Acute-Onset, Painful Acral Granuloma Annulare a Report of 4 Cases and a Discussion of the Clinical and Histologic Spectrum of the Disease

Home , Granuloma, Granuloma annulare

OBSERVATION Acute-Onset, Painful Acral Granuloma Annulare A Report of 4 Cases and a Discussion of the Clinical and Histologic Spectrum of the Disease

Nicole Vessels Brey, MD; Janine Malone, MD; Jeffrey P. Callen, MD

Background: Granuloma annulare is a benign cutane- with acute-onset, painful acral granuloma annulare. ous inflammatory disease of unknown etiology most commonly presenting on the hands and feet and consisting Conclusions: It is possible for granuloma annulare to pre- of asymptomatic to mildly pruritic, flesh-colored to ery- sent as a painful eruption with an acute onset and an acral thematous annular plaques. To our knowledge, an acute- distribution. Biopsy results are a crucial factor when es- onset, painful acral eruption has not been previously tablishing the diagnosis of this atypical clinical presenta- recognized. tion of granuloma annulare.

Observations: We report 4 patients who presented Arch Dermatol. 2006;142:49-54

RANULOMA ANNULARE has been reported to range from 3.5% to (GA) is a benign cutane- 40%.3 Romero and Kantor3 found eosin- ous inflammatory dis- ophils to be predominantly perivascular ease of unknown etiol- when present and more often associated ogy most commonly with a palisaded pattern and necrobiosis. presentingG on the hands and feet.1 The erup- We report 4 patients with an atypical tion most often consists of asymptomatic clinical presentation characterized by an to mildly pruritic flesh-colored to erythem- acute onset, acral location, and pain with atous annular plaques. Spontaneous reso- emphasis on the importance of the clini- lution usually occurs within 2 years of ini- copathologic correlation in establishing the tial presentation; however, recurrence at the correct diagnosis. original site approaches 40%.1 Five clinical morphologic patterns of REPORT OF CASES GA have been recognized: localized, generalized, perforating, subcutaneous, and patch type. Histopathologically, local- OBSERVATIONS ized GA consists of foci of granuloma- Table 1 summarizes the clinical charac- tous inflammation and collagen alter- teristics of 4 women with an unusual pre- ation in the upper to middle dermis. There sentation of GA (also see Figure 1). is an infiltration of histiocytes, lymphocytes, and occasional giant cells with pe- Case 1 ripheral palisading of the infiltrate around degenerative collagen bundles. Deposi- Patient 1 was a 42-year-old, previously tion of acid mucopolysaccharides on and healthy woman who awoke with a painful between collagen fibers is also character- rash on her hands, legs, and feet. Five days istic. Dabski and Winkelmann2 found this later, she developed arthralgias of the knees classic pattern in only 25% of original bi- and ankles. Her only medications were mul- opsy specimens reviewed. Generalized tivitamins and supplemental calcium. The cases typically present with an interstitial patient’s condition was initially evaluated histiocytic infiltrate with less apparent col- by a rheumatologist and an expert in in- Author Affiliations: Division of lagen alteration. In their review, 53% of fectious diseases who noted an elevated Dermatology, Department of generalized GA lesions displayed some erythrocyte sedimentation rate of 56 with Medicine, School of Medicine, form of collagen necrobiosis, whereas 79% otherwise unremarkable findings from labo- University of Louisville, of localized GA cases exhibited collagen ratory evaluations for cryoglobulins, anti- Louisville, Ky. alteration. The prevalence of eosinophils neutrophilic cytoplasmic antibody, anti-

