- Email: [email protected]
Early-stage mycosis fungoides variants: case-based review
Available online at www.sciencedirect.com
Annals of Diagnostic Pathology 14 (2010) 369 – 385
Review Article
Early-stage mycosis fungoides variants: case-based review Jeong Hee Cho-Vega, MD, PhDa,⁎, Jaime A. Tschen, MDa , Madeleine Duvic, MDb , Francisco Vega, MD, PhDc a St Joseph Dermatopathology, Houston, TX 77030, USA Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA c Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA b
Abstract
Keywords:
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. The diagnosis of classic MF is based on a combination of clinical presentation, histopathology, and T-cell monoclonality detected by molecular studies. However, the diagnosis can be difficult in cases of early MF because of the subtle nature of histologic findings and, in cases of variants of MF, because of the unusual clinical and/or pathologic features. In this review, we presented the most frequent variants of MF at early stage including hypopigmented, folliculotropic, pagetoid reticulosis, unilesional, granulomatous, and ichthyosis forms. This case-based clinicopathologic review provides the notion that a comprehensive clinicopathologic correlation is of substantial importance to render the diagnosis of MF. In addition, we discuss the role of molecular studies, which are highly sensitive and recently more applicable to routinely processed skin biopsy specimens in the diagnosis of MF. © 2010 Elsevier Inc. All rights reserved. Mycosis fungoides, Early stage, cutaneous T-cell lymphoma; MF Variants, TCR gene rearrangment
1. Introduction Mycosis fungoides (MF) is the most common form of primary cutaneous lymphoma, representing approximately 50% of all primary cutaneous lymphomas, with an annual incidence of 6 or 7 cases per 1 million persons [1]. There is a substantial rise in the incidence of MF that is likely due, at least in part, to increased efficiency of detection and improvement of the diagnostic methods. Mycosis fungoides is predominantly a disease of adults usually in the fifth to sixth decade, although any age group may be involved. Incidence is higher among blacks than among whites and is higher among men than among women [1]. Clinically, patients have patches, plaques, and eventually tumors that typically occur on sun-protected skin (breast, axilla, and buttocks being the most common sites). The most common presentation is one of patches and plaques [2].
⁎ Corresponding author. Tel.: +1 713 660 9444; fax: +1 713 660 9466. E-mail address: [email protected] (J.H. Cho-Vega). 1092-9134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.06.003
Diagnosis of MF can be difficult in some cases, in particular in cases of early MF as well as in cases of so-called MF variants. These variant forms are rare and manifest with unusual clinical and/or pathologic features, making its recognition difficult. These “variants” include unusual anatomical sites of involvement (palmoplantar, isolated alopecia), a solitary lesion (pagetoid reticulosis, unilesional MF), clinical variations (hypopigmented MF, granulomatous slack skin [GSS]), or association with masking clinical conditions (MF and ichthyosis). To date, approximately 15 variant forms of MF have been described. Classic morphologic diagnostic criteria of MF includes all the following: lichenoid lymphoid infiltrate with “Indian file” or “toy soldier” lining up of atypical lymphoid cells at the dermoepidermal junction, epidermotropism with little spongiosis, Pautrier microabscesses (clustering of T-cells around Langerhans cells), and wiry collagen in the papillary dermis. Usually, the epidermotropic lymphocytes have more atypical nuclear cytologic features than those in the dermis [3-6]. The definition of atypical lymphocytes is subjective, but they have been defined as small- to medium-sized lymphocytes with
370
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
convoluted hyperchromatic nuclei and inconspicuous nucleoli. In the right clinical context, if some, but not all, of the above-mentioned features are present, a diagnosis of atypical lymphoid infiltrate suspicious for MF may be rendered. On the other hand, the following morphologic features are unusual for classic MF: marked spongiosis, vacuolar change, keratinocyte necrosis, or numerous eosinophils and/or neutrophils. The variants of MF may show classic features of MF or show unusual features. Folliculotropic MF shows “atypical” lymphocytes around and within the epithelium of the hair follicles, often with follicular mucinosis and relatively lack of infiltration of the surface epithelium. A granulomatous inflammatory infiltrate may be seen in granulomatous MF (GMF) or GSS, but should be accompanied by other diagnostic features of MF. Prominent epidermal involvement of atypical lymphoid cells with a pagetoid pattern is seen in pagetoid reticulosis. Immunophenotypically, classic and MF variants are usually neoplasms of CD4+ T-helper cells. Other phenotypes of otherwise classic MF have been described including CD8 + MF, which often presents with hypopigmented lesions or in pagetoid reticulosis; CD56+ MF; and double-negative CD4/CD8 MF [7,8]. These immunophenotypes do not appear to be of prognostic impact [9]. Mycosis fungoides is a clonal expansion of T-cells, and the molecular detection of a clonal T-cell expansion has been exploited for diagnostic purposes [10]. However, nonneoplastic skin diseases may be associated with Tcell clonality [11]; for this reason, it is important to emphasize that the diagnosis of MF requires clinicopathologic correlation and cannot be established by molecular data alone. The diagnosis of either classic or variant forms of MF is based on a combination of clinical presentation and histopathology with the help of molecular studies [5,6,12]. It is important to note that none of these factors exclusively determines the diagnosis and that clinicopathologic correlation is of substantial importance to render the diagnosis of MF. Diagnosis of MF can be difficult because of a highly variable number of clinical presentations and the sometimes nonspecific nature of the histologic findings. In early MF, not all of the pathologic findings are present; and distinction from an inflammatory infiltrate can be difficult [5]. Molecular studies may help to confirm the diagnosis in particular in those cases of early MF and in those cases in which the clinical
371
features and/or the pathologic findings are not typical for MF. This review addresses the comprehensive clinicopathologic spectrum of early MF, focusing on the most frequent “variants” of this disease. Recognition of these clinicopathologic presentations can be of great diagnostic utility. We will also discuss the role of molecular studies as an additional help for the diagnosis.
2. Case-based MF variants 2.1. Early hypopigmented MF 2.1.1. Case 1. Early juvenile and hypopigmented variant of MF, CD8 positive 2.1.1.1. Clinical findings. The patient is an 18-year-old African American woman. She has a long history of eczema since she was a baby. The rash was most prominent in her antecubital and popliteal fossae. Since 4 years ago, she has been developing small light spots, which started in her hips and legs. Recently, these white spots have increase in intensity; and they have spread to her upper back, legs, and arms (Fig. 1A-C). She denies itching. A 4-mm punch biopsy was taken from one of these white spots. 2.1.1.2. Pathology findings. The skin biopsy showed a subtle and focal atypical lymphoid infiltrate within the epidermis (Fig. 1D, arrows) with focal Pautrier microabscesses (Fig. 1E). Atypical lymphocytes showed irregular nuclear contours and hyperchromasia aligned along the dermal-epidermal junction (Fig. 1F-G). The vast majority of atypical lymphocytes were CD8+ T-cells (Fig. 1H) with a significantly decreased CD4:CD8 ratio (approximately 1:4) (Fig. 1I). Most of the epidermotropic lymphocytes were positive for CD8 (Fig. 1H). 2.1.1.3. Molecular findings. Monoclonal TCR-γ gene rearrangements were detected by polymerase chain reaction (PCR) analysis (V-γIII segment) (Fig. 1J, arrow). Monoclonal TCR-β gene rearrangements were not detected. 2.1.1.4. Staging, treatment, and follow-up. The patient was diagnosed with MF, stage Ib, juvenile, hypopigmented type. Flow cytometry immunophenotypic studies performed on a peripheral blood sample failed to detect immunophenotypic abnormalities. The patient is being treated with
Fig. 1. (A-C) Mottled small hypopigmented lesions (b2 cm) were seen on the anterior and posterior aspects of both legs. They were also noted on the arms. (D-G). Histologic sections from a hypopigmented lesion showed a subtle superficial lymphoid infiltrate (D, arrows). Higher magnification revealed that the infiltrate was epidermotropic and was composed of small to intermediate lymphoid cells with halos along the dermoepidermal junction (E-G). Few Pautrier microabscesses were seen (E). Noted that no pigmentation was identified in the basal keratinocytes (H-I). CD8 (H) highlighted atypical lymphocytes in the epidermis and dermis, whereas those cells were negative for CD4 (I) (D, low power; E-F, medium power; G, high power; H, I, DAB, medium power). (J) A monoclonal TCR-γ gene rearrangement of 141 base pairs (bp) was detected by PCR analysis (V-γIII segment, arrow). The small red peaks corresponded to internal size standards. The other 2 black peaks more than 270 bp represented amplification of the house-keeping gene (β-actin; internal control).
372
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
narrow-band UV-B 2 to 3 times weakly and triamcinolone. Her skin lesions are improving. 2.1.2. Case 2. Hypopigmented and poikilodermatous variant of MF, CD8 positive 2.1.2.1. Clinical findings. The patient is a 47-year-old African American woman. She had bilateral white coin-sized
patches on her lateral forearms since the age of 13 years. During junior high school, these lesions spread to her legs, arms, and torso and increased in number. Since 1988, different dermatologists performed several skin biopsies from different sites that rendered nonspecific diagnoses. Around 1996, she developed hyperpigmented dark lesions as well as hypopigmented lesions. These lesions were not responding to topical steroid creams and/or UV light
Fig. 2. Numerous hypopigmented patches were present on the entire body (A-C). Several reticulated hyperpigmented patches (A-B, arrows) were present on the posterior thighs, buttock, chest, and the lower back consistent with poikiloderma (D-H). The biopsy from the left thigh showed atrophic epidermis and fibrosis, increased blood vessels, and pigment incontinence in the upper dermis, features resembling those of poikiloderma vasculare atrophicans (E, G, H). Minimal epidermotropic atypical lymphocytic infiltrate and decreased basal pigmentation were also observed. The biopsy from the right thigh (D, F) showed less atrophic epidermis and higher number of atypical lymphocyte infiltrate in the epidermis than the biopsy from the left thigh. The vast majority of atypical lymphocytes in the epidermis were CD8+ T-cells (I) and were negative for CD4 (J) with a decreased ratio of CD4:CD8 (approximately 1:3). The CD4:CD8 ratio in the dermis was 2:1 (D, E, G, low power; F-H, medium power; I, J, DAB, medium power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
exposure. In 2008, 3 skin biopsies confirmed MF. Currently, she has numerous hypopigmented patches on the entire body, hyperpigmented patches on her left shoulder, and reticulated hyperpigmented patches on the inner aspects of her thighs consistent with poikiloderma vasculare atrophicans (Fig. 2A-C). 2.1.2.2. Pathology findings. The skin biopsy from the right thigh (Fig. 2D and F) showed a mildly atypical epidermotropic lymphoid infiltrate. The biopsy from the left thigh (Fig. 2E, G, and H) demonstrated atrophic epidermis and a minimal, mildly atypical epidermotropic lymphoid infiltrate. The upper dermis showed fibrosis, increased blood vessels, and pigment incontinence, features resembling those of poikiloderma vasculare atrophicans. The vast majority of T-cells in the epidermis were weakly positive for CD8 (Fig. 2I) and was negative for CD4 (Fig. 2J) and CD7, with a decreased ratio of CD4: CD8 (approximately 1:3). The CD4:CD8 ratio in the dermis was 2:1.
