Subcutaneous Annulare in Childhood: Clinicopathologic Features in 34 Cases

Karen L. Grogg, MD, and Antonio G. Nascimento, MD

ABSTRACT. Objective. To gather clinicopathologic pseudorheumatoid nodule, subcutaneous palisading data on subcutaneous (SGA), a sub- granuloma, and the more general term necrobiotic type of granuloma annulare that occurs exclusively in granuloma. children and is histologically similar to rheumatoid nod- In adults, granuloma annulare and its variants as ules. well as rheumatoid-like nodules have been reported Design. Retrospective record review. in association with connective tissue disease, diabe- Patients. Children <10 years old in whom SGA, deep 3–5 granuloma annulare, or necrobiotic granuloma was diag- tes, and other conditions. In contrast, several series nosed at the Mayo Clinic (Rochester, MN) from 1983 to in the pathology and literature have 1998. demonstrated that the presence of these lesions in Results. Thirty-four patients (21 girls and 13 boys; children is not a harbinger of connective tissue dis- average age at diagnosis: 4.6 years) were found to have ease.6–8 However, SGA is not commonly encoun- SGA. The lesions predominantly occurred in the lower tered in pathologic practice and so continues to be a extremity, especially in a pretibial location. Local recur- source of question in our pathology consultation ser- rence within 1 month to 7 years was documented in vice. We report our experience with the subcutane- 38.2%; recurrence at other locations was documented in ous variant of granuloma annulare and suggest a 14.7%. Average follow-up was 60 months; during follow- possible association of SGA with in chil- up, no patients developed signs or symptoms of rheuma- tologic disease. Insulin-dependent diabetes mellitus was dren. diagnosed in 2 patients, 1 before the development of SGA and 1 after it by 1 month. METHODS Conclusions. SGA is a lesion that presents as subcu- The pathology files at the Mayo Clinic (Rochester, MN) from taneous nodules on the lower extremities, hands, or scalp 1983 through 1998 were searched for cases in which SGA, deep in young children. Recurrence is common but usually granuloma annulare, or necrobiotic granuloma was diagnosed in children Ͻ10 years old. All cases were reviewed for histologic does not warrant additional biopsy. Pediatrics confirmation of SGA; immunohistochemical methods were used 2001;107(3). URL: http://www.pediatrics.org/cgi/content/ when necessary to rule out infectious (Gomori’s methenamine- full/107/3/e42; childhood, diabetes mellitus, insulin-depen- silver stain, acid-fast bacillus stain) or neoplastic (cytokeratin dent, granuloma annulare, necrobiotic granuloma, subcu- AE1/AE3) causes for the granulomatous lesions. Medical records taneous granuloma annulare. were reviewed for clinical features and postoperative course. For consultation cases (approximately half of the cases), a question- naire was sent to the referring pathologist requesting information ABBREVIATION. SGA, subcutaneous granuloma annulare. on the patient’s clinical status before biopsy and at last follow-up. The questionnaire specifically inquired about the presence of rheumatologic or other connective tissue disease, diabetes melli- ranuloma annulare is a self-limited inflam- tus, and recurrence of the lesion. If the pathologist did not have matory skin lesion occurring in both adults access to the medical records, the questionnaire was forwarded to Gand children.1 Subtypes with distinct clinical the child’s