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Granulomatous Alopecia: A Variantof Alopecia Areata?

Paniz Mondolfi AE1,2, Cressey BD1, Ahmad A3, Tapia-Centola B1,2, Cohen LM4,5 and Mahmoodi M1

1Miraca Life Sciences Research Institute/Tufts Medical Center, Department of Dermatology, 800 Washington Street, Box 114, Boston, MA 02111,2Instituto de Biomedicina, MSDS/UCV/IVSS, Caracas, Venezuela,

3Department of Pathology, Duke University Medical Center, Durham, NC 27710,4Department of Pathology, Massachusetts General Hospital, Boston, MA, and

5Harvard Medical School, Boston, MA

e-mail: Alberto.PanizMondolfi@bcm.edu

Keywords: alopecia, alopecia areata, granulomatous alopecia, non-scarring

Accepted for publication December 2, 2012

Alopecia areata (AA) represents a T-cell mediateddisorder characterized by non-scarring hair lossinvolving the scalp and/or any hair-bearing surfaceon the body. A wide range of clinical presenta-tions can occur, ranging from a single patch of hairloss to complete loss of hair on the scalp (alope-cia totalis) or the entire body (alopecia universalis).Histopathologically, AA is characterized by a denseperibulbar lymphocytic infiltrate, follicular miniatur-ization, increased catagen and telogen follicles, andoccasional perifollicular fibrosis. AA is not known tobe a granulomatous disorder. In the context of alope-cia, the identification of granulomatous inflammationis extremely rare and is sparsely described in the lit-erature in association with sarcoidosis and syphilis.1

Recently we have encountered two cases ofalopecia presenting with prominent granulomatousinflammation but lacking any history of syphilis,sarcoidosis, or any other granulomatous disease.The first patient was a 65-year-old Latina presentingwith a one-month history of a patch of alopecia inthe occipital region. Clinical examination revealed awell demarcated bald area on scalp with exclamationhairs at periphery. Histopathologic examination ofa biopsy specimen revealed a peribulbar infiltratewith prominent granulomatous inflammation (Figs 1and 2). Special stains for fungi, acid-fast bacilli andTreponema pallidum were negative. A complete bloodcount, a comprehensive metabolic panel, liver andrenal function tests, and erythrocyte sedimentationrate were all within normal limits. Thyroid studies,anti-nuclear antibodies (ANA), rheumatoid factor,

Fig. 1. Examination of transverse sections (Patient 1) revealed aperibulbar infiltrate that included a prominent granulomatouscomponent.

complement levels and angiotensin convertingenzyme (ACE) level were also within normal limits.PPD and Treponema pallidum titers were negativeand a review of previous imaging studies failed toreveal any evidence of granulomatous stigmata. Thepatient was treated with topical steroids (Clobetasol0.05%) and intralesional steroids (triamcinoloneacetonide 5 mg/mL) with significant regrowth after3 months, at which point she was lost to follow-up.

The second patient was a 27-year-old Latinawho presented with a generalized body rash. Abiopsy of her forearm was performed and revealed

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Fig. 2. The granulomatous infiltrate involved many follicles withinthe biopsy.

a granulomatous perifollicular infiltrate. The patientthen developed a single alopecic patch, which quicklyprogressed to alopecia totalis. Histopathologicexamination of a biopsy from the scalp revealeda peribulbar infiltrate that was prominentlygranulomatous. Stains for bacteria, fungi, Treponemapallidum and acid-fast bacilli were also negative. Anextensive laboratory and imaging workup, includingACE serum level, was unremarkable. Assessmentof ANA was negative. PPD and Treponema pallidumtiters were also negative. The patient was treatedwith several courses of high potency topical steroids,which failed. Subsequently, she received clofazimine100 mg every other day and achieved a substantialdegree of hair growth after two months.

Both patients had negative hepatitis serologypanels and no other clinical sign of systemicillness, such as pyrexia, arthralgias, pulmonaryfibrosis, hilar lymphadenopathy, uveitis, or anendocrine disturbance. There was no history orclinical evidence of chronic granulomatous disease(CGD) or inflammatory bowel disease. Additionally,both patients denied any significant contact withchemicals or environmental products.

Histopathologically, transverse sections of thebiopsies from both patients showed numerous cata-gen and telogen phase follicles. There was markedperibulbar inflammation including eosinophils, andin some of the follicles a prominent granuloma-tous reaction was appreciated. Lymphocytes wereobserved permeating some of the granulomas, andperipheral plasma cells with Russell bodies could beseen in some granulomas. Trichomalacia was notedin multiple hair follicles. No fungi were detected witha periodic acid-Schiff and Gomori-Grocott stains. Acolloidal iron stain failed to reveal increased mucinwithin hair follicles, but focal mucin was noted withinroutine sections. While the presence of granulomas

was somewhat unusual, the overall features favoredthe diagnosis of AA.

