Background

This common rash is sometimes classified as a dermal mucinosis and sometimes as a granulomatous disease. Several clinical variants have been described. This disease is more common in women and can affect any age group. Lesions may spontaneously regress although 40% of cases recur. The generalized form has a poor response to therapy.

Many theories have been advanced regarding the etiology of this disease. In the generalized variant, there is a higher frequency of HLA-BW35. In addition, occasional familial cases have been reported. The sporadic cases have been associated with arthropod bites, sites of trauma, and scars. In addition, several systemic diseases have been associated.

Diabetes mellitus
Hodgkin's and Non-Hodgkin's Lymphoma
Metastatic adenocarcinoma
AIDS

OUTLINE

Pathogenesis
Disease Associations
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
EOSINOPHILS
Eosinophils are not a clue to the pathogenesis of granuloma annulare. Romero LS, Kantor GR. Department of Dermatology, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania, USA.	Am J Dermatopathol 1998 Feb;20(1):29-34 Abstract quote Eosinophils are variably present in biopsy specimens of granuloma annulare (GA). A retrospective study of 77 biopsy specimens from 73 patients with GA was performed to quantitate eosinophils and correlate the findings with both histologic and clinical features. Specimens were divided into absent, low (10 > x > or = 1 eosinophils per 3 sections), and high (x > or = 10 eosinophils per 3 sections) eosinophil groups and evaluated for eight histologic and 11 clinical features. Eosinophils were identified in 66% (51/77) of biopsy specimens, with 51.9% (40/77) and 14.3% (11/77) in the low and high eosinophil groups, respectively. Clinically, patients in the high eosinophil group were found to be significantly younger with a propensity towards nonannular, localized disease. These patients also did not have diabetes or use systemic medications. Histologically, the presence of eosinophils was strongly associated with palisaded architectural pattern and the presence of necrobiosis. Eosinophils were not present in areas of necrobiosis but were found predominantly perivascularly. A moderate to marked lymphocytic infiltrate at the periphery of the granulomas and reactive vessel changes were common in all three groups, but vasculitis was not identified. In summary, this study showed eosinophils to be commonly present in GA but was unable to correlate their presence with specific clinical or histologic features supportive of an allergic precipitant. A cell-mediated immune mechanism is likely involved in GA, with eosinophils recruited nonspecifically by mediators released during granuloma formation.
MUCIN
Abundance of interstitial heparan sulfate in granuloma annulare but not in other mucinous skin diseases. Bandel C, DePrisco G, Cockerell CJ, Ehrig T. Department of Dermatology, University of Texas South-Western Medical School, Dallas, TX, USA.	J Cutan Pathol 2002 Oct;29(9):524-8 Abstract quote BACKGROUND: Heparan sulfate (HS), unlike other glycosaminoglycans, is mainly located on cell surfaces but can be shed into the interstitium by a regulated process. It has been found in interstitial fluid drained from cutaneous wounds, but otherwise the conditions under which the release of HS from the cell surface occurs are unknown. To better characterize this process, we have investigated the presence of interstitial HS in various skin diseases with glycosaminoglycan accumulation. METHODS: Histologic routine material was stained immunohistochemically using an antibody recognizing HS. RESULTS: Heparan sulfate immunoreactivity is present in the interstitium of young cutaneous scars and in the interstitium of the inflammatory infiltrate of granuloma annulare. No reactivity was found in a number of non-inflammatory skin diseases with mucin deposition. CONCLUSIONS: The selective presence of interstitial HS in only two of the investigated skin conditions supports the existence of a regulated mechanism to release HS from the surface of cells into the interstitium. It is suggested that HS modulates the biologic actions of growth factors and cytokines not only during wound repair but possibly also in inflammatory skin diseases such as granuloma annulare.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
ALAGILLE SYNDROME
Papular umbilicated granuloma annulare in association with Alagille syndrome. Kibarian MA, Mallory SB, Keating J, Shitabata P. Department of Dermatology, Washington University School of Medicine, St Louis, Missouri, USA.	Int J Dermatol 1997 Mar;36(3):207-9
BARTONELLA
Granuloma Annulare Another Manifestation of Bartonella Infection? Bruce R. Smoller, M.D.; Kunapali T. Madhusudhan, Ph.D.; Margie A. Scott, M.D.; Thomas D. Horn, M.D. From the Departments of Pathology (B.R.S., K.T.M., M.A.S.) and Dermatology (B.R.S., T.D.H.), University of Arkansas for Medical Sciences, Little Rock, Arkansas.	Am J Dermatopathol 2001;23:510-513 Abstract quote Granuloma annulare (GA) is a common cutaneous eruption whose pathogenesis remains unknown. Recent literature has suggested a relation between Borrelia infection and GA, a relation that has not been widely accepted. Earlier works attempted unsuccessfully to implicate various other infectious agents. Some reports have demonstrated the increased frequency of GA in patients with human immunodeficiency virus infection, again raising the possibility of an infectious etiology. Using polymerase chain reaction amplification, we examined 19 biopsy specimens from 19 patients with GA (14 with classic palisading GA and 5 with an interstitial pattern) for the presence of a 153–base pair sequence specific for Bartonella henselae or Bartonella quintana. None of our patients were known to be human immunodeficiency virus–positive. These primers failed to detect B. henselae and B. quintana DNA in any of the specimens examined. Our findings do not support the hypothesis that GA represents a granulomatous reaction pattern to cutaneous Bartonella infection. Nevertheless, we cannot exclude the possibility that there may be a relation in other geographic locations or in immunocompromised patients or that GA represents an autosensitization reaction in response to a distant site of infection. Additional studies are needed to address these hypotheses.
DIABETES MELLITUS
An unusual form of generalized granuloma annulare in a patient with insulin-dependent diabetes mellitus. Erkek E, Karaduman A, Bukulmez G, Senturk N, Ozkaya O. Hacettepe University Faculty of Medicine, Ankara, Turkey.	Acta Derm Venereol 2001 Jan-Feb;81(1):48-50 Abstract quote The generalized form of granuloma annulare may be associated with systemic disorders, including diabetes mellitus. We describe here an unusual form of generalized granuloma annulare in a patient with complicated insulin-dependent diabetes mellitus. The cutaneous eruption had been present for decades as non-pruritic, persistent, violet-brown patches with raised edges. There were flexion deformities of the small joints of the hands and feet associated with thickening of the skin over dorsa of the fingers. The patient is currently on isotretinoin therapy, with partial resolution of lesions at 3 months follow-up.
