Poikilodermatous mycosis fungoides (PMF) is a rare clinical variant of early-stage MF with peculiar histological features. Poikiloderma occurs in many different clinical conditions, which makes a diagnostic procedure more complicated. PMF belongs to a group of MF variants with low risk of disease progression. We report a case of a 64-year-old woman, who presented with mottled skin aspect of erythema, poikilodermatous patches (hypopigmentation, hyperpigmentation, atrophy, and telangiectasia) on more than 80% of the body. Based on clinical, histopathological, and immunohistochemical findings, we established the diagnosis of PMF. Staging procedure determined stage IIA. As skin-directed therapy was the treatment of choice, the patient was successfully treated with psoralen-UVA (PUVA), nbUVB plus retinoid (Re-nbUVB), and PUVA plus retinoid (Re-PUVA), however, with rapid recurrence. </p

Ivana Ilić

Kresimir Kostović

Mirna Bradamante

Romana Čeović

Sandra Jerković Gulin

Zrinka Bukvić Mokos

English

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Poikilodermatous Mycosis Fungoides – Rare Entity, Different Treatment ModalitiesSandra Jerković Gulin1, Romana Čeović2, Ivana Ilić3, Mirna Bradamante2, Zrinka Bukvić Mokos2, Krešimir Kostović21Department of Dermatovenereology and Infectious Diseases, General Hospital Šibenik, Šibenik, Croatia; 2Department of Dermatovenereology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia; 3Department of Pathology and Cytology, University Hospital Center Zagreb and University of Zagreb School of Medicine, Zagreb, CroatiaCorresponding author:Prof. Romana Čeović, MD, PhDDepartment of DermatovenereologyUniversity Hospital Center ZagrebUniversity of Zagreb School of Medicine Šalata 410000 ZagrebCroatiaromana.ceovic@gmail.com,Received: February 2, 2017Accepted: February 17, 2018ACTA DERMATOVENEROLOGICA CROATICA48Acta Dermatovenerol Croat                                 2018;26(1):48-52                                     CASE REPORTABSTRACT Poikilodermatous mycosis fungoides (PMF) is a rare clinical vari-ant of early-stage MF with peculiar histological features. Poikiloderma oc-curs in many different clinical conditions, which makes a diagnostic proce-dure more complicated. PMF belongs to a group of MF variants with low risk of disease progression. We report a case of a 64-year-old woman, who presented with mottled skin aspect of erythema, poikilodermatous patches (hypopigmentation, hyperpigmentation, atrophy, and telangiectasia) on more than 80% of the body. Based on clinical, histopathological, and im-munohistochemical findings, we established the diagnosis of PMF. Staging procedure determined stage IIA. As skin-directed therapy was the treatment of choice, the patient was successfully treated with psoralen-UVA (PUVA), nbUVB plus retinoid (Re-nbUVB), and PUVA plus retinoid (Re-PUVA), how-ever, with rapid recurrence.  KEY WORDS: cutaneous T-cell lymphoma, poikilodermatous mycosis fun-goides, poikiloderma vasculare atrophicans, poikiloderma INTRODUCTIONMycosis fungoides (MF) is the most common type of cutaneous lymphoma. MF shows varieties in both its clinicopathological presentation and immu-nophenotype. Poikilodermatous mycosis fungoides (PMF), also called poikiloderma vasculare atrophicans (PVA), is a rare clinical variant of early-stage MF, char-acterized by localized or diffuse large macules and patches of mottled hypopigmentation and hyper-pigmentation with atrophy and prominent telangiec-tasia (poikiloderma). Lesions have a predilection for the trunk (especially breasts) and buttocks, but they may be generalized (1,2). Rarely, the retiform pattern of atrophic patches occurs, which was previously termed parakeratosis variegata (3). Some authors de-fine PVA as a clinicopathological entity distinct from PMF because PVA has CD8+ T-cell infiltrate and a long benign course (4). PMF usually presents at a younger age than classic MF and is more frequently associated with lymphomatoid papulosis (5). The lesions may be asymptomatic, rarely mildly pruritic, or with a sting-ing sensation. Histological findings in PMF are: atro-phic epidermis, loss of rete ridges, band-like infiltrate of lymphocytes, epidermotropism, dilated capillaries, necrotic keratinocytes, pigment incontinence, and a thickened papillary dermis (2). Histopathological and immunological features of PMF are similar to those of 49ACTA DERMATOVENEROLOGICA CROATICAJerkovic Gulin et al. Acta Dermatovenerol CroatPoikilodermatous mycosis fungoides     2018;26(1):48-52classic MF in early stages with CD2+, CD3+, CD4+, CD7, CD45RO+, CD8- T-cell immunophenotype, although some recent studies and case reports suggest a cyto-toxic phenotype (CD8+, CD4-, CD56+) (5). Poikiloder-ma occurs in many clinical conditions that should be considered in differential diagnosis: dermatomyositis, lupus erythematosus, systemic sclerosis, pigmented atrophic lichen planus, poikiloderma of Civatte, xe-roderma pigmentosum, Kindler syndrome, etc.