Are You Confident of the Diagnosis?
Follicular mucinosis (FM) is a rare skin disorder; it may be idiopathic, found in association with cutaneous T-cell lymphoma (CTCL) or, more rarely, incidentally noted (clinically and/or histologically) in other neoplastic or inflammatory conditions. When incidentally encountered microscopically, it may be simply viewed as a histologic reaction pattern.
Characteristic findings on physical examination
Lesions are often asymptomatic but may itch or burn; they develop over weeks or months (not days). FM generally presents as pink-red papules, patches, or plaques (Figure 1, Figure 2, Figure 3, Figure 4).
On hair-bearing skin (e.g. scalp), overlying alopecia is notable, hence the term “alopecia mucinosa” (see Figure 5). Plaques are often composed of densely aggregated individual papules, many of which have a central spine. The number of lesions ranges from one or two to several dozen; they are typically distributed on the face, scalp, or neck; the trunk and extremities are less often affected. Mucosal surfaces, genitalia, and acral (palms and soles) areas are usually spared.
Expected results of diagnostic studies
Skin biopsies are required for diagnosis. The diagnostic light microscopic feature is intrafollicular mucin (mucin within the pilosebaceous subunit), as seen with H&E stain in Figure 6.
The presence of intrafollicular mucin can be confirmed with colloidal iron tissue stains. Perifollicular and perivascular lymphocytes are typically present in all types of FM. In the lymphoma-associated type, atypical lymphocytes and/or other features supportive of CTCL (e.g. folliculotropism, epidermotropism) may be present. However, the absence of these features does not definitively exclude the possibility of CTCL-associated FM.
In any subtype of FM, lesional skin polymerase chain reaction (PCR) based molecular testing for T-cell clonality may be positive, thereby suggesting monoclonality of the infiltrating T lymphocytes. However, monoclonality does not distinguish lymphoma-associated FM from idiopathic FM.
Analysis of lesional skin for T-cell clonality (using PCR for T cell receptor[TCR] gene rearrangements) should be considered in patients with known or suspected FM, but is not required for diagnosis. If the patient’s clinical presentation is highly suspicious for mycosis fungoides (MF) or other CTCL, analysis of lesional tissue for T-cell clonality may be helpful in supporting the clinical impression, particularly when classic histological features of CTCL are absent.
No serological or imaging studies are useful for establishing the diagnosis of FM.
Who is at Risk for Developing this Disease?
Due to its rarity, epidemiologic studies are limited; no predisposing factors have been identified, and no racial or gender predilection has been established. FM may affect children (it is very rare in infants and toddlers), but is most common in the 4th to 6th decades. The epidemiology of FM associated with MF/CTCL parallels that of MF/CTCL and is most common in adults in their 6th decade or older.
FM has been reported as an incidental finding in a variety of inflammatory skin disorders, such as acne, insect bite reactions, and lichen planus. It has also been rarely reported in patients with neoplastic diseases, most commonly hematologic-based malignancies.
What is the Cause of the Disease?
The etiology is not known. Accumulation of mucin, which is composed of hyaluronate and sulfated glycosaminoglycans, in the follicle results in disruption of cellular attachments and destruction of the pilosebaceous subunit. With loss of the follicle, alopecia may be evident clinically.
Controversy exists as to whether the disease is a neoplastic process or a reactive process. It may be due to dysfunctional T cells inducing mucin production by fibroblasts surrounding follicular epithelium, or due to excess production of mucin by follicular keratinocytes. Some investigators propose that FM is in fact a form of MF/CTCL, with a relatively benign or unpredictable course, while others propose that it may be a cutaneous T-cell lymphoid dyscrasia.
Systemic Implications and Complications
There is no known way to differentiate idiopathic FM from MF/CTCL-associated FM with certainty. In general, patients with idiopathic FM tend to be younger and have fewer and more localized lesions (on the head or neck). No reliable distinguishing clinical, histological, or molecular parameter exists.
Unless patients have or develop clinical and histological evidence of MF/CTCL (e.g. poikilodermatous patches, arcuate plaques on exam, cytologically atypical lymphocytes with epidermotropism histologically), it is difficult or impossible to predict which patients will progress.