ERYTHEMA MULTIFORME
Disseminated granuloma annulare following erythema multiforme minor. Abraham Z, Feuerman EJ, Schafer I, Feinmesser M. Department of Dermatology, Reish Policlinic, Haifa, Israel.	Australas J Dermatol 2000 Nov;41(4):238-41 Abstract quote A 44-year-old woman presented with erythema multiforme minor followed by disseminated granuloma annulare 4 weeks later. The patient was not taking any medication and had no history of herpes simplex infection. Involvement of a delayed-type hypersensitivity reaction in the pathogenesis of these two well known disorders, as suggested by immunological investigations, may explain their concurrence in our patient. The substitution of the erythema multiforme minor lesions by an eruption of disseminated granuloma annulare at the same sites suggests the possibility of a Koebner phenomenon or an isotopic response.
HEPATITIS
Chronic hepatitis C virus infection associated with a generalized granuloma annulare. Granel B, Serratrice J, Rey J, Bouvier C, Weiller-Merli C, Disdier P, Pellissier JF, Weiller PJ. Service de Medecine Interne, Hopital de la Timone, 264 rue Saint-lerre, 13385 Marseille Cedex 5, France.	J Am Acad Dermatol 2000 Nov;43(5 Pt 2):918-9 Abstract quote We report the first case of generalized granuloma annulare occurring in a 65-year-old woman who was chronically infected with hepatitis C virus. Granuloma annulare totally regressed during alpha-interferon treatment. As chronic hepatitis C virus infection is frequent, a serodiagnosis would be of interest in patients who have generalized granuloma annulare. A link between these 2 diseases may be strongly suspected.
HERPES ZOSTER
Granuloma annulare in herpes zoster scars. Ohata C, Shirabe H, Takagi K, Kawatsu T. Department of Dermatology, Osaka Teishin Hospital, Japan.	J Dermatol 2000 Mar;27(3):166-9 Abstract quote A 54-year-old Japanese female developed granuloma annulare twice in herpes zoster scars. Soon after the second event, she developed ulcerative colitis, which was well controlled by sulfonamides and corticosteroid suppository. She had no history of diabetes mellitus. There was no recurrence of granuloma annulare by June of 1999. Granuloma annulare might have contributed to the complications of ulcerative colitis, although this had not been noticed before.
HIV
Granuloma annulare and human immunodeficiency virus infection. Toro JR, Chu P, Yen TS, LeBoit PE. Department of Dermatology, University of California-San Francisco School of Medicine, 94115, USA.	Arch Dermatol 1999 Nov;135(11):1341-6 Abstract quote OBJECTIVES: To characterize human immunodeficiency virus (HIV)-associated granuloma annulare (GA) by clinical, microscopic, and molecular methods and to investigate the role of Epstein-Barr virus infection in the pathogenesis of GA. DESIGN: Patients were evaluated clinically, and biopsy specimens of lesional skin were examined by light microscopy. Polymerase chain reaction and in situ hybridization for Epstein-Barr virus were performed on 4 and 12 biopsy specimens, respectively. SETTING: Academic referral center. PATIENTS: Thirty-four consecutive HIV-positive patients who have a clinical and histological diagnosis of GA. OUTCOME MEASURES: Clinical distribution of lesions, light-microscopic features, and the presence of Epstein-Barr virus DNA and RNA in biopsy specimens. RESULTS: Granuloma annulare was generalized in 20 patients and localized in 14. Twenty patients (59%) presented with acquired immunodeficiency syndrome. Unusual features were the presence of oral lesions in 1 patient, perforating lesions in 2 patients, and the coexistence of GA and Kaposi sarcoma in 1 biopsy specimen. Microscopic examination of 34 biopsy specimens showed a granulomatous pattern that was interstitial in 8, palisaded in 18, perforating in 2, and mixed interstitial and palisaded in 6. Special staining of all specimens was negative for organisms. Epstein-Barr virus infection was not detected by either polymerase chain reaction or in situ hybridization. CONCLUSIONS: Generalized GA is the most common clinical pattern in HIV infection. Granuloma annulare associated with HIV can present at all stages of HIV infection, but it is slightly more common in patients with acquired immunodeficiency syndrome. Epstein-Barr virus is an unlikely causative agent of HIV-associated GA. Granuloma annulare may be a manifestation of increasing immune dysregulation.
HIV-associated granuloma annulare (HAGA): a report of six cases. O'Moore EJ, Nandawni R, Uthayakumar S, Nayagam AT, Darley CR.	Br J Dermatol 2000 May;142(5):1054-6
ISOTRETINOIN
Granuloma annulare following waxing induced pseudofolliculitis-resolution with isotretinoin. Young HS, Coulson IH. Department of Dermatology, University of Manchester School of Medicine, Hope Hospital, Manchester, UK.	Clin Exp Dermatol 2000 Jun;25(4):274-6 Abstract quote We report a case of localized granuloma annulare, successfully treated with isotretinoin, which occurred as a consequence of waxing-induced pseudofolliculitis. To our knowledge this is the first reported clearance of localized granuloma annulare with isotretinoin and the first reported case of granuloma annulare as a sequel to pseudofolliculitis.
LYMPHOMA
Granuloma annulare in patients with malignant lymphoma: clinicopathologic study of thirteen new cases. Barksdale SK, Perniciaro C, Halling KC, Strickler JG. Department of Dermatology, Mayo Clinic, Rochester, Minnesota.	J Am Acad Dermatol 1994 Jul;31(1):42-8 Abstract quote BACKGROUND: Reports of necrobiotic granulomas or granuloma annulare in patients with malignant lymphoma are rare. OBJECTIVE: Our intent was to determine any unique clinical or histopathologic features in patients with granuloma annulare and lymphoma. METHODS: We reviewed the medical records and biopsy material from 13 patients with granuloma annulare and lymphoma. RESULTS: Three patients had Hodgkin's disease and 10 had non-Hodgkin's lymphoma. The granuloma annulare lesions showed typical histopathologic features. However, the clinical pattern was frequently atypical, with painful lesions in unusual locations including the palms and soles. Three patients displayed granulomatous inflammation in noncutaneous sites, either within the malignant lymphoma or in uninvolved tissues, and all three had atypical clinical presentations of granuloma annulare. CONCLUSION: Granuloma annulare with atypical clinical presentations may be associated with an underlying hematopoietic malignancy and may be part of a generalized granulomatous reaction to malignant lymphoma.
