J Cutan Pathol 2015: 42: 22–31 doi: 10.1111/cup.12423 John Wiley & Sons. Printed in Singapore

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Journal of Cutaneous Pathology

The clinical features and histopathologic patterns of folliculotropic mycosis fungoides in a series of 38 cases Background: The recognition of folliculotropic mycosis fungoides (FMF) may pose diagnostic challenges, owing to the variety of histopathological findings. Objective: In this study, our aim is to describe the broad spectrum of the histopathological patterns in a total of 86 biopsies from 38 patients with FMF, together with the clinical features. Results: The most frequent histopathologic pattern was the folliculocentric/folliculotropic pattern, with or without follicular mucinosis. Keratin-filled cysts and comedones were the second most common pattern in the biopsies. Other less common findings included widening of the hair follicle orifis with keratotic plugging, reminiscent of keratosis pilaris, granuloma formation, eosinophilic or suppurative folliculitis and basaloid folliculolymphoid hyperplasia. Coexisting syringotropism was present in some biopsies. The CD4 : CD8 ratio was at least 4 : 1 or more in most biopsies. Grouped follicular papules and patch/plaque lesions with follicular prominence were the most frequent clinical findings. Folliculocentric lesions such as milia, cysts and acneiform lesions, alopecia, loss of hair or eyebrows were also seen. In 6 out of 38 (15.8%) patients, transformation to large-cell lymphoma was observed during the follow-up. Conclusion: The awareness and the identification of the various histopathological presentations of FMF by pathologists, as well as by clinicians, are imperative to prevent diagnostic errors. Keywords: Cutaneous T-cell lymphoma, Folliculotropic mycosis fungoides, Pathology Demirkesen C, Esirgen G, Engin B, Songur A, O˘guz O. The clinical features and histopathologic patterns of folliculotropic mycosis fungoides in a series of 38 cases. J Cutan Pathol 2015; 42: 22–31. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

According to the recent classification of the World Health Organization-European Organization on Research and Treatment of Cancer (WHO-EORTC), folliculotropic mycosis

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Cuyan Demirkesen1 , Galip Esirgen1 , Burhan Engin2 , Abdullah Songur2 and Oya O˘guz2 1

Department of Pathology, Cerrahpa¸sa Medical Faculty, Istanbul University, Istanbul, Turkey and 2 Departments of Dermatology, Cerrahpa¸sa Medical Faculty, Istanbul University, Istanbul, Turkey

Prof. Dr. Cuyan Demirkesen Department of Pathology, Cerrahpa¸sa Medical Faculty, Cerrahpa¸sa, Istanbul 34303, Turkey Tel : 0090 5332569267 Fax : +90 2124143000 21850 e-mail: [email protected] Accepted for publication October 12, 2014

fungoides (FMF) is considered as a distinct entity.1 The clinical and histopathologic features in FMF differ from those of the classical mycosis fungoides (MF).2 The patients with FMF usually

Clinical features of FMF Table 1. Summary of clinical features of follicular MF

A

B

Number of patients (%) Sites of involvement Head and neck Trunk Extremities Alopecia Loss of hair/eyebrow Follicular papules Folliculocentric lesions such as milia, cysts and acneiform lesions Keratosis pilaris-like lesions Intense pruritis Patch/plaque lesions Erythroderma

18 (47.4%) 28 (73.7%) 17 (44.7%) 8 (21%) 9 (23.7%) 31 (81.6%) 16 (42.1%) 2 (5.3%) 12 (31.6%) 31 (81.6%) 7 (18.4%)

C

MF, mycosis fungoides.

Fig. 2. A) Large reddish-brown plaque lesions involved the lateral lumbar regions of the patient. B) Keratosis pilaris-like lesions involved the gluteal region. C) Comedo-like lesions were clearly visible.

Fig. 1. Follicular mycosis fungoides (FMF) patient showing infiltrated plaques with typical follicular papules involving the back.