Patients with FM require a thorough review of systems, full skin and lymph node exam, and long-term follow up. Given the association with CTCL, as well as much rarer associations with other hematologic malignancies (e.g. acute myeloblastic leukemia), a baseline complete blood count (CBC) with differential and lactate dehydrogenase (LDH) level should be obtained, and chest radiograph should be considered.
tretinoin 0.01% gel
phototherapy—UVA1, photochemotherapy (psoralen plus ultraviolet light [PUVA])
electron beam radiation
Optimal Therapeutic Approach for this Disease
Therapy should be tailored to the individual patient, with consideration given to the extent of involvement (lesion location, size, number). Therapeutic options and efficacy are based on retrospective case series or anecdotal reports; no controlled trials exist. If associated with an underlying neoplastic or inflammatory disorder, treatment of the associated disease is warranted. Dose, frequency, and duration of therapy is indicated where available and is based on published literature.
Solitary or Localized Lesions
For solitary or localized lesions, topical agents are first line because they are low risk, easy to administer, and low cost. Intralesional corticosteroids or excision should be considered for refractory or localized lesions, where cosmetically acceptable. Photodynamic therapy is an option, but availability is more limited and may be more costly. Suggested therapies are based on anecdotal reports or small case series.
Topical corticosteroids (mid to high potency)—response expected within 3 months
Tretinoin 0.01% gel daily—response expected within months
Pimecrolimus cream twice daily—response expected within 3 months; given the putative association of cutaneous lymphoma with FM, consider warning patients or parents of young patients with FM about the FDA’s black box warning of potential increased risk of lymphoma and skin malignancy with use of pimecrolimus.
Intralesional corticosteroids—triamcinolone acetonide, 2.5 to 10mg/ml, volume based on lesion size
Photodynamic therapy—topical methylaminolevulinic acid, occluded 3 hours, followed by red light (630nm, 37J/cm2, 7.5 minutes); single session per lesion; response expected within 2 months.
Numerous or Widespread Lesions/Unresponsive or Intolerant
For more numerous or widespread lesions, or if the patient shows no response or is intolerant to the options above, the following are first-line oral therapeutic options:
Hydroxychloroquine 200mg orally, three times daily for 10 days, followed by 200mg orally, twice daily; response noted within 6 months, begin taper after lesions have cleared. Treatment based on single case series of six patients.
Minocycline 100mg orally, twice daily; response noted within 6 months; begin to taper slowly over months after lesions have cleared. Avoid use in patients under age 8. Treatment based on several case reports.
The following options have been anecdotally reported to be effective; selection is based on individual patient tolerance and comorbidities, and on the comfort level of the prescribing physician. Consider if patient is intolerant or unresponsive to first-line agents.
Indomethacin 25mg orally, twice daily; monitor for gastrointestinal adverse effects, electrolytes, and creatinine. Caution if used in patients with gastritis, peptic ulcer disease, or renal insufficiency. Response within 3 months; recurrence may occur upon discontinuation.
Isotretinoin 0.5mg/kg/day orally; response within 3 months; begin taper over several weeks, after lesions have cleared. In the United States, iPLEDGE enrollment is required for isotretinoin use. Isotretinoin is pregnancy category X. If given to females of childbearing potential, monitor closely for pregnancy. Routine laboratory monitoring is suggested (i.e. chemistries, lipids).
Dapsone 100mg orally, daily; response within 3 months; taper not defined, recurrence may occur upon discontinuation. Laboratory monitoring required (i.e. CBC, hepatic panel). Contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency.
Phototherapy using PUVA; caution in patients with history of melanoma and/or aggressive non-melanoma skin cancers or photosensitivity disorders.
Relative to interventions noted above, these agents are associated with a potentially higher risk or higher cost; or, response and/or dosing are not as well defined.
Quinacrine 100mg; not available in the United States
Corticosteroids, oral—dose not delineated in reports
Radiation therapy—skin-directed electron beam or conventional radiation
Interferon alfa-2a, intralesional 3 million units biweekly X 5, then monthly
Discontinue therapy or consider slow titration (over months or years) after complete response is evident. If recurrence is noted upon withdrawal, consider reinstitution of either the same or a new therapy. Of note, FM may resolve spontaneously.
Patients should be advised of the potential relationship with MF/CTCL, and of the difficulty in distinguishing idiopathic from MF/CTCL-associated FM with certainty. No data suggest that lack of response to therapy is predictive of higher likelihood of MF/CTCL association.