Subcutaneous granuloma annulare with Hodgkin's disease. Miyamoto T, Mihara M. Department of Dermatology, Tsuyama Central Hospital, Japan.	J Dermatol 1996 Jun;23(6):405-7 Abstract quote We report an 85-year-old woman with subcutaneous granuloma annulare. Three nodules developed on her scalp and sacral regions and gradually increased with tenderness. Histologically, a biopsy specimen of the nodule was interpreted as subcutaneous granuloma annulare because palisading granuloma was present in the dermis and subcutaneous fatty tissue. Laboratory tests, including RA, showed no remarkable changes except for hyperglycemia and glycosuria. These nodules spontaneously regressed without medication. One year later, she noted swelling of some lymph nodules in the left axillary region. These were diagnosed as Hodgkin's disease (mixed cellularity type). She was treated with chemotherapy, but died after two months. Subcutaneous granuloma annulare which occurs suddenly in the elderly may be a dermadrome of malignant blood disease.
MALIGNANCY
Granuloma annulare and malignant neoplasms. Li A, Hogan DJ, Sanusi ID, Smoller BR.	Am J Dermatopathol 2003 Apr;25(2):113-6 Abstract quote The relationship between granuloma annulare (GA) and malignant neoplasms is uncertain. Several case reports and clinical correlation studies have addressed this issue; however, no review articles have summarized those reported cases and statistically analyzed the association. Fourteen case reports and two correlation studies directly addressing the relationship of GA and malignant neoplasms were found from the Medline database from 1966-2001. A total of 16 cases from case reports were available with the mean age of 54. Most of the GA patients had an atypical clinical presentation. The time between the onset of GA and the discovery of the malignant neoplasms varied from 18 months before (median = 5 months) to 7 years after (median = 42 months). More than half of those cases were associated with lymphoma. No definite relationship was found between GA and malignant neoplasms. Older patients with skin lesions not clinically typical of GA but that histologically resemble classic GA, may be considered for investigation of underlying malignant lymphoma or other malignancies.
Granuloma annulare associated with malignancy. Cohen PR. Department of Dermatology, University of Texas-Houston Medical School 77030, USA.	South Med J 1997 Oct;90(10):1056-9 Abstract quote Granuloma annulare is a benign dermatosis. Although granuloma annulare usually occurs as an idiopathic condition, it has been described in oncology patients. I report the case of a man in whom the appearance and resolution of granuloma annulare occurred in a paraneoplastic manner. The diagnosis of his previously unsuspected pulmonary adenocarcinoma was preceded by the concurrent onset of granuloma annulare lesions and tumor-related systemic symptoms. Two other patients with malignancy-associated granuloma annulare are discussed: a woman with breast cancer and a woman with cervical cancer. In these cases, the appearance of granuloma annulare was also temporally associated with the detection of a previously undiagnosed malignancy or the discovery of recurrent metastatic disease. The resolution of the dermatosis was temporally associated with the successful treatment of the neoplasm in these individuals. Granuloma annulare should be added to the list of cutaneous paraneoplastic syndromes that may occur in patients with solid tumors.
MORPHEA
Coexisting morphoea and granuloma annulare-are the conditions related? Ben-Amitai D, Hodak E, Lapidoth M, David M. Pediatric Dermatology Unit, Schneider Children' Medical Center of Israel.	Clin Exp Dermatol 1999 Mar;24(2):86-9 Abstract quote Granuloma annulare and localized morphoea are both well described in the dermatological literature. We now present two patients with both of these diseases, a comorbidity rarely described. A possible pathogenic relationship is discussed.
MYCOSIS FUNGOIDES
Generalized granuloma annulare associated with granulomatous mycosis fungoides. Wong WR, Yang LJ, Kuo Tt, Chan HL. Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan.	Dermatology 2000;200(1):54-6 Abstract quote We describe a 68-year-old man with plaque stage mycosis fungoides (MF) for 8 years. He developed tumorous lesions of granulomatous MF (GrMF) and generalized granuloma annulare (GA) after a previously indolent clinical course. Since then, the clinical course was aggressive with involvement of the bone marrow and lymph nodes, and leukemic change occurred. Systemic chemotherapy was given, but the patient died 9 months later due to neutropenic fever and septic shock. GA in malignant lymphoma has been reported most frequently in association with Hodgkin's disease. To the best of our knowledge, GA associated with GrMF has never been reported in the English language literature. The prognostic significance of the association of granulomatous inflammation and malignancy is reviewed.
SARCOIDOSIS
Can granuloma annulare evolve into cutaneous sarcoidosis? Lupton JR, Figueroa P, Berberian BJ, Sulica VI. Department of Dermatology, George Washington University Medical Center, Washington, DC, USA	Cutis 2000 Nov;66(5):390-2 Abstract quote We report the unique case of a 50-year-old African American female with pulmonary sarcoidosis who presented with a new ichthyosiform eruption symmetrically located on the anterior shins and surrounded by red, translucent, intradermal papules. A skin biopsy of a new red papule showed features consistent with granuloma annulare (GA) with positive mucin staining, and an older hyperpigmented papule showed classic dermal noncaseating granulomas consistent with sarcoidosis. Recent reports have clearly demonstrated GA occurring in association with sarcoidosis, but this is the first report that suggests that a GA lesion may develop into a sarcoidal granuloma. We propose that GA may act as a precursor lesion to the more mature sarcoidal granuloma. This case further underscores the importance of careful clinicopathologic correlation.
THYROIDITIS
Localized granuloma annulare and autoimmune thyroiditis in adult women: A case-control study. Vazquez-Lopez F, Pereiro M Jr, Haces JA, Lopez MA, Sanchez TS, Coto TF, Oliva NP, Toribio J. Departments of Dermatology, Central University Hospital, University of Oviedo, and Complejo Hospitalario Universitario, University of Santiago de Compostela.	J Am Acad Dermatol 2003 Apr;48(4):517-20 Abstract quote BACKGROUND: The coexistence of granuloma annulare (GA) and autoimmune thyroiditis (AT) has been sporadically observed in female patients, but the significance of this rarely reported association remains uncertain. OBJECTIVE: To investigate for the first time the frequency and type of thyroid disease in adult women with localized granuloma annulare (LGA) compared with a matched control group. METHODS: Twenty-four adult women with histology-proven LGA and a control group of 100 age-matched female patients with other unrelated cutaneous diseases were screened for thyroid disease in a tertiary teaching hospital in northern Spain. Laboratory evaluation included routine hematologic and chemistry analysis, antinuclear antibody, rheumatoid factor, thyroid function test (sensitive thyroid-stimulating hormone [TSH]), thyroid autoantibody levels, and antibodies to thyroid peroxidase in all patients and controls. Thyroid hormones (free triiodothyroxine and free thyroxine) were measured when TSH value was abnormal. AT was defined as hypothyroidism (TSH value >5 mU/L) and in addition to elevated antithyroid antibodies or characteristic thyroid biopsy. The results were compared using Fisher's exact test. RESULTS: Statistical evaluation of the findings obtained in this study showed mainly that the frequency of AT was increased significantly in the group of adult women with LGA (3/24, 12%) compared with the matched control group (1/100) (Fisher's exact test: P =.022). CONCLUSION: Although little can be inferred from a single investigation, the results of this pilot study indicate an association between LGA and AT in adult female patients, supporting the theory that at least a subset of GA belongs to the spectrum of autoimmune diseases.
