Cases 17-19 -

Non-Infectious Granulomas Roger H. Weenig, M.D.

Although special stains for micro-organisms, polarization microscopy, and occasionally immunoperoxidase stains may be required to exclude infection, a foreign body, or a neoplastic cause of granulomatous inflammation, pattern recognition usually allows dermatopathologists to correctly diagnose non-infectious granulomas of the skin. Cutaneous Sarcoidal Granulomas Sarcoidal granulomatous inflammation in the skin is a relatively frequent finding in dermatopathology practice. In addition to cutaneous involvement by sarcoid, cutaneous sarcoidal granulomatous inflammation occurs in other, non-sarcoid illnesses. Conditions which may be associated with mucosal and cutaneous sarcoidal granulomatous inflammation include: cutaneous Crohn's disease, Oral-facial granulomatosis (Melkerson-Rosenthal syndrome and Cheilitis Granulomatosis) , granulomatous acne rosacea, foreign body reaction (including reaction to tattoo pigment), herpes zoster scar, and some cases of cutaneous T-cell lymphoma. Case 17: A 79-year-old female presents with a 2 month history of progressive pink - red papules and plaques on the trunk, face, and extremities. Several of the papules and plaques are ulcerated. The patients past medical history is positive for 2 primary lung adenocarcinomas treated surgically 5 and 7 years ago respectively, and a history of breast cancer treated with mastectomy. The patient also carried a diagnosis of sero-negative rheumatoid arthritis. Case 17 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Skin involvement by sarcoidosis may occur in association with systemic sarcoidosis or in isolation. There are no consistent clinical or histologic presentations of cutaneous sarcoidosis that indicate if a patient will have systemic sarcoidosis. The clinical presentation is highly variable, but includes papules, plaques, and dermal or subcutaneous nodules. Other clinical presentations include: alopecic, ichthyosiform, ulcerative, verrucous, erythrodermic, and scar sarcoidosis. Sarcoidal skin lesions often impart a characteristic red to golden-brown "apple jelly" color. Histopathologic findings in cutaneous sarcoidal granulomatous inflammation include circumscribed aggregates of non-necrotizing, epthelioid histocytes with minimal surrounding lymphocytic inflammation in the dermis and or subcutis. Special stains for microorganisms are negative. However, polarization microscopy may identify polarizable material in patients with sarcoidosis, or in sarcoidal granulomas associated with tattoo pigments, Beryllium, Zirconium, nylon fibers, keratin, medications, and other foreign substances. Energy-dispersive x-ray microanalysis has identified inorganic elements in the granulomas from patients with sarcoidosis. [1] Cutaneous Oil-injection Granulomas (Lipogranuloma) Injection of oily materials in the skin may result from accidental, patient induced, or iatrogenic cutaneous injection of a variety of substances. Tissue augmentation with oily substances (such as mineral oil, silicone, or paraffin), injection of certain medications (pentazocine abuse), or grease gun injury results in a lipogranuloma. Case 18: A 28-year-old female, physical trainer / professional "dancer" presents with a two-month history of indurated, slightly erythematous plaques on her thighs in association with fevers, chills, night sweats and joint aches. The day prior to the onset of symptoms, the patient was doing a leg workout which was of moderate intensity. The next morning she noted some tenderness, redness and thickening of the skin overlying her anterior hip region. Case 18 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Clinically, patients present with indurated, variably tender, inflamed nodules or plaques. Areas of depression central to the indurated process may occur. Spread of the material to the lymph nodes or lungs may result in lymphadenopathy and pulmonary infiltrates. Lipogranulomas are characterized by numerous, variably-sized empty spaces surrounded by small ribbons of collagen within the dermis and subcutis. The empty vacuoles have been described as imparting a "swiss cheese-like" pattern. Admixed histiocytes, lipophagia, granuloma formation, fat necrosis, and sclerosis are seen to varying degrees. An acute lobular panniculitis may be the initial histologic