Follicular mycosis fungoides: A clinicohistopathologic study

Follicular mycosis fungoides: A clinicohistopathologic study Neville G. Pereyo, MD, a Luis Requena, MD, c Jenny Galloway, MD, d and Omar P. Sangtieza, MD a, b Augusta, Georgia, Madrid, Spain, and Portland, Oregon

Background." Follicular mycosis fungoides (FMF) is a recently described variant of cutaneous T-cell lymphorna, histopathologically characterized by infiltrates of atypical CD4 + T lymphocytes around and within the epithelium of the hair follicles (folliculotropism). To date, only four cases of FMF have been reported. Objective: Our goal was to identify cases of FMF and compare them with those previously reported. Methods: The clinical and histopatbologic features of three cases of FMF were analyzed. In addition, in one case immunohistochemical analysis in paraffin-embedded and frozen tissue as well as genotypic studies were performed. Results: The three reported cases showed typical histologic findings of FMF, namely, perifollicular and intrafollicular infiltrates of atypical lymphocytes, in the absence of either epidermotropism or follicular mucinosis. Clinically, the lesions were sinailar to classic MF, but also contained follicular papules. Immunohistochemistry and gene rearrangement studies showed findings similar to classic MF. Conclusion: FMF is a rare variant of cutaneous T-cell lymphoma. Including our three cases, only seven patients have been reported. We hypothesize that the follicular epithelium in patients with FMF may express increased levels of skin-selective homing receptors and adhesion molecules. These may be involved in the induction of the folliculolropism of atypical lymphocytes. (J Am Acad Dermatol 1997;36:563-8.)

Mycosis fungoides (MF) is a malignancy of CD4 + helper IT lymphocytes that primarily affects the skin l and m a y later involve other organs. Cutaneous manifestations typically include eczematous patches, plaque~, and tumors. Less common presentations include granulomatous MF, 1 hyperkeratotic MF, 2 hypopigmented MF, 3 M F associated with follicular mucin0sis, 4 M F bullosa, 5 M F palmaris et plantaris, 6 granul~matous slack skin,7 and pagetoid reticulosis. 8 FolliCular mycosis fungoides (FMF) is an unusual and reqently described variant. 9-11 W e report three additional cases and compme them with the four previously reported cases. From the Departments of Medicine (Division of Dermatology)a and Pathology,b Medical College of Georgia, Augusta; the Department of Dermatology, Fundacion Jimenez Diaz, MadridC; and the Department of Pathology, Oregon Health Sciences University, Portland.d i Accepted for publication Nov. 12, 1996. RepNlt requests: Omar P. Sang/Jeza, MD, Department of Pathology, BAE 21D, Medical College of Georgia, Augusta, GA 30904. Copyright ~ 1997 by the American Academy of Dermatology, Inc. 0190-9622Y97/$5.00+ 0 16/1/79207

MATERIAL AND METHODS Three cases of FMF were retrieved from our files. In one patient (patient 2) multiple skin biopsy specimens were obtained. The samples were bisected and one-half of each specimen was snap-frozen for immunologic and genotypic analysis. The remaining haft of each specimen as well as all the specimens from patients 1 and 3 were fixed in 10% buffered formalin, paraffin embedded, and stained with hematoxylin and eosin. In one case frozen material was available. Immunologic analysis was performed on multiple 4 ~ma thick frozen sections. The slides were stained with a series of antibodies to lymphoid antigens (Table I) by means of the standard avidin-biotin complex immunoperoxidase technique for both paraffin-embedded and frozen tissue. Southern blot analysis for demonstration of clonal Tcell receptor gene rearrangement was performed on DNA extracted from frozen sections using a standard method. 12 RESULTS Clinical features Patient 1. A 58-year-old white woman had severe pruritus and a burning sensation of the skin since 563

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Fig. 1. Patient 1. Erythematous, scaly plaques admixed with follicular papules.

Fig. 2. Patient 2. Perifollicular and intrafollicular infiltrates of lymphocytes. Destruction of hair follicles in some areas. Sparing of epidermis by neoplastic lymphocytes. (Hematoxylin-eosin stain; original magnification

1991. Subsequently, erythematous, scaly plaques and follicular papules developed on the right side of the face, trunk, arms, and hands. The plaques on the fight side of the face and the inframammary areas were deeply erythematous, indurated, and scaling (Fig. 1). Treatment with triamcinolone acetonide 0.1% ointment, mechlorethamine hydrochloride ointment, and electron beam irradiation to the fight side of her face produced improvement. Patient 2. A 63-year-old white woman with a 15-year history of photosensitivity developed severn pmritic indurated nodules and foUicular papules on the left cheek. The disease gradually progressed to involve the scalp, neck, upper extremities, and upper mink with typical MF plaques. She was treated with electron beam irradiation to the upper body with marked improvement, but the lesions never regressed completely and new lesions appeared continuously. Patient 3. A 56-year-old white man had a 1-year history of a pmritic eruption consisting of multiple infdtrated plaques, nodules, and papules on the face, neck, trunk, arms, and feet. Some papules were fop licular. Diffuse erythema was prominent. The patient was treated with mechlorethamine hydrochloride ointment and photophoresis that produced some improvement.

x40.)