Fig. 3. Aggregates of comedo-like lesions and large milia with facial alopecia occurred on erythematous background.

present with acneiform lesions, comedones and cysts, follicular papules with a variable degree of keratosis, hair loss, and occasionally tend to form plaques or tumors. The typical histopathologic feature is the presence of atypical T-cells with a tropism to hair follicle epithelium. Gerami and Guitart described five characteristic histopathologic patterns of FMF recently.3 Owing to the broad spectrum of histopathological findings, the recognition of this variant may pose diagnostic challenges, resulting in delay in diagnosis. Some studies reveal a more aggressive clinical course and poorer prognosis for FMF.2,4,5 Therefore, the therapeutic responses and survival of FMF are indicated to be different from those of the conventional MF. In this study, attempt has been made to describe the various histopathological patterns in patients with FMF, in a series of 38 cases, in order to increase the ability to recognize

the challenging histopathologic findings. The clinical features and outcome of FMF patients were also been reviewed. Materials and methods A total of 86 biopsies from 38 patients with FMF were collected from our archives of the Department of Pathology from 1999 to 2013. All the patients were followed in our multidisciplinary cutaneous lymphoma clinic. The defining criteria for the diagnosis of FMF were the presence of progressive clinical lesions with follicular prominence and a dominant histopathologic pattern of folliculotropism, as indicated by Gerami and Guitart.3 Cases of follicular mucinosis unassociated with clear-cut findings of MF were not included in this study. The hematoxylin and eosin-stained sections were reviewed by two pathologists, and the histopathological patterns described by Gerami and Guitart were analyzed.3

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Demirkesen et al. A

B

Fig. 4. A), B) Alopecia, infiltrated plaques and comedo-like lesions involved the face, scalp and the ear lobes.

The presence or absence of follicular mucinosis, conventional epidermotropism outside of the follicles, basaloid folliculolymphoid hyperplasia, an eosinophilic or suppurative folliculitis like pattern, granuloma, cyst and comedo formation were noted. The number of eosinophils was counted on a semiquantitive scale, noted as minimal to absent, meaning 5 or less eosinophils per the whole area of each biopsy, or indicated as moderate with 5–20, or extensive, meaning more than 20 eosinophils. The presence of syringotropism was noted. Immunophenotypic studies were performed in 55 biopsy samples taken from 24 patients, using a panel of monoclonal antibodies for CD3 (1 : 75, clone E272, Biocare Medical, Concord, CA, USA), CD4 (clone 1F6, Novocastro, Buffalo Grove, IL, USA), CD5 (1 : 100, clone SP19, Thermo Scientific, Fremont, CA, USA), CD7 (1 : 40, clone 7C03, Thermo Scientific, Fremont, CA, USA), CD8 (1 : 40, clone 1A5, Novocastro, Buffalo Grove, IL, USA), CD20 (1 : 250, clone L26, Thermo Scientific, Fremont, CA, USA) and CD30 (1 : 200, clone BER-H2, Cell Marque, Molenstroat, NL, USA) with Ventana Benchmark XT Immunostainer. The CD4 : CD8 ratio was recorded. Colloidal iron and alcian blue stains were used to demonstrate the mucin accumulation in the follicular epithelium. Using paraffin-embedded tissues, PCR analyses for the T-cell receptor (TCR) γ-chain gene were carried out in the initial biopsies of two patients, which were highly suspicious, but not definite for FMF. Additionally, the clinical data of these patients, including the clinical presentation (presence of alopecia and/or loss of eyebrows, hair follicles, elsewhere in the body, follicular papules, cystic or comedonal features, localization and extent of these lesions, and presence of additional patch/plaque lesions), their

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treatments, response to therapy and follow-up were all recorded. Results Clinical findings Among the 38 patients, 26 were male and 12 were female. The ages ranged from 19 to 91 years, with an average of 56 years. Median follow-up time was 43.5 months (range, 2–236 months). The clinical features of FMF patients are provided in Table 1. Grouped follicular papules and patch/plaque lesions were the most common findings seen in FMF (81.6%) (Figs. 1 and 2). Most of these patch/plaque lesions had follicular prominence. A few patients had some patch and plaque lesions of conventional MF. However, these lesions developed during the course of the disease and these patients had still follicular-based lesions as the dominant feature. Folliculocentric lesions such as milia, cysts and acneiform lesions were observed in almost half of the patients (42.1%). Alopecia, loss of hair or eyebrows were less common (21 and 23.7%, respectively; Figs. 3 and 4). Intense pruritus was a complaint in 12 patients (31.6%). Erythroderma developed in seven cases (18.4%). The therapies and the outcomes of the patients are summarized in Table 2. Seven patients died of lymphoma (18.4%) within 14–96 months. Histopathologic and immunohistochemical findings As we reviewed all 86 biopsies, it was noted that many of the patients with multiple biopsies showed different histopathologic patterns in different biopsies (Table 3). In some biopsies, more than one pattern was detected. FMF represented 7% (38/539 patients ) of all MF patients in our