Localized granuloma annulare and autoimmune thyroiditis: a new case report. Vazquez-Lopez F, Gonzalez-Lopez MA, Raya-Aguado C, Perez-Oliva N. Department of Dermatology, Central University Hospital, University of Oviedo, Spain.	J Am Acad Dermatol 2000 Nov;43(5 Pt 2):943-5 Abstract quote We present further evidence that granuloma annulare and autoimmune thyroiditis may be associated. Only 11 cases have been previously reported with this association as far as we know. It may be advantageous to consider checking the thyroid-stimulating hormone and/or antithyroid antibodies before administering medications that could affect thyroid function in patients with granuloma annulare.
VACCINATION SITES
Generalized granuloma annulare sparing vaccination sites. Huilgol SC, Liddell K, Black MM. St John's Institute of Dermatology, St Thomas' Hospital, London, UK.	Clin Exp Dermatol 1995 Jan;20(1):51-3 Abstract quote Generalized granuloma annulare (GA) is a chronic and widespread form of GA, less common than the localized type, in which the primary papular lesions may be arranged in either predominantly annular or non-annular configurations. Associations with numerous systemic disorders, including malignancies of the haematopoietic system, have been reported. There is a marked tendency to show the isomorphic or Koebner phenomenon. We report a most unusual case of generalized non-annular GA associated with chronic myelomonocytic leukaemia and myelodysplasia, in which the eruption showed striking sparing of vaccination sites.

 

LABORATORY/ RADIOLOGIC	CHARACTERIZATION
Association of generalized granuloma annulare with autoantibodies. Tada J, Seno A, Ueda M, Arata J, Nagao Y. Department of Dermatology, Okayama University Medical School, Japan.	J Dermatol 1993 May;20(5):293-7 Abstract quote Granuloma annulare is a degenerative disease of the skin histopathologically characterized by focal degeneration of collagen with a surrounding infiltrate of lymphoid cells, histiocytic cells, and multinucleated giant cells. Immunological abnormalities such as delayed-type hypersensitivity and vasculitic origin are suspected in the pathogenesis. We describe three patients with generalized granuloma annulare, in whom autoantibodies, including antinuclear antibody, antithyroid stimulating hormone receptor antibody, and immune complex, were detected.
RADIOLOGIC
Subcutaneous granuloma annulare: MR imaging findings. De Maeseneer M, Vande Walle H, Lenchik L, Machiels F, Desprechins B. Department of Radiology, Vrije Universiteit Brussel, Jette, Belgium.	Skeletal Radiol 1998 Apr;27(4):215-7 Abstract quote We present a case of subcutaneous granuloma annulare evaluated with MR imaging. The mass was poorly defined and showed thickened interconnecting strands with low signal intensity on T1- and T2-weighted MR images. When a poorly defined subcutaneous mass with low signal intensity on both T1- and T2-weighted MR images is observed in an otherwise healthy child, subcutaneous granuloma annulare should receive serious consideration. Subcutaneous granuloma annulare should be added to the list of tumors with short T2.
Granuloma annulare: radiographic demonstration of progressive mutilating arthropathy with vanishing bones. Bancroft LW, Perniciaro C, Berquist TH. Department of Diagnostic Radiology, Mayo Clinic Jacksonville, FL 32224, USA.	Skeletal Radiol 1998 Apr;27(4):211-4 Abstract quote Granuloma annulare, a relatively common cutaneous disorder of unknown origin, is named for its predominantly papular lesions, which tend to group and coalesce in an annular fashion. Clinically distinct subtypes are divided into localized, generalized, perforating, and subcutaneous forms. Only the superficial granulomata of the extremities in subcutaneous granuloma annulare have been radiographically depicted in the literature. We describe and illustrate what we believe is the first radiographic presentation of bone and joint involvement with advanced, generalized granuloma annulare.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
Localized	80% of cases Erythematous or flesh colored papules grouped in annular or arciform plaques Hands, feet, arms, legs
Papular	Umbilicated papular lesions More common in children Dorsum of hands and fingers
Generalized	15% of cases Middle aged to elderly adults Multiple macules, papules, and nodules Trunk and limbs
Perforating	Grouped papules with central umbilication and scale Extremities
Subcutaneous or deep	Deep dermal or subcutaneous nodules Children and adolescents Lower legs, hands, head and buttocks Associated papules in 25%
VARIANTS
ACRAL-PAINFUL
Acute-onset, painful acral granuloma annulare: a report of 4 cases and a discussion of the clinical and histologic spectrum of the disease. Brey NV, Malone J, Callen JP. Division of Dermatology, Department of Medicine, School of Medicine, University of Louisville, KY 40202, USA.	Arch Dermatol. 2006 Jan;142(1):49-54. Abstract quote   BACKGROUND: Granuloma annulare is a benign cutaneous inflammatory disease of unknown etiology most commonly presenting on the hands and feet and consisting of asymptomatic to mildly pruritic, flesh-colored to erythematous annular plaques. To our knowledge, an acute-onset, painful acral eruption has not been previously recognized. OBSERVATIONS: We report 4 patients who presented with acute-onset, painful acral granuloma annulare. CONCLUSIONS: It is possible for granuloma annulare to present as a painful eruption with an acute onset and an acral distribution. Biopsy results are a crucial factor when establishing the diagnosis of this atypical clinical presentation of granuloma annulare.
LINEAR
Linear granuloma annulare. Harpster EF, Mauro T, Barr RJ. Department of Dermatology, University of California, Davis.	J Am Acad Dermatol 1989 Nov;21(5 Pt 2):1138-41 Abstract quote Granuloma annulare is a benign dermatosis with multiple clinical presentations and a common histologic picture, which is characterized by areas of degenerated collagen surrounded by palisading histiocytes. A case of granuloma annulare that presented as progressive, asymptomatic, symmetric truncal bands is described. The varied clinical presentations and possible pathogenetic mechanisms of granuloma annulare are reviewed.