(REPRINTED) ARCH DERMATOL/ VOL 142, JAN 2006 WWW.ARCHDERMATOL.COM 49

Patient No./ Duration/ Associated Age, y Location Symptoms Medications Laboratory Treatment Response 1/42 Hands, legs, feet 2 Months/arthralgias Multivitamins, calcium Qualitative Hydroxychloroquine sulfate 100% Reduction of of knees and supplementation cryofibrinogen,* RF, (200 mg QD) cutaneous ankles ANA, anti-Ro/-SSA, disease and anti-La/-SSB, ANCA, arthritic anticardiolipin antibody, symptoms anti-dsDNA antibody, CK, ESR, cryoglobulins, CRP, hepatitis C antibody, G6PD, ␤-2 glycoprotein 1 antibody 2/50 Lateral and dorsal 3 Months/none Montelukast sodium, RF,* ESR, ACE, CMP, Intralesional triamcinolone 100% Reduction hands† fexofenadine SPEP, CXR acetonide (3 mg/mL), with continued hydrochloride, fluticasone propionate pain in fingertips amitriptyline cream, hydrochloride, lisinopril, nicotinamide–folic fluticasone propionate acid–zinc oxide inhaler, multivitamins, combination (750 calcium supplementation mg-500 µg-25 mg, BID) 3/48 Dorsal and marginal 1 Week/diffuse Conjugated estrogens ANA (1:80),* ESR, Hydroxychloroquine sulfate 100% Reduction of hands, wrists, arthralgias hepatitis C antibody, (200 mg BID), cutaneous upper and lower SPEP, ANCA, hydrocortisone disease and extremities, trunk, anti-Ro/-SSA, acetate/pramoxine, arthritic occipital scalp anti-La/-SSB, CMP hydrochloride lotion symptoms 4/65 Upper and lower 2 Weeks/none Lisinopril, amlodipine NA 2-Week 40-mg prednisone 90% Reduction of palms besylate, atorvastatin taper, topical cutaneous calcium, zolpidem betamethasone disease and tartrate, conjugated diproprionate ointment arthritic estrogens/ symptoms medroxyprogesterone

Abbreviations: ACE, angiotensin-converting enzyme; ANA, antinuclear antibody; ANCA, antineutrophilic cytoplasmic antibody; BID, twice daily; CK, creatine kinase; CMP, complete metabolic profile; CRP, C-reactive protein; CXR, chest x-ray film; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; G6PD, glucose 6-phosphate dehydrogenase; NA, not available; QD, daily; RF, rheumatoid factor; SPEP, serum protein electrophoresis. *Abnormal laboratory value. †See Figure 1.

She was treated with oral colchicine and valdecoxib, which improved her arthralgias, but she continued to develop cutaneous lesions. Findings from biopsies performed at another institution had been interpreted as demonstrating an occlusive vasculopathy with dermal necrosis, and Dego disease was strongly suggested to be the differential diagnosis. She was subsequently referred to our practice (J.P.C.). Physical examination revealed tender, erythematous, annular plaques on her hands with an erythematous, firm, dermal nodule on her toe and postinflamma- tory pigmentary alteration involving her legs (Figure 2 and Figure 3). Findings from repeated laboratory tests revealed a posi- tive qualitative cryofibrinogen on 1 occasion. Results from all other laboratory testing was either in the reference range or negative, including findings for rheumatoid factor, antinuclear antibody, anti-Ro/-SSA, anti-La/-SSB antibodies, antineutrophilic cytoplasmic antibody, anticardiolipin antibody, anti–double-stranded DNA antibody, creatine kinase, erythrocyte sedimentation rate, cryoglobulins, C-reactive protein, hepatitis C antibody, glu- Figure 1. Patient 2: tender, erythematous plaque on the distal fourth digit. cose 6-phosphate dehydrogenase, and ␤-2 glycoprotein cardiolipin antibodies, factor V Leiden mutation, hepatitis 1 antibody. B serology, rheumatoid factor, rapid plasma reagin, Lyme The initial biopsy results from the patient’s left thigh disease titers, urinalysis, and complete metabolic profile. were reviewed. Irregular epidermal acanthosis, spongio-

(REPRINTED) ARCH DERMATOL/ VOL 142, JAN 2006 WWW.ARCHDERMATOL.COM 50

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Figure 4. Patient 1: mononuclear and multinucleate histiocytes in an interstitial array surround a zone of incomplete collagenolysis (hematoxylin-eosin, original magnification ϫ100).

