Background

Granulomas of the skin may have several different etiologies. In general, both infectious and non-infectious causes must be investigated. Some of the additional tests a pathologist may utilize include special stains such as an Acid Fast, Fite, Gram, Warthin-Starry, PAS, and GMS stains. In addition, polarization with refractile light examination may be helpful in identifying some causes of a foreign body giant cell reaction.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
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

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
ACUPUNCTURE
Acupuncture granulomas Rhoda M. Alani, MD Klaus Busam, MD New York, New York	J Am Acad Dermatol 2001;45:S225-6 Abstract quote Silicone compounds have recently been a source of controversy with regard to their potential role in the genesis of collagen vascular diseases. Foreign body reactions to injectable silicone were noted early in its cosmetic use and led to subsequent abandonment of this procedure. Here we report the first documented case of silicone granulomas to occur after acupuncture.
ALUMINUM CHLORIDE (DRYSOL)
Histiocytic reaction associated with topical aluminum chloride (Drysol reaction) Barr RJ, Alpern KS, Jay S. Department of Dermatology, University of California, Irvine.	J Dermatol Surg Oncol 1993 Nov;19(11):1017-21 Abstract quote BACKGROUND. In the past few years, dermatologists have begun to use aluminum chloride (Drysol) as a hemostatic agent for minor surgical procedures. An unusual histiocytic reaction was noted in biopsies of skin previously treated with aluminum chloride. This reaction consisted of a proliferation of histiocytic cells that contained prominent basophilic cytoplasmic granules. OBJECTIVE. To determine the cause of this reaction and the nature of the basophilic granular material within the histiocytic cells. METHODS. Four cases are presented in which re-excised tissue previously treated with aluminum chloride were examined with special histochemistry staining and roentgen diffraction studies. RESULTS. The granules of these histiocytes stained positively with the aluminon stain, a stain specific for aluminum, although no aluminum was found using the less sensitive roentgen diffraction studies. CONCLUSION. These studies support the concept that aluminum chloride can cause a proliferative histiocytic reaction when used as a topical cauterizing agent.
INTERERON ALPHA INJECTIONS
Granulomatous and suppurative dermatitis at interferon alfa injection sites: report of 2 cases. Sanders S, Busam K, Tahan SR, Johnson RA, Sachs D. Department of Dermatology, New York Hospital, NY, USA.	J Am Acad Dermatol 2002 Apr;46(4):611-6 Abstract quote It has previously been reported that interferon alfa injection sites may develop pyoderma gangrenosum, interface dermatitis, vasculitis, or, more commonly, ulcers characterized by intravascular thrombi and a mixed inflammatory cell infiltrate. We describe 2 patients in whom granulomatous and suppurative dermatitis developed at interferon alfa injection sites. These cases extend the spectrum of interferon alfa injection site reactions. The histologic and clinical similarities of these cases with pyoderma gangrenosum and cutaneous Crohn's disease are explored.
COLLAGEN INJECTIONS
Delayed skin test reaction to injectable collagen implant (Zyderm). The histopathologic comparative study. Barr RJ, Stegman SJ.	J Am Acad Dermatol 1984 Apr;10(4):652-8 Abstract quote The histopathologic comparative study. Barr RJ, Stegman SJ. Ten cases of persistent positive test site responses to enzyme-digested purified bovine collagen solution (EPC; Zyderm Collagen Implant) were reviewed. Specimens were stained with hematoxylin and eosin, Gomori's trichrome, colloidal iron, elastic van Gieson, Snook 's reticulum, and polarized light. These granulomatous-like reactions were compared with cases of granuloma annulare, hypertrophic scarring, keloids, and rheumatoid nodules. These studies make it possible to differentiate a normal EPC implant from normal reticular dermis. The granulomatous reaction around the EPC implant can be differentiated from granuloma annulare, scars and keloids, and rheumatoid nodules. It is our conclusion that the granulomatous material is probably a combination of EPC and small amounts of altered human collagen.
DERMALIVE