2.1.2.3. Molecular findings. been performed
373
Molecular studies have not
2.1.2.4. Staging, treatment, and follow-up. She was diagnosed as having hypopigmented and poikilodermatous variant of MF, stage Ib, with a CD8+ immunophenotype. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect immunophenotypic abnormalities. She is being treated with topical triamcinolone, 40% nitrogen mustard, and UV light without significant improvement. 2.1.3. Discussion of hypopigmented MF Hypopigmented MF is a rare clinical variant of MF predominantly found in children and adolescents and in dark-skinned patients [13-16]. Hypopigmented MF has a reported higher prevalence in females than males. Hypopigmented MF displays the same histopathologic findings as classic MF [16-19]. The reason behind the loss of pigmentation is not clear; it is believe that it is due to the cytotoxic effect of CD8 T-cells on melanocytes (at least in
Fig. 3. (A-D) The skin biopsy specimen obtained from the normal skin adjacent to the vitiligo lesion (A and B) revealed multifocal preserved melanin pigment and melanocytes in the basal layer of the epidermis. The dermis was unremarkable. The biopsy from the hypopigmented lesion showed absence of any melanin pigment and melanocytes in the basal layer of the epidermis (C), which was well illustrated by the Fontana-Masson stain (D). Mild perivascular lymphocytic infiltrate was present (C). This skin punch biopsy specimen showed subtle loss of basal pigmentation and was consistent with pityriasis alba (E and F) (A, C, low power; B, D, Fontana-Masson, low power; E, scanning power; F, medium power).
374
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
those cases with a CD8 phenotype) [20]. The skin lesions are usually localized on sun-protected skin of the body and may be associated with classic erythematous patches, plaques, or tumors, in particular in white patients [21]. In contrast to classic MF, in which the tumor cells are usually CD4+, the neoplastic cells in hypopigmented MF are frequently CD8+ (cytotoxic phenotype) [16,18,20]. A variety of clinical entities may present with areas of hypopigmentation and share similar clinical picture with hypopigmented MF, especially vitiligo, lichen sclerosus et atrophicus, atopic dermatitis, pityriasis alba, pityriasis lichenoides chronica, tinea versicolor, onchocerciasis, syphilis, and lepra. 2.1.3.1. Vitiligo. Vitiligo is a common skin disease characterized by the presence of well-circumscribed, depigmented macules and patches. The lesions tend to be symmetrical without scaling and with predilection for the face, back of the hands, axillae, groins, umbilicus, and genitalia. The histopathologic features of vitiligo, especially when biopsies are taken from the periphery of the lesions, may show similarity to early patch hypopigmented MF (shown in case 1). Cases of vitiligo mimicking MF have been described; and vice versa, MF may simulate vitiligo [14,22]. The following features are more commonly seen in hypopigmented MF than in vitiligo: marked epidermotropism, hydropic degeneration of basal cells, partial loss of pigment, preservation of some melanocytes, presence of lymphocytes within the papillary dermis, and wiry fibrosis [23]. On the other hand, focal thickening of the basement membrane, complete loss of pigmentation, total absence of melanocytes, as well as absence or sparseness of lymphocytes in the dermal papillae are findings more frequently seen in vitiligo (Fig. 3A-D) [23]. In challenging cases, molecular studies may be helpful to support a diagnosis of early hypopigmented MF over vitiligo [16,21,24]. 2.1.3.2. Pityriasis alba. Pityriasis alba consists of variable hypopigmented scaly patches with a predilection for the face, neck, and shoulders of children usually, but also of young adults. Morphologic findings are not specific, either no obvious pathologic alterations except loss of melanin pigmentation in basal keratinocytes or, rarely, a sparse superficial perivascular infiltrate of lymphocytes (Fig. 3E and F). 2.2. Early folliculotropic MF 2.2.1. Case 1. Early acneiform folliculotropic MF 2.2.1.1. Clinical findings. The patient is a 48-year-old white woman with a long history of dry, itchy patches on the
arms and back of the elbows. These lesions were responsive to topical steroids and UV-B. Recently, she developed a follicular rash on the left anterior thigh (Fig. 4A) that was not responsive to topical steroids. A 4-mm punch skin biopsy was performed. 2.2.1.2. Pathology findings. The skin biopsy demonstrated a dense predominantly periadnexal and folliculotropic infiltrate (Fig. 4B) with atypical lymphocytes and numerous eosinophils (Fig. 4C-E). Follicular mucinosis was also observed (Fig. 4F). The overlying epidermis showed a focal epidermotropic atypical lymphoid infiltrate associated with spongiosis and parakeratosis. The vast majority of atypical lymphocytes were positive for CD3 (Fig. 4G) and CD4 (Fig. 4I), with a significantly increased dermal ratio of CD4:CD8 (4:1) (Fig. 4J) and with many of the epidermotropic and folliculotropic lymphocytes also positive for CD4. Partial loss of CD7 expression was also observed. Clusters of B-cells CD20+ were also observed (Fig. 4H). 2.2.1.3. Molecular findings. performed.
Molecular tests were not
2.2.1.4. Staging, treatment, and follow-up. The patient was diagnosed as having folliculotropic MF, stage 1A. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect immunophenotypically aberrant Tcells. She has been receiving topical nitrogen mustard treatment resulting in a partial response. 2.2.2. Case 2. Folliculotropic MF presented as alopecia in sun-exposed skin 2.2.2.1. Clinical findings. The patient is a 52-year-old white man with a history of rash for approximately 5 years. The rash began on his left buttock and subsequently spread to his left thigh and left eyebrow. He noticed the left eyebrow lesion approximately 3 years ago. The patient has a large indurated plaque with alopecia over the left lateral eyebrow (Fig. 5A) as well as an indurated plaque also associated with alopecia on the right jawline (Fig. 5B). He also has erythematous patches, accentuated follicular papules, and comedones (Fig. 5C) and patches on the right scalp, back, chest, upper arms, and the left distal thigh. Skin biopsies of the left eyebrow and the jawline plaques were performed. 2.2.2.2. Pathologic findings. Both skin biopsies from the left eyebrow (Fig. 5D) and the right jawline (Fig. 5E) show similar findings. There was a dense atypical lymphoid infiltrate composed of small to intermediate lymphoid
Fig. 4. (A) Folliculotropic rash on the left anterior thigh. (B-F) Skin biopsy demonstrated a dense, predominantly periadnexal and folliculotropic lymphoid infiltrate (B) with atypical lymphocytes and eosinophils (C-E). Follicular mucinosis was also observed (F). The overlying epidermis showed mild epidermotropism of atypical lymphocytes as well as spongiosis and parakeratosis (C). The vast majority of atypical lymphocytes expressed CD3 (G) and CD4 (I), particularly infiltrates in the epidermis, with a significantly increased ratio of CD4: CD8 (J) (4:1). A number of CD20+ B-cells were also present (H) (B, scanning power; C, D, E, F, medium power; G, DAB, scanning power; H, I, J, DAB, low power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
375
376
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
Fig. 5. (A) Large indurated plaque associated with alopecia over the left lateral eyebrow. (B) Similar lesion in the right jawline. The plaque had elevated borders and was associated with alopecia (C). A group of follicular papules appearing as comedones on the thigh (D-G). Skin biopsy specimens from the left eyebrow (D) and the right jawline (E) revealed similar histologic features. They showed a dense atypical lymphoid infiltrate with striking perifollicular and follicular epidermotropism associated with follicular mucinosis (F and G). The overlying epidermis showed minimal epidermotropism of atypical lymphocytes. These atypical lymphocytes were CD4+ T cells (H) with a significantly increased ratio of CD4:CD8 (I) (N10:1) (D and E, scanning power; F, G, medium power; H, J, DAB, low power).
cells showing striking perifollicular and intrafollicular involvement with minimal and focal follicular mucinosis (Fig. 5F and G). Surface epidermotropism was minimal. The atypical lymphoid infiltrate was composed predominantly of CD4+ T cells (Fig. 5H) with a significantly increased intraepidermal ratio of CD4:CD8 (N10:1) (Fig. 5H and I).
