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Follicular mucinosis: Clinical, histologic, and molecular remission with minocycline
Follicular mucinosis: Clinical, histologic, and molecular remission with minocycline Sareeta R. S. Parker, MD, and Emma Murad, MD Atlanta, Georgia Follicular mucinosis is an uncommon inflammatory disorder characterized histologically by mucin accumulation in the follicular epithelium. The condition is generally divided into primary and secondary forms, the latter being frequently associated with mycosis fungoides. Lesional skin T-cell clonality has been documented in some patients with follicular mucinosis, even those with no histologic evidence of cutaneous lymphoma. In this report, we describe a patient with clonal idiopathic primary follicular mucinosis who had complete clinical, histologic, and molecular remission with minocycline therapy. ( J Am Acad Dermatol 2010;62:139-41.) Key words: clonality; follicular mucinosis; minocycline; therapy.
F
ollicular mucinosis (FM) is an uncommon cutaneous disorder of unclear etiology. Follicular mucin accumulation may be idiopathic (primary follicular mucinosis), or found in association with mycosis fungoides/cutaneous T-cell lymphoma (MF/CTCL). Less commonly, FM is incidentally noted in other neoplastic or inflammatory conditions.1-3 T-cell clonality is detectable in lesional skin of some patients with FM, even those with no histologic evidence of MF/CTCL. No specific therapy has been found to be consistently effective for patients with idiopathic FM. Herein we report the case of a patient with clonal idiopathic primary FM who had complete clinical, histologic, and molecular remission with oral minocycline.
CASE REPORT A 28-year-old Chilean man presented with a 1- to 2-year history of asymptomatic, pink plaques on his trunk and extremities. He had no significant past medical or family history and was taking no medications. Examination revealed a well-appearing man with no peripheral lymphadenopathy. Skin examination revealed several pink, thin plaques, many From the Department of Dermatology, Emory University School of Medicine. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Sareeta R. S. Parker, MD, Department of Dermatology, Emory University School of Medicine, 1365 Clifton Rd, NE, Building A, 1st Floor, Atlanta, GA 30322. E-mail: [email protected]. Published online July 27, 2009. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.01.031
Abbreviations used: CTCL: FM: MF: TCR:
cutaneous T-cell lymphoma follicular mucinosis mycosis fungoides T-cell receptor
with overlying alopecia, on his trunk and extremities (Fig 1). The majority of plaques were composed of densely aggregated, barely elevated, pink papules. Several lesional skin biopsy specimens revealed mucin deposition within the follicular unit, with a mild lymphocytic infiltrate in a perivascular and follicular distribution (Fig 2). No evidence of epidermotropism, folliculotropism, or lymphocyte atypia was detected. Tissue polymerase chain reactione based molecular analysis revealed the presence of a clonal rearrangement of the T-cell receptor gamma chain gene (TCR-g). Peripheral blood studies including complete blood cell count, lactate dehydrogenase, flow cytometric assays for aberrant T-cell populations and TCR-g molecular studies were normal or negative. Empirical therapy with oral minocycline, 100 mg twice daily, was initiated. At follow-up 3 months later, complete clinical resolution was noted (Fig 3). One year later, repeat skin biopsy of a previously affected site revealed no detectable histologic involvement. Repeat tissue TCR-g molecular studies obtained from the site of a previously TCR-g positive lesion, was negative. Therapy with oral minocycline was then reduced to 100 mg once daily, and the patient has remained free of disease for 3 years while on this regimen. Our patient has experienced no adverse effects related to minocycline. Because of his 139
140 Case reports
J AM ACAD DERMATOL JANUARY 2010
Fig 1. Erythematous thin plaques on posterior trunk.
dramatic response to this agent and the potential association of FM with cutaneous lymphoma, he was reluctant to discontinue treatment and remains on a once-daily dose of 100 mg. He has had no clinical or histologic evidence of MF/CTCL for 5 years since onset of the FM.
DISCUSSION FM is a rare dermatosis classically described as occurring in 3 settings: idiopathic, in association with MF/CTCL, and in association with other neoplastic and inflammatory conditions.1-4 Because of the close association with MF/CTCL and because in some cases T-cell clonality is detectable, controversy exists as to whether FM is in fact a neoplastic process (variant of lymphoma) or a clonal inflammatory condition.4-7 The significance of T-cell clonality in FM is unclear. It has been suggested that FM may be an inflammatory disease with a tendency to develop self-limited clones of lymphocytes.5 An alternative view is that FM, given its frequency of occurrence in patients with MF and detection of lesional skin T-cell clonality, is in fact MF. That some cases of FM fail to progress to an aggressive form of cutaneous lymphoma can be likened to another variant of MF, Woringer-Kolopp (unilesional pagetoid reticulosis), which characteristically exhibits a benign clinical course.6 It has also been suggested that lesional clonality in FM may portend a higher risk for developing cutaneous lymphoma.6-8 However, although the data are quite limited, an increased likelihood of progression to frank MF/CTCL in patients with clonal primary idiopathic FM (relative to non-clonal) has not been demonstrated.7 To date, no consistently reliable features (ie, patient age, distribution of
Fig 2. Photomicrographs of histopathology demonstrate increased intrafollicular mucin and associated lymphocytic infiltrate. (A and B, Hematoxylin-eosin stain; original magnifications: A, 340; B, 3200.)