In order to more comprehensively excludethe presence of occult microorganisms or thepresence of genomic material from granuloma-lysed organisms, formalin-fixed, paraffin embeddedtissue blocks were sectioned and submitted formolecular microbiology testing. DNA source yieldednegative results by 16S rRNA-gene polymerase chainreaction (PCR) amplification and sequencing forbacterial DNA.

We posit that peribulbar granulomatous inflam-mation represents a rare and novel finding withinthe broad spectrum of AA. In the context of alopeciathat may have granulomas identified histopathologi-cally, the described associations include sarcoidosis,syphilis, and rosacea.1 Our two patients do not haveany history of these disorders. To the best of ourknowledge, granulomatous AA has not been previ-ously reported.

The differential diagnosis for possible triggers of agranulomatous immune response include infectionssuch as atypical mycobacteria, tuberculoid leprosy,tularemia, cat scratch disease, lymphogranulomavenereum, protozoa (such as Leishmania sp.), andfungi. Non-infectious inflammatory causes includeforeign body implantation, sarcoidosis, Crohndisease, and Wegener granulomatosis.2,3 Granulo-matous inflammation can also be seen in associationwith underlying lymphoma.4,5 Our two patientsdid not have clinical or laboratory evidence ofany of these infectious, inflammatory, or neoplasticdisorders.

Granuloma formation is a complex process initi-ated by activation of monocytes or macrophages inresponse to a foreign antigen or body.1 Macrophagesplay a significant role through the release ofchemokines and adhesion molecules, which elicitsincreased neutrophil entry into the area. A complexinterplay of immune cell recruitment throughchemokines such as Chemokine (C-C motif) ligand2 (CCL2), osteopontin, and tumor necrosis factor-alpha (TNF-α), amongst others, ultimately leads togranuloma formation.6 Interestingly, cytokine levelsin localized and generalized AA have been studied.In localized AA, IL-1α and IL-4 may be elevated,in contrast to IFN-γ and IL-2 elevation in alopeciauniversalis.7 IFN-γ and IL-2 are known to drivethe TH1 cellular response that may eventuate withgranuloma formation.

While the exact mechanism underlying gran-ulomatous AA remains unclear, one possibleexplanation is the exposure of the hair antigens tothe immune system. Hair follicles are not usuallyexposed to immune surveillance; the proximal hairfollicle epithelium generates and maintains an area of

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relative immune privilege during a defined segmentof the hair cycle (i.e. during anagen phase). Thisimmune privilege is chiefly characterized by a verylow level of expression of major histocompatibilitycomplex (MHC) class Ia antigens and by the localproduction of potent immunosuppressive agents,such as alpha-melanocyte-stimulating hormone(α-MSH) and transforming growth factor beta(TGF-beta1).8,9 Failure of this barrier could yieldexposure of hair antigens, resulting in a foreign bodyTh1-type granulomatous reaction. We hypothesizethat past trauma or inflammation may have triggeredtransient lymphohistiocytic folliculotropism that

blossomed into a granulomatous foreign body-typereaction directed against follicular bulbar epithelium.

Fig 3. There is scant trichomalacia centrallysurrounded by histiocytic giant cells.

Figs 4 and 5. Transverse sections through thebiopsy of Patient 2 demonstrate a granulomatousperibulbar infiltrate with associated plasma cells.

Fig 6. Permeating plasma cells and Russell bodyformation are noted at the center of somegranulomas.

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T cell contributions to the different phases ofgranuloma formation. Immunol Lett. Mar 292004;92(1–2):135–142

4. Eisman S, O’Toole EA, Jones A, Whittaker SJ.Granulomatous mycosis fungoides presentingas an acquired ichthyosis. Clin Exp Dermatol.Mar 2003; 28: 174.

5. Garcovich A, Garcovich S, Massi G. An

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7. Teraki Y, Imanishi K, Shiohara T. Cytokinesin alopecia areata: contrasting cytokine profilesin localized form and extensive form (alopeciauniversalis). Acta Derm Venereol. Nov 1996;76: 421.

8. Paus R, Ito N, Takigawa M, Ito T. Thehair follicle and immune privilege. J InvestigDermatol Symp Proc. Oct 2003; 8: 188.

9. Paus R, Nickoloff BJ, Ito T. A ’hairy’ privilege.Trends Immunol. Jan 2005; 26: 32.

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