MYCOSIS FUNGOIDES-LIKE
Granuloma annulare with a mycosis fungoides-like distribution and palisaded granulomas of CD68-positive histiocytes. Wu H, Barusevicius A, Lessin SR. Departments of Pathology, and Medical Oncology, Fox Chase Cancer Center, Philadelphia, and MDR Global Systems, LLC, Windber, USA.	J Am Acad Dermatol. 2004 Jul;51(1 Pt 1):39-44. Abstract quote   We describe 3 unusual cases of granuloma annulare with multiple macular lesions in a distribution that simulated mycosis fungoides in patients with no associated underlying diseases. Repeated biopsies showed typical well-formed palisading granulomas and no evidence of an atypical lymphocytic infiltrate. There was no vasculitis, neutrophilic, eosinophilic, or interstitial infiltrate. The patients had no associated underlying diseases. Most of the histiocytes in the palisading granulomas were strongly positive for CD68. The lymphocytes were a minor component of the granulomatous inflammation and were predominantly CD8(+) T-cells. The findings in these cases add to the spectrum of previously defined granulomatous eruptions of the skin.
PALMAR
Granuloma annulare localized to the palms. Hsu S, Lehner AC, Chang JR. Department of Dermatology, Baylor College of Medicine, Houston, Texas, USA.	J Am Acad Dermatol 1999 Aug;41(2 Pt 2):287-8 Abstract quote Granuloma annulare typically affects the hands and the feet, sparing the volar surfaces. A case of granuloma annulare localized to the palms is described.
PATCH
Patch granuloma annulare: clinicopathologic study of 6 patients. Mutasim DF, Bridges AG. Department of Dermatology, University of Cincinnati Medical Center, Ohio, USA.	J Am Acad Dermatol 2000 Mar;42(3):417-21 Abstract quote BACKGROUND: Granuloma annulare is a common skin disorder that usually presents with smooth papules arranged as annular plaques. Variants, such as disseminated, subcutaneous, and perforating granuloma annulare, have been described. OBJECTIVE: The purpose of this study is to describe the clinical and histologic features of a distinct patch form of granuloma annulare. METHODS: The clinical and histologic features of 6 patients with patch granuloma annulare were evaluated. RESULTS: Six women 27 to 72 years of age had patches on the extremities. Two patients also had a lesion on the trunk. Only one patient had annular patches. Histologic examination showed an interstitial infiltrate of lymphocytes and histiocytes with diffuse necrobiosis. CONCLUSION: Patch granuloma annulare is a distinct variant with rather subtle clinical and histologic features. A high index of suspicion both clinically and histologically aids in making the diagnosis.
PERIOCULAR
Periocular granuloma annulare, nodular type. Occurrence in late middle age. Burnstine MA, Headington JT, Reifler DM, Oestreicher JH, Elner VM. Department of Ophthalmology, W. K. Kellogg Eye Center.	Arch Ophthalmol 1994 Dec;112(12):1590-3 Abstract quote We describe the two oldest individuals with nodular granuloma annulare (pseudorheumatoid nodules) in the ophthalmologic literature and propose a unified classification scheme that recognizes pseudorheumatoid nodules to be granuloma annulare, nodular type. All lesions in both cases revealed so-called necrobiotic granulomas, characterized by an acellular central area containing mucin (hyaluronic acid) surrounded by palisading histiocytes (macrophages), diagnostic of granuloma annulare. These features are identical to those reported in the ophthalmologic and older general pathology literature as pseudorheumatoid nodules and the contemporary general and dermatologic pathology literature as granuloma annulare. We believe the diagnosis of nodular granuloma annulare should be employed for necrobiotic lesions displaying distinctive clinicopathologic features to unite the ophthalmologic, general, and dermatologic pathology literature. Granuloma annulare, nodular type, must also be considered in the differential diagnosis of ocular and periocular lesions at any age.
PSEUDORHEUMATOID NODULES
Pseudorheumatoid nodules in adults: a juxta-articular form of nodular granuloma annulare. Barzilai A, Huszar M, Shpiro D, Nass D, Trau H. Department of Dermatology, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.	Am J Dermatopathol. 2005 Feb;27(1):1-5. Abstract quote Pseudorheumatoid nodules are considered a deep form of granuloma annulare. Most cases are described in children, occur mainly on the lower legs and scalp, and have favorable prognosis. Their appearance in adults is rare. In this series, fourteen women with pseudorheumatoid nodules were studied. The average age of onset was 36 years old. Lesions consisted of erythematous, violaceous, or skin-colored nodules located mainly on the small joints of the hands. None of the patients developed collagen vascular disease. Persistence was common. Biopsy specimens showed deep dermal nodules composed of epithelioid granulomata separated by thickened collagen bundles. In some areas eosinophilic material was surrounded by histiocytes in a palisaded array. Granuloma annulare was present at the periphery of eight cases. Special stains revealed that most of the eosinophilic material was collagen and mucin was present in eleven cases. In sum these findings demonstrate that pseudorheumatoid nodules in adults are a distinct clinical and pathologic entity, which may be mistaken for rheumatoid nodules. They are probably a juxta-articular variant of granuloma annulare.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General
VARIANTS
Necrobiotic granulomas	Areas of necrobiosis surrounded by lymphocytes and histiocytes in the superficial and mid-dermis Multinucleated giant cells Necrobiosis may contain mucin Rarely neutrophilis and nuclear dust
Deep subcutaneous form	Large areas of necrobiosis in deep dermis, subcutaneous adipose tissue, and rarely deep soft tissue Eosinophils more common
Deep granuloma annulare (pseudorheumatoid nodule) in children: clinicopathologic study of 35 cases. McDermott MB, Lind AC, Marley EF, Dehner LP. Lauren V. Ackerman Laboratory of Surgical Pathology, Barnes-Jewish Hospital, St. Louis, MO, USA.	Pediatr Dev Pathol 1998 Jul-Aug;1(4):300-8 Abstract quote Deep granuloma annulare (DGA) is one of several lesions of skin and superficial soft tissues whose histologic character is a palisading granuloma with a small central focus of necrosis or necrobiosis. Unlike the other palisading necrobiotic lesions, DGA has a predilection for children in the first 5 to 6 years of life. A painless subcutaneous nodule(s) in the lower anterior tibial region or foot and the scalp, typically in the occiput, was the most common presenting feature in this study of 35 cases. Additional or recurrent lesions were reported in approximately 70% of cases with clinical follow-up. All lesions showed the presence of necrobiosis; however, one of the characteristic features was the multinodular character of the predominantly mononuclear cellular aggregates. The presence of vascular spaces at the periphery of the nodular profiles served as a clue to the diagnosis of DGA. The palisading arrangement of the mononuclear cells was evident only in those foci with central necrobiosis. A histiocytic disorder or fibrohistiocytic process was a common consideration in the differential diagnosis, especially in those cases with less apparent foci of necrosis. Palisading histiocytes with prominent eosinophilic cytoplasm and some nuclear atypism were problematic with regard to possible epithelioid sarcoma. Our study failed to identify any underlying or predisposing factors in the development of DGA. Despite the fact that DGA is a well-documented lesion in children, it occurs sufficiently infrequently that it is often not considered clinically when it presents as a subcutaneous mass or masses in a child. Its recognition by the pathologist is especially important as the occurrence of additional lesions in a high proportion of children can be anticipated without undue concern.