Facial granulomas secondary to dermalive microimplants: report of a case with histopathologic differential diagnosis among the granulomas secondary to different injectable permanent filler materials. Vargas-Machuca I, Gonzalez-Guerra E, Angulo J, Del Carmen Farina M, Martin L, Requena L. Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.	Am J Dermatopathol. 2006 Apr;28(2):173-7. Abstract quote   Wrinkle reduction and the correction of skin defects using injectable aesthetic microimplants are now widely performed by dermatologists and plastic surgeons. In recent years, dermal filler substances containing polymer particle suspensions such as Bioplastique, Artecoll, and Dermalive are the most commonly used materials. These microimplants are permanent, non-biodegradable, and generally well tolerated, although various adverse reactions are still possible. We describe here a patient with facial granulomas secondary to Dermalive injections for correction of naso-labial folds and wrinkles. The particular shape of the injected particles allows for correct identification of the implanted material. Therefore, histopathologic examination is the best means to obtain the correct diagnosis of foreign body granuloma and to identify the type of filler particles. We discuss the histopathologic differential diagnosis among the granulomas secondary to the most commonly used aesthetic permanent filler materials.
LYMPHOMA, SYSTEMIC
Different histologic patterns of cutaneous granulomas in systemic lymphoma. Rongioletti F, Cerroni L, Massone C, Basso M, Ciambellotti A, Rebora A. Center of Dermatopathology and Section of Dermatology, DISEM, University of Genoa, Italy.	J Am Acad Dermatol. 2004 Oct;51(4):600-5. Abstract quote   BACKGROUND: Patients with Hodgkin's and non-Hodgkin's lymphomas may develop non-infectious granulomas in both involved and uninvolved organs, but rarely in the skin. Cutaneous granulomas in the setting of a systemic lymphoma are of two types. The first type is characterized by granulomatous infiltrates admixed with neoplastic cells within specific skin lesions of malignant lymphomas. The second type consists of granulomatous skin processes that are non-specific manifestations of the underlying lymphoma. OBJECTIVE: To describe the variegate histologic patterns of cutaneous granulomatous reactions of the second type in patients with systemic lymphomas. METHODS: We describe three patients with systemic lymphomas who exhibited three different histologic patterns of cutaneous granulomatous lesions. RESULTS: The first patient had non-Hodgkin's lymphoma with cutaneous tuberculoid-type granuloma mimicking tuberculoid leprosy; the second patient had Hodgkin's lymphoma with palisaded, necrobiotic granuloma of granuloma annulare-type; and the third patient had non-Hodgkin's lymphoma with sarcoid-type granuloma. No evidence of the underlying systemic lymphoma was found in the cutaneous lesions involved by the granulomatous process. CONCLUSIONS: Cutaneous granulomas may be a non-specific sign of an underlying systemic lymphoma. Their histologic patterns are variegate and include sarcoid-type granuloma, palisaded and necrobiotic granuloma of granuloma annulare-type, and tuberculoid granuloma. In patients who present with non-infectious, granulomatous skin reactions in the absence of another sound explanation, the possibility of a systemic lymphoma should be considered.
PARAFFINOMA
Paraffinomas of the scalp. Klein JA, Cole G, Barr RJ, Bartlow G, Fulwider C.	Arch Dermatol 1985 Mar;121(3):382-5 Abstract quote Four cases of scalp paraffinoma were seen in our clinics within the past year. This unusual condition results from intradermal injection of substances containing paraffin. The presence of paraffin in excised tissue was confirmed by thin-layer chromatography and infrared absorption spectrophotometry. Our patients received their treatments 35 to 42 years ago after responding to radio or newspaper advertisements that promised a cure for baldness. Two patients were initially observed with severe scalp inflammation and two were completely asymptomatic other than having lumpy scalps. Although these cases were readily diagnosed by history, eliminating other possibilities was greatly aided by use of xeroradiography, obviating the need for biopsy in asymptomatic cases.
Penile paraffinoma: Self-injection with mineral oil. Cohen JL, Keoleian CM, Krull EA. Departments of Dermatology and Urology, Henry Ford Hospital	J Am Acad Dermatol 2002 Nov;47(5 Suppl):S251-3 Abstract quote We present a 64-year-old patient with a 9-cm firm, irregular penile mass associated with phimosis, erectile dysfunction, and voiding difficulty. After he reluctantly admitted to multiple penile mineral oil self-injections for enlargement, surgical excision was performed. Pathologic examination was consistent with mineral oil granuloma (paraffinoma). Within several weeks after surgery, his erectile dysfunction and voiding complaints resolved. Paraffinomas have been encountered with the use of various oily substances injected for cosmetic purposes. Despite early warnings, these agents continued to be used to treat conditions ranging from hemorrhoids to wrinkles and even baldness. Fortunately, most of these fads have been abandoned by medical professionals, but the complicating lesions have been documented as having lag times as long as 30 years. Complete surgical excision remains the treatment of choice to prevent recurrence. Increased public awareness is needed for the prevention of this physically and psychologically debilitating problem.

