), including the palms, soles, andface,occurred in seven of the 13patients. Thisfind­ing isremarkable when compared witha studyof26patientswithgeneralized GA byDicken et al.36 whohad no patients with involvement of the palms orsoles, onepatientwith a lesion on the face, onewithtenderness, and four with pruritus. Noneof the pa­tients in their study had malignant lymphoma. Infive of our seven patients with atypical clinical fea­tures skin lesions developed before the diagnosis oflymphoma. The interval between diagnosis of GAand lymphoma ranged from 4 months to 3 years.Overall, the time between the diagnosis of GA andlymphoma was shorter in the group with atypicalclinical lesions than in the patients withmore typi­calclinical features ofGA.Twoofthecases reportedpreviously in the literaturealso had atypical clinicalfeatures (Table I); onepatient with Hodgkin's dis­easehad painfullesions.'! and the patientwithmy­cosis fungoides had lesions on the face. 29

We found that three patients who had granulo­matousinflammation elsewhere, whether within thelymphoma or in a remotesite, all had atypical clin­icallesions of GA. Each of thesepatients had a dif-

Barksdale et al. 47

ferenttypeofmalignant lymphoma: Hodgkin's dis­ease, diffuse large-cell lymphoma of B-cell pheno­type, and small lymphocytic lymphoma withplasmacytoid features. Hodgkin's disease and smalllymphocytic lymphoma have been associated withproliferations of epithelioid histiocytes.l- 7Suchpa­tients maybe demonstrating a generalized granulo­matous response related to a lymphoid malignancy,and atypical GA may manifest as part of thatresponse. Lymphoma was notpresent in any ofthecutaneous biopsy specimens fromthese patients, soit seems unlikely that an immunologic reactiondirected toward tumor cells located in the dennisunderlies the GA.

Our patients demonstrated a wide variety of his­tologic subtypes oflymphoma, andthereseems tobeno relation between a particular type of malignantlymphoma and GA. Only one of the patients hadSezarysyndrome, andonly this patient hadpruritusas a symptom ofGA.Thepreviously reported casesdemonstrated an excess number ofHodgkin's dis­ease, but this islikely a reporting bias resulting fromthe long-standing interest ingranulomatous inflam­mation in Hodgkin's disease.

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