Figure 2. Patient 1: tender, erythematous annular plaque on the palm.

Figure 5. Patient 1: mononuclear and multinucleate histiocytes in an interstitial array (hematoxylin-eosin, original magnification ϫ200).

of fibrin deposition in a vessel lumina to suggest a vas- culitic process. Repeated biopsy specimens were subsequently ob- tained from the patient’s left second toe, finger, and palm. Results of the biopsy of the toe showed irregular epidermal acanthosis and an underlying dermis with a super- ficial and deep perivascular and interstitial lymphohis- tiocytic infiltrate. Histiocytes seemed to palisade around zones of necrobiotic collagen (Figure 4). There was no definitive evidence of vascular damage. A colloidal iron stain demonstrated increased mucin in the areas of necrobiosis. Results from the biopsy (Figure 5) of her left second finger revealed an interstitial histiocytic infiltrate in the upper and middle reticular dermis admixed with a perivascular lymphocytic infiltrate with interstitial mucin deposition on colloidal iron staining. The third Figure 3. Patient 1: tender, erythematous annular plaques on the palm. biopsy specimen showed a perivascular and interstitial infiltrate composed of histiocytes, lymphocytes, and gi- sis, and focal parakeratosis were noted, overlying a broad ant cells. The histiocytes seemed to focally palisade around zone of necrobiosis with scattered neutrophils sur- areas of mild necrobiosis (Figure 6). Vascular damage rounded by a palisaded infiltrate of histiocytes. A peri- was not appreciated, and interstitial mucin deposition was vascular and periappendageal lymphocytic infiltrate was seen on a colloidal iron stain. Periodic acid–Schiff stain- also noted; however, there was only a focal suggestion ing was negative for pathogenic fungi in all of the bi-

