Mihaela Paula Toader

Mirela Grigorovici

Tatiana Taranu

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ACTA DERMATOVENEROLOGICA CROATICA292Subcutaneous Granuloma AnnulareActa Dermatovenerol Croat  2017;25(4):292-294                            LETTER TO THE EDITORDear Editor,Subcutaneous granuloma annulare (SGA) is con-sidered a rare clinical variant of granuloma annulare, a common self-healing chronic inflammatory disor-der that may appear in childhood as well as in adult age (1-3). A 29-year-old female patient reported the onset of several small subcutaneous nodules on the dorsal aspect of the second interphalangeal joint of the left medius finger and the left elbow, accompanied by vague joint pain, had occurred 13 years ago. Specific markers for rheumatoid arthritis were negative, lead-ing to a diagnosis of sero-negative rheumatoid arthri-tis, for which treatment with methotrexate was initi-ated. No clinical benefit was obtained and the treat-ment was abandoned. New nodules continued to appear on several distal joints of the fingers of both hands and, in the last 6 months, on the second right toe. The course of the disease included spontaneous remission of some of the nodules. Personal medical history was significant for a thyroid nodule, surgically removed at the age of 22.A general physical exam did not reveal pathologi-cal changes. A clinical dermatological exam at the time of presentation revealed several round to oval, deep subcutaneous, indurated, asymptomatic, dis-creetly pigmented lesions with a diameter of 4-6 mm, located on the dorsal aspect of the interphalangeal joints of the fingers of both hands (Figure 1) and the second right toe.Hematologic and biochemical tests were within normal limits, as well as the serological tests for rheu-matoid factor, ANCA, ANA, and anti-CCP antibody. Hand radiographs did not show geodes, marginal erosions, or narrow joint spaces. A pathological exam of a subcutaneous nodule showed focally altered collagen surrounded by fibro-blasts, phagocytes, rare lymphocytes, and neutro-phils, as well as small capillaries (Figures 2-5), com-patible with the diagnosis of a pseudorheumatoid nodule or benign rheumatoid nodule in the clinical and paraclinical context.SGA is considered a rare clinical and histological variant of granuloma annulare that predominantly affects children and occasionally young adults (1-6). In 1941, Ziegler first described a case of subcutane-ous nodules that appeared concomitantly with classi-cal cutaneous lesions of granuloma annulare, as well as the histological aspect of these nodules similar to that of rheumatoid nodules (RN) (7). Since then, sev-eral case reports in the literature refer to the subcuta-neous lesions of GA as “pseudorheumatoid nodules”, “deep granuloma annulare” or “palisading granuloma” (3,4,8). Most reported cases of SGA occur in the first three decades of life: 98% according to Muhlemann, 79% according to Andersen and Verdich, 62% accord-ing to Studer; most cases occur in children between 2 and 6 years of age (9). Lesions often regress spon-taneously, but recurrences are common in 19%-75% of the patients, often on the same anatomical areas (9,10). Reported SGA cases in adult patients predomi-nantly affected women, and typically involved mul-tiple lesions located on the hands, feet, ankles, and inferior pretibial area (4-6).Figure 1. Juxta-articular solitary and grouped nodules on the fingers of the right hand.293ACTA DERMATOVENEROLOGICA CROATICAActa Dermatovenerol CroatLetter to the editor     2017;25(4):292-294The etiology and pathogenesis of SGA are not completely understood. Precipitating factors such as insect bites, infections with Borellia spp., herpetic virus, EBV, Streptococcus spp., PUVA-therapy, several drugs, physical trauma, acute phlebitis, and post-sur-gery sepsis have been considered (8). There is evi-dence for the pathogenic involvement of an immu-nological mechanism, possibly a delayed type hyper-sensitivity reaction mediated by T-cells that triggers a panniculitis-type inflammatory response (8,10). Cor-relations between SGA and systemic diseases such as diabetes mellitus, sarcoidosis, HIV infection, or auto-immune diseases have not been found (8).A positive diagnosis of pseudorheumatoid nod-ules relies on clinical and anamnestic data. Differen-tial diagnosis includes rheumatoid nodules, benign rheumatoid nodules, foreign body reactions, hema-tomas, abscesses, and infectious granulomas (3,5). Pseudorheumatoid nodules and SGA have a low risk of progression to a systemic connective