presentation or it may accompany the granulomatous inflammation. Precise identification of the foreign material is often infeasible, but energy-dispersive x-ray microanalysis can identify inorganic material, such as silicone. Cutaneous Palisaded Granulomas The major diagnoses to consider when encountering palisading granulomatous inflammation in the skin includes: granuloma annulare, necrobiosis lipoidica, necrobiotic xanthogranuloma, rheumatoid nodule, and palisaded neutrophilic and granulomatous dermatitis. Each of the forgoing conditions has classic clinical and histologic presentations, but subtypes and variations are often encountered in daily practice. Infectious diseases may also present with palisaded granulomatous inflammation. [2] Case 19: A 56-year-old male presents for evaluation of a suspected drug eruption due to itraconazole. The patient had been taking itraconazole for 4 months for presumed pulmonary histoplasmosis, diagnosed by serologic study, a positive M-band histoplasmosis-immunodiffusion assay, and ung biopsy findings of fibrocaseous granulomatous inflammation. The patient also noted recent development of induration in areas of previous scaring on distal extremities. Physical exam revealed diffuse pink papules distributed on the trunk and extremities. Involving the scalp, several 3 - 4 cm, well-circumscribed annular brown plaques were note. Several scars on the distal extremities showed induration and a brownish coloration. The submitted biopsy is from a right forearm scar. Case 19 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Granuloma annulare: The prototypic palisading granuloma, granuloma annulare (GA) is a common inflammatory dermatosis with an unknown pathogenesis. An association between diabetes mellitus and GA remains controversial, but appears more common in generalized GA. [3] Medications, infections, autoimmune diseases, and neoplasms have been reported in association with GA in the literature but unconfirmed. Patients present with few to innumerable erythematous papules, arcuate to annular plaques, erythematous patches, and subcutaneous nodules. Ulceration has only been observed in perforating GA. Distal extremities are a predisposed location and facial or genital involvement is rare. The classic histologic presentation of GA displays a palisade of histiocytes surrounding foci of mucinous collagen degeneration with admixed lymphocytes and eosinophils in the superficial to mid dermis. Subcutaneous GA resembles a rheumatoid nodule with large areas of altered (necrobiotic) collagen. Mucinous necrobiosis favors GA and fibrinoid necrobiosis favors rheumatoid nodule. Interstitial (or "incomplete") granuloma annulare shows a mild lymphohistiocytic infiltrate coursing between collagen bundles with minimal necrobiosis. Necrobiosis lipoidica Necrobiosis lipoidica (NL) is a relatively rare inflammatory dermatosis that is associated with diabetes approximately 1/3 of patients. Whereas, NL occurs in up to 0.3% of patients with diabetes mellitus (hence the other designation, necrobiosis lipoidica diabeticorum). [4] The clinical presentation of NL is typically characterized by circumscribed pink-red/brown atrophic plaques on the lower extremities (especially the anterior tibial region). Lesions on other body sites, including the face (also designated "atypical NL"), may occur. However, facial (particularly periorbital) involvement by lesions that clinically and histologically resemble NL should raise concern for necrobiotic xanthogranuloma. Ulceration in NL in may also occur. Histopathologic findings in NL are typified by palisades of histiocytes in the dermis and subcutis in layer-like pattern with interposed necrobiotic collagen. Giant cells and plasmacytic inflammation are more common in NL than in granuloma annulare. Necrobiotic xanthogranuloma Necrobiotic xanthogranuloma (NXG) is a rare disorder associated with paraproteinemia in most patients. [5] Patients present with reddish-yellow plaques and nodules on the head & neck (especially periorbital) skin, trunk, and extremities. Ulceration is frequent. The histopathologic findings in NXG include expanded zones of hyalinized collagen (necrobiosis) surrounded by dense granulomatous inflammation with characteristically large, bi-polar giant cells and foamy (xanthomatized) histiocytes. Admixed plasma