Necrotizing infundibular crystalline folliculitis: Not yet crystal clear

By Warren R. Heymann, MD, FAAD
Jan. 29, 2025
Vol. 7, No. 4

Time and exposure to several articles are necessary to crystallize a novel clinicopathological correlation in my mind. Such is the case with necrotizing infundibular crystalline folliculitis (NICF). I suspect that I have seen this condition but have never diagnosed it for one of two reasons: 1) I did not recognize it, or 2) the disorder was empirically treated and resolved, so no biopsy was performed that could have rendered the diagnosis. This commentary will focus on recent literature of this peculiar dermatosis.

Lucke et al. described two men, aged 79 and 68, with umbilicated papules on the back with “central waxy plugs” of keratinaceous material. Histopathology revealed transepidermal elimination of pale-staining eosinophilic material with a crystalline structure appearing as negatively birefringent needle-shaped crystals surrounded by granulomatous inflammation. The crystals were described as “urate-like,” although there was no history or serologic evidence of gout (in the first patient). Crystal analysis in the first patient demonstrated calcium palmitate; an absorption band in the second patient suggested hydroxyapatite crystals. The lesions resolved quickly with emollients in the first patient and a combination of betamethasone and salicylic acid in the second patient. The authors conjectured that this may be a new perforating disorder. (1)

Kossard et al. coined the term NICF when reporting a 22-year-old woman with a background of acne who developed multiple folliculocentric facial papules associated with sharply demarcated waxy, keratotic plugs demonstrating a virtually identical histologic picture as described by Lucke et al. Serial sections showed vacuolar and filamentous destruction of the infundibular and adjacent perifollicular epithelium and a close relationship of the crystalline necrosis to follicles. Electron microscopy revealed that the filamentous bundles were tonofilaments. The authors stated, “Our case indicates that the process may represent crystalline folliculocentric necrosis rather than a primary perforating disorder. The nature and basis of the crystals that have a urate-like appearance remain to be determined.” (2)

Clinicopathological characterization of 9 patients with NICF and a second group of 7 patients with coincidental findings of NICF in the vicinity of epithelial skin neoplasms was conducted by Denisjuk et al. This is the largest series of patients with NICF in the literature. The authors observed that NICF is both a distinct entity and an epiphenomenon in the context of other disorders. NICF is characterized by multiple waxy papules with a predilection for the forehead (56%), neck, and back. Birefringent crystalline deposits were present in the follicular ostia and enclosed by parakeratotic columns in all cases. Necrosis of the follicular epithelium was found in 89% and a perifollicular neutrophilic infiltrate in 22% of the biopsy specimens. Both yeasts (resembling Malassezia) and gram-positive bacteria (corresponding to Propionibacterium [now Cutibacterium] acnes) were identified within the affected follicles in 56% in the first group and 86% in the second group of coincidental NICF. The authors hypothesized that NICF is pathogenetically linked to these organisms, with sebum accumulation (and crystallization) serving as a nutrient medium for yeasts and bacteria. They also observed that the crystals were mostly located in the ostia of the hair follicles and only rarely in the infundibular region — they proposed that the term NICF be modified to “necrotizing ostial crystalline folliculitis” (NOCF). (3) Both terms appear in the literature, but most use the appellation NICF.

Unusual clinical variants of NICF include intertriginous lesions (“inverse” NICF) (4) and dermatomal lesions following herpes zoster; the latter was reported in a 70+ year-old man with metastatic renal cell carcinoma treated with the PD-1 inhibitor nivolumab. It is unclear if his NICF was due to the varicella-zoster virus, the drug, or Wolf’s isotopic response. (5) Other drugs implicated in NICF include the VEGF inhibitor bevacizumab and the EGFR inhibitor panitumumab. NICF presenting as an acneiform eruption may be seen in cystic fibrosis treated with triple therapy combining 2 CFTR correctors, elexacaftor (ELX) and tezacaftor (TEZ), and a CFTR potentiator, ivacaftor (IVA), indicated for patients with at least 1 F508del CFTR variant. (7) Ibriheim et al. suggest that several drugs are pathogenic in NICF by disturbing sebaceous gland differentiation, destroying the infundibular stem cells, and altering the integrity of the follicular infundibulum. (4)

Rendering the diagnosis of NICF is based on clinicopathological correlation; the likelihood of underdiagnosis is because mimickers such as acne, bacterial folliculitis, and Malassezia folliculitis are usually not biopsied.

Regarding treatment, Roux et al. state, “There is no evidence-based therapy for NICF. Topical and systemic antiacne drugs, including the tetracyclines; topical antibiotics, benzoyl peroxide, and retinoids, as well as topical and systemic antimycotics appear to be effective suggesting a role for Propionibacterium acnes and Malassezia yeasts. Topical corticosteroids have also been used with mixed results. The mean time of clearance is approximately 83 days. Spontaneous clearing may occur.” (8)

Crystalizing my thoughts on NICF, I’ll conclude that I have probably encountered the disorder but did not realize it. Fortunately, NICF appears to be an oddity of minimal clinical significance that will resolve with time or routine topical agents.