Histopathologic findings All biopsy specimens from the three patients had similar features. They showed perifollicular as well as intrafollicular infiltrates of atypical lymphocytes (Figs. 2 and 3). The lymphocytes had an enlarged, convoluted nucleus. In a few areas collections of lymphocytes were evident within the epithelium of

the hair follicle (Fig. 4). Alignment of lymphocytes along the dermoepidermal junction and fibrosis of the adventitial dermis was observed in some areas. There was no evidence of infiltration of the epidermis or follicular mucinosis. In some specimens the infiltrates of atypical lymphocytes had almost completely destroyed hair follicles, leaving only fragments of epithelium containing atypical lymphocytes (Fig. 2). In one specimen areas of necrosis around hair follicles was a conspicuous feature (Fig. 2).

Immunohistochemical findings Immunohistochemical analysis in patient 2 showed a polymorphous infiltrate. CD20, a B-cell reagent, stained about 10% of the infiltrating population of cells. These cells were scattered and generally had the appearance of small lymphocytes. CD68 demonstrated numerous maerophages, many of which were organized into small granulomas. The pan-T reagents CD2, CD3, and CD5 showed staining on the majority of the lymphoid cells with the exception of CD7, which was present on considerably fewer cells than the other three pan-T reagents. CD4 showed strong staining in the majority of cells, whereas only rare CD8 ÷ cells were present. CD30 showed scattered, large lymphoid cells but failed to stain any large atypical lymphoid cells.

Gene rearrangement studies Gene rearrangement studies in patient 2 showed the presence of clonal [g-T-cell receptor rearrangements.

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Fig. 3. Patient 2. Perifollicular and intrafolllcular infiltrates are composed of atypical lymphocytes. (Hematoxylin-eosin stain; original magnification MOO.)

Table

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Fig. 4. Patient 3. Extensive infiltration of hair follicles by atypical lymphocytes, in some areas forming small collections. (Hematoxylln-eosin stain; original magnification MOO.)

I. Antibodies and specificities

Antibody CD2 CD3 CD4 CD5 CD7 CD8 CD20 CD30 CD68

I

Specificity T cells T cells T cells T cells T cells T cells 13 cells Reed-Steinberg cells Macrophages

DISCUSSION MF is an unusual clinical variant of M F in which atypical CD4 + T lymphocytes infiltrate and surround hair follicles (folliculotropism) usually without evidence of ~pidermal involvement (epidermotropism). Atypical lymphocytes are present either as solitary

I

Dilution 1/10 1/10 Prediluted Prediluted Prediluted 1/50 Prediluted 1/20 Prediluted

I

Source DAKO DAKO DAKO DAKO DAKO DAKO DAKO Biogenex DAKO

units or in collections (Pautrier collections) within the epithelium of the hair follicle. In some cases the neoplastic lymphocytes destroy the hair follicles, leaving only fragments of epithelium. The adventitial dermis adjacent to the follicular epithelium shows evidence of fibrosis with thick collagen fibers

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Table II. Clinicopathologic characteristics of reported follicular MF cases

I Patient I No.

Age

(yr)

Race

Sex

Kim9 Lacour et al.10

1 2

N/R 78

N/R W

N/R M

Lacour et al.10 Goldenhersh, Zlotogorski, and Rosenmannl This study This study This study

3 4

75 39

W N/R

M M

Scalp, face, back, legs Face, shoulder, arm, leg

5 6 7

58 63 56

W W W

F F M

Face, trunk, inframammary, hands Scalp, face, neck, trunk, arms Face, neck, trunk, arms, feet

Author(s)

Site of lesions

N/R Scalp, face

N/R, Not reported; W. white.