lesions, light microscopic/histopathologic features, molecular studies) have been shown to predictably distinguish ‘‘benign’’ FM from lymphoma-associated FM.4-7,9 Effective therapeutic options for patients with primary idiopathic FM are limited. Response to photodynamic therapy,10 isotretinoin,11 indomethacin,12 dapsone,13 and interferon14 have been anecdotally reported. In 2000, Yotsumoto, Uchimiya, and Kanzaki15 reported successful treatment of FM with minocycline. They described a 36-year-old Japanese man with idiopathic FM who responded to oral minocycline in 2 weeks. The proposed mechanism of action of minocycline is through its anti-inflammatory effects.15,16 Subsequently, Anderson, Mackley, and Helm17 described a 53-year-old man with FM that cleared within 5 weeks of therapy with minocycline. However, these reports provide no long-term followup. Additionally, lesional skin molecular studies for the presence of T-cell clonality were not documented in either of the patients described. To our knowledge, this is the first report of minocycline-induced clinical, histologic, and molecular
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Fig 3. Resolution of skin lesions 3 months after minocycline therapy. FM before (A and B) and after (C and D) initiation of therapy.
clearing of clonal FM. Our patient remains in remission after 3 years of continued therapy. Depending on our patient’s willingness, further titration and ultimately complete withdrawal of minocycline is planned. It will be interesting to note whether relapse occurs upon complete withdrawal of therapy, and whether clonality is again detectable if relapse occurs. Despite our patient’s response, ongoing surveillance for development of MF/CTCL is planned. REFERENCES 1. Sumner WT, Grichnik JM, Shea CR, Moore JO, Miller WS, Burton CS. Follicular mucinosis as a presenting sign of acute myeloblastic leukemia. J Am Acad Dermatol 1998;38:803-5. 2. Walchner M, Messer G, Rust A, Sander C, Rocken M. Follicular mucinosis in association with squamous cell carcinoma of the tongue. J Am Acad Dermatol 1998;38:622-4. 3. Wolff HH, Kinney J, Ackerman AB. Angiolymphoid hyperplasia with follicular mucinosis. Arch Dermatol 1978;114:229-32. 4. Cerroni L, Fink-Puches R, Ba¨ck B, Kerl H. Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sezary syndrome. Arch Dermatol 2002;138:182-9. 5. Leboit PE. Alopecia mucinosa, inflammatory disease or mycosis fungoides: Must we choose? And are there other choices? Am J Dermatopathol 2004;26:167-70. 6. Bo¨er A, Guo Y, Ackerman B. Alopecia mucinosa is mycosis fungoides. Am J Dermatopathol 2004;26:33-52.
7. 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 2002;47:856-62. 8. Wittenberg GP, Gibson LE, Pittelkow MR, el-Azhary RA. Follicular mucinosis presenting as an acneiform eruption: report of four cases. J Am Acad Dermatol 1998;38:849-51. 9. Gibson L. Follicular mucinosis: clinical and histologic study. J Am Acad Dermatol 1989;20:441-6. 10. Ferna´ndez-Guarino M, Harto Castan˜o A, Carrillo R, Jae´n P. Primary follicular mucinosis: excellent response to treatment with photodynamic therapy. J Eur Acad Dermatol Venereol 2008;22:393-4. 11. Arca E, Ko¨se O, Tas xtan HB, Gu¨r AR, Safali M. Follicular mucinosis responding to isotretinoin treatment. J Dermatolog Treat 2004;15:391-5. 12. Kodama H, Umemura S, Nohara N. Follicular mucinosis response to indomethacin. J Dermatol 1988;12:72-5. 13. Kubba RK, Stewart TW. Follicular mucinosis responding to dapsone. Br J Dermatol 1974;91:217-20. 14. Meissner K, Weyer U, Kowalzick L, Altenhoff J. Successful treatment of primary progressive follicular mucinosis with interferons. J Am Acad Dermatol 1991;24:848-50. 15. Yotsumoto S, Uchimiya H, Kanzaki T. A case of follicular mucinosis treated successfully with minocycline. Br J Dermatol 2000;142:841-2. 16. Kloppenburg M, Verweij CL, Miltenburg AM, Werhoeven AJ, Daha MR, Dijkmans BA, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol 1995;102:635-41. 17. Anderson BE, Mackley CL, Helm KF. Alopecia mucinosa: report of a case and review. J Cutan Med Surg 2003;7:124-8.