2.2.2.3. Molecular findings. performed.
Molecular tests were not
2.2.2.4. Staging, treatment, and follow-up. He was diagnosed as having folliculotropic MF, stage 1A. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect abnormal T-cells. A computed
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
tomographic scan of the pelvis and abdomen revealed no enlarged lymph nodes. He was treated with radiation therapy (a total dose of 30 Gy in 15 treatments) to the right mandible and left upper eyebrow. He has had an excellent response to the radiation. However, he still had few persistent plaques of follicular accentuation on the back and thigh and follicular pink patches on the left chest and abdomen that are being treated with topical bexarotene. 2.2.3. Case 3. Folliculotropic MF with follicular mucinosis 2.2.3.1. Clinical findings. The patient is a 38-year-old woman who has history of adrenal insufficiency and hypothyroidism. She initially developed scaly raised pink papules on her upper arms. Those lesions have progressed to her back, chest, and abdomen. The more recent physical examination revealed hypopigmented macules and scaly papules on her back (Fig. 6A), hypopigmented macules on her upper arm, and scaly papules on her anterior trunk and upper arms. A punch skin biopsy of one of the lesions on the right shoulder was performed. 2.2.3.2. Pathologic findings. Histologic sections revealed a single hair follicle infiltrated by small-sized lymphocytes associated with marked mucin deposition (follicular mucinosis) (Fig. 6B and C). Occasional eosinophils were seen. Superficial epidermotropism was minimal. Although the lymphoid cells showed no obvious morphologic atypia, the vast majority of these lymphocytes were CD4+ T-cells (Fig. 6D and F) with significant increase of CD4:CD8 ratio in the intra- and perifollicular infiltrate (Fig. 6E). An additional skin biopsy (not shown) from the left upper shoulder showed an atypical folliculotropic and perifollicular lymphoid infiltrate associated with mild follicular mucinosis. In this skin biopsy specimen, the lymphoid infiltrate was also positive for CD3 and CD4 with an increase of CD4:CD8 ratio. No significant loss of CD7 expression was identified. 2.2.3.3. Molecular findings. No monoclonal TCR-γ gene rearrangements were identified by PCR; however, low levels of a monoclonal TCR-β gene rearrangement were detected. 2.2.3.4. Staging, treatment, and follow-up. The patient was diagnosed with folliculotropic MF, stage 1A. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect abnormal T-cells. The patient was treated with topical isotretinoin on her face and triamcinolone on her body, resulting in minimal improvement. She also received topical tazarotene and triamcinolone, which resolved some of lesions; but new pink papules appeared on the arms and trunk. In the last follow-up, the total body surface area involvement was 1.5% plaques, which improved from 2.5% plaques at the initial visit. 2.2.4. Discussion of folliculotropic MF Folliculotropic MF, also referred to as pilotropic MF, is a relatively common variant characterized by atypical lymphocytes around and within the epithelium of the hair
377
follicles with relative lack of infiltration of the surface epithelium. Folliculotropic MF can present with a wide variety of clinical pictures including acneiform lesions, comedones, cysts, alopecia with or without scarring, and nodular prurigo-like lesions. The head and neck region, in particular the scalp or face, is most commonly involved. Pruritus is especially common [25,26]. The disease course is aggressive, the response to topical therapy is poor even in the early stage of the disease, and many patients show a poor outcome particularly between 10 and 15 years after the initial onset of disease [26-28]. The mechanism of folliculotropism is poorly understood. Several histologic patterns of folliculotropic MF have been described including the classic pattern of folliculotropism with or without follicular mucinosis, eosinophilic folliculitis-like pattern, cystic pattern, basaloid folliculolymphoid hyperplasia, granulomatous pattern, and a mixed folliculotropic and syringotropic pattern [25,26,29,30]. Marked mucin accumulation in the follicle (follicular mucinosis) and dermis is often present (50% of the cases), and follicular destruction can be present. Large cell transformation (more than 25% of large T-cells) can be seen in a third of the patients. Syringotropic MF is a rare form of MF; less than 30 cases have been reported, characterized by infiltrates of atypical lymphocytes located in and around hyperplastic eccrine glands and ducts. Clinically, syringotropic MF presents as small papules (1-3 mm in diameter). Although syringotropic MF is considered a histopathologic variant of folliculotropic MF, the relationship between these 2 MF subtypes remains tenuous. Most patients with syringotropism have coexisting folliculotropism. The current World Health Organization/ European Organisation for Research and Treatment of Cancer classification of cutaneous neoplasms places syringotropic and folliculotropic MF in the same group, defining them as a single clinical variant of MF. However, some differences have been noted. In contrast to folliculotropic MF, most of the patients with syringotropic MF had lesions on the trunk, hips, breast, buttocks, or groin, suggesting that syringotropic MF closely parallels the presentation of classic MF, which preferentially affects chronically sun-protected areas. In comparison with folliculotropic MF, most reported cases of syringotropic MF have had a benign chronic course and a prognosis similar to classic MF, with 10-year survival ranging from 83% to 97% [27]. 2.3. Pagetoid reticulosis (Woringer-Kolopp disease) 2.3.1. Pagetoid reticulosis presenting as a single small scaly plaque on the foot 2.3.1.1. Clinical findings. The patient is a 24-year-old woman with 10.0 × 10.0 mm dermal plaque on her right medial dorsum of foot, which was noticed for the first time 7 months ago. The lesion started as a small red spot that was slowly increasing in size. The patient is otherwise healthy without significant medical history. The lesion is a small round dermal plaque with scaling in the center and raised,
378
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
Fig. 6. (A) Scattered hypopigmented macules and scaly pearly or pink papules accentuating follicles on the back. (B-C) Skin biopsy from the right shoulder revealed a single hair follicle infiltrated by small-sized lymphocytes and abundant mucin deposition inside the follicular epithelium. The vast majority of these infiltrating lymphocytes were CD4+ T-cells (D and F) with significant increase of CD4:CD8 (G) ratio, particularly inside the follicular epithelium (B, medium power; C, high power; D, E, DAB, low power; F, DAB, high power).
sharply demarcated, red peripheral borders. The clinical differential diagnosis included dermatofibroma, porokeratosis, or granuloma annulare. A skin punch biopsy of the border of the lesion was taken. 2.3.1.2. Pathologic findings. Histologic sections showed a psoriasiform epidermis with acanthosis and hyperkeratosis associated with a dense epidermotropic atypical lymphoid infiltrate located predominantly in the basal layer with a pagetoid pattern (Fig. 7A). The atypical lymphoid cells were small to intermediate in size with irregular nuclear contours, hyperchromatic nuclei, some with distinct nucleoli, and some with a perinuclear halo (Fig. 7B and C). Rare mitotic figures were also observed. The superficial dermis contained a mild perivascular lymphohistiocytic infiltrate with rare atypical-appearing cells. Immunohistochemical studies revealed that the neoplastic cells were positive for CD3 (Fig. 7D) and CD8 (Fig. 7E and G) and were negative for CD4 (Fig. 7F and H) and CD7 (Fig. 7I). Reactive T-cells positive for CD4 (Fig. 7F) and rare B-cells positive for CD20 were observed in the upper dermis. 2.3.1.3. Molecular findings. No monoclonal TCR-γ gene rearrangements were identified by PCR. 2.3.1.4. Staging, treatment, and follow-up. She was diagnosed with pagetoid reticulosis. Patient went back to her home country for staging and local radiation treatment.
2.3.2. Discussion of pagetoid reticulosis Pagetoid reticulosis is an extremely rare variant of MF with relatively consistent clinical and histopathologic findings [31-33]. The typical presentation is a solitary, localized psoriasiform or hyperkeratotic plaque located on the foot or hand. It is more frequent in females, with a wide median age at presentation including early childhood. It often mimics other common skin dermatoses that may result in a considerable delay in the diagnosis. Pagetoid reticulosis usually has an indolent clinical course but with potential for frankly malignant behavior. The disease responds well to radiation therapy. Histopathologic findings are epidermal hyperplasia with parakeratosis and prominent epidermotropic atypical lymphoid infiltrate (particularly in the basal layer) with Pautrier microabscesses. Many cases of pagetoid reticulosis have a CD8+ immunophenotype, and analysis of TCR genes has identified clonality in the majority of cases. The differential diagnosis of pagetoid reticulosis includes MF palmaris et plantaris, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, and unilesional MF. 2.3.2.1. MF palmaris et plantaris. It is a rare manifestation of MF (0.6% of cases) [34] that clinically present as thin acral plaques that mimic hand or foot dermatitis. The neoplastic lymphoid infiltrate is usually present both above and below the dermal-epidermal junction and may contain eosinophils. In contrast, pagetoid reticulosis presents with
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
379
Fig. 7. (A-C) Histologic sections showed an almost completely intraepidermal infiltrate of atypical mononuclear cells at a low power (A). The epidermis showed a psoriasiform appearance with hyperkeratosis and acanthosis. The epidermis was infiltrated particularly in the basal layer by the atypical lymphoid cells. They were intermediate to large with hyperchromatic and irregular nuclei, some with distinct nucleoli, and variable amounts of pale-staining cytoplasm (B). Some of the lymphoid cells had a perinuclear halo, representing retraction artifact. The basement membrane region to the epidermis was focally intact and well demarcated (C). The upper dermis contained minimal perivascular lymphohistiocytic infiltrate. Neoplastic cells were positive for CD3 (D) and CD8 (E and G) and were negative for CD4 (F and H). A considerable number of reactive T-cells positive for CD4 were observed in the upper dermis (F). Most of all neoplastic cells lost CD7 expression (I) (A, scanning power; B, medium power; C, high power; D, E, DAB, scanning power; F, DAB, medium power; G, H, I, DAB, high power).
verrucous, scaly, and hyperkeratotic plaques. The tumor cells are almost exclusively located in the epidermis, and eosinophils are not seen [32,35].
2.3.2.3. Unilesional MF See case below.
2.3.2.2. Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. It is a distinct and aggressive cutaneous T-cell lymphoma that clinically presents as localized or disseminated nodules, plaques, and tumors often with ulceration and necrosis [36-38]. Its characteristic is the rapid progression with extracutaneous dissemination to unusual sites, such as the central nervous system, lung, testis, and oral mucosa [36]. It is important to know that there is some histologic and immunophenotypic overlap between indolent and aggressive cases of cutaneous CD8+ T-cell lymphomas. Thus, the clinical features and disease course are important to establish the diagnosis of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma.
2.4.1. Unilesional MF presenting as a single papule on the neck
2.4. Unilesional MF
2.4.1.1. Clinical findings. The patient is a 76-year-old woman. She noticed a 9-mm pearly papule on the right side of her posterior neck described as a pimple. She also had numerous warty papules consistent with seborrheic keratoses on the trunk that were treated with liquid nitrogen. A shave biopsy of the neck lesion was performed. 2.4.1.2. Pathology findings. The skin shave biopsy showed a dense, atypical lymphoid infiltrate comprising a mixed population of small, medium, and large lymphocytes, extending full thickness of the dermis with minimal
380
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
epidermotropism (Fig. 8A and B). The larger lymphocytes were atypical with irregular nuclear contour and hyperchromatic nuclei (Fig. 8C). Mitoses were noted. The vast majority of atypical lymphocytes were positive for CD3 (Fig. 8D) and CD4 (Fig. 8E and H) and were negative for CD8 (Fig. 8F) and CD7. A subset of the large atypical cells showed weakly positive for CD30. Rare clusters of CD20+ B-cells (Fig. 8G) were also present within the infiltrate. 2.4.1.3. Molecular findings. Molecular PCR studies demonstrated monoclonal gene rearrangements of the TCR-γ (Fig. 8I) and TCR-β genes. 2.4.1.4. Staging, treatment, and follow-up. She was diagnosed as having unilesional MF. Result of a full staging evaluation including bone marrow and peripheral blood analyses and computed tomographic scans of the pelvis, abdomen, and thorax was negative for systemic lymphoma.
The patient is being followed without receiving any treatment. The patient has been followed for 4 months; and to date, there is no evidence of local and/or systemic relapse. 2.4.2. Discussion of unilesional MF Unilesional MF is defined as a single area of involvement by MF covering less than 5% of the body surface [39]. The lesions are usually found in body regions typical for classic MF, and the histopathologic findings are identical to those seen in classic MF [39]. Patients with unilesional MF demonstrate an excellent response to topical chemotherapy or irradiation. Recurrences may occur after surgical excision. 2.5. Granilomatous Mycosis Fungoides (GMF) and GSS 2.5.1. MF with granulomatous features 2.5.1.1. Clinical findings. A 68-year-old white woman developed a mildly pruritic single pink papule on her right
Fig. 8. The skin biopsy specimen showed a dense lymphoid infiltrate involving the full thickness of the dermis and showing focal epidermotropism. The epidermis showed compact hyperkeratosis (A and B). The lymphoid infiltrate was composed of a mixed population of small, medium, and occasional large lymphocytes. The larger lymphocytes were atypical with irregular nuclear contours and hyperchromatic nuclei (C). The vast majority of atypical lymphocytes were CD3+ (D) and CD4+ (E) T-cells, whereas lymphocytes showing positive staining for CD8 (F) were relatively scarce. CD4 (H) highlighted the epidermotropic atypical lymphocytes. Rare clusters of CD20+ B-cells were present within the infiltrate (G). A monoclonal TCR-γ gene rearrangement of 178 bp was detected by PCR analysis (V-γII segment). The small red peaks corresponded to internal size standards (A, scanning power; B, medium power; C, high power; D-G, DAB, scanning power; H, high power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
lateral thigh. The lesion did not improve with topical antibiotics, and a shave biopsy was performed. In 2007, a biopsy from a red, firm, 1-cm nodule in the left posterior calf revealed GMF. 2.5.1.2. Pathology findings. Histologic sections showed a dense atypical lymphoid infiltrate involving the dermis with multifocal epidermotropism (Fig. 9A and D). The lymphocytes were small to intermediate in size, some with convoluted nuclear contours. In addition, a granulomatous reaction with multinucleated giant cells and elastophago-
381
cytosis were also present (Fig. 9B and C). The vast majority of infiltrating atypical lymphocytes were positive for CD3 (Fig. 9E) with a predominance of CD4+ cells (Fig. 9H) over CD8+ cells (Fig. 9I), particularly in the epidermotropic atypical cells (Fig. 9G). Few B-cells were noted (Fig. 9F). 2.5.1.3. Molecular findings. Molecular studies confirmed the presence of a monoclonal TCR-γ gene rearrangement (using the family VγIV) (Fig. 9J). Polymerase chain reaction studies for the TCR-β gene revealed an oligoclonal pattern.