Clinical features of FMF Table 2. Therapy and outcomes of 38 patients with follicular MF Case

Age (years)

Sex

Nodal involvement

1 2

67 60

F M

N1 (LN0) N1 (LN0)

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

52 77 61 57 71 41 73 63 36 59 19 83 65 35 44 84 63 64 91 29 73 64 48 35 56 20 49 67 75 36 67

M M M F M F M F F M M M M M F F M F M F M M M M M M M M F M M

N1 (LN0) – N1 (LN0) N1 (LN0) – – – N1 (LN0) – N1 (LN0) – N1 (LN0) – – – N1 (LN0) N1 (LN0) – N3 (LN4) – – – – N1 (LN0) N3 (LN4) – – – N3 (LN4) N3 (LN4)

34 35 36 37 38

22 55 41 76 51

F M M M F

– – – N1 (LN0) –

Therapy

Outcome, follow-up time (months)

PUVA Local NM, UVB, PUVA, MTX, Inf-A, Iso, CHOP PUVA, asitretin UVB Local NM, Imi, PUVA, Inf-A, MTX, RT PUVA, CHOP NA PUVA, MTX Int-A PUVA, CHOP NA PUVA, Inf-A, Iso, CHOP No therapy* PUVA NA PUVA, Trans Local NM PUVA NA Topical steroids PUVA PUVA PUVA Topical steroids, PUVA, Inf-A CHOP, BMT PUVA, Asitretin, Bexaroten topical, Inf-A PUVA, CHOP NA Iso, PUVA PUVA Topical steroids, PUVA, Inf-A, MTX PUVA Topical steroids, UVB, PUVA, Inf-A, MTX, RT, alemtuzumab + chlorambusil, CHOP MTX, PUVA MTX, PUVA PUVA, asitretin PUVA, CHOP NA

DOL (48) DOL (24) AWD (168) AWD (24) AWD (168) DOL (96) NA AWD (204) AWD (2) AWD (120) NA AWD (180) AWD (3) DOL (52) NA AWD (120) AWD (5) DOL (26) NA AWD (39) DOL (14) AWD (132) AWD (3) AWD (96) AWOD (81) AWD (19) DOL (74) NA AWD (38) AWD (21) AWD (36) AWD (33) AWD (96) AWD (38) AWD (128) AWD (13) AWD (236) NA

F, Female; M, Male; AFD, alive free of disease; AWD, alive with disease; DOL, dead of lymphoma; AWOD, alive without disease; LN, Lymph node; NA, data was unavailable; NM, nitrogen mustard; MTX, methotrexate; PUVA, psoralen plus ultraviolet; UV, ultraviolet; CHOP, cyclophosphamide, adryamicine, vincristine and prednisone; Inf-A, ınterferon A; Iso, Isoretinoin; Imi, Imiquimod; RT, radiotherapy; Trans, transretinoic acid; BMT, bone marrow transplantation. *Since the lesion was localized, no therapy was given (wait and see protocol).

archives. The most common histopathologic pattern was the folliculocentric/folliculotropic pattern, which was identified in 71 biopsies (82.6%) (Fig. 5). Intact follicles with perifollicular and intrafollicular infiltration and with or without follicular mucinosis were observed in these

specimens. In some sections, intrafollicular collections of atypical lymphocytes, reminiscent of Pautrier’s microabscesses, were seen (Fig. 6). Follicular mucinosis was found in 52 biopsy samples (60.5%; Fig. 7). Although epidermotropism was not the dominant feature in any of the biopsies, focal and sparse epidermotropism was observed

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Demirkesen et al. Table 3. Summary of histopathologic features of follicular MF

Folliculotropic/folliculocentric pattern Cystic or comedonal pattern Granulomatous pattern Eosinophilic folliculitis-like pattern Basaloid folliculolymphoid hyperplasia Suppurative folliculitis Follicular mucinosis Keratosis pilaris-like pattern Mild epidermotropism Moderate/extensive eosinophils Eosinophilic spongiosis Prominent spongiosis of the epidermis Plasma cells Syringotropism Transformation to large-cell lymphoma

Number of patient with FMF (n = 38)