F
ollicular mucinosis (FM) is an uncommon cutaneous disorder of unclear etiology. Follicular mucin accumulation may be idiopathic (primary follicular mucinosis), or found in association with mycosis fungoides/cutaneous T-cell lymphoma (MF/CTCL). Less commonly, FM is incidentally noted in other neoplastic or inflammatory conditions.1-3 T-cell clonality is detectable in lesional skin of some patients with FM, even those with no histologic evidence of MF/CTCL. No specific therapy has been found to be consistently effective for patients with idiopathic FM. Herein we report the case of a patient with clonal idiopathic primary FM who had complete clinical, histologic, and molecular remission with oral minocycline.
CASE REPORT A 28-year-old Chilean man presented with a 1- to 2-year history of asymptomatic, pink plaques on his trunk and extremities. He had no significant past medical or family history and was taking no medications. Examination revealed a well-appearing man with no peripheral lymphadenopathy. Skin examination revealed several pink, thin plaques, many From the Department of Dermatology, Emory University School of Medicine. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Sareeta R. S. Parker, MD, Department of Dermatology, Emory University School of Medicine, 1365 Clifton Rd, NE, Building A, 1st Floor, Atlanta, GA 30322. E-mail: [email protected]. Published online July 27, 2009. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.01.031
Abbreviations used: CTCL: FM: MF: TCR:
cutaneous T-cell lymphoma follicular mucinosis mycosis fungoides T-cell receptor
with overlying alopecia, on his trunk and extremities (Fig 1). The majority of plaques were composed of densely aggregated, barely elevated, pink papules. Several lesional skin biopsy specimens revealed mucin deposition within the follicular unit, with a mild lymphocytic infiltrate in a perivascular and follicular distribution (Fig 2). No evidence of epidermotropism, folliculotropism, or lymphocyte atypia was detected. Tissue polymerase chain reactione based molecular analysis revealed the presence of a clonal rearrangement of the T-cell receptor gamma chain gene (TCR-g). Peripheral blood studies including complete blood cell count, lactate dehydrogenase, flow cytometric assays for aberrant T-cell populations and TCR-g molecular studies were normal or negative. Empirical therapy with oral minocycline, 100 mg twice daily, was initiated. At follow-up 3 months later, complete clinical resolution was noted (Fig 3). One year later, repeat skin biopsy of a previously affected site revealed no detectable histologic involvement. Repeat tissue TCR-g molecular studies obtained from the site of a previously TCR-g positive lesion, was negative. Therapy with oral minocycline was then reduced to 100 mg once daily, and the patient has remained free of disease for 3 years while on this regimen. Our patient has experienced no adverse effects related to minocycline. Because of his 139
140 Case reports
J AM ACAD DERMATOL JANUARY 2010
Fig 1. Erythematous thin plaques on posterior trunk.
dramatic response to this agent and the potential association of FM with cutaneous lymphoma, he was reluctant to discontinue treatment and remains on a once-daily dose of 100 mg. He has had no clinical or histologic evidence of MF/CTCL for 5 years since onset of the FM.
DISCUSSION FM is a rare dermatosis classically described as occurring in 3 settings: idiopathic, in association with MF/CTCL, and in association with other neoplastic and inflammatory conditions.1-4 Because of the close association with MF/CTCL and because in some cases T-cell clonality is detectable, controversy exists as to whether FM is in fact a neoplastic process (variant of lymphoma) or a clonal inflammatory condition.4-7 The significance of T-cell clonality in FM is unclear. It has been suggested that FM may be an inflammatory disease with a tendency to develop self-limited clones of lymphocytes.5 An alternative view is that FM, given its frequency of occurrence in patients with MF and detection of lesional skin T-cell clonality, is in fact MF. That some cases of FM fail to progress to an aggressive form of cutaneous lymphoma can be likened to another variant of MF, Woringer-Kolopp (unilesional pagetoid reticulosis), which characteristically exhibits a benign clinical course.6 It has also been suggested that lesional clonality in FM may portend a higher risk for developing cutaneous lymphoma.6-8 However, although the data are quite limited, an increased likelihood of progression to frank MF/CTCL in patients with clonal primary idiopathic FM (relative to non-clonal) has not been demonstrated.7 To date, no consistently reliable features (ie, patient age, distribution of
Fig 2. Photomicrographs of histopathology demonstrate increased intrafollicular mucin and associated lymphocytic infiltrate. (A and B, Hematoxylin-eosin stain; original magnifications: A, 340; B, 3200.)