Fig. 9. Histologic sections showed a variable dense lymphoid infiltrate involving the dermis associated with multifocal epidermotropism (A, D). Multinucleated giant cells were also present (B and C). The vast majority of infiltrating atypical lymphocytes were CD3+ T-cells (E) with a predominance of CD4+ cells (H) over CD8+ cells (I), particularly in the epidermotropic component (G). A small subset of dermal infiltrates was CD20+ B-cells (F). A monoclonal TCR-γ gene rearrangement of 178 bp was detected by PCR analysis (V-γIV segment) (J). The small red peaks corresponded to internal size standards. The other 2 black peaks more than 270 bp represented amplification of the house-keeping gene (β-actin; internal control) (A, scanning power; B, low power; C, medium power; D, high power; E, F, H, I, DAB, low power; G, DAB, high power).
382
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
2.5.1.4. Stage, treatment, and follow-up. Because the tumor reached the subcutaneous tissue, a 6-mm punch biopsy for a complete removal was performed at the previous biopsy site to include subcutaneous tissue. Flow cytometry immunophenotypic studies of the peripheral blood failed to detect an aberrant T-cell population. This biopsy was negative for residual MF. She is being closely followed up with no additional treatment. 2.5.2. Discussion of GMF and GSS Ackerman and Flaxman [40] proposed the term granulomatous mycosis fungoides in 1970. Ackerman added the term granulomatous slack skin disease in 1978. The most common form of granulomatous cutaneous T-cell lymphoma is GMF [41]. This term is used for tumors with the histologic pattern of typical MF in which the histiocytic or granulomatous inflammation is prominent but without the preferential flexural skin involvement. Granulomatous MF is most frequently seen in adults, usually in the fifth to sixth decade, with the trunk representing the predilection site [41]. The clinical presentation of skin lesions in GMF is not indicative of the granulomatous histology. There is a dermal lymphohistiocytic infiltrate (diffuse, nodular, perivascular, or periadnexal) of small- to medium-sized lymphocytes associated with nonnecrotizing granulomas and/or multinucleated giant cells with numerous nuclei. A granuloma annular-like pattern can be seen in a small subset of patients. Epidermotropism can be seen. Loss of elastic fibers throughout the infiltrated areas is frequently seen, but lymphophaghocytosis and elastophagocytosis are less frequent than in GSS [41,42]. Granulomatous slack skin is an indolent and very rare form of MF (∼50 cases described). It is considered a distinct subtype of MF with characteristic clinical and histologic features [43]. Granulomatous slack skin is clinically characterized by large pendulous skin folds in flexural regions particularly the axilla and the groin [41]. It is most frequently seen in adults, usually in the fifth to sixth decade of life. Histologically, there is a dermal lymphohistiocytic infiltrate of small- to mediumsized lymphocytes associated with uniformly distributed giant cells with numerous nuclei (frequently more than 10 per cell) arranged in a wreath-like fashion [6,41]. Characteristically, there is minimal epidermotropism [6,41]. Giant cells show emperipolesis of small lymphocytes (lymphophagocytosis) or contain phagocytized elastic fibers (elastophagocytosis). Eosinophils and plasma cells are frequently seen. Infiltration of large veins in the subcutis by multinucleated giant cells and lymphocytes can be seen [6,41]. A Verhoeff–van Gieson stain (elastic stain) will confirm the destruction and loss of elastic fibers in the dermis and elastophagocytosis. Similar to classic MF, nearly all GSS cases have a CD3+, CD4+/CD8− immunophenotype and clonal TCR gene rearrangements [41,44]. The clinical
course of GSS is generally more indolent than MF. It is interesting that GSS has been described to be associated with other neoplasms including classic Hodgkin lymphoma in a rate higher than that seen in patients with classic MF [45-47]. There are clinical differences between GMF and GSS, but they also show overlapping histologic findings and thus cannot be discriminated by histologic examination alone [42]. Some studies found that the 5-year survival rate of GMF is worse than that of classic MF and similar to that of folliculotropic MF [41,48]. Similar to GSS, GMF also appears to be associated with a high risk for the development of second lymphoid neoplasm.
Fig. 10. (A-B) Hypopigmented and hyperpigmented areas with a reticulate appearance on the thigh and leg. (C-E) The recent skin biopsy from the left lateral thigh revealed compact and thick hyperkeratosis, acanthosis, and a thinned granular cell layer consistent with ichthyosis (C and D) and multifocal subtle atypical lymphocyte infiltrate in the epidermis (E). A mild perivascular lymphoid infiltrate and pigment incontinence were also noted (E) (C, scanning power; D, low power; E, high power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
2.6. Ichthyosiform MF 2.6.1. Ichthyosis induced by MF 2.6.1.1. Clinical findings. This is a 54-year-old African American woman who has a long history of a skin rash since 1992, which started as an erythematous to brownish patch approximately the size of a palm on her right anterior thigh. She started triamcinolone cream in 1995 for a presumed diagnosis of psoriasis. In 1996, the rash worsened and spread down, covering the feet, up over her back, and into the stomach area. At that point, she was treated with oral steroids and triamcinolone. The rash continued to worsen; and a skin biopsy was obtained in October 1999, which revealed MF. At that time, she had multiple lymph node enlargement and erythematous macules and plaques with significant scale over about approximately 65% of her body surface area with sparing of the popliteal and antecubital fossa bilaterally and the palms and soles. Many of these areas have a reticulate appearance with alternating hyper- and hypopigmented areas. After extensive skin-directed treatment, she has relapsed with hypopigmented skin lesions on the posterior thighs and buttocks in 2004. In March 2010, she developed
383
also new hyperpigmented patches, mostly on the posterior trunk and posterior thigh and leg, as well as ichthyosis on the legs (Fig. 10A and B). 2.6.1.2. Pathologic findings. The initial skin biopsy from the abdomen performed in 2000 demonstrated an atypical lymphoid infiltrate present at the dermal-epidermal junction and in the superficial dermis surrounding blood vessels with multifocal epidermotropism. Immunohistochemical studies revealed that neoplastic cells were T-cells of a helper cell lineage, positive for CD4 and negative for CD8. In 2009, a skin biopsy from the left lateral thigh revealed compact and thick hyperkeratosis with a thinned granular cell layer consistent with ichthyosis (Fig. 10C and D) as well as a subtle epidermotropic atypical lymphoid infiltrate (Fig. 10E). 2.6.1.3. Molecular findings. not performed
Molecular tests were
2.6.1.4. Staging, treatment, and follow-up. The patient was diagnosed as having MF, stage IIA, and ichthyosis induced by MF. The patient has previously been treated with
Fig. 11. (A) Schematic diagram of the human TCR-γ locus on chromosome band 7p14 (above). Four sets of consensus Vγ and Jγ primer (bars) are used. Each Vγ family primer is end-labeled with a different fluorescent dye. Thus, if one of the segments of the VγI family is used in the gene rearrangement, the PCR products will be fluorescently labeled with corresponding dye and will show a specific color. If VγII, III, and IV are used, the PCR products will be fluorescently labeled with different colors and will show corresponding labeled dyes, respectively. Following PCR, amplified products are denatured and separated by highresolution capillary electrophoresis. Fluorescence data are analyzed. The PCR assay is performed for each case in duplicate, and only those cases with reproducible peaks in 2 determinations are considered clonal gene rearrangement. One dominant amplified clone (peak) is consistent with a monoallelic gene rearrangement, and 2 peaks are consistent with biallelic gene rearrangements. Three or more clonal gene rearrangements that are reproducible, distinct, and quantifiable above the polyclonal background characterize an oligoclonal pattern. Below. Two dominant TCR-γ gene rearrangement peaks of 231 and 239 bp (arrows) using the VγI primer. The other 2 black peaks more than 270 bp represent amplification of the house-keeping gene (β-actin; internal control). (B) Schematic diagram of the human TCR-β locus on chromosome band 7q34.
384
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
psoralen–UVA, interferon, total body surface electron beam, nitrogen mustard, triamcinolone, and tazarotene creams. She also was diagnosed with breast cancer in June 2009, and she completed 12 cycles of chemotherapy in December 2009. In the last follow-up (March 2010), she had few patches, mostly on the posterior trunk and posterior thigh and leg. She had also persistent ichthyosis on the lower legs. She is currently applying topical nitrogen mustard and triamcinolone. 2.6.2. Discussion of MF with ichthyosis There are a small number of reports documenting acquired ichthyosis associated with MF [49-52]. The patients have usually a fine scaling eruption resembling autosomal dominant ichthyosis vulgaris. The ichthyosis may be localized to the lower extremities or may have a widespread involvement [51]. Histologically, the features of ichthyosis (hyperkeratosis, acanthosis with a thinned granular cell layer) are superimposed upon MF. The immunophenotype is that of classic MF, and molecular studies usually confirm the presence of a monoclonal Tcell population [51,52]. In our case, the ichthyosis was not present at the time of the initial diagnosis of MF and was induced during the treatment of MF. 3. Role of TCR gene rearrangement for the diagnosis of MF Although epidermotropism and atypia of lymphocytes remain the morphologic hallmarks of MF, the presence of monoclonal T-cell population can support the diagnosis [10]. Polymerase chain reaction methods to assess clonality at the TCR-γ locus (Fig. 11A) have been widely used because of its high sensitivity and applicability to routinely processed skin biopsy specimens. In these analyses, the presence of a dominant amplified clone (peak) following electrophoresis of the PCR products is consistent with a monoallelic gene rearrangement. Two peaks are consistent with biallelic gene rearrangements (Fig. 11A, below). Three or more distinct and reproducible peaks above the polyclonal background characterize an oligoclonal pattern. Lack of distinct peaks indicates a polyclonal T-cell population. The TCR-γ PCR is a very sensitive test and detects more than 90% of T-cell neoplasm [53]. However, the simple configuration of TCR-γ locus (Fig. 11A) may give rise to “false”-positive results (pseudoclonality) and/or oligoclonal T-cell expansions in benign reactive conditions. In contrast, TCR-β PCR is a more specific test and less prone to false-positive results because of the larger numbers of V and J segments (Fig. 11B) than the TCR-γ locus but is less sensitive and technically more challenging. The presence of a prominent monoclonal TCR gene rearrangement detected by TCR-γ and/or TCR-β PCR supports the diagnosis of T-cell lymphoma [54]. However, nonneoplastic skin diseases including drug reactions, atopic dermatitis, allergic contact dermatitis, and psoriasis, just to name a few, can be associated with the presence of
small clones of T-cells; for this reason, it is important to emphasize again that the diagnosis of MF requires clinicopathologic correlation and cannot be established by molecular data alone. Reviewing the PCR results to see if the reported gene rearrangement is small or prominent may also help. On the other hand, a negative TCR-γ PCR test result does not exclude the diagnosis if the clinicopathologic findings are those of MF. In addition to diagnostic purposes, it is interesting to know that TCR-γ PCR analyses can be used for monitoring disease progression. We previously reported that if detection of the same clone is evident in more than one lesion or in a given patient over time, there is an increased risk of disease progression [55].