tissue disorder. In the presence of subcutaneous nodular lesions with an uncertain clinical diagnosis, cutaneous bi-opsy, hematological and immunological tests, and imaging may be performed to establish a positive diagnosis.Skin biopsy is the most useful test for the diagnos-tic approach because, even though it is sometimes difficult to interpret, a pathological exam may offer important data to distinguish between rheumatoid and pseudorheumatoid nodules. Necrobiosis may be identified in the deep dermis and subcutaneous tis-sue, and rarely in the deep soft tissues. Necrobiosis is less important and less deep than in rheumatoid nod-ules, as well as less extensive and less diffuse than in lipoidic necrobiosis (6). Anomalies in the morphology of the deep cutaneous structures may coexist with typical changes in classical granuloma annulare. Im-munohistochemical studies using specific histiocyte markers such as CD68/PGM1 proved to be occasion-ally useful in differentiating SGA from other granulo-matous conditions (11). Figure 2. Subcutaneous nodule surrounded by chronic in-flammatory infiltrate in the deep dermis (hematoxylin and eosin, ×40).Figure 3. Altered and normal collagen bundles (VG ×40).Figure 4. Fibrinoid necrosis (hematoxylin and eosin, ×40).Figure 5. Fibrinoid necrosis (hematoxylin and eosin, ×40, polarized).294 ACTA DERMATOVENEROLOGICA CROATICASeveral tests are necessary to exclude an asso-ciation with a systemic disease: hemoleucogram (absence of leucocytosis), ESR (normal values), acute phase reactants (negative fibrinogen, RCP), auto-antibodies (negative ANA), and rheumatoid factor (negative).SGA is a benign disorder with esthetic implica-tions and sometimes functional impairment. Surgical excision is only required for juxta-articular nodules causing functional impairment. Partial therapeutic benefit was reported after the administration of dap-sone, clorambucil, isotretinoin, potassium iodide, or intralesional/topical steroids. Even though the risk of systemic involvement is low, periodical follow-up of these patients is required given the reported cases of associated systemic connective tissue disorders (8,12).References:1.  Argent JD, Fairhurst JJ, Clarke NM. Subcutaneous granuloma annulare: four cases and review of the literature. Pediatr Radiol. 1994;24: 527-9.2.  Felner EI, Steinberg JB, Weinberg AG. Subcuta-neous granuloma annulare: a review of 47 cases. Pediatrics. 1997;100:965-7.3.  Requena L, Fernández-Figueras MT. Subcutaneo-us granuloma annulare. Semin Cutan Med Surg. 2007;26:96-9.4.  Mijlković J, Krajnc I. Subcutaneous granuloma annulare in an adult. Wien Klin Wochenschr. 2003;115:309-11.5.  Barzilai A, Huszar M, Shapiro D, Nass D, Trau H. Pseudorheumatoid nodules in adults: a juxta-ar-ticular form of nodular  granuloma annular. Am J Dermatopathol. 2005;27:1-5.6.  Salomon RJ, Gardepe SF, Woodley DT. Deep granuloma annulare in adults. Int J Dermatol. 1986;25:109-12.7.  Ziegler E. Rheumatismus nodosus als einzige Ma-nifestation der Rheumatischen Krankheit. Arch. Kindeerh. 1941;1221-6.8.  Tse CT, Jong KK. Subcutaneous granuloma annu-lare presented as multiple nodules of the lower leg. H K Dermatol Venereol Bull. 2004;12:33-6.9.  Chung S, Frush DP, Prose NS, Shea CR, Laor T, Bis-set GS. Subcutaneous granuloma annulare: Mag-netic Resonance Imaging Features in six Children. Radiology 1999;210:845-9.10. Grogg KL, Nascimento AG. Subcutaneous granu-loma annulare in childhood: clinicopathologic features in 34 cases. Pediatrics. 2001;107:E42.11.  Pesce V, Notamicola A, Moretti B. Diagnostic di-lemma of a subcutaneous nodule following a trauma in a child: immunohistochemical exami-nation put the final diagnosis of deep granuloma annulare. Musculoskeletal Surgery. 2010;94:49-51.12. Gale M, Gilbert E, Blumenthal D. Isolated rheu-matoid nodules: a diagnostic dilemma. Case Rep Med. 2015;2015:352352.Tatiana Ţăranu1, Mirela Grigorovici2, Magda Constantin3, Mihaela Paula Toader11Department of Oral Dermatology, Faculty of Dental Medicine, T. Popa University of Medi-cine and Pharmacy, Iasi, Romania2Pathology Laboratory, Railways Clinical Hospital, Iasi, Romania³Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, RomaniaCorresponding author:Mihaela Paula Toader MD, PhD T. Popa University of Medicine and Pharmacy, Iasi, Romania16 Universitatii str. 700115IasiRomaniatoaderpaula@gmail.comReceived: July 4, 2016Accepted: November 4, 2017Acta Dermatovenerol CroatLetter to the editor     2017;25(4):292-294

Subcutaneous granuloma annulare

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