(REPRINTED) ARCH DERMATOL/ VOL 142, JAN 2006 WWW.ARCHDERMATOL.COM 51

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 from a histologic standpoint, although the diffuse interstitial pattern often exhibits numerous eosinophils, few to absent giant cells, and scant mucin deposition, in con- trast to conditions found in GA.4-8 The palisaded pattern, with the formation of basophilic necrobiotic zones containing neutrophils and neutrophilic debris with variable vascular fibrin deposition (or so-called Churg- Strauss granuloma), may more closely mimic GA histo- logically.8 The diffuse interstitial pattern was not seen in our patients’ biopsy specimens, nor did their clinical presentation reveal the intertriginous and symmetrically dis- tributed lesions typically noted in interstitial granulomatous dermatitis and other related disorders. Although fibrin deposition and perivascular neutrophils were seen in the biopsy findings from patient 1, overt changes of vasculitis were not seen, and these findings have been Figure 6. Patient 1: a palisading granuloma with incomplete collagenolysis reported in patients with GA. In addition, the negative fills the reticular dermis in this fragment of acral skin (hematoxylin-eosin, original magnification ϫ40). findings from serologic studies in our patients and the absence of clinical findings to substantiate a diagnosis of autoimmune disease would further refute one of the im- opsy specimens. These findings were felt to be histo- munologically mediated conditions mimicking GA. pathologically consistent with a diagnosis of GA. Given the rapid progression of arthritic symptoms in The patient’s cutaneous disease and arthralgias re- our third patient, we considered multicentric reticulo- solved within 4 weeks after initiating treatment with 200 histiocytosis in her differential diagnosis; however, the mg of oral hydroxychloroquine sulfate twice daily. Af- patient did not develop mucosal involvement, and her ter 10 months of successful therapy, the patient decided biopsy results did not reveal findings consistent with that to discontinue treatment in October 2004. diagnosis.9 An interstitial granulomatous drug reaction may also COMMENT mimic GA and has been attributed to angiotensin- converting enzyme inhibitors, calcium channel blockers, Granuloma annulare may clinically mimic lichen planus, ␤-blockers, antihistamines, anticonvulsants, antidepres- insect bites, sarcoidosis, annular elastolytic giant cell granu- sants, and lipid-lowering agents.10 Patients with intersti- loma, foreign body granuloma, erythema multiforme, and tial granulomatous drug reactions present with intertrigi- acute febrile neutrophilic dermatosis. Histopathologi- nous erythematous to violaceous annular plaques, although cally, GA may be included in the spectrum of other inter- papules have also been reported.10,11 Biopsy findings from stitial or palisading granulomatous dermatitides (Table 2), these patients resemble a GA pattern or a GA-like pattern including interstitial granulomatous dermatitis with ar- but may be distinguished from other interstitial granulo- thritis (cord and plaque types), interstitial granuloma- matous dermatitides by the presence of vacuolar inter- tous drug reaction, annular elastolytic giant cell granu- face changes, focal basilar and suprabasilar dyskeratosis, loma, necrobiosis lipoidica diabeticorum, cutaneous absent vasculopathic changes, and variable lymphoid atypia extravascular necrobiotic granuloma, rheumatoid nod- and mucin deposition. Although patients 1 and 2 had been ule, sarcoidosis, and infectious granulomata. A clinico- taking an angiotensin-converting enzyme inhibitor, they pathologic correlation is essential to establish a final di- did not have intertriginous involvement, and findings from agnosis given the substantial overlap in histopathologic their biopsies did not demonstrate vacuolar changes and features of the various granulomatous dermatitides. lymphoid atypia. Patients 1 and 3 presented with arthralgias, which in- Annular elastolytic giant cell granuloma is character- creased our concern that their disease might represent ized by annular erythematous plaques with hypopig- an early manifestation of an autoimmune disease. A va- mented centers on sun-damaged skin of the face, neck, or riety of clinical presentations, including papules, plaques, other exposed areas.12 There have also been reports9 of or linear cords, often with a bilateral and symmetrical dis- papular lesions occurring on nonexposed skin. The pres- tribution, have been reported under a variety of moni- ence of elastolysis with dermal elastic fibers within the cy- kers, including interstitial granulomatous dermatitis with toplasm of histiocytes and the absence of collagen necro- arthritis, Churg-Strauss granuloma, palisaded neutro- biosis and mucin are the primary features that distinguish philic and granulomatous dermatitis, rheumatoid pap- annular elastolytic giant cell granuloma from GA. Al- ule or vasculitis, and, more recently, interstitial granu- though there was evidence of focal elastophagocytosis in lomatous dermatitis with plaques.4-8 All of these conditions 1 patient, it was accompanied by collagen necrobiosis and may clinically mimic generalized GA and are to be con- mucin deposition, which are generally not observed in pa- sidered manifestations of a number of immunologically tients with annular elastolytic giant cell granuloma.12,13 mediated diseases, including, but not limited to, rheu- Also included in the differential diagnosis of palisad- matoid arthritis, collagen vascular disease, Wegener granu- ing granulomas are necrobiosis lipoidica, rheumatoid nod- lomatosis, inflammatory bowel disease, and lymphopro- ules, and cutaneous sarcoidosis. The presence of plasma liferative disorders. These conditions may also mimic GA cells, increased numbers of giant cells, less mucin depo-

(REPRINTED) ARCH DERMATOL/ VOL 142, JAN 2006 WWW.ARCHDERMATOL.COM 52

Palisaded Annular Interstitial Neutrophilic and Interstitial Elastolytic Granuloma Granulomatous Granulomatous Multicentric Granulomatous Giant Cell Necrobiosis Rheumatoid Feature Annulare Dermatitis Dermatitis Reticulohistiocytosis Drug Reaction Granuloma Lipoidica Nodules Sarcoidosis Collagen necrobiosis ϩϩϩ; Early stage, − ϩ − ϩϩ − fully developed, final stage Mucin ϩ ± ±; Fully developed, − ϩ −± − − final stage Fibrin ± − ϩ; Fully − ϩ −−ϩ ± developed, final stage Vasculitis − − ϩ; Early stage − − − − − − Elastophagocytosis ± − − − ϩϩ−−− Histiocytes ϩϩϩ ϩ ϩϩϩϩϩ Multinucleated giant ϩϩϩ ϩ ϩϩ± ϩϩ cells Neutrophils − ϩϩ; Early stage, −−−−ϩ − fully developed, final stage Lymphocytes ± ϩ ±; Fully developed, ± ϩϩϩϩ± final stage Eosinophils ± ϩ ±; Fully developed, ϩ −−−±− final stage Plasma cells − − − − − ± ϩ ±− Dermoepidermal −−− − ϩ −− − − vacuolar changes