References [1] Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol 2007; 143:854-9. [2] Massone C, Kodama K, Kerl H, Cerroni L. Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol 2005;29: 550-60. [3] Nickoloff BJ. Light-microscopic assessment of 100 patients with patch/plaque-stage mycosis fungoides. Am J Dermatopathol 1988;10: 469-77. [4] Smoller BR, Bishop K, Glusac E, Kim YH, Hendrickson M. Reassessment of histologic parameters in the diagnosis of mycosis fungoides. Am J Surg Pathol 1995;19:1423-30. [5] Naraghi ZS, Seirafi H, Valikhani M, et al. Assessment of histologic criteria in the diagnosis of mycosis fungoides. Int J Dermatol 2003;42: 45-52. [6] Kinney MC, Jones D. Cutaneous T-cell and NK-cell lymphomas: the WHO-EORTC classification and the increasing recognition of specialized tumor types. Am J Clin Pathol 2007;127:670-86. [7] Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol 2004;18: 397-415. [8] Hodak E, David M, Maron L, et al. CD4/CD8 double-negative epidermotropic cutaneous T-cell lymphoma: an immunohistochemical variant of mycosis fungoides. J Am Acad Dermatol 2006;55:276-84. [9] Massone C, Crisman G, Kerl H, Cerroni L. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol 2008;159:881-6. [10] Krafft AE, Taubenberger JK, Sheng ZM, et al. Enhanced sensitivity with a novel TCRgamma PCR assay for clonality studies in 569 formalin-fixed, paraffin-embedded (FFPE) cases. Mol Diagn 1999;4: 119-33. [11] Dereure O, Levi E, Kadin ME. T-cell clonality in pityriasis lichenoides et varioliformis acuta: a heteroduplex analysis of 20 cases. Arch Dermatol 2000;136:1483-6. [12] Willemze R, Meijer CJ. Rationale of a new classification for the group of primary cutaneous lymphomas. Semin Cutan Med Surg 2000;19: 71-7. [13] Pope E, Weitzman S, Ngan B, et al. Mycosis fungoides in the pediatric population: report from an international Childhood Registry of Cutaneous Lymphoma. J Cutan Med Surg 14:1-6. [14] Ngo JT, Trotter MJ, Haber RM. Juvenile-onset hypopigmented mycosis fungoides mimicking vitiligo. J Cutan Med Surg 2009;13: 230-3.
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385 [15] Neuhaus IM, Ramos-Caro FA, Hassanein AM. Hypopigmented mycosis fungoides in childhood and adolescence. Pediatr Dermatol 2000;17:403-6. [16] El-Shabrawi-Caelen L, Cerroni L, Medeiros LJ, McCalmont TH. Hypopigmented mycosis fungoides: frequent expression of a CD8+ Tcell phenotype. Am J Surg Pathol 2002;26:450-7. [17] Werner B, Brown S, Ackerman AB. “Hypopigmented mycosis fungoides” is not always mycosis fungoides! Am J Dermatopathol 2005;27:56-67. [18] Wain EM, Orchard GE, Whittaker SJ, Spittle MSMF, Russell-Jones R. Outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study. Cancer 2003;98: 2282-90. [19] Lambroza E, Cohen SR, Phelps R, et al. Hypopigmented variant of mycosis fungoides: demography, histopathology, and treatment of seven cases. J Am Acad Dermatol 1995;32:987-93. [20] Singh ZN, Tretiakova MS, Shea CR, Petronic-Rosic VM. Decreased CD117 expression in hypopigmented mycosis fungoides correlates with hypomelanosis: lessons learned from vitiligo. Mod Pathol 2006; 19:1255-60. [21] Ardigo M, Borroni G, Muscardin L, Kerl H, Cerroni L. Hypopigmented mycosis fungoides in Caucasian patients: a clinicopathologic study of 7 cases. J Am Acad Dermatol 2003;49:264-70. [22] Petit T, Cribier B, Bagot M, Wechsler J. Inflammatory vitiligo-like macules that simulate hypopigmented mycosis fungoides. Eur J Dermatol 2003;13:410-2. [23] El-Darouti MA, Marzouk SA, Azzam O, et al. Vitiligo vs. hypopigmented mycosis fungoides (histopathological and immunohistochemical study, univariate analysis). Eur J Dermatol 2006;16: 17-22. [24] Volkenandt M, Soyer HP, Cerroni L, et al. Molecular detection of clone-specific DNA in hypopigmented lesions of a patient with early evolving mycosis fungoides. Br J Dermatol 1993; 128:423-8. [25] Gerami P, Guitart J. The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol 2007;31:1430-8. [26] Gerami P, Rosen S, Kuzel T, Boone SL, Guitart J. Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 2008;144:738-46. [27] 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;138:191-8. [28] Cerroni L, Fink-Puches R, Back 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. [29] Flaig MJ, Cerroni L, Schuhmann K, et al. Follicular mycosis fungoides. A histopathologic analysis of nine cases. J Cutan Pathol 2001;28:525-30. [30] Kossard S, White A, Killingsworth M. Basaloid folliculolymphoid hyperplasia with alopecia as an expression of mycosis fungoides (CTCL). J Cutan Pathol 1995;22:466-71. [31] Steffen C. Ketron-Goodman disease, Woringer-Kolopp disease, and pagetoid reticulosis. Am J Dermatopathol 2005;27:68-85. [32] Haghighi B, Smoller BR, LeBoit PE, et al. Pagetoid reticulosis (Woringer-Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study. Mod Pathol 2000;13:502-10. [33] Lee J, Viakhireva N, Cesca C, et al. Clinicopathologic features and treatment outcomes in Woringer-Kolopp disease. J Am Acad Dermatol 2008;59:706-12. [34] Oliver GF, Winkelmann RK. Unilesional mycosis fungoides: a distinct entity. J Am Acad Dermatol 1989;20:63-70. [35] Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma). A
[36]
[37]
[38]
[39]
[40] [41]
[42]
[43] [44]
[45]
[46]
[47]
[48]
[49]
[50] [51] [52]
[53]
[54]
[55]
385
review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol 1994;18: 645-67. Berti E, Tomasini D, Vermeer MH, et al. Primary cutaneous CD8positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol 1999;155:483-92. Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T cell lymphoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol 1990;22:569-77. Gormley RH, Hess SD, Anand D, et al. Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. J Am Acad Dermatol 2009; 62:300-7. Heald PW, Glusac EJ. Unilesional cutaneous T-cell lymphoma: clinical features, therapy, and follow-up of 10 patients with a treatment-responsive mycosis fungoides variant. J Am Acad Dermatol 2000;42:283-5. Ackerman AB, Flaxman BA. Granulomatous mycosis fungoides. Br J Dermatol 1970;82:397-401. Kempf W, Ostheeren-Michaelis S, Paulli M, et al. Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC). Arch Dermatol 2008;144:1609-17. Metzler G, Schlagenhauff B, Krober SM, et al. Granulomatous mycosis fungoides: report of a case with some histopathologic features of granulomatous slack skin. Am J Dermatopathol 1999;21:156-60. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. Willemze R, Meijer CJ. Classification of cutaneous T-cell lymphoma: from Alibert to WHO-EORTC. J Cutan Pathol 2006;33(Suppl 1): 18-26. DeGregorio R, Fenske NA, Glass LF. Granulomatous slack skin: a possible precursor of Hodgkin's disease. J Am Acad Dermatol 1995; 33:1044-7. van Haselen CW, Toonstra J, van der Putte SJ, et al. Granulomatous slack skin. Report of three patients with an updated review of the literature. Dermatology 1998;196:382-91. Noto G, Pravata G, Miceli S, Arico M. Granulomatous slack skin: report of a case associated with Hodgkin's disease and a review of the literature. Br J Dermatol 1994;131:275-9. Papadavid E, Yu RC, Bunker C, Scoones D, Chu AC. Tumour progression in a patient with granulomatous mycosis fungoides. Br J Dermatol 1996;134:740-3. Kutting B, Metze D, Luger TA, Bonsmann G. Mycosis fungoides presenting as an acquired ichthyosis. J Am Acad Dermatol 1996;34: 887-9. Marzano AV, Borghi A, Facchetti M, Alessi E. Ichthyosiform mycosis fungoides. Dermatology 2002;204:124-9. Badawy E, D'Incan M, El Majjaoui S, et al. Ichthyosiform mycosis fungoides. Eur J Dermatol 2002;12:594-6. Eisman S, O'Toole EA, Jones A, Whittaker SJ. Granulomatous mycosis fungoides presenting as an acquired ichthyosis. Clin Exp Dermatol 2003;28:174-6. Vega F, Medeiros LJ, Jones D, et al. A novel four-color PCR assay to assess T-cell receptor gamma gene rearrangements in lymphoproliferative lesions. Am J Clin Pathol 2001;116:17-24. Wood GS, Tung RM, Haeffner AC, et al. Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/ Sezary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol 1994; 103:34-41. Vega F, Luthra R, Medeiros LJ, et al. Clonal heterogeneity in mycosis fungoides and its relationship to clinical course. Blood 2002;100: 3369-73.
Annals of Diagnostic Pathology 14 (2010) 369 – 385
Review Article
Early-stage mycosis fungoides variants: case-based review Jeong Hee Cho-Vega, MD, PhDa,⁎, Jaime A. Tschen, MDa , Madeleine Duvic, MDb , Francisco Vega, MD, PhDc a St Joseph Dermatopathology, Houston, TX 77030, USA Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA c Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA b
Abstract
Keywords:
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. The diagnosis of classic MF is based on a combination of clinical presentation, histopathology, and T-cell monoclonality detected by molecular studies. However, the diagnosis can be difficult in cases of early MF because of the subtle nature of histologic findings and, in cases of variants of MF, because of the unusual clinical and/or pathologic features. In this review, we presented the most frequent variants of MF at early stage including hypopigmented, folliculotropic, pagetoid reticulosis, unilesional, granulomatous, and ichthyosis forms. This case-based clinicopathologic review provides the notion that a comprehensive clinicopathologic correlation is of substantial importance to render the diagnosis of MF. In addition, we discuss the role of molecular studies, which are highly sensitive and recently more applicable to routinely processed skin biopsy specimens in the diagnosis of MF. © 2010 Elsevier Inc. All rights reserved. Mycosis fungoides, Early stage, cutaneous T-cell lymphoma; MF Variants, TCR gene rearrangment
1. Introduction Mycosis fungoides (MF) is the most common form of primary cutaneous lymphoma, representing approximately 50% of all primary cutaneous lymphomas, with an annual incidence of 6 or 7 cases per 1 million persons [1]. There is a substantial rise in the incidence of MF that is likely due, at least in part, to increased efficiency of detection and improvement of the diagnostic methods. Mycosis fungoides is predominantly a disease of adults usually in the fifth to sixth decade, although any age group may be involved. Incidence is higher among blacks than among whites and is higher among men than among women [1]. Clinically, patients have patches, plaques, and eventually tumors that typically occur on sun-protected skin (breast, axilla, and buttocks being the most common sites). The most common presentation is one of patches and plaques [2].