Subcutaneous granuloma annulare of the extremities in children. Letts M, Carpenter B, Soucy P, Davidson D. Division of Orthopaedics, Children's Hospital of Eastern Ontario, 401 Smyth Rd., Ottawa, ON K1H 8L1.	Can J Surg 2000 Dec;43(6):425-30 Abstract quote OBJECTIVE: To familiarize surgeons to the natural history and treatment of granuloma annulare of the extremities in children. DESIGN: Case review and follow-up by appointment and questionnaire. SETTING: The Children's Hospital of Eastern Ontario, a tertiary referral centre. PATIENTS: Twenty-seven children (23 girls, 4 boys) seen between 1983 and 1998 with subcutaneous granuloma annulare, proven pathologically. The mean age at initial presentation was 8.3 years (range from 1.8 years to 16.7 years). The mean follow-up was 45 weeks (range from 1 week to 5 years). INTERVENTION: Biopsy excision of the lesions. OUTCOME MEASURES: The incidence multiple lesions, the commonest site of occurrence and the incidence of recurrence. RESULTS: Six children presented with multiple lesions for a total of 46 lesions. The anterior pretibial area was the most frequently affected site (16 lesions), followed by the ankle (6 lesions) and the long finger (4 lesions). Five patients suffered recurrence of the lesion, with a total of 7 lesions recurring. CONCLUSIONS: Subcutaneous granuloma annulare is a benign inflammatory skin lesion occurring most frequently in the anterior pretibial area in children, predominantly girls. The incidence of recurrence and of multiple lesions is high. Biopsy is required for definitive diagnosis. The lesion resolves spontaneously without treatment.
Subcutaneous granuloma annulare in childhood: clinicopathologic features in 34 cases. Grogg KL, Nascimento AG. Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.	Pediatrics 2001 Mar;107(3):E42 Abstract quote OBJECTIVE: To gather clinicopathologic data on subcutaneous granuloma annulare (SGA), a subtype of granuloma annulare that occurs exclusively in children and is histologically similar to rheumatoid nodules. DESIGN: Retrospective record review. PATIENTS: Children <10 years old in whom SGA, deep granuloma annulare, or necrobiotic granuloma was diagnosed at the Mayo Clinic (Rochester, MN) from 1983 to 1998. RESULTS: Thirty-four patients (21 girls and 13 boys; average age at diagnosis: 4.6 years) were found to have SGA. The lesions predominantly occurred in the lower extremity, especially in a pretibial location. Local recurrence within 1 month to 7 years was documented in 38.2%; recurrence at other locations was documented in 14.7%. Average follow-up was 60 months; during follow-up, no patients developed signs or symptoms of rheumatologic disease. Insulin-dependent diabetes mellitus was diagnosed in 2 patients, 1 before the development of SGA and 1 after it by 1 month. CONCLUSIONS: SGA is a lesion that presents as subcutaneous nodules on the lower extremities, hands, or scalp in young children. Recurrence is common but usually does not warrant additional biopsy.
Disseminated form	Superficial granulomas within papillary dermis, may resemble lichen nitidus
Interstitial form	Interstitial proliferation of lymphocytes and histiocytes with mucin No formed areas of necrobiosis
Sarcoidal or tuberculoid type	Sarcoidal type granulomas with increased eosinophils and mucin
Perforating type	Central epidermal perforation communicating with underlying necrobiotic granuloma
Perforating granuloma annulare. Penas PF, Jones-Caballero M, Fraga J, Sanchez-Perez J, Garcia-Diez A. Department of Dermatology, Hospital Universitario de la Princesa, Madrid, Spain.	Int J Dermatol 1997 May;36(5):340-8 Abstract quote BACKGROUND: Perforating granuloma annulare (PGA) is considered an histologic subtype of granuloma annulare (GA) and it is described as a very rare disease, usually of children, affecting the dorsum of the hands. Mechanisms leading to perforation are unknown. Our experience suggested a different clinical presentation, so we decided to review our patients and the cases published. METHODS: We present six cases of PGA and review 52 PGA cases reported in the literature. Data regarding sex, age, time of evolution of disease, clinical features, laboratory findings, treatment, and follow-up were collected. The significance level was determined by the chi 2 or Student t test when appropriate. RESULTS: The prevalence of PGA could be up to 5% of GA. Pustular-like lesions can be found in 26% of cases, and scars in 37%; papular, umbilicated, and crusted lesions being the most common finding. While PGA appears as a single lesion in only 9% of cases, and half of the patients are older than 30 years. In GA 50% of cases present as a single lesion and 80% of patients are younger than 30 years. CONCLUSIONS: PGA is different to GA not only histologically but also clinically. It is a disseminated disease, affecting both children and adults, which is characterized by the presence of multiple papules, most of them umbilicated and/or crusted, and characteristically pustular lesions and scars. Histology suggests that the superficial localization of the necrobiotic granuloma leads to the epidermal perforation. Treatment is disappointing.

 

SPECIAL STAINS/ IMMUNOPEROXIDASE	CHARACTERIZATION
Special stains
Immunoperoxidase
Granuloma annulare: an immunohistochemical study. Mullans E, Helm KF. Department of Medicine, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033.	J Cutan Pathol 1994 Apr;21(2):135-9 Abstract quote The monocyte/histiocytic response in granuloma annulare has not been extensively studied. We studied the immunohistochemical staining pattern in granuloma annulare by using a panel of markers for "histiocytic" cells including Ham 56, KP1, factor XIIIa, Mac 387, vimentin, and lysozyme. The infiltrate failed to stain with the histiocytic markers, except with antibodies against vimentin and lysozyme. Commonly used histiocytic markers for infectious, immunogenic, and foreign body granulomas fail to stain the infiltrate in granuloma annulare. We hypothesize that a locally derived, immunologically distinct population of histiocytes produces the reaction pattern of granuloma annulare.