 

PATHOGENESIS

CHARACTERIZATION

Interstitial heparan sulfate in granulomatous inflammatory skin diseases. Deprisco G, Bandel C, Cockerell CJ, Ehrig T.

J Am Acad Dermatol. 2004 Feb;50(2):253-7. Abstract quote   BACKGROUND: Heparan sulfate (HS) is a glycosaminoglycan that is anchored to the outside of cell membranes. Under ordinary circumstances, it is not present in the interstitium, but under certain circumstances, mainly in the setting of inflammation and tissue repair, HS can be shed from the cell surface into the interstitium in a regulated fashion. Under these circumstances, interstitial HS seems to have an immunomodulatory function because of its binding of many cytokines. However, it is not known which cell types present at an inflammatory site are responsible for this shedding. OBJECTIVE: We have investigated the presence of interstitial HS by immunohistochemistry in various inflammatory skin diseases characterized by different compositions of the inflammatory infiltrate. RESULTS: Strong interstitial HS immunoreactivity was present only in diseases with a predominantly histiocytic infiltrate but not in diseases with a predominantly lymphocytic or neutrophilic infiltrate. CONCLUSIONS: This indicates that histiocytes have a direct or indirect role in the HS shedding process. In the well-formed granulomas of sarcoidosis, interstitial HS immunoreactivity was spatially associated with the fibrotic ring at the periphery of the granulomas, but not with the center harboring the histiocytes. This suggests that histiocytes can stimulate fibroblasts to shed HS into the interstitium.

 

CLINICAL VARIANTS	CHARACTERIZATION
FACIAL DISEASE
INFECTIOUS	Tuberculosis and papulonecrotic tuberculid Leprosy Atypical Mycobacteria Late secondary and tertiary syphilis Cat-scratch disease Pseudomycoses (actinomycosis, nocardiosis, botryomycosis) Deep fungal infections Leishmaniasis Demodicidosis
INFLAMMATORY, UNKNOWN CAUSE	Granulomatous rosacea Sarcoidosis Lupus miliaris disseminatus faciei Acne agminata Crohn disease Granulomatous cheilitis and Melkersson-Rosenthal Granuloma annulare and actinic granuloma Necrobiosis lipoidica Necrobiotic xanthogranuloma Granulomatous vasculitis (Wegener's, Churg-Strauss disease)
INFLAMMATORY, IDENTIFIABLE ETIOLOGY	Foreign body granuloma
NEOPLASTIC	Granulomatous Mycosis Fungoides Lymphomas with prominent reactive histiocytic infiltration (Lennert's disease)
NONGRANULOMATOUS DISEASES MISNAMED AS GRANULOMA	Granuloma faciale Lymphomatoid granulomatosis Lethal midline granuloma

HISTOPATHOLOGY	CHARACTERIZATION
GENERAL
Non-infectious granulomatous dermatitis: a clinicopathological study. Mohan H, Bal A, Dhami GP. Department of Pathology, Government Medical College & Hospital, Chandigarh, India.	J Cutan Pathol. 2006 Dec;33(12):767-71 Abstract quote Background: Granulomatous dermatitis frequently presents a diagnostic challenge to dermatopathologists because an identical histologic picture is produced by several causes, and conversely, a single cause may produce varied histologic patterns. Methods: A retrospective analysis of skin biopsies received over a period of 7 years was performed, and cases of non-infectious granulomatous dermatitis diagnosed on histopathological examination were retrieved. Results: Out of a total of 586 cases of granulomatous dermatitis, 71 cases (12.11%) were categorized as non-infectious granulomatous dermatitis on the basis of clinicopathological findings. Further subcategorization was done based on morphology of granulomas as epithelioid granulomas; 15 cases of sarcoidosis, 21.1%, one case of Crohn's vulvitis, 1.4%, necrobiotic granulomas; 11 cases of granuloma annulare, 15.4%, two cases of rheumatoid nodule, 2.8%, 10 cases of foreign body granulomas, 14.0%; 32 cases of miscellaneous group, 45%. Conclusions: Morphology alone is seldom specific and cannot be used as a diagnostic tool for identification of specific diseases. Adequate clinical data and work up in combination of pathological resources can help in elucidation of specific etiology of granulomatous dermatitis.

Am J Dermatopathol 2001;23:8-15
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
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
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated January 8, 2007

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