⁎ Corresponding author. Tel.: +1 713 660 9444; fax: +1 713 660 9466. E-mail address: [email protected] (J.H. Cho-Vega). 1092-9134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.06.003
Diagnosis of MF can be difficult in some cases, in particular in cases of early MF as well as in cases of so-called MF variants. These variant forms are rare and manifest with unusual clinical and/or pathologic features, making its recognition difficult. These “variants” include unusual anatomical sites of involvement (palmoplantar, isolated alopecia), a solitary lesion (pagetoid reticulosis, unilesional MF), clinical variations (hypopigmented MF, granulomatous slack skin [GSS]), or association with masking clinical conditions (MF and ichthyosis). To date, approximately 15 variant forms of MF have been described. Classic morphologic diagnostic criteria of MF includes all the following: lichenoid lymphoid infiltrate with “Indian file” or “toy soldier” lining up of atypical lymphoid cells at the dermoepidermal junction, epidermotropism with little spongiosis, Pautrier microabscesses (clustering of T-cells around Langerhans cells), and wiry collagen in the papillary dermis. Usually, the epidermotropic lymphocytes have more atypical nuclear cytologic features than those in the dermis [3-6]. The definition of atypical lymphocytes is subjective, but they have been defined as small- to medium-sized lymphocytes with
370
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
convoluted hyperchromatic nuclei and inconspicuous nucleoli. In the right clinical context, if some, but not all, of the above-mentioned features are present, a diagnosis of atypical lymphoid infiltrate suspicious for MF may be rendered. On the other hand, the following morphologic features are unusual for classic MF: marked spongiosis, vacuolar change, keratinocyte necrosis, or numerous eosinophils and/or neutrophils. The variants of MF may show classic features of MF or show unusual features. Folliculotropic MF shows “atypical” lymphocytes around and within the epithelium of the hair follicles, often with follicular mucinosis and relatively lack of infiltration of the surface epithelium. A granulomatous inflammatory infiltrate may be seen in granulomatous MF (GMF) or GSS, but should be accompanied by other diagnostic features of MF. Prominent epidermal involvement of atypical lymphoid cells with a pagetoid pattern is seen in pagetoid reticulosis. Immunophenotypically, classic and MF variants are usually neoplasms of CD4+ T-helper cells. Other phenotypes of otherwise classic MF have been described including CD8 + MF, which often presents with hypopigmented lesions or in pagetoid reticulosis; CD56+ MF; and double-negative CD4/CD8 MF [7,8]. These immunophenotypes do not appear to be of prognostic impact [9]. Mycosis fungoides is a clonal expansion of T-cells, and the molecular detection of a clonal T-cell expansion has been exploited for diagnostic purposes [10]. However, nonneoplastic skin diseases may be associated with Tcell clonality [11]; for this reason, it is important to emphasize that the diagnosis of MF requires clinicopathologic correlation and cannot be established by molecular data alone. The diagnosis of either classic or variant forms of MF is based on a combination of clinical presentation and histopathology with the help of molecular studies [5,6,12]. It is important to note that none of these factors exclusively determines the diagnosis and that clinicopathologic correlation is of substantial importance to render the diagnosis of MF. Diagnosis of MF can be difficult because of a highly variable number of clinical presentations and the sometimes nonspecific nature of the histologic findings. In early MF, not all of the pathologic findings are present; and distinction from an inflammatory infiltrate can be difficult [5]. Molecular studies may help to confirm the diagnosis in particular in those cases of early MF and in those cases in which the clinical
371
features and/or the pathologic findings are not typical for MF. This review addresses the comprehensive clinicopathologic spectrum of early MF, focusing on the most frequent “variants” of this disease. Recognition of these clinicopathologic presentations can be of great diagnostic utility. We will also discuss the role of molecular studies as an additional help for the diagnosis.
2. Case-based MF variants 2.1. Early hypopigmented MF 2.1.1. Case 1. Early juvenile and hypopigmented variant of MF, CD8 positive 2.1.1.1. Clinical findings. The patient is an 18-year-old African American woman. She has a long history of eczema since she was a baby. The rash was most prominent in her antecubital and popliteal fossae. Since 4 years ago, she has been developing small light spots, which started in her hips and legs. Recently, these white spots have increase in intensity; and they have spread to her upper back, legs, and arms (Fig. 1A-C). She denies itching. A 4-mm punch biopsy was taken from one of these white spots. 2.1.1.2. Pathology findings. The skin biopsy showed a subtle and focal atypical lymphoid infiltrate within the epidermis (Fig. 1D, arrows) with focal Pautrier microabscesses (Fig. 1E). Atypical lymphocytes showed irregular nuclear contours and hyperchromasia aligned along the dermal-epidermal junction (Fig. 1F-G). The vast majority of atypical lymphocytes were CD8+ T-cells (Fig. 1H) with a significantly decreased CD4:CD8 ratio (approximately 1:4) (Fig. 1I). Most of the epidermotropic lymphocytes were positive for CD8 (Fig. 1H). 2.1.1.3. Molecular findings. Monoclonal TCR-γ gene rearrangements were detected by polymerase chain reaction (PCR) analysis (V-γIII segment) (Fig. 1J, arrow). Monoclonal TCR-β gene rearrangements were not detected. 2.1.1.4. Staging, treatment, and follow-up. The patient was diagnosed with MF, stage Ib, juvenile, hypopigmented type. Flow cytometry immunophenotypic studies performed on a peripheral blood sample failed to detect immunophenotypic abnormalities. The patient is being treated with
Fig. 1. (A-C) Mottled small hypopigmented lesions (b2 cm) were seen on the anterior and posterior aspects of both legs. They were also noted on the arms. (D-G). Histologic sections from a hypopigmented lesion showed a subtle superficial lymphoid infiltrate (D, arrows). Higher magnification revealed that the infiltrate was epidermotropic and was composed of small to intermediate lymphoid cells with halos along the dermoepidermal junction (E-G). Few Pautrier microabscesses were seen (E). Noted that no pigmentation was identified in the basal keratinocytes (H-I). CD8 (H) highlighted atypical lymphocytes in the epidermis and dermis, whereas those cells were negative for CD4 (I) (D, low power; E-F, medium power; G, high power; H, I, DAB, medium power). (J) A monoclonal TCR-γ gene rearrangement of 141 base pairs (bp) was detected by PCR analysis (V-γIII segment, arrow). The small red peaks corresponded to internal size standards. The other 2 black peaks more than 270 bp represented amplification of the house-keeping gene (β-actin; internal control).
372
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
narrow-band UV-B 2 to 3 times weakly and triamcinolone. Her skin lesions are improving. 2.1.2. Case 2. Hypopigmented and poikilodermatous variant of MF, CD8 positive 2.1.2.1. Clinical findings. The patient is a 47-year-old African American woman. She had bilateral white coin-sized
patches on her lateral forearms since the age of 13 years. During junior high school, these lesions spread to her legs, arms, and torso and increased in number. Since 1988, different dermatologists performed several skin biopsies from different sites that rendered nonspecific diagnoses. Around 1996, she developed hyperpigmented dark lesions as well as hypopigmented lesions. These lesions were not responding to topical steroid creams and/or UV light
Fig. 2. Numerous hypopigmented patches were present on the entire body (A-C). Several reticulated hyperpigmented patches (A-B, arrows) were present on the posterior thighs, buttock, chest, and the lower back consistent with poikiloderma (D-H). The biopsy from the left thigh showed atrophic epidermis and fibrosis, increased blood vessels, and pigment incontinence in the upper dermis, features resembling those of poikiloderma vasculare atrophicans (E, G, H). Minimal epidermotropic atypical lymphocytic infiltrate and decreased basal pigmentation were also observed. The biopsy from the right thigh (D, F) showed less atrophic epidermis and higher number of atypical lymphocyte infiltrate in the epidermis than the biopsy from the left thigh. The vast majority of atypical lymphocytes in the epidermis were CD8+ T-cells (I) and were negative for CD4 (J) with a decreased ratio of CD4:CD8 (approximately 1:3). The CD4:CD8 ratio in the dermis was 2:1 (D, E, G, low power; F-H, medium power; I, J, DAB, medium power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
exposure. In 2008, 3 skin biopsies confirmed MF. Currently, she has numerous hypopigmented patches on the entire body, hyperpigmented patches on her left shoulder, and reticulated hyperpigmented patches on the inner aspects of her thighs consistent with poikiloderma vasculare atrophicans (Fig. 2A-C). 2.1.2.2. Pathology findings. The skin biopsy from the right thigh (Fig. 2D and F) showed a mildly atypical epidermotropic lymphoid infiltrate. The biopsy from the left thigh (Fig. 2E, G, and H) demonstrated atrophic epidermis and a minimal, mildly atypical epidermotropic lymphoid infiltrate. The upper dermis showed fibrosis, increased blood vessels, and pigment incontinence, features resembling those of poikiloderma vasculare atrophicans. The vast majority of T-cells in the epidermis were weakly positive for CD8 (Fig. 2I) and was negative for CD4 (Fig. 2J) and CD7, with a decreased ratio of CD4: CD8 (approximately 1:3). The CD4:CD8 ratio in the dermis was 2:1.
2.1.2.3. Molecular findings. been performed
373
Molecular studies have not
2.1.2.4. Staging, treatment, and follow-up. She was diagnosed as having hypopigmented and poikilodermatous variant of MF, stage Ib, with a CD8+ immunophenotype. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect immunophenotypic abnormalities. She is being treated with topical triamcinolone, 40% nitrogen mustard, and UV light without significant improvement. 2.1.3. Discussion of hypopigmented MF Hypopigmented MF is a rare clinical variant of MF predominantly found in children and adolescents and in dark-skinned patients [13-16]. Hypopigmented MF has a reported higher prevalence in females than males. Hypopigmented MF displays the same histopathologic findings as classic MF [16-19]. The reason behind the loss of pigmentation is not clear; it is believe that it is due to the cytotoxic effect of CD8 T-cells on melanocytes (at least in
Fig. 3. (A-D) The skin biopsy specimen obtained from the normal skin adjacent to the vitiligo lesion (A and B) revealed multifocal preserved melanin pigment and melanocytes in the basal layer of the epidermis. The dermis was unremarkable. The biopsy from the hypopigmented lesion showed absence of any melanin pigment and melanocytes in the basal layer of the epidermis (C), which was well illustrated by the Fontana-Masson stain (D). Mild perivascular lymphocytic infiltrate was present (C). This skin punch biopsy specimen showed subtle loss of basal pigmentation and was consistent with pityriasis alba (E and F) (A, C, low power; B, D, Fontana-Masson, low power; E, scanning power; F, medium power).