lesions, light microscopic/histopathologic features, molecular studies) have been shown to predictably distinguish ‘‘benign’’ FM from lymphoma-associated FM.4-7,9 Effective therapeutic options for patients with primary idiopathic FM are limited. Response to photodynamic therapy,10 isotretinoin,11 indomethacin,12 dapsone,13 and interferon14 have been anecdotally reported. In 2000, Yotsumoto, Uchimiya, and Kanzaki15 reported successful treatment of FM with minocycline. They described a 36-year-old Japanese man with idiopathic FM who responded to oral minocycline in 2 weeks. The proposed mechanism of action of minocycline is through its anti-inflammatory effects.15,16 Subsequently, Anderson, Mackley, and Helm17 described a 53-year-old man with FM that cleared within 5 weeks of therapy with minocycline. However, these reports provide no long-term followup. Additionally, lesional skin molecular studies for the presence of T-cell clonality were not documented in either of the patients described. To our knowledge, this is the first report of minocycline-induced clinical, histologic, and molecular
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Fig 3. Resolution of skin lesions 3 months after minocycline therapy. FM before (A and B) and after (C and D) initiation of therapy.
clearing of clonal FM. Our patient remains in remission after 3 years of continued therapy. Depending on our patient’s willingness, further titration and ultimately complete withdrawal of minocycline is planned. It will be interesting to note whether relapse occurs upon complete withdrawal of therapy, and whether clonality is again detectable if relapse occurs. Despite our patient’s response, ongoing surveillance for development of MF/CTCL is planned. REFERENCES 1. Sumner WT, Grichnik JM, Shea CR, Moore JO, Miller WS, Burton CS. Follicular mucinosis as a presenting sign of acute myeloblastic leukemia. J Am Acad Dermatol 1998;38:803-5. 2. Walchner M, Messer G, Rust A, Sander C, Rocken M. Follicular mucinosis in association with squamous cell carcinoma of the tongue. J Am Acad Dermatol 1998;38:622-4. 3. Wolff HH, Kinney J, Ackerman AB. Angiolymphoid hyperplasia with follicular mucinosis. Arch Dermatol 1978;114:229-32. 4. Cerroni L, Fink-Puches R, Ba¨ck B, Kerl H. Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sezary syndrome. Arch Dermatol 2002;138:182-9. 5. Leboit PE. Alopecia mucinosa, inflammatory disease or mycosis fungoides: Must we choose? And are there other choices? Am J Dermatopathol 2004;26:167-70. 6. Bo¨er A, Guo Y, Ackerman B. Alopecia mucinosa is mycosis fungoides. Am J Dermatopathol 2004;26:33-52.
7. 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 2002;47:856-62. 8. Wittenberg GP, Gibson LE, Pittelkow MR, el-Azhary RA. Follicular mucinosis presenting as an acneiform eruption: report of four cases. J Am Acad Dermatol 1998;38:849-51. 9. Gibson L. Follicular mucinosis: clinical and histologic study. J Am Acad Dermatol 1989;20:441-6. 10. Ferna´ndez-Guarino M, Harto Castan˜o A, Carrillo R, Jae´n P. Primary follicular mucinosis: excellent response to treatment with photodynamic therapy. J Eur Acad Dermatol Venereol 2008;22:393-4. 11. Arca E, Ko¨se O, Tas xtan HB, Gu¨r AR, Safali M. Follicular mucinosis responding to isotretinoin treatment. J Dermatolog Treat 2004;15:391-5. 12. Kodama H, Umemura S, Nohara N. Follicular mucinosis response to indomethacin. J Dermatol 1988;12:72-5. 13. Kubba RK, Stewart TW. Follicular mucinosis responding to dapsone. Br J Dermatol 1974;91:217-20. 14. Meissner K, Weyer U, Kowalzick L, Altenhoff J. Successful treatment of primary progressive follicular mucinosis with interferons. J Am Acad Dermatol 1991;24:848-50. 15. Yotsumoto S, Uchimiya H, Kanzaki T. A case of follicular mucinosis treated successfully with minocycline. Br J Dermatol 2000;142:841-2. 16. Kloppenburg M, Verweij CL, Miltenburg AM, Werhoeven AJ, Daha MR, Dijkmans BA, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol 1995;102:635-41. 17. Anderson BE, Mackley CL, Helm KF. Alopecia mucinosa: report of a case and review. J Cutan Med Surg 2003;7:124-8.