surrounding the follicular structures. 13 The usual clinical presentation is characterized by erythematous, scaly plaques, with or without infiltration, associated with lesional or perilesional comedo-like lesions, plugged follicles, or follicular papules.lO, 1~, 14 Involvement of the scalp usually causes alopecia. Therefore follicular accentuation within otherwise typical plaques of MF should raise the possibility of FMF. To our knowledge, our three patients constitute cases five, six, and seven reported to have FMF. Also, these are the first two reported cases of FMF in women. Clinically and histologically, our three cases are comparable to those previously reported (Table U). Except for the patients described by K i n l 9 and Goldenhersh, Zlotogorski, and Roseumann ~1 in which race was not mentioned, all other reported cases have occurred in white patients with ages ranging from 39 to 78 years. Sanchez and Ackerman13 found that adnexal epithelium, in addition to epidermis, may be involved by an atypical lymphocytic infiltrate in lesions of typical MF, like the case described by Oliwiecki and Ashworth. 15 In contrast, FMF constitutes a unique clinicopathologic entity by demonstrating primarily folliculotropism in the absence of either epidermotropism or follicular mucinosis. 16 Patients with FMF may also simultaneously have lesions of classic MF, like the case described by Goldenhersh, Zlotogorski, and Roseumann. 11 It is important to differentiate FMF from follicular mucinosis associated with MF. Follicular mucinosis is characterized by areas of mucin deposition within the follicular epithelium and a superficial and deep mixed perivascular and interstitial infiltrate composed of lymphocytes, eosinophils, and other

inflammatory cells. Although histopathologic distinction is clearly possible, follicular mucinosis associated with MF may present clinically as follicular papules with a tendency to coalesce that may be difficult to distinguish from FMF. In this regard, one of the cases reported by K i m 9 appears not to be a true FMF, because deposits of mucin were present within the epithelium of the hair follicle. Immunohistochemistry and gene rearrangement studies show similar findings in FMF and epidermotropic MF. Immunohistochemically, classicalMF usually shows aberrant expression of one or more pan-T-cell antigens, more commonly lack of expression of CD-7 and Leu-8.17' 18 Genotypically, rearrangement of the beta chain of the T-cell receptor can be present in patients with MF. 19,20 Both findings were present in our second patient. The reason that FMF presents mainly with folliculotropism but lacks epidermotropism and mucin deposition is unknown. It has been suggested that the relation of FMF to classic MF is similar to that between lichen planopilaris and lichen planus. 11 Another explanation could be inferred from the concept of skin-selective homing receptors. Lymphocytes acquire these receptors in their areas of development and because of these tend to return to their site of origin. On this model adhesion receptor molecules also are important in cell-to-cell interactions and immunoproliferative cutaneous responses. These include lymphocyte adhesion to keratinocytes and other inflammatory and cytotoxic cellular responses. 21 Patients with MF have increased epidermal lesional levels of interleukin-1 (IL-1) and IL-8. 22 IL-1 induces leukocyte chemotaxis, directly or indirectly, through the production of IL-8. IL- 1 also stimulates keratinocytes and endothelial cells to produce sev-

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Type of lesions

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Epidermotropism

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Follicular mucinosis

N/R Alopecia, plaques, plugged hair follicles, comedo-like lesions Alopecia, plaques, follicular keratosis, comedo-like lesions P!aques, follicular keratotic papules P!aques, follicular papules Plaques, nodules, follicular papules Plaques, nodules, follicular papules

eral cytotdne mediators of inflammation and adhesion-receptor molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (recently renamed E-selectin). IL-1 also serves as a promoter of T-cell proliferation. 21 Cutaneous IL-1 production is achieved by keratinocytes and Langerhans cells. These suggest that T ceils in patients with M F regulate the epidermal production of lymphokines, as well as the focal expression of ICAM-1 within the epithelium of hair follicles, 1°,23 which could mediate lymphocyte chemotaxis, adhesion, and proliferation. In addition, skin-associated lymphocytes axe primarily T cells, displaying the cell-surface phenotype of memory Tcells (CD45RO+), and they selectively express the cell surface determinant cutaneous lymphocyte-associated antigen (CLA), a tissue-selective homing receptor involved in directing T-cell traffic to inflarned sldn.24, 25 C L A is an oligosaccharide ligand for E-sel~tin, and it is thought that the CLA:E-selectin interaction is involved in the epidermotropism characteristic of cutaneous T-cell lymphoma. 24 W e hypothesize that in cases of FMF, the epithelium of the hair follicle m a y express higher levels of skin-selective homing receptors mad adhesion molecules tharl the epidermis, leading to the preferential migration of neoplastic lymphocytes to this area. The differential diagnosis of F M F includes mostly follicular lymphomatoid papulosis, 26-28 especially those cases of type B or " l y m p h o c y t i c " variant of folliculdr lymphomatoid papulosis. 28 In both there is a dense l infiltrate of hyperchromatic atypical lymphocytes in a perifollicular distribution. However, follicular papules of lymphomatoid papulosis tend to involute spontaneously and heal with scarring. In FMF, lesions improve only after treatment and do

not leave scars. Histopathologically, in follicular lymphomatoid papulosis, the infiltrate exhibits a perifollicular distribution with sparse or absent folliculotropism, whereas in F M F folliculotropism is a critical feature. REFERENCES

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