PG-M1
Expression of the histiocytic marker PG-M1 in granuloma annulare and rheumatoid nodules of the skin. Groisman GM, Schafer I, Amar M, Sabo E. Hillel Yaffe Medical Center, Hadera, HaEmek Medical Center, Afula, Carmel Medical Center, Haifa, Israel.	J Cutan Pathol 2002 Nov;29(10):590-5 Abstract quote BACKGROUND: The expression of PG-M1, the most specific histiocytic marker, has not yet been studied in granuloma annulare (GA) and other palisaded granulomas of the skin. We evaluated the reactivity of PG-M1 with a series of GA and rheumatoid nodules (RN) to establish the sensitivity and potential usefulness of this marker in the diagnosis and characterization of these entities. METHODS: Histological sections from 30 GA and 15 RN were immunostained with PG-M1. For comparison, additional sections were stained with KP-1 and lysozyme. The stains were recorded as negative, weakly positive (1+) and strongly positive (2+). RESULTS: PG-M1 stained all cases of GA (100%). KP-1 and lysozyme stained 26 (86%) and 18 (60%) GA cases, respectively. PG-M1 exhibited a significantly stronger staining intensity (1.8 +/- 0.07) when compared with KP-1 (1.4 +/- 0.13) (p = 0.018) and with lysozyme (0.9 +/- 0.15) (p < 0.0001). All RN were stained by PG-M1 (100%). KP-1 and lysozyme stained 14 (93%) and six (40%) RN cases, respectively. PG-M1 staining intensity (1.6 +/- 0.13) was slightly higher than that of KP-1 (1.4 +/- 0.18) (p = 0.27) and significantly higher than that of lysozyme (0.4 +/- 0.13) (p < 0.0001). CONCLUSIONS: PG-M1 is consistently and strongly expressed by the histiocytic population of GA and RN, being more sensitive and reliable than other histiocytic markers. We recommend its use in difficult cases in which the histiocytic nature of the lesion needs to be confirmed.
Direct immunofluorescence (DIF)	Fibrin in the necrobiotic areas Occasional cases show IgM and C3 within the blood vessel wall although this is not a consistent finding.
Electron microscopy (EM)
Granuloma annulare: an elastic tissue disease? Case report and literature review. Hanna WM, Moreno-Merlo F, Andrighetti L. Women's College Hospital, The University of Toronto, Ontario, Canada.	Ultrastruct Pathol 1999 Jan-Feb;23(1):33-8 Abstract quote Granuloma annulare (GA) is a condition characterized by the presence of palisading granulomas usually in the dermis. Traditionally, the histopathological changes are described as consisting of focal degeneration of dermal collagen fibers. However, no convincing evidence for such alteration is found in the literature. A histopathological study was done to ascertain the nature of the dermal abnormality. Ten skin biopsies showing lesions of GA were studied by light and electron microscopy. On light microscopy, all lesions showed focal dermal degeneration with near total loss of elastic fibers. Ultrastructural examination in nine cases demonstrated degenerated elastic fibers with loss of peripheral microfibrils and abnormal elastic matrix. The degenerated elastic fibers were surrounded by intact collagen fibers. These findings show that the main alteration in GA is elastic fiber degeneration and strongly suggest that the primary target leading to the development of this disorder is injury to the elastic tissue.

 

DIFFERENTIAL DIAGNOSIS	CHARACTERIZATION
ACTINIC GRANULOMA
Actinic Granuloma is a Unique and Distinct Entity: A Comparative Study With Granuloma Annulare Ibrahim A. Al-Hoqail, M.D.; Abdulmonem M. Al-Ghamdi, M.D.; Magda Martinka, M.D.; Richard I. Crawford, M.D.	Am J Dermatopathol 2002; 24(3):209-212 Abstract quote Since the initial description of actinic granuloma (AG), debate has continued over whether it should be considered a specific condition or simply granuloma annulare (GA) located in sun-exposed areas of skin. We conducted a case-control study to clarify this issue. Twenty cases given the diagnosis of AG between 1991 and 2001 were retrieved from our archives. We applied the following inclusion criteria: extensive loss of elastic tissue in or at the side of the granuloma, and elastophagocytosis. Sixteen cases of GA that involved sun-exposed and non-sun-exposed sites, 8 cases from each group, were randomly selected as controls. Histologic parameters were quantitated on hematoxylin-eosin, Verhoeff van Gieson, and Alcian blue stains for each case. Results were statistically analyzed by SPSS program version 9. Fourteen cases of AG met our inclusion criteria. Presence of mucin, occurrence of multinucleated giant cells, and the type of granulomata were of high statistical significance (p < 0.01) in distinguishing the two entities. We also found that the location of the granulomata in these conditions is different and of statistical significance (p < 0.05). Based on histomorphology, we believe that AG should be considered a separate, independent condition and should be distinguished from GA even in sun-exposed areas of skin.
EPITHELIOID SARCOMA
Epithelioid sarcoma masquerading as perforating granuloma annulare. Lopez-Rios F, Rodriguez-Peralto JL, Castano E, Gil R.	Histopathology 1997 Jul;31(1):102-3
KAPOSI'S SARCOMA
Human herpesvirus 8 and iron staining are useful in differentiating kaposi sarcoma from interstitial granuloma annulare. Wada DA, Perkins SL, Tripp S, Coffin CM, Florell SR. Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132-2409, USA.	Am J Clin Pathol. 2007 Feb;127(2):263-70. Abstract quote We studied 20 granuloma annulare (GA) cases (10 interstitial and 10 palisaded) and 19 Kaposi sarcoma (KS) cases (9 "early" and 10 typical). Tissue sections were stained for iron, Hale colloidal iron, human herpesvirus 8 (HHV-8), CD31, CD34, CD68, collagen IV, factor XIIIa, and MIB-1. Iron staining of dermal tissue associated with the lesion was confirmed in all KS cases and no GA cases. Immunohistochemical stains for HHV-8 were positive in all 9 cases of early KS and most cases (9/10) of typical KS. All 20 cases of GA were HHV-8-. CD31, CD34, CD68, factor XIIIa, and MIB-1 were also stained but were difficult to interpret and did not seem specific for GA or KS. Iron staining and immunohistochemical HHV-8 staining in combination were reliable markers for KS compared with interstitial GA. MIB-1 fractions of less than 5% favored a diagnosis of GA, whereas fractions greater than 10% favored a diagnosis of KS. This study provides novel data characterizing iron staining in KS and details the use of iron staining, HHV-8, and MIB-1 to distinguish KS from GA.