pediatrician. features include localized granuloma annulare, gen- RESULTS eralized granuloma annulare, perforating granuloma For the 15 years studied, 34 cases of SGA in chil- annulare, and subcutaneous granuloma annulare dren Ͻ10 years old were identified for whom clinical (SGA). SGA occurs exclusively in children and con- information was available. The lesion predominantly sists of deep dermal or subcutaneous nodules. On occurred in girls (21 girls and 13 boys; ratio of 1.6: histologic evaluation, these nodules are similar to the 1.0). Average age at diagnosis was 4.6 years. In 30 nodules seen in adults with rheumatoid arthritis1 and to the lesion recognized in adult diabetic pa- cases, SGA presented as slowly enlarging painless tients as lipoidica diabeticorum.2 Syn- nodules; in 4 cases, as slight tenderness to palpation. onyms for SGA include deep granuloma annulare, In the 34 cases, SGA occurred at the following sites (Table 1): leg or foot, 28 cases (76%); hand or finger, 5 cases (15%); and forehead or scalp, 3 cases (9%). In Ͼ From the Division of Anatomic Pathology, Mayo Clinic, Rochester, Minne- 9 cases (26.5%), lesions were found in 1 location at sota. initial presentation. The pretibial location was the Received for publication Jul 17, 2000; accepted Nov 2, 2000. single most common site, with SGA occurring there Reprint requests to (A.G.N.) Division of Anatomic Pathology, Mayo Clinic, in 8 cases (24%). The average time between onset and 200 First St SW, Rochester, MN 55905. E-mail: nascimento.antonio@ mayo.edu biopsy for diagnosis was 4 months. PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- Follow-up information was unavailable in only 3 emy of Pediatrics. cases. Average follow-up was 60 months (range: 3 http://www.pediatrics.org/cgi/content/full/107/3/Downloaded from www.aappublications.org/newse42 by guestPEDIATRICS on October 2, Vol. 2021 107 No. 3 March 2001 1of4 TABLE 1. Location of SGA in 34 Cases the deep and subcutaneous tissue with cen- Location Cases, tral degenerative and admixed mucin. The n (%) sharply demarcated areas of necrobiosis were sur- Leg or foot 26 (76) rounded by palisading histiocytes and a peripheral Pretibial area 8 (24) zone of mononuclear inflammatory cells. The over- Hand or finger 5 (15) lying was not atrophic. Forehead or scalp 3 (9) No child developed or symp- toms of other connective tissue disease. One child had a father who had severe rheumatoid arthritis. months to 14 years). Local recurrence within 1 month to 7 years of the initial lesion was clinically docu- Two children had diabetes mellitus. In 1 of these mented in 13 cases (38.2%). Typically, these consisted children, diabetes mellitus was diagnosed 2 years of multiple recurrences over several years, with le- before the development of SGA; in the other child sion persistence for months to years. Recurrence at diabetes mellitus developed 1 month after the diag- other locations was noted in 5 cases (14.7%). In 1 case nosis of SGA. In both cases, the lesions were located (2.9%), a syndrome of generalized granuloma annu- on the lower leg or ankle, and there were multiple lare developed, waxing and waning for 3 years. local recurrences over months to years. The histo- In all cases the results of histologic evaluation were logic evaluation of these lesions did not differ from consistent with those previously described for SGA that of the other cases. Recurrences were observed (Fig 1). The lesions consisted of multiple nodules in without biopsy.