Point to Remember: Necrotizing infundibular (ostial) crystalline folliculitis is an underrecognized disorder characterized by folliculocentric waxy papules in the seborrheic areas of adult patients. An increasing number of cases are drug related. The diagnosis requires histopathologic confirmation demonstrating intrafollicular filamentous birefringent crystalline deposits.

Our expert’s viewpoint

Jeff North, MD, FAAD
Managing Director, UCSF Dermatopathology
Professor of Dermatology and Pathology, UCSF School of Medicine

I thought that with diligent study and dedication to clinical duties in 3 years of residency I would learn about every skin disease that existed. As my dermatopathology fellowship progressed at UCSF, it became obvious that my logic was flawed. I can still remember the first case of NICF I saw during fellowship. It is clearly an innate human response to find beauty in crystals. Anyone who has wandered into a jewelry store is aware of this. This innate appreciation also translates to the viewing of crystals under the microscope. It only took one example of seeing the refringent crystalline deposits in hair follicles to cement the diagnosis in my brain. Each subsequent time I have seen these crystals in hair follicles, it has brought a smile to my face.

While there are some histopathologic features that overlap with perforating disorders, the primary pathologic process in NICF is a follicular pathology. As is the case in many hair follicle disorders (e.g. acne vulgaris), NICF is multifactorial in etiology, including intrinsic qualities to some people’s hair follicles and extrinsic factors including microbiome and medication side effects. The most characteristic appearance of the disease is an umbillicated papule with surrounding erythema, though not all cases have this morphology. First line therapy is topical treatments aimed at reducing the number of microorganisms in hair follicles (both bacteria and yeast) with or without topical corticosteroids. In my lecture on folliculitis to UCSF residents, I categorize NICF as a superstar diagnosis. When you make it, everyone is impressed. I applaud Dr. Heymann for highlighting this uncommon disease, and believe he is in good company with many dermatologists that have seen this condition but never made the diagnosis.

1. Lucke TW, Fallowfield ME, Evans A, Lowe JG, MacKie RM. Transepidermal elimination of urate-like crystals: a new perforating disorder? Br J Dermatol. 1999 Aug;141(2):310-4. doi: 10.1046/j.1365-2133.1999.02983.x. PMID: 10468807.

2. Kossard S, Scurry J, Killingsworth M. Necrotizing infundibular crystalline folliculitis. Br J Dermatol. 2001 Jul;145(1):165-8. doi: 10.1046/j.1365-2133.2001.04305.x. PMID: 11453930.

3. Denisjuk N, Hilty N, Pfaltz M, Kempf W. Necrotizing infundibular crystalline folliculitis: a clinicopathological study. J Am Acad Dermatol. 2012 May;66(5):823-6. doi: 10.1016/j.jaad.2011.05.050. Epub 2011 Oct 19. PMID: 22015152.

4. Ibraheim MK, Storey L, North JP. Recurrent inverse necrotizing infundibular crystalline folliculitis. J Cutan Pathol. 2024 Jul;51(7):496-499. doi: 10.1111/cup.14617. Epub 2024 Apr 2. PMID: 38563487.

5. Fischer AS, Pei S, Shields BE, Rosenbach M, Rubin AI. Dermatomal necrotizing infundibular crystalline folliculitis following herpes zoster in a patient on PD-1 inhibitor therapy. J Cutan Pathol. 2020 Jun;47(6):501-505. doi: 10.1111/cup.13653. PMID: 32428371.

6. Fattouh K, Collet-Benzaquen D, Provensal AM, Desseigne F, Castillo C, Combemale P, de la Fouchardière A. Necrotizing Infundibular Crystalline Folliculitis (NICF) Induced by Anti-Tumoral Therapies: Report of 2 Cases. Am J Dermatopathol. 2017 Oct;39(10):764-766. doi: 10.1097/DAD.0000000000000743. PMID: 27779486.

7. Okroglic L, Sohier P, Martin C, Lheure C, Franck N, Honoré I, Kanaan R, Burgel PR, Carlotti A, Dupin N, Oulès B. Acneiform Eruption Following Elexacaftor-Tezacaftor-Ivacaftor Treatment in Patients With Cystic Fibrosis. JAMA Dermatol. 2023 Jan 1;159(1):68-72. doi: 10.1001/jamadermatol.2022.5208. PMID: 36449298; PMCID: PMC9713678.

8. Roux GA, Fraitag S. Necrotizing infundibular (ostial) crystalline folliculitis. Clin Dermatol. 2021 Mar-Apr;39(2):194-198. doi: 10.1016/j.clindermatol.2020.10.013. Epub 2020 Oct 16. PMID: 34272008.

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