cells, lymphoid follicles, and cholesterol clefts may also be observed. Rheumatoid nodule Although the frequency of rheumatoid nodule (RN) has been reported to occur in up to 20% of patients with rheumatoid arthritis, RN are observed less frequently nowadays. Clinically, RN tends to occur in juxta-articular location as variably-sized slightly red, flesh-colored, or whitish subcutaneous nodules. The classical histologic findings in RN consist of a subcutaneous nodular or multinodular lymphohistiocytic infiltrate surrounding large aggregates of fibrinoid necrobiosis (hyalinized degeneration of collagen). Mucin deposition or myxoid collagen degeneration favor subcutaneous GA over RN. Leukocytoclastic vasculitis may be observed in adjacent blood vessels. Palisaded neutrophilic and granulomatous dermatitis Palisaded neutrophilic and granulomatous dermatitis (PNGD) is the least settled entity in the group of non-infectious, palisading cutaneous granulomas. The red papules over bone prominences with the histology of PNGD were originally recognized in 1951 by Churg and Strass in association with allergic granulomatosis. Histologically identical but clinically distinct linear subcutaneous bands in the setting or rheumatoid arthritis were described by Dykman, et al in 1965. Several series of patients were reported by Winkelmann and colleagues beginning in 1977 and formally designated "extravascular necrotizing granuloma" in 1983. A variety of conditions, inflammatory, infectious, and neoplastic were associated with Winkelmann's patients. In 1982, Jorizzo reported "superficial ulcerating rheumatoid necrobiosis," then in 1989 as "rheumatoid papules." In 1993, Ackerman coined "interstitial granulomatous dermatitis with arthritis." Finally, in 1994 Chu & Leboit offered a designation of "Palisaded Neutrophilic and Granulomatous Dermatitis." However, in the same year Wilmoth & Perniciaro offer "Winkelmann Granuloma" as the preferred term. Nine years later Kroesen, et al countered with "Ackerman Syndrome" in 2003. The clinical lesions of PNGD are variable, two patterns are most frequently observed. (1) Flesh-colored to pink-red, 2 – 4 mm, umbilicated papules over boney prominences (especially elbows and the dorsal aspect of digits), and (2) Linear indurated cord-like plaques on the proximal extremities or the flanks. However, large arcuate to annular plaques and even a livedo vasculare-like presentation may be seen. The skin lesions of PNGD are often asymptomatic but tend to develop superficial ulceration. Diseases reported in association with PNGD include: Collagen Vascular / Systemic Inflammatory Diseases (rheumatoid arthritis, sero-negative arthritis, Still's disease, systemic lupus erythematous, Wegener granulomatosis, Chrug-Strauss syndrome, Behcet disease, Takayasu aortitis, inflammatory bowel disease, mixed cryoglobulinemia, and hepatitis); Infectious (sub-acute bacterial endocarditis, pulmonary and Coccidioidomycosis); Lymphoproliferative disorders (non- Hodgkin lymphoma, chronic lymphocytic leukemia, and myelodysplastic syndrome); Carcinoma (pulmonary adenocarcinoma, metastatic prostate carcinoma); Drugs: (methotrexate, penicillin, TNF- a inhibitors, including: lenalidomide, infliximab, etanercept, ACE-inhibitor, furosemide, fluindione); and Silicosis. Histopathologic findings in PNGD may be thought of as a hybrid between granuloma annulare and leukocytoclastic vasculitis. At low power, one observes dermal palisades of histiocytes and lymphocytes surrounding areas of basophilic collagen. At higher magnification, interstitial aggregates of neutrophils, leukocytoclasis, and basophilic debris are appreciated. Some of perivascular infiltrates may suggest leukocytoclastic vasculitis, but fibrinoid vascular necrosis is rarely identified. References Kim Y, Triffet M, Gibson LE. Foreign Bodies in Sarcoidosis. American Journal of Dermatopathology. 2000;22:408-412. Su WP, Kuechle MK, Peters MS, Palisading granulomas caused by infectious diseases. Am J Dermatopathol. 1992;14:211-5. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol. 1989;20:39-47. Muller SA, Winkelmann FK. Necrobiosis lipoidica diabeticorum. A clinical and pathologic investigation of 171 cases. Arch Dermatol. 1966;93:272-81. Kossard S, Winkelmann RK. Necrotiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol. 1980;21:85-88.