Number of biopsies from 38 patients (n = 86)

37(97.4%)

71 (82.6%)

14 (36.8%) 10 (26.3%) 3 (7.9%)

25 (29%) 14 (16.3%) 4 (4.7%)

2 (5.3%)

2 (2.3%)

4 (10.5%) 33 (86.8%) 2 (5.3%) 29 (76.3%) 20 (52.6%) 2 (5.3%) 2 (5.3%)

4 (4.7%) 52 (60.5%) 2 (2.3%) 49 (57%) 39 (45.3%) 4 (4.7%) 2 (2.3%)

9 (23.7%) 6 (15.8%) 6 (15.8%)

15 (17.4%) 7 (8.1%) 6 (6.97%)

FMF, folliculotropic mycosis fungoides.

in 49 biopsies (57%). Keratin-filled cysts and comedones were the second most common feature in the biopsies (25/86, 29%) (Fig. 8). These large dilated cystic structures were lined by atrophic epithelium, usually without significant mucin deposition. The follicular epithelium was infiltrated by small lymphocytes, with convoluted nuclei. Widening of the hair follicle orifice with keratotic plugging, reminiscent of keratosis pilaris, was identified in two patients (5.3%) (Fig. 9). In 14 biopsy samples (16.3%), granuloma formation or collections of foreign body giant cells were seen as a result of the destroyed hair follicles (Fig. 10). Mostly, granulomatous infiltration was adjacent to the follicles, some of which showed cystic dilatation. In some cases, remnants of hair follicles were seen within the dermis. Eosinophilic folliculitis, characterized by abundant eosinophils around or within the follicular epithelium, together with lymphocytes, was present in four specimens (4.7%) (Fig. 11). Suppurative folliculitis was also found in four specimens (4.7%) (Fig. 12). Basaloid folliculolymphoid hyperplasia was the least common pattern, detected in only two biopsies (2.3%) (Fig. 13). In this pattern, proliferation of the basaloid epithelial cells, extending from intact hair follicles, was identified. These basaloid cells were infiltrated by atypical lymphocytes.

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Fig. 5. A folliculocentric and folliculotropic infiltrate of atypical lymphocytes lacked prominent epidermotropism in the nonfollicular epidermis (hematoxylin/eosin staining, ×100).

Fig. 6. Intrafollicular collections of atypical lymphocytes were reminiscent of Pautrier collections (hematoxylin/eosin, ×200).

Moderate or extensive eosinophils in the dermal infiltration was seen in 6 (7%) and 33 biopsies (38.4%), respectively. In the rest of the biopsies, eosinophils were sparse or absent. Eosinophilic spongiosis within the hair follicle epithelium was observed in four biopsies (4.7%). Plasma cells were present in 15 biopsies (17.4%). Spongiosis in the epidermis was slight or absent in most of

Clinical features of FMF

Fig. 7. Follicular mucinosis: mucin deposition results in dissolution of cellular attachments in the follicular epithelium (hematoxylin/eosin, ×100).

the cases, but it was prominent in two biopsies (2.3%). In 6 cases out of 38 (15.8%), transformation to large-cell lymphoma was observed during the follow-up of these patients. In those biopsies, the presence of large cells with prominent nuclei and abundant cytoplasm, intermingled with hyperchromatic, convoluted small- to medium-sized lymphocytes, was observed in the superficial part of the dermis or within the whole dermis (Fig. 14). In seven specimens (8.1%), coexisting syringotropism, characterized by infiltration of the ecrine glands and ducts with atypical lymphocytes, was present (Fig. 15). Lymphocytes in the dermal infiltrate and within the follicle epithelium expressed T-cell antigens, CD3, CD4 and less frequently CD5. Expression of CD8 was seen in only a small number of lymphocytes. The CD4 : CD8 ratio was at least 4 : 1 or more in 32 specimens. In the remaining three biopsy samples, although the predominant cells were CD4(+) T cells, the ratios were less than 4 : 1. In a few biopsies, clusters of small B cells, demonstrating immunoreactivity for CD20, were present. Loss of CD7 expression was seen in only one case. In our series, transformation to large-cell lymphoma was detected in six cases

Fig. 8. Cystic dilatation of a follicle, which is filled with keratinous material. Note the atrophy of the follicular epithelium and follicular mucinosis (hematoxylin/eosin, ×200).