*A minus sign indicates that a feature is absent; a plus sign, that it is present; and a plus-minus sign, that it is variably present.

sition, and the depth of granulomatous inflammation help The clinical presentation of GA is variable and may histopathologically to distinguish necrobiosis lipoidica be associated with mild pruritus or occasional burning. from GA.14 Our patients did not have previous diag- Our patients presented with painful papules and plaques. noses of diabetes mellitus, none presented with pre- One patient also presented with a dermal nodule on her tibial plaques characteristic of necrobiosis lipoidica, and foot. These symptoms are unusual, and, to our knowl- their biopsy specimens did not have histologic findings edge, this is the first documented presentation of GA as- to suggest such a diagnosis. sociated with pain. Weston and Morelli17 previously re- Rheumatoid nodules are estimated to occur in ap- ported a case of “painful” GA due to Munchausen proximately 20% of patients with rheumatoid arthritis syndrome by proxy. This case report documented a moth- and are usually associated with high titers of rheuma- er’s complaint that her child’s eruption was painful and toid factor. Two of our patients had arthritic com- disabling in order to subject the child to unnecessary sur- plaints, and another had an elevated serum rheumatoid gical procedures for financial gain. However, on re- factor level, but neither met the criteria defined by the peated physician examination, the papules were non- American College of Rheumatology for rheumatoid ar- tender. Whether the symptoms in our patients are thritis. In addition, our patients did not present with nod- attributable to the GA lesions themselves or due to lo- ules on the bony prominences but did have tender pap- cality is uncertain. ules and plaques, with results from their biopsies showing These 4 cases should alert clinicians to become aware upper to middle dermal involvement. With careful clini- of patients who present with similar clinical findings copathologic correlation and the presence of mucin rather and symptoms of tenderness and/or pain and to consider than fibrin deposition, GA may be differentiated from GA in their differential diagnosis. Laboratory investiga- rheumatoid nodules.15 tion should focus on a patient’s symptoms and clinical Sarcoidosis is a disease of unknown etiology with cu- examination to exclude other possible etiologies. Single- taneous findings occurring in approximately 20% to 30% or multiple-agent therapy with topical and/or intrale- of patients with systemic disease. The cutaneous mani- sional corticosteroids, nicotinamide, hydroxychloro- festations are variable, including brown erythematous or quine, or other treatment modalities should also be purple papules and plaques that may appear annular.16 guided by these principles.18 There was an initial concern that patient 2 had cutaneous sarcoidosis because of her clinical presentation; how- Accepted for Publication: June 16, 2005. ever, biopsy findings did not reveal naked sarcoidal granu- Author Contributions: Study concept and design: Callen lomas, x-ray films of her chest did not reveal hilar and Brey. Acquisition of data: Brey, Malone and Callen. adenopathy, and findings from serologic studies were Drafting of the manuscript: Brey. Critical revision of the manu- negative for sarcoidosis. script for important intellectual content: Callen and Malone.