374
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
those cases with a CD8 phenotype) [20]. The skin lesions are usually localized on sun-protected skin of the body and may be associated with classic erythematous patches, plaques, or tumors, in particular in white patients [21]. In contrast to classic MF, in which the tumor cells are usually CD4+, the neoplastic cells in hypopigmented MF are frequently CD8+ (cytotoxic phenotype) [16,18,20]. A variety of clinical entities may present with areas of hypopigmentation and share similar clinical picture with hypopigmented MF, especially vitiligo, lichen sclerosus et atrophicus, atopic dermatitis, pityriasis alba, pityriasis lichenoides chronica, tinea versicolor, onchocerciasis, syphilis, and lepra. 2.1.3.1. Vitiligo. Vitiligo is a common skin disease characterized by the presence of well-circumscribed, depigmented macules and patches. The lesions tend to be symmetrical without scaling and with predilection for the face, back of the hands, axillae, groins, umbilicus, and genitalia. The histopathologic features of vitiligo, especially when biopsies are taken from the periphery of the lesions, may show similarity to early patch hypopigmented MF (shown in case 1). Cases of vitiligo mimicking MF have been described; and vice versa, MF may simulate vitiligo [14,22]. The following features are more commonly seen in hypopigmented MF than in vitiligo: marked epidermotropism, hydropic degeneration of basal cells, partial loss of pigment, preservation of some melanocytes, presence of lymphocytes within the papillary dermis, and wiry fibrosis [23]. On the other hand, focal thickening of the basement membrane, complete loss of pigmentation, total absence of melanocytes, as well as absence or sparseness of lymphocytes in the dermal papillae are findings more frequently seen in vitiligo (Fig. 3A-D) [23]. In challenging cases, molecular studies may be helpful to support a diagnosis of early hypopigmented MF over vitiligo [16,21,24]. 2.1.3.2. Pityriasis alba. Pityriasis alba consists of variable hypopigmented scaly patches with a predilection for the face, neck, and shoulders of children usually, but also of young adults. Morphologic findings are not specific, either no obvious pathologic alterations except loss of melanin pigmentation in basal keratinocytes or, rarely, a sparse superficial perivascular infiltrate of lymphocytes (Fig. 3E and F). 2.2. Early folliculotropic MF 2.2.1. Case 1. Early acneiform folliculotropic MF 2.2.1.1. Clinical findings. The patient is a 48-year-old white woman with a long history of dry, itchy patches on the
arms and back of the elbows. These lesions were responsive to topical steroids and UV-B. Recently, she developed a follicular rash on the left anterior thigh (Fig. 4A) that was not responsive to topical steroids. A 4-mm punch skin biopsy was performed. 2.2.1.2. Pathology findings. The skin biopsy demonstrated a dense predominantly periadnexal and folliculotropic infiltrate (Fig. 4B) with atypical lymphocytes and numerous eosinophils (Fig. 4C-E). Follicular mucinosis was also observed (Fig. 4F). The overlying epidermis showed a focal epidermotropic atypical lymphoid infiltrate associated with spongiosis and parakeratosis. The vast majority of atypical lymphocytes were positive for CD3 (Fig. 4G) and CD4 (Fig. 4I), with a significantly increased dermal ratio of CD4:CD8 (4:1) (Fig. 4J) and with many of the epidermotropic and folliculotropic lymphocytes also positive for CD4. Partial loss of CD7 expression was also observed. Clusters of B-cells CD20+ were also observed (Fig. 4H). 2.2.1.3. Molecular findings. performed.
Molecular tests were not
2.2.1.4. Staging, treatment, and follow-up. The patient was diagnosed as having folliculotropic MF, stage 1A. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect immunophenotypically aberrant Tcells. She has been receiving topical nitrogen mustard treatment resulting in a partial response. 2.2.2. Case 2. Folliculotropic MF presented as alopecia in sun-exposed skin 2.2.2.1. Clinical findings. The patient is a 52-year-old white man with a history of rash for approximately 5 years. The rash began on his left buttock and subsequently spread to his left thigh and left eyebrow. He noticed the left eyebrow lesion approximately 3 years ago. The patient has a large indurated plaque with alopecia over the left lateral eyebrow (Fig. 5A) as well as an indurated plaque also associated with alopecia on the right jawline (Fig. 5B). He also has erythematous patches, accentuated follicular papules, and comedones (Fig. 5C) and patches on the right scalp, back, chest, upper arms, and the left distal thigh. Skin biopsies of the left eyebrow and the jawline plaques were performed. 2.2.2.2. Pathologic findings. Both skin biopsies from the left eyebrow (Fig. 5D) and the right jawline (Fig. 5E) show similar findings. There was a dense atypical lymphoid infiltrate composed of small to intermediate lymphoid
Fig. 4. (A) Folliculotropic rash on the left anterior thigh. (B-F) Skin biopsy demonstrated a dense, predominantly periadnexal and folliculotropic lymphoid infiltrate (B) with atypical lymphocytes and eosinophils (C-E). Follicular mucinosis was also observed (F). The overlying epidermis showed mild epidermotropism of atypical lymphocytes as well as spongiosis and parakeratosis (C). The vast majority of atypical lymphocytes expressed CD3 (G) and CD4 (I), particularly infiltrates in the epidermis, with a significantly increased ratio of CD4: CD8 (J) (4:1). A number of CD20+ B-cells were also present (H) (B, scanning power; C, D, E, F, medium power; G, DAB, scanning power; H, I, J, DAB, low power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
375
376
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
Fig. 5. (A) Large indurated plaque associated with alopecia over the left lateral eyebrow. (B) Similar lesion in the right jawline. The plaque had elevated borders and was associated with alopecia (C). A group of follicular papules appearing as comedones on the thigh (D-G). Skin biopsy specimens from the left eyebrow (D) and the right jawline (E) revealed similar histologic features. They showed a dense atypical lymphoid infiltrate with striking perifollicular and follicular epidermotropism associated with follicular mucinosis (F and G). The overlying epidermis showed minimal epidermotropism of atypical lymphocytes. These atypical lymphocytes were CD4+ T cells (H) with a significantly increased ratio of CD4:CD8 (I) (N10:1) (D and E, scanning power; F, G, medium power; H, J, DAB, low power).
cells showing striking perifollicular and intrafollicular involvement with minimal and focal follicular mucinosis (Fig. 5F and G). Surface epidermotropism was minimal. The atypical lymphoid infiltrate was composed predominantly of CD4+ T cells (Fig. 5H) with a significantly increased intraepidermal ratio of CD4:CD8 (N10:1) (Fig. 5H and I).
2.2.2.3. Molecular findings. performed.
Molecular tests were not
2.2.2.4. Staging, treatment, and follow-up. He was diagnosed as having folliculotropic MF, stage 1A. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect abnormal T-cells. A computed
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
tomographic scan of the pelvis and abdomen revealed no enlarged lymph nodes. He was treated with radiation therapy (a total dose of 30 Gy in 15 treatments) to the right mandible and left upper eyebrow. He has had an excellent response to the radiation. However, he still had few persistent plaques of follicular accentuation on the back and thigh and follicular pink patches on the left chest and abdomen that are being treated with topical bexarotene. 2.2.3. Case 3. Folliculotropic MF with follicular mucinosis 2.2.3.1. Clinical findings. The patient is a 38-year-old woman who has history of adrenal insufficiency and hypothyroidism. She initially developed scaly raised pink papules on her upper arms. Those lesions have progressed to her back, chest, and abdomen. The more recent physical examination revealed hypopigmented macules and scaly papules on her back (Fig. 6A), hypopigmented macules on her upper arm, and scaly papules on her anterior trunk and upper arms. A punch skin biopsy of one of the lesions on the right shoulder was performed. 2.2.3.2. Pathologic findings. Histologic sections revealed a single hair follicle infiltrated by small-sized lymphocytes associated with marked mucin deposition (follicular mucinosis) (Fig. 6B and C). Occasional eosinophils were seen. Superficial epidermotropism was minimal. Although the lymphoid cells showed no obvious morphologic atypia, the vast majority of these lymphocytes were CD4+ T-cells (Fig. 6D and F) with significant increase of CD4:CD8 ratio in the intra- and perifollicular infiltrate (Fig. 6E). An additional skin biopsy (not shown) from the left upper shoulder showed an atypical folliculotropic and perifollicular lymphoid infiltrate associated with mild follicular mucinosis. In this skin biopsy specimen, the lymphoid infiltrate was also positive for CD3 and CD4 with an increase of CD4:CD8 ratio. No significant loss of CD7 expression was identified. 2.2.3.3. Molecular findings. No monoclonal TCR-γ gene rearrangements were identified by PCR; however, low levels of a monoclonal TCR-β gene rearrangement were detected. 2.2.3.4. Staging, treatment, and follow-up. The patient was diagnosed with folliculotropic MF, stage 1A. Flow cytometry immunophenotypic studies of a peripheral blood specimen failed to detect abnormal T-cells. The patient was treated with topical isotretinoin on her face and triamcinolone on her body, resulting in minimal improvement. She also received topical tazarotene and triamcinolone, which resolved some of lesions; but new pink papules appeared on the arms and trunk. In the last follow-up, the total body surface area involvement was 1.5% plaques, which improved from 2.5% plaques at the initial visit. 2.2.4. Discussion of folliculotropic MF Folliculotropic MF, also referred to as pilotropic MF, is a relatively common variant characterized by atypical lymphocytes around and within the epithelium of the hair
377
follicles with relative lack of infiltration of the surface epithelium. Folliculotropic MF can present with a wide variety of clinical pictures including acneiform lesions, comedones, cysts, alopecia with or without scarring, and nodular prurigo-like lesions. The head and neck region, in particular the scalp or face, is most commonly involved. Pruritus is especially common [25,26]. The disease course is aggressive, the response to topical therapy is poor even in the early stage of the disease, and many patients show a poor outcome particularly between 10 and 15 years after the initial onset of disease [26-28]. The mechanism of folliculotropism is poorly understood. Several histologic patterns of folliculotropic MF have been described including the classic pattern of folliculotropism with or without follicular mucinosis, eosinophilic folliculitis-like pattern, cystic pattern, basaloid folliculolymphoid hyperplasia, granulomatous pattern, and a mixed folliculotropic and syringotropic pattern [25,26,29,30]. Marked mucin accumulation in the follicle (follicular mucinosis) and dermis is often present (50% of the cases), and follicular destruction can be present. Large cell transformation (more than 25% of large T-cells) can be seen in a third of the patients. Syringotropic MF is a rare form of MF; less than 30 cases have been reported, characterized by infiltrates of atypical lymphocytes located in and around hyperplastic eccrine glands and ducts. Clinically, syringotropic MF presents as small papules (1-3 mm in diameter). Although syringotropic MF is considered a histopathologic variant of folliculotropic MF, the relationship between these 2 MF subtypes remains tenuous. Most patients with syringotropism have coexisting folliculotropism. The current World Health Organization/ European Organisation for Research and Treatment of Cancer classification of cutaneous neoplasms places syringotropic and folliculotropic MF in the same group, defining them as a single clinical variant of MF. However, some differences have been noted. In contrast to folliculotropic MF, most of the patients with syringotropic MF had lesions on the trunk, hips, breast, buttocks, or groin, suggesting that syringotropic MF closely parallels the presentation of classic MF, which preferentially affects chronically sun-protected areas. In comparison with folliculotropic MF, most reported cases of syringotropic MF have had a benign chronic course and a prognosis similar to classic MF, with 10-year survival ranging from 83% to 97% [27]. 2.3. Pagetoid reticulosis (Woringer-Kolopp disease) 2.3.1. Pagetoid reticulosis presenting as a single small scaly plaque on the foot 2.3.1.1. Clinical findings. The patient is a 24-year-old woman with 10.0 × 10.0 mm dermal plaque on her right medial dorsum of foot, which was noticed for the first time 7 months ago. The lesion started as a small red spot that was slowly increasing in size. The patient is otherwise healthy without significant medical history. The lesion is a small round dermal plaque with scaling in the center and raised,
378
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
Fig. 6. (A) Scattered hypopigmented macules and scaly pearly or pink papules accentuating follicles on the back. (B-C) Skin biopsy from the right shoulder revealed a single hair follicle infiltrated by small-sized lymphocytes and abundant mucin deposition inside the follicular epithelium. The vast majority of these infiltrating lymphocytes were CD4+ T-cells (D and F) with significant increase of CD4:CD8 (G) ratio, particularly inside the follicular epithelium (B, medium power; C, high power; D, E, DAB, low power; F, DAB, high power).