(15.8%), and except in one, 50–90% of the large cells revealed CD30 expression. In the case of exception, the large cells were negative for CD30. In nine biopsies, scattered CD30(+) large cells were detected, but the percentage of these cells was less than 20%. The analysis of TCR γ-chain gene in two cases (Cases 8 and 34) showed monoclonal arrangements. Discussion In the recent WHO-EORTC classification, FMF has been designated as an unusual variant of MF with distinct clinical and histopathological features, therapeutic responses and survival rates.1,2 Historically, MF with follicular involvement was divided into those cases with or without follicular mucinosis such as ‘MF, associated with follicular mucinosis’ and ‘purely follicular or pilotropic MF’.2 Later, FMF began to be proposed to define both groups with the implication that these patients have a worse prognosis.2,4,6,7 The overall survival rates of FMF at 5 years ranged from 60 to 87% compared with >90% for the classic patch and plaque stage MF. Moreover, Gerami et al. declared that the survival rates of early-staged FMF (≤IIA) steeply dropped after 15 years, differing from conventional MF with a similar

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Demirkesen et al.

Fig. 10. Collections of foreign body giant cells can be seen due to destruction of hair follicles (hematoxylin/eosin, ×200). Fig. 9. Widening of the hair follicle orifice with keratotic plugging, reminiscent of keratosis pilaris, is seen (hematoxylin/eosin, ×100).

stage.4 The broad spectrum of histopathological patterns causes these patients to be erroneously diagnosed with nodulocystic acne, infundibular cyst, comedo, keratosis pilaris, scarring alopecia, eosinophilic or suppurative folliculitis, and granulomatous dermatitis. In this study, we went through all the biopsies of 38 patients with FMF, to emphasize the challenging histopathological patterns of FMF. For the diagnosis of FMF, the presence of aytpical lymphocytes within the follicular epithelium is the crucial finding. In addition, in a recent paper, five characteristic patterns have been identified; the classic pattern of folliculotropic and folliculocentric infiltration with or without follicular mucinosis, a cystic pattern, an eosinophilic folliculitis like pattern, basaloid follicololymphoid hyperplasia, and a granulomatous pattern.3 In our series, the classic pattern of folliculotropic and folliculocentric infiltration was the most frequent pattern (82.6% of all the biopsies), congruent with other series in the literature.3,4 Almost every patient displayed this pattern in at least one of his multiple biopsies (97.4% of the patients). In such biopsies, folliculocentric lymphocytic dermatoses, such as

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Fig. 11. An eosinophilic folliculitis-like pattern: there were abundant eosinophils around or within follicular epithelium (hematoxylin/eosin, ×400).

follicular lichen planus, discoid lupus erytematosus, pseudolymphomatous folliculitis, dissecting cellulitis of the scalp should be considered in the differential diagnosis. The detection of atypical lymphocytes, especially forming collections within the follicular epithelium, is the key feature for the diagnosis of FMF. However, it should be kept in mind that the nuclear atypia may be slight in some cases, and atypical lymphocytes

Clinical features of FMF A

B

Fig. 12. Suppurative folliculitis is present together with follicular mucinosis ((A) hematoxylin/eosin, ×200, (B) colloidal iron, ×200).

Fig. 13. Follicular-lymphoid hyperplasia characterized by the proliferation of basaloid epithelial cells, extending from intact hair follicles (hematoxylin/eosin, ×200).

may be intermingled with other inflammatory cells, such as neutrophils, plasma cells, eosinophils and even some multinucleated giant cells, obscuring the diagnosis of FMF. The presence of intrafollicular mucin deposits may be a

diagnostic pitfall; however, it is not a constant feature. Prominent follicular mucinosis was seen in most of the patients (86.8%), but not in every biopsy (60.5%). A cystic or comedonal pattern was detected in 36.8% of the patients and 29% of the biopsies. Folliculotropic lymphocytes in these cystic lesions could be easily overlooked. In the majority of instances with this pattern, deposition of mucin in the follicular epithelium was absent. However, rare cases with even mucin pools were evident. In the granulomatous pattern, epitheloid histiocytes and multinucleated giant cells, adjacent to the remnants of the destroyed hair follicles, might give rise to an erroneous diagnosis of scarring alopesia or be confused with granulomatous MF. When the lesions are mainly located on the face, granulomatous rosacea may be a challenging diagnosis. This pattern was present in 26.3% of the patients and 16.3% of all biopsies. Less commonly, an eosinophilic folliculitis-like pattern and basaloid folliculolymphoid hyperplasia were identified in some biopsies. An eosinophilic folliculitis-like pattern could be confused with a number of dermatoses, including HIV-related condition, Ofuji disease, parasitic disease, or arthropod bites.3 Basaloid folliculolymphoid hyperplasia was identified in 18% of patients in the series, reported by Gerami and Guitart, whereas it was detected in only 5.3% in our series.3 Suppurative folliculitis, sometimes together with follicular mucinosis and histopathologic features resembling keratosis pilaris, were the most misleading findings that compromised the diagnosis of FMF. In regard to the histopathologic differential diagnosis