(4). Treatment of PMF depends on disease stage, patient age, and general health, and includes both skin-di-rected and systemic treatments. PMF has a lower risk of disease progression and better survival, just like hypopigmented MF, when compared with other clini-cal variants of MF (6).CASE PRESENTATIONWe report a case of a 64-year-old woman who pre-sented to our Dermatology Department with mottled skin aspect of erythema, patches with hypopigmenta-tion, hyperpigmentation, atrophy, and telangiectasia localized on the trunk and upper and lower extremi-ties involving more than 80% of the body surface (Fig-ure 1). She complained of itching and reported first lesion onset at age 59 on her right breast followed by similar lesions on the abdomen, with periods of almost complete remission after sun exposure. Her personal and family medical history was without significance for diagnosis. Two biopsy specimens were taken from lesions in the gluteal and presternal region. Histopa-thology revealed epidermotropism with Pautrier’s microabscesses (PMAs), basal alignment of atypical lymphocytes, and lichenoid dermal infiltrate of atypi-cal lymphocytes (Figure 2). Immunohistochemical evaluation showed small atypical CD3+, CD4+, CD2+, CD5-, CD7- T-lymphocytes in the dermis and epidermis and scattered CD8+ lymphocytes within the epidermis (Figure 3). The diagnosis of PMF was established ac-cording to clinical findings, histology, and immuno-histochemistry. Computed tomography (CT) scans of the thorax, abdomen, and pelvis, as well as aspiration of the sternal bone marrow for cytological assess-ment were performed to determine the stage of the disease. Laboratory data: C-reactive protein (CRP) 11.1 (normal range 0.0-5.0mg/L), lactate dehydrogenase (LDH) 173 (normal <240 U/L), triglycerides 3.8 (<1.7 mmol/L). Only reactive lymphadenopathy was found (axillary lymph nodes and inguinal up to 1.3 cm × 1cm, histologically uninvolved). As investigations excluded extracutaneous disease involvement, PMF stage IIA (T2N1M0) was determined. We decided to start PUVA therapy: UVA irradiation two hours after oral admin-istration of 8-methoxypsoralen (8-MOP) 40 mg/daily. The patient received a cumulative UVA dose of 21.5 J/cm2 during a course of 13 exposures that resulted in only partial regression of erythema and induration. Figure 1. Clinical findings: mottled skin aspect of erythema, patches with hypopigmentation, hyperpigmentation, atrophy, and telangiectasia (poikiloderma) involving more than 80% of the body surface.Figure 2. Histological features: atrophic and flattened epidermis, dilated blood vessels, epidermotropism, basal alignment of atypical lymphocytes, and lichenoid dermal infiltrate of atypical lymphocytes (hematoxylin and eosin, ×10).50 ACTA DERMATOVENEROLOGICA CROATICASubsequently, we decided to add oral retinoid (acitre-tin 30 mg/daily) and perform Re-PUVA with the addi-tional local application of betamethasone cream twice daily for two weeks. The patient received an additional cumulative UVA dose of 7.5 J/cm2 during a course of another nine exposures that resulted in complete re-gression of erythema and loss of induration.The patient was readmitted to the hospital due to recurrence of skin lesions after five months. This time she was treated with PUVA therapy and received a cumulative UVA dose of 8.5 J/cm2 during a course of eight exposures, but the therapy was discontinued due to unavailability of 8-MOP on the market. There-fore, combined treatment with acitretin (initial dose of 50 mg/daily) and nbUVB phototherapy (Re-nbUVB) was started. Betamethasone cream was applied twice daily for two weeks. The patient received a cumula-tive nbUVB dose of 5.8 J/cm2 during a course of elev-en exposures that