(REPRINTED) ARCH DERMATOL/ VOL 142, JAN 2006 WWW.ARCHDERMATOL.COM 53

©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Administrative, technical, and material support: Callen. 7. Tomasini C, Pippione M. Interstitial granulomatous dermatitis with plaques. Study supervision: Callen. J Am Acad Dermatol. 2002;46:892-899. 8. Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neu- Correspondence: Jeffrey P. Callen, MD, Division of Der- trophilic and granulomatous dermatitis in patients with collagen vascular disease. matology, Department of Medicine, University of Lou- Arch Dermatol. 1994;130:1278-1283. isville School of Medicine, 310 E Broadway, Louisville, 9. Bogle MA, Tschen JA, Sairam S, McNearney T, Orsak G, Knox JM. Multicentric KY 40202 ([email protected]). reticulohistiocytosis with pulmonary involvement. J Am Acad Dermatol. 2003; Financial Disclosure: None. 49:1125-1127. Disclaimer: Dr Callen is the associate editor of the 10. Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol. 1998;25: ARCHIVES, but he was not involved in the editorial 72-78. evaluation or decision to accept this article for publi- 11. Perrin C, Lacour JP, Castanet J, Michiels JF. Interstitial granulomatous drug re- cation. action with a histological pattern of interstitial granulomatous dermatitis. Am J Dermatopathol. 2001;23:295-298. 12. Hanke CW, Bailin PL, Roenigk HH. Annular elastolytic giant cell granuloma. REFERENCES J Am Acad Dermatol. 1979;1:413-421. 13. Burket JM, Zelickson AS. Intracellular elastin in generalized granuloma annulare. 1. Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol. 1997; J Am Acad Dermatol. 1986;14:975-981. 36:326-333. 14. Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis li- 2. Dabski K, Winkelmann RK. Generalized granuloma annulare: histopathology and poidica tissue reactions as a manifestation of systemic disease. Hum Pathol. 1996; immunology: systematic review of 100 cases and comparison with localized granu- 27:50-56. loma annulare. J Am Acad Dermatol. 1989;20:28-39. 15. Smith ML, Jorizzo JL, Semble E, Arrington JH, White WL. Rheumatoid papules: 3. Romero LS, Kantor GR. Eosinophils are not a clue to the pathogenesis of granu- lesions showing features of vasculitis and palisading granuloma. J Am Acad loma annulare. Am J Dermatopathol. 1998;20:29-34. Dermatol. 1989;20:348-352. 4. Long D, Thiboutot DM, Majeski JT, Vasily DB, Helm KF. Interstitial granuloma- 16. Ehrich EW, McGuire JL, Kim YH. Association of granuloma annulare with tous dermatitis with arthritis. J Am Acad Dermatol. 1996;34:957-961. sarcoidosis. Arch Dermatol. 1992;128:855-856. 5. Verneuil L, Dompmartin A, Comoz F, Pasquier CJ, Leroy D. Interstitial granulo- 17. Weston WL, Morelli JG. “Painful and disabling granuloma annulare”: a case of matous dermatitis with cutaneous cords and arthritis: a disorder associated with Munchausen by proxy. Pediatr Dermatol. 1997;14:363-364. autoantibodies. J Am Acad Dermatol. 2001;45:286-291. 18. Howard A, White CR. Non-infectious granulomas. In: Bolognia JL, Jorizzo JL, 6. Aloi F, Tomasini C, Pippione M. Interstitial granulomatous dermatitis with plaques. Rapini RP, et al, eds. Dermatology. Vol. 2. London, England: Mosby; 2003:1455- Am J Dermatopathol. 1999;21:320-323. 1469.

News and Notes

First Congress of the International Dermoscopy Society. Naples, Italy, April 27 to 29, 2006. The recently founded International Dermoscopy Society organizes a meeting designed for all colleagues interested in the diagnosis and management of pigmented skin lesions. Special emphasis is given on guidelines for management, standard- ization of reports, and, particularly, on the develop- ment of machine vision in dermoscopy. In addition, seminars in discussion format and half-day workshops with special emphasis on pertinent issues in dermoscopy will be conducted. The detailed program is presented on the Web site: http://www.dermoscopy-ids.org. For further information please contact Giuseppe Argen- ziano, MD, Department of Dermatology, Second University of Naples, Naples, Italy ([email protected]).

(REPRINTED) ARCH DERMATOL/ VOL 142, JAN 2006 WWW.ARCHDERMATOL.COM 54