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Demirkesen et al. A

B

Fig. 14. A) Follicular mycosis fungoides (FMF) showing transformation to large-cell lymphoma in the superficial part of the dermis (hematoxylin/eosin, ×400). B) Roughly half of the large cells displayed immunreactivity with CD30 antibody (×200). Table 4. Histopathologic differential diagnosis of follicular MF Follicular lichen planus Discoid lupus erythematosus Dissecting cellulitis of the scalp Scarring alopecia Pseudolymphomatous folliculitis Acneiform lesions such as acne vulgaris, nodulocystic acne Infundibular cyst Keratosis pilaris Granulomatous rosacea Eosinophilic folliculitis due to fungal infection, human immunodeficiency virus (HIV) disease, and Ofuji disease Suppurative folliculitis MF, mycosis fungoides. Fig. 15. Syringotropism was characterized by infiltration of the eccrine glands and ducts with atypical lymphocytes (hematoxylin/eosin, ×200).

of FMF, it should be emphasized that various differential diagnoses take place depending on the microscopic patterns of FMF. (Table 4). Sometimes, clear distinction may not be possible in the histopathologic evaluation. Correlation with the clinical findings and close follow-up may be required to establish the diagnosis with certainty. Multiple biopsies can be useful to enhance the range of histopathologic findings, some of which may help to reach the accurate diagnosis. Prominent epidermotropism of nonfollicular epidermis was not detected in any of the biopsies of FMF. Yet, it was reported to be present in approximately 15% of patients in the series of Gerami and Guitart.3 However, focal and sparse epidermotropism was present in more than half of the biopsies (57%) in our series. In many cases of FMF, in the reticular dermis adjacent to the hair follicles, inflammatory cells such as eosinophils, plasma cells and histiocytes could be identified intermingled with atypical lymphocytes. Moderate or dense eosinophils

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were seen in almost half of the biopsies (45.3%), similar to the other series published in the literature.3,8 Plasma cells were evident in a small number of biopsies (17.4%). Less commonly, FMF may present with the involvement of the eccrine gland, associated or not associated with syringohyperplasia.3,9 Coexisting syringotropism, mainly involving the coil and dermal ducts, was seen in 15.8% of the patients and 8.1% of the biopsies without any syringohyperplasia. Most of these biopsies were taken from acral areas. It was clear that in these cases, adnexotropic behaviour of atypical lymphocytes was a prominent feature, which may be explained by the lymphocyte homing mechanisms, such as upregulation of intercellular adhesion molecule 1 (ICAM-1) on follicular and eccrine epithelium.9 In our patients with FMF, male predominance was recorded, which is in agreement with previous studies.2,5,6 The head and the neck are usually spared regions in classical MF. They are noted as predilection sites for FMF involvement.2 – 4 However, in our patients the trunk was the major predilection site, like some other series in the literature.6,10

Clinical features of FMF Reported cases of FMF present clinicallly with a variety of cutaneous lesions.4,8,11 These lesions were described as plaques, erythematous follicular papules, cysts or comedo-like lesions, alopecia, excoriated nodules, resembling prurigo nodularis, xanthomatous changes, pustules, and rarely diffuse erythroderma.4,8,11 Grouped follicular papules and patch/plaque lesions were the most common clinical findings in our series, seen in 81.6% of the patients. Other clinical signs were folliculocentric lesions such as milia, cysts and acneiform lesions, which were present in almost half of the patients (42.1%). Alopecia and loss of hair or eyebrows were observed in a small number of patients (21% and 23.7%, respectively). Intense pruritus was reported as a rather frequent feature in FMF.4,11 Gerami et al. noted that 68% of their patients had severe pruritus requiring seperate treatment aside from lymphoma.4 However, in our series, only 31.6% of the patients complained of intense pruritus, resulting in excoriated papules. There was only one case with a solitary lesion in our series. Mostly, there were more than one lesion involving less than 10% of the skin surface. In 18.4% of the cases, erythroderma developed during the follow-up period. The therapy and outcomes of 38 patients with FMF are summarized in Table 2. These 38 patients included 13 patients with stage