resulted in complete regression of erythema and partial loss of induration.Due to worsening of the disease in the form of erythema, poikilodermatous patches, and plaques, pityriasiform desquamation on the upper eyelid and scalp, and clinically enlarged submandibular lymph nodes, the patient was admitted for the third time to the hospital after eleven months. Laboratory data showed CRP 13.1 (normal range 0.0-5.0 mg/L), LDH 208 (normal <240 U/L), leukocytes 10.9 (3.4-9.7 10e9/L), triglycerides 2.92 (<1.7 mmol/L). The whole staging procedure was performed again. CT scans re-vealed reactive inguinal and axillary lymphadenopa-thy (right axillary lymph nodes up to 1.9 cm × 1.3 cm, left axillary lymph nodes 1.8 cm × 1.1cm, left inguinal lymph nodes up to 1.8 cm × 1.4 cm, histologically un-involved). PMF stage IIA (T2N1M0) was determined. The patient was referred to a hematologist for con-sultation. Due to a lack of signs of extracutaneous dis-ease propagation, the hematologist recommended PUVA therapy. The patient underwent PUVA therapy over the course of twenty exposures (cumulative UVA dose 33.5 J/cm2 ) and local betamethasone therapy that resulted in complete disappearance of erythema, scaling, and induration, leaving only poikiloderma. The patient was recommended regular check-ups.DISCUSSIONRare clinical variants of MF include hypopigment-ed MF, granulomatous slack skin, pagetoid reticulosis, and folliculotropic and poikilodermatous MF. It is still debatable whether PMF is a clinical variant of early-stage MF or special entity. We must also bear in mind the fact that is has been reported that poikiloderma can coexist with classical MF lesions, so PMF can only be considered when poikilodermatous lesions are predominant (>50% of lesions), as in our case where poikilodermatous lesions covered almost 80% of the body surface (5). Histology and immunohistochemistry revealed MF, but due to specific clinical findings (poikiloder-ma), we established the diagnosis of very rare clini-cal variant – PMF. The most commonly found immu-nophenotype in PMF is predominantly CD4+ (5), as in our case, although the predominance of CD8+ and double negative (CD4- and CD8-) was found infre-quently. Recent data suggest that the CD4+CD8- im-munophenotype and CD8+CD4- immunophenotype in PMF do not differ in prognosis (5). T-cell receptor (TCR) gene rearrangement by using PCR is not lymphoma-specific; in other words, mono-clonality does not necessarily mean malignancy (7), and positive TCR gene rearrangement (monoclonal-ity of T-cell infiltrate) is not required for the diagnosis (5). Furthermore, monoclonality may be lacking in lymphomas and may be found in a distinct propor-tion of pseudolymphomas (3). Some authors propose that undetectable monoclonality should be con-sidered pre-mycosis (8). A TCR gene rearrangement study was not performed in our case.Lymphadenopathy is a frequent finding in pa-tients with MF, but it does not necessarily correlate with histological lymphomatous involvement. Der-matopathic lymphadenitis is often observed in such patients, as in our case, where the axillary and ingui-nal lymph nodes were slightly enlarged but still only Jerkovic Gulin et al. Acta Dermatovenerol CroatPoikilodermatous mycosis fungoides     2018;26(1):48-52Figure 3. Immunohistochemical features: tumor cells show epidermotropism with diffuse expression of a) CD3, b) CD4  (immunohistochemistry CD3 and CD4, ×40).ACTA DERMATOVENEROLOGICA CROATICA 51up to 2 cm in diameter without histological involve-ment (9).Choice of treatment for PMF, as for classic MF, is based on staging and includes skin-directed thera-pies (topical corticosteroids, bexarotene, carmustine, mechlorethamine, nbUVB, PUVA, radiation) and sys-temic therapies. PUVA and nbUVB were found to be equally effective (with complete response to treat-ment in approximately 60% of patients) in retrospec-tive studies with early-stage MF (10,11). Narrowband UVB therapy should be included in first-line treat-ment options of MF given its efficacy, convenience, and the likelihood of fewer long-term adverse effects only for the patch stage (11). New treatment options for MF have recently expanded to include UVA1 and excimer laser (12). A combination of PUVA with sys-temic therapy is used to diminish the total UVA ex-posure and therefore minimize the long-term side-ef-fects. The most