sharply demarcated, red peripheral borders. The clinical differential diagnosis included dermatofibroma, porokeratosis, or granuloma annulare. A skin punch biopsy of the border of the lesion was taken. 2.3.1.2. Pathologic findings. Histologic sections showed a psoriasiform epidermis with acanthosis and hyperkeratosis associated with a dense epidermotropic atypical lymphoid infiltrate located predominantly in the basal layer with a pagetoid pattern (Fig. 7A). The atypical lymphoid cells were small to intermediate in size with irregular nuclear contours, hyperchromatic nuclei, some with distinct nucleoli, and some with a perinuclear halo (Fig. 7B and C). Rare mitotic figures were also observed. The superficial dermis contained a mild perivascular lymphohistiocytic infiltrate with rare atypical-appearing cells. Immunohistochemical studies revealed that the neoplastic cells were positive for CD3 (Fig. 7D) and CD8 (Fig. 7E and G) and were negative for CD4 (Fig. 7F and H) and CD7 (Fig. 7I). Reactive T-cells positive for CD4 (Fig. 7F) and rare B-cells positive for CD20 were observed in the upper dermis. 2.3.1.3. Molecular findings. No monoclonal TCR-γ gene rearrangements were identified by PCR. 2.3.1.4. Staging, treatment, and follow-up. She was diagnosed with pagetoid reticulosis. Patient went back to her home country for staging and local radiation treatment.
2.3.2. Discussion of pagetoid reticulosis Pagetoid reticulosis is an extremely rare variant of MF with relatively consistent clinical and histopathologic findings [31-33]. The typical presentation is a solitary, localized psoriasiform or hyperkeratotic plaque located on the foot or hand. It is more frequent in females, with a wide median age at presentation including early childhood. It often mimics other common skin dermatoses that may result in a considerable delay in the diagnosis. Pagetoid reticulosis usually has an indolent clinical course but with potential for frankly malignant behavior. The disease responds well to radiation therapy. Histopathologic findings are epidermal hyperplasia with parakeratosis and prominent epidermotropic atypical lymphoid infiltrate (particularly in the basal layer) with Pautrier microabscesses. Many cases of pagetoid reticulosis have a CD8+ immunophenotype, and analysis of TCR genes has identified clonality in the majority of cases. The differential diagnosis of pagetoid reticulosis includes MF palmaris et plantaris, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, and unilesional MF. 2.3.2.1. MF palmaris et plantaris. It is a rare manifestation of MF (0.6% of cases) [34] that clinically present as thin acral plaques that mimic hand or foot dermatitis. The neoplastic lymphoid infiltrate is usually present both above and below the dermal-epidermal junction and may contain eosinophils. In contrast, pagetoid reticulosis presents with
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
379
Fig. 7. (A-C) Histologic sections showed an almost completely intraepidermal infiltrate of atypical mononuclear cells at a low power (A). The epidermis showed a psoriasiform appearance with hyperkeratosis and acanthosis. The epidermis was infiltrated particularly in the basal layer by the atypical lymphoid cells. They were intermediate to large with hyperchromatic and irregular nuclei, some with distinct nucleoli, and variable amounts of pale-staining cytoplasm (B). Some of the lymphoid cells had a perinuclear halo, representing retraction artifact. The basement membrane region to the epidermis was focally intact and well demarcated (C). The upper dermis contained minimal perivascular lymphohistiocytic infiltrate. Neoplastic cells were positive for CD3 (D) and CD8 (E and G) and were negative for CD4 (F and H). A considerable number of reactive T-cells positive for CD4 were observed in the upper dermis (F). Most of all neoplastic cells lost CD7 expression (I) (A, scanning power; B, medium power; C, high power; D, E, DAB, scanning power; F, DAB, medium power; G, H, I, DAB, high power).
verrucous, scaly, and hyperkeratotic plaques. The tumor cells are almost exclusively located in the epidermis, and eosinophils are not seen [32,35].
2.3.2.3. Unilesional MF See case below.
2.3.2.2. Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. It is a distinct and aggressive cutaneous T-cell lymphoma that clinically presents as localized or disseminated nodules, plaques, and tumors often with ulceration and necrosis [36-38]. Its characteristic is the rapid progression with extracutaneous dissemination to unusual sites, such as the central nervous system, lung, testis, and oral mucosa [36]. It is important to know that there is some histologic and immunophenotypic overlap between indolent and aggressive cases of cutaneous CD8+ T-cell lymphomas. Thus, the clinical features and disease course are important to establish the diagnosis of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma.
2.4.1. Unilesional MF presenting as a single papule on the neck
2.4. Unilesional MF
2.4.1.1. Clinical findings. The patient is a 76-year-old woman. She noticed a 9-mm pearly papule on the right side of her posterior neck described as a pimple. She also had numerous warty papules consistent with seborrheic keratoses on the trunk that were treated with liquid nitrogen. A shave biopsy of the neck lesion was performed. 2.4.1.2. Pathology findings. The skin shave biopsy showed a dense, atypical lymphoid infiltrate comprising a mixed population of small, medium, and large lymphocytes, extending full thickness of the dermis with minimal
380
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
epidermotropism (Fig. 8A and B). The larger lymphocytes were atypical with irregular nuclear contour and hyperchromatic nuclei (Fig. 8C). Mitoses were noted. The vast majority of atypical lymphocytes were positive for CD3 (Fig. 8D) and CD4 (Fig. 8E and H) and were negative for CD8 (Fig. 8F) and CD7. A subset of the large atypical cells showed weakly positive for CD30. Rare clusters of CD20+ B-cells (Fig. 8G) were also present within the infiltrate. 2.4.1.3. Molecular findings. Molecular PCR studies demonstrated monoclonal gene rearrangements of the TCR-γ (Fig. 8I) and TCR-β genes. 2.4.1.4. Staging, treatment, and follow-up. She was diagnosed as having unilesional MF. Result of a full staging evaluation including bone marrow and peripheral blood analyses and computed tomographic scans of the pelvis, abdomen, and thorax was negative for systemic lymphoma.
The patient is being followed without receiving any treatment. The patient has been followed for 4 months; and to date, there is no evidence of local and/or systemic relapse. 2.4.2. Discussion of unilesional MF Unilesional MF is defined as a single area of involvement by MF covering less than 5% of the body surface [39]. The lesions are usually found in body regions typical for classic MF, and the histopathologic findings are identical to those seen in classic MF [39]. Patients with unilesional MF demonstrate an excellent response to topical chemotherapy or irradiation. Recurrences may occur after surgical excision. 2.5. Granilomatous Mycosis Fungoides (GMF) and GSS 2.5.1. MF with granulomatous features 2.5.1.1. Clinical findings. A 68-year-old white woman developed a mildly pruritic single pink papule on her right
Fig. 8. The skin biopsy specimen showed a dense lymphoid infiltrate involving the full thickness of the dermis and showing focal epidermotropism. The epidermis showed compact hyperkeratosis (A and B). The lymphoid infiltrate was composed of a mixed population of small, medium, and occasional large lymphocytes. The larger lymphocytes were atypical with irregular nuclear contours and hyperchromatic nuclei (C). The vast majority of atypical lymphocytes were CD3+ (D) and CD4+ (E) T-cells, whereas lymphocytes showing positive staining for CD8 (F) were relatively scarce. CD4 (H) highlighted the epidermotropic atypical lymphocytes. Rare clusters of CD20+ B-cells were present within the infiltrate (G). A monoclonal TCR-γ gene rearrangement of 178 bp was detected by PCR analysis (V-γII segment). The small red peaks corresponded to internal size standards (A, scanning power; B, medium power; C, high power; D-G, DAB, scanning power; H, high power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
lateral thigh. The lesion did not improve with topical antibiotics, and a shave biopsy was performed. In 2007, a biopsy from a red, firm, 1-cm nodule in the left posterior calf revealed GMF. 2.5.1.2. Pathology findings. Histologic sections showed a dense atypical lymphoid infiltrate involving the dermis with multifocal epidermotropism (Fig. 9A and D). The lymphocytes were small to intermediate in size, some with convoluted nuclear contours. In addition, a granulomatous reaction with multinucleated giant cells and elastophago-
381
cytosis were also present (Fig. 9B and C). The vast majority of infiltrating atypical lymphocytes were positive for CD3 (Fig. 9E) with a predominance of CD4+ cells (Fig. 9H) over CD8+ cells (Fig. 9I), particularly in the epidermotropic atypical cells (Fig. 9G). Few B-cells were noted (Fig. 9F). 2.5.1.3. Molecular findings. Molecular studies confirmed the presence of a monoclonal TCR-γ gene rearrangement (using the family VγIV) (Fig. 9J). Polymerase chain reaction studies for the TCR-β gene revealed an oligoclonal pattern.
Fig. 9. Histologic sections showed a variable dense lymphoid infiltrate involving the dermis associated with multifocal epidermotropism (A, D). Multinucleated giant cells were also present (B and C). The vast majority of infiltrating atypical lymphocytes were CD3+ T-cells (E) with a predominance of CD4+ cells (H) over CD8+ cells (I), particularly in the epidermotropic component (G). A small subset of dermal infiltrates was CD20+ B-cells (F). A monoclonal TCR-γ gene rearrangement of 178 bp