Inflammatory Diseases of the Skin
Moderator: Dr. Lorenzo Cerroni
Cases 17-19 -
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
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. 
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
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. 
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
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.  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 (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
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 (NXG) is a rare disorder associated with paraproteinemia in most
patients.  Patients present with reddish-yellow plaques
and nodules on the head & neck (especially periorbital) skin, trunk, and extremities. Ulceration is
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.
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.
- 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.