IA disease, 8 with stage IB, 6 with IIA, 5 with stage IIB, 2 with stage III, and 4 with stage IVA. Current TNM classification does not meet true staging criteria for FMF patients. The reason for this is the deeper infiltration in plaques of FMF, compared with classical MF. Therefore, our patients with FMF received more aggressive and combined treatments for their disease. Outcomes were comparable with the literature. Only a few FMF with transformation to a large-cell lymphoma have been reported.7,12 – 15 Large-cell transformation was detected in six patients (15.8%) in our series. These patients progressed to a large-cell lymphoma preceding typical clinical manifestations of FMF within 4–11 years. Except in one case, most of the large cells seen in the biopsies expressed CD30. In conclusion, the recognition of rare histopathologic features of FMF, such as keratin filled cysts, widening of the hair follicle orifis with keratotic plugging, reminiscent of keratosis pilaris, granuloma formation or collections of foreign body giant cells, eosinophilic or suppurative folliculitis and basaloid folliculolymphoid hyperplasia, is imperative to prevent diagnostic errors. It should also be emphasized that the proper diagnosis of FMF can be approached by incorporating clinical and histopathological findings with the careful follow-up of patients.

References 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768. 2. van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol 2002; 138: 191. 3. Gerami P, Guitart J. The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol 2007; 31: 1430. 4. Gerami P, Rosen S, Kuzel T, Boone SL, Guitart J. Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 2008; 144: 738. 5. Mantaka P, Helsing P, Gjersvik P, Bassarova A, Clausen OP, Delabie J. Clinical and histopathological features of folliculotropic mycosis fungoides: a Norwegian patient series. Acta Derm Venereol 2013; 93: 325.

6. Lehman JS, Cook-Norris RH, Weed BR, et al. Folliculotropic mycosis fungoides. Single-center study and systematic review. Arch Dermatol 2010; 146: 607. 7. Kempf W, Kazakov DV, Schermesser M, et al. Unilesional follicular mycosis fungoides: report of two cases with proggression to tumor stage and review of the literature. J Cutan Pathol 2012; 39: 853. 8. Flaig MJ, Cerroni L, Schuhmann K, et al. Follicular mycosis fungoides. A histopathologic analysis of nine cases. J Cutan Pathol 2001; 28: 525. 9. Rongioletti F, Smoller B. The histologic value of adnexal (ecrine gland and follicle) infiltration in mycosis fungoides. J Cutan Pathol 2000; 27: 406. 10. Hodak E, Feinmesser M, Segal T, et al. Follicular cutaneous T-cell lymphoma: a clinicopathological study of nine cases. Br J Dermatol 1999; 141: 315. 11. Muniesa C, Estrach T, Pujol R, et al. Follicular mycosis fungoides: clinicopathological features and outcome in a series of 20 cases. J Am Acad Dermatol 2010; 62: 418.

12. Bonta MD, Tannous ZS, Demierre MF, Gonzalez E, Harris NL, Duncan LM. Rapidly progressing mycosis fungoides presenting as follicular mucinosis. J Am Acad Dermatol 2000; 43: 635. 13. Apisarnthanarax N, Ha CS, Duvic M. Mycosis fungoides with follicular mucinosis displaying aggressive tumor-stage transformation: successful treatment using radiation therapy plus oral bexarotene combination therapy. Am J Clin Dermatol 2003; 4: 429. 14. Ishibashi M, Ohshima K, Chen KR. Folliculotropic mycosis fungoides with eosinophilia and CD30+ large-cell transformation: a case with a fatal outcome presenting with multifocal lesions and leonine facies. Clin Exp Dermatol 2010; 35: e133. 15. Mitteldorf C, Stadler R, Bertsch HP, Neumann C. Folliculotropic mycosis fungoides with CD30+ large-cell transformation in a young woman: beneficial effect of bexarotene. Br J Dermatol 2007; 156: 584.

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