common systemic drugs for use with PUVA in MF are either retinoids (acitretin, isotretinoin, and bexarotene) or interferon-alfa. However, it is still an open question whether combination treatments are more efficacious than PUVA alone in early disease (12). PUVA is more effective than UVB for thicker le-sions – plaques – or in individuals with dark skin be-cause UVA penetrates deeper than UVB (12). PUVA therapy is associated with an increased risk of non-melanoma skin cancer, and maintenance therapy is not recommended because prolonged disease-free intervals are possible. Combined PUVA and retinoid therapy may be considered in patients who rapidly relapse after PUVA treatment, as was the case with our patient. Also, hyper- and hypopigmentation will not resolve after treatment, in contrast to erythema, itching, desquamation, and induration that are treat-able (5). PUVA, Re-PUVA, and Re-nbUVB therapy in our patient resulted in residual hyper- and hypopig-mentations. A case of treatment failure of PMF pre-senting with erythroderma has also been reported in the literature (13). The overall prognosis for PMF is favorable (most patients will have non-progressive disease), although recent study revealed PMF cases with progression to lymphomatoid papulosis stage III (LyP) and PMF stage IVB (5). CONCLUSIONPMF is a rare clinical entity with little data in the literature on its clinical, histopathological, immuno-phenotypic, molecular, and prognostic features. We can conclude from published data that first-line treat-ment for PMF (stages IA, IB, IIA) in the patch-stage could be nbUVB and for plaque-stage PUVA. In our case, Re-PUVA had very good treatment results, and this combined therapy probably resulted in fewer treatment sessions and lower cumulative UVA dose. An individual approach is obligatory as different treatment modalities could be successful in the case of early-stage PMF. PMF must be considered a ma-lignant disease that may stay at the same stage with many rapid/non-rapid recurrences or may progress. Although overall prognosis is good, careful monitor-ing and appropriate treatment of PMF is necessary.  References:1.  Whittaker SJ, Marsden JR, Spittle M, Russell Jo-nes R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol. 2003;149:1095-107. 2.  Cerroni L. Mycosis fungoides. In: Cerroni L. Skin Lymphoma: the illustrated guide. Fourth ed. West Sussex: Wiley Blackwell; 2014. pp. 11-74. 3.  Cerroni L. Cutaneous NK/T-cell lymphomas. Skin Lymphoma: the illustrated guide. Fourth edi. West Sussex: Wiley Blackwell; 2014. pp. 48-53. 4.  Mahajan VK, Chauhan PS, Mehta KS, Sharma AL. Poikiloderma vasculare atrophicans: a distinct clinical entity? Indian J Dermatol. 2015;60:216. 5.  Abbott RA, Sahni D, Robson A, Agar N, Whitta-ker S, Scarisbrick JJ. Poikilodermatous mycosis fungoides: a study of its clinicopathological, im-munophenotypic, and prognostic features. J Am Acad Dermatol. 2011;65:313-9.6.  Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Or-ganisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28:4730-9. 7.  van Krieken JHJM, Langerak AW, Macintyre EA, Kneba M, Hodges E, Sanz RG, et al. Improved relia-bility of lymphoma diagnostics via PCR-based clo-nality testing: report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia. 2007;21:201-6. 8.  Kikuchi A, Naka W, Nishikawa T. Cutaneous T-cell lymphoma arising from parakeratosis variegata: long-term observation with monitoring of T-cell receptor gene rearrangements. Dermatology. 1995;190:124-7. 9.  Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53:1053-63. Jerkovic Gulin et al. Acta Dermatovenerol CroatPoikilodermatous mycosis fungoides     2018;26(1):48-525210.  Ahmad K, Rogers S, McNicholas PD, Collins P. Nar-rowband UVB and PUVA in the treatment of my-cosis fungoides: a retrospective study. Acta Derm Venereol. 2007;87:413-7. 11.  El-Mofty M, El-Darouty M, Salonas M, Bosseila M, Sobeih S, Leheta T, et al. Narrow band UVB (311 nm), psoralen UVB (311 nm) and PUVA therapy in the treatment of early-stage mycosis fungoides: a right-left comparative study. Photodermatol Pho-toimmunol Photomed. 2005;21:281-6. ACTA DERMATOVENEROLOGICA CROATICA12.  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Poikilodermatous mycosis fungoides – rare entity, different treatment modalities

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