Fig 1. SGA: the lesion consists of nodules of histio- cytic cells arranged around a central necrotic zone (hematoxylin-eosin). A, ϫ140; B, ϫ280.

2of4 SUBCUTANEOUSDownloaded GRANULOMA from www.aappublications.org/news ANNULARE IN CHILDHOOD by guest on October 2, 2021 DISCUSSION sulin levels in patients with granuloma annulare. Granuloma annulare was first described by Col- However, other studies looking for carbohydrate cott Fox in 1895. Ziegler9 in 1941 was the first to note intolerance by glucose tolerance testing17–20 or hemo- the presence of subcutaneous pseudorheumatoid globin A1C values21 failed to find an increased prev- nodules occurring concomitantly in a patient with alence of altered carbohydrate metabolism in pa- localized granuloma annulare. These subcutaneous tients with granuloma annulare. lesions, seen on histologic evaluation to have a cen- An association of SGA with diabetes mellitus in tral zone of necrotic collagen surrounded by palisad- children has not been established in the medical ing histiocytes and mononuclear inflammatory cells, literature. Two of 34 patients (5.9%) in our series had have since been recognized as a distinct subtype of concomitant or subsequent diabetes mellitus. Histo- granuloma annulare, occurring exclusively in chil- logically, the lesions in these patients were not dis- dren, in isolation or in temporal association with tinctly different from those of the other children. In a 8 localized granuloma annulare.1 series of 20 children with SGA, Evans et al noted In our pathology files we identified 34 cases of that 1 child also had diabetes mellitus. Given the SGA that occurred in a period of 15 years. Although rarity of childhood diabetes (0.16% of US population Ͻ 22 this relatively small number suggests a low preva- 20 years old), this finding in these 2 studies may suggest an association between these 2 entities. Other lence of this entity, this number may underrepresent 6–8,11–15 the actual frequency of the lesion. Lesions that are series have focused on rheumatologic disease clinically recognized may be observed without bi- and did not comment on the presence or absence of opsy. diabetes. Additional series with larger numbers of The clinicopathologic features observed in the 34 patients and prospective study design would be re- quired to confirm an association. children in this study are consistent with those pre- Although their clinical features are distinct, SGA viously reported. Children with SGA are usually 2 to shares histologic features with 5 years old and otherwise healthy.7,8,10,11 The most diabeticorum, a well-recognized dermatologic com- common lesion location is the lower extremity, espe- plication of diabetes mellitus. In both conditions, cially the pretibial area, followed by the hands and palisading histiocytes surround zones of degener- scalp.7,8,11 Local or distant recurrences over months ated collagen. Necrobiosis lipoidica diabeticorum to years are common, being reported in 30% to 75% 7,8,10 usually involves the entire dermis and subcutis, with of cases. the palisading histiocytes arranged in a tiered linear Adults presenting with rheumatoid nodules, his- manner combined with dermal sclerosis, thickened tologically identical to SGA, are at significant risk for subcutaneous septae, thickened blood vessels, and a the development of rheumatoid arthritis or other mixed infiltrate of plasma cells, lymphocytes, and, on connective tissue disease. Because of this association, occasion, giant cells.2,4 The overlying epidermis is efforts have been made to determine whether chil- characteristically atrophic.4 SGA is characterized by dren with these lesions are at similar risk. Draheim et 12 smaller, rounder, multiple foci of degenerated col- al collected 54 cases at the Armed Forces Institute lagen associated with more abundant mucin and of Pathology in 1959; in no case did connective tissue involving only the deeper dermis and subcutis. Ex- disease develop after 1 to 14 years of follow-up. tensive chronic inflammatory infiltrate, vascular al- Subsequent reports with smaller numbers of cases terations, and epidermal are uncommon have also concluded that there is no increased risk in SGA.4 Given the histologic similarities between for systemic rheumatologic disease in these chil- granuloma annulare and necrobiosis lipoidica dia- 6,8,13–15 dren ; however, scattered reports of necrobi- beticorum, these conditions may be 2 points along a otic granuloma in children with known rheumatoid continuum representing the same dermal process. disease have perpetuated concern about these le- Indeed, in 1 study, several of the adult patients with sions.11 A recent review of 47 cases by Felner et al7 localized granuloma annulare and diabetes mellitus confirmed the self-limited course of SGA. Our find- later developed lesions more characteristic of necro- ings corroborate these reports, with no patients de- biosis lipoidica diabeticorum.5 Similarly, SGA may veloping connective tissue disease after a lengthy represent an early-stage dermatologic manifestation follow-up period. of diabetes in a subset of children. Several investigators have attempted to demon- strate a relationship of granuloma annulare with CONCLUSION other systemic diseases, most notably with diabetes SGA is a lesion that presents as subcutaneous nod- mellitus. The association of granuloma annulare with ules on the lower extremities, hands, or scalp of diabetes mellitus is not yet established. Studer et al3 young children. Recognition of its natural history noted diabetes mellitus in 12% of 84 adult patients allows the physician to alleviate anxiety and avoid with granuloma annulare (localized or generalized), unnecessary medical investigation when no sign of as opposed to the 5% prevalence of diabetes mellitus systemic connective tissue disease is present. Recur- among the regional population. Comparison with an rences locally or at other sites are common but usu- age-matched population was not performed. A large ally do not warrant additional biopsy. population study by Muhlemann and Williams5 also found an increased coincidence of localized granu- REFERENCES 16 loma annulare and diabetes mellitus, and Kidd et al 1. Barron DF, Cootauco MH, Cohen BA. Granuloma annulare: a clinical reported a reduced glucose tolerance and higher in- review. Lippincotts Prim Care Pract. 1997;1:33–39

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Subcutaneous Granuloma Annulare in Childhood: Clinicopathologic Features in 34 Cases Karen L. Grogg and Antonio G. Nascimento Pediatrics 2001;107;e42 DOI: 10.1542/peds.107.3.e42

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