Long-term dermatologic follow up is necessary; a reasonable frequency for skin and lymph node exam is every 3-6 months initially, then annually. Periodic laboratory studies (i.e. CBC with differential and LDH) should be performed; frequency should be based on the patient’s symptoms and exam. Baseline blood molecular assay for TCR clonality should be considered if lesional skin is positive for T-cell clonality; baseline blood flow cytometry leukemia/lymphoma profile should also be considered, particularly if the blood molecular is positive for T-cell clonality.
If lesional morphology should change considerably, skin biopsies should be repeated. If highly suspicious clinically and histologically for MF/CTCL, proper evaluation and staging studies should be performed.
Unusual Clinical Scenarios to Consider in Patient Management
Serial skin biopsies every 1-2 years to evaluate for MF/CTCL are warranted for patients whose lesions fail to regress, for patients who develop more widespread lesions despite therapy, and for patients in whom there is a significant change in lesion morphology (e.g. patches progress to thick plaques).
The presence of lesional skin T-cell clonality in FM does not portend a poorer prognosis. Clonal FM may regress completely. Long-term clinical monitoring of patients with FM is suggested.
Controversy exists as to whether FM is in fact a form of MF/CTCL. Many MF/CTCL patients with limited disease have an overall good prognosis.
What is the Evidence?
Anderson, BE, Mackley, CL, Helm, KF. “Alopecia mucinosa: report of a case and review”. J Cut Med Surg. vol. 7. 2003. pp. 124-8. (This is a comprehensive review of the clinical presentations, subtypes, associations, and previously reported therapies for follicular mucinosis.)
Brown, HA, Gibson, LE, Pujol, RM, Lust, JA, Pittelkow, MR. “Primary follicular mucinosis: long-term follow-up of patients younger than 40 years with and without clonal T-cell receptor gene rearrangement”. J Am Acad Dermatol. vol. 47. 2002. pp. 856-62. (This report highlights the inability to distinguish—in seven young adults—idiopathic from lymphoma-associated follicular mucinosis, based on the presence of lesional skin T-cell clonality. All patients were followed for a minimum of 5 years.)
Cerroni, L. “Pilotropic mycosis fungoides”. Arch Dermatol. vol. 146. 2010. pp. 662-4. (The author provides a comprehensive review of follicular mycosis fungoides as it relates to follicular mucinosis.)
Guitart, J, Magro, C. “Cutaneous T-cell lymphoid dyscrasia”. Arch Dermatol. vol. 143. 2007. pp. 921-32. (The authors discuss various clonal dermatoses, including follicular mucinosis, and highlight their relationship to cutaneous T-cell lymphoma.)
LeBoit, PE. “Alopecia mucinosa, inflammatory disease or mycosis fungoides: must we choose? And are there other choices?”. Am J Dermatopath. vol. 26. 2004. pp. 167-70. (The author proposes possible explanations regarding the relationship between follicular mucinosis and mycosis fungoides.)
Parker, SRS, Murad, E. “Follicular mucinosis: clinical, histological and molecular remission with minocycline”. J Am Acad Dermatol. vol. 62. 2010. pp. 139-41. (This is a detailed report of a single patient with clonal follicular mucinosis, whose response to minocycline was demonstrated on a clinical, histological, and molecular level.)
Rongioletti, F, Lucchi, SD, Meyes, D, Mora, M, Rebora, A. “Follicular mucinosis: a clinicopathologic, histochemical, immunohistochemical and molecular study comparing the primary benign form and the mycosis fungoides-associated follicular mucinosis”. J Cut Path. vol. 37. 2010. pp. 15-9. (This report summarizes the results of clinical and laboratory studies of thirty-one patients with follicular mucinosis. The authors compare and contrast features of idiopathic follicular mucinosis with those of lymphoma-associated follicular mucinosis. They propose that subtle differences may be detectable.)
Schneider, SW, Metze, D, Bonsmann, G. “Treatment of so-called idiopathic follicular mucinosis with hydroxychloroquine”. Br J Dermatol. vol. 163. 2010. pp. 420-3. (This is a retrospective case series of six patients with idiopathic follicular mucinosis who had complete response to oral hydroxychloroquine. No relapse was noted during the follow-up period, which ranged from 3 to 23 years, and no patient developed lymphoma.)
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