MYCOBACTERIUM INFECTION
Mycobacterium marinum Infection Simulating Interstitial Granuloma Annulare: A Report of Two Cases. Barr KL, Lowe L, Su LD.	Am J Dermatopathol 2003 Apr;25(2):148-51 Abstract quote We report two cases of Mycobacterium marinum infection that histologically simulated interstitial granuloma annulare (GA). In one case, an infectious etiology was not suspected in histologic sections, but a tissue culture performed during the patient's clinic visit identified M. marinum, and a subsequent Fite stain revealed mycobacteria. Interstitial granulomatous dermatitis is a rare presentation for cutaneous nontuberculous mycobacteria and has yet to be attributed specifically to M. marinum. In both immunocompetent and immunosuppressed patients, infection with M. marinum should be considered in lesions histologically resembling interstitial GA, particularly when there is clinical suspicion for an infectious process.
PAPULAR ELASTOLYCTIC GIANT CELL GRANULOMA
Papular elastolytic giant cell granuloma: a clinical variant of annular elastolytic giant cell granuloma or generalized granuloma annulare? Morita K, Okamoto H, Miyachi Y. Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.	Eur J Dermatol 1999 Dec;9(8):647-9 Abstract quote A 71-year-old man with asymptomatic red papules on the trunk and upper arms was reported as a case of papular elastolytic giant cell granuloma. A skin biopsy specimen from a papule on the back showed similar findings to those of annular elastolytic giant cell granuloma. However, centrifugal annular lesions were not clinically observed. He was successfully treated with tranilast and topical steroids.
SYPHILIS
Nodular tertiary syphilis mimicking granuloma annulare. Wu SJ, Nguyen EQ, Nielsen TA, Pellegrini AE. Division of Dermatology, The Ohio State University, Columbus 43210, USA.	J Am Acad Dermatol 2000 Feb;42(2 Pt 2):378-80 Abstract quote We describe a 47-year-old man with annular plaques on the arms and torso that were treated as granuloma annulare, based on clinical and histopathologic findings. Exacerbation of the lesions during treatment with topical corticosteroids prompted a search for an infectious cause, which proved to be syphilis in the tertiary stage. The clinician should maintain a high index of suspicion for syphilis in the differential diagnosis of unusual annular skin lesions in a patient with noncaseating granulomas seen on skin biopsy.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Resolution of patch-type granuloma annulare lesions after biopsy Nikki A. Levin, MD, PhD James W. Patterson, MD Luke L. Yao Barbara B. Wilson, MD Charlottesville, Virginia	J Am Acad Dermatol 2002;46:426-9 Abstract quote We describe a patient with patch-type granuloma annulare whose lesions resolved after biopsy on 2 occasions. The lesions not subjected to biopsy persisted. There is a paucity of literature on the relation between biopsy and resolution of granuloma annulare, with one frequently cited article implying that biopsy is not related to resolution. We briefly consider possible mechanisms through which involution of lesions of granuloma annulare could result after biopsy or other form of trauma.
TREATMENT	CHARACTERIZATION
PUVA
Photochemotherapy of generalized granuloma annulare. Kerker BJ, Huang CP, Morison WL. Department of Dermatology, Johns Hopkins Medical Institutions, Baltimore, Md. 21205.	Arch Dermatol 1990 Mar;126(3):359-61 Abstract quote Various forms of treatment for generalized granuloma annulare have been employed with little success. The results of treatment with topical and intralesional corticosteroids, as well as systemic therapy with corticosteroids, salicylates, aspirin, niacinamide, and chloroquine, have been generally disappointing. We describe five patients with generalized granuloma annulare of several years' duration who were treated with oral psoralen plus ultraviolet A irradiation. Lesions were present on the extremities, buttocks, and trunk in the form of macules, papules, and plaques. One patient also had perforating lesions on her thighs. Flattening of the lesions with decreased erythema and pigmentation was noted as early as 1 month after initiation of treatment. Complete clearance was achieved in all patients. Maintenance therapy has been required, resulting in prolonged disease-free intervals. Although the mechanism of action of oral psoralen plus ultraviolet A irradiation in granuloma annulare is unclear, one possibility is selective elimination of the cells that are responsible for initiating the disease.
Generalised granuloma annulare successfully treated with PUVA. Setterfield J, Huilgol SC, Black MM. St John's Institute of Dermatology, St Thomas' Hospital, London.	Clin Exp Dermatol 1999 Nov;24(6):458-60 Abstract quote Disseminated granuloma annulare is an uncommon disorder in which both topical and systemic therapy may have limited success. Anecdotal reports have suggested that PUVA may result in complete clearance of disease; however, maintenance PUVA therapy has usually been required in order to maintain remission. We report the successful treatment of a patient with 5-methoxypsoralen over a 7-month period who remained in remission during a 20-month follow up period.
Cream psoralen plus ultraviolet A therapy for granuloma annulare. Grundmann-Kollmann M, Ochsendorf FR, Zollner TM, Tegeder I, Kaufmann R, Podda M. Department of Dermatology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.	Br J Dermatol 2001 May;144(5):996-9 Abstract quote BACKGROUND: Treatment modalities for granuloma annulare (GA) often remain unsatisfactory or can be accompanied by potentially hazardous side-effects. Psoralen plus ultraviolet (UV) A (PUVA) bath photochemotherapy has been reported to be highly effective in the treatment of GA. Another form of topical PUVA therapy, using 8-methoxypsoralen-containing cream or gel preparations, has been proven to be as effective as bath PUVA therapy in the treatment of palmoplantar dermatoses. OBJECTIVES: To assess the efficacy of cream PUVA photochemotherapy in patients with GA. METHODS: Five patients with GA were treated. The diagnosis was confirmed by pretreatment skin biopsies. Cream PUVA therapy was performed four times a week: the mean number of treatments was 26 (range 17-40) and mean cumulative UVA dose was 55.9 J cm-2 (range 18.2-109.2). RESULTS: Cream PUVA photochemotherapy induced significant clinical improvement (one patient) or clearance (four patients) of GA in all patients. Clearance was documented clinically and histopathologically. CONCLUSIONS: Cream PUVA phototherapy can be highly effective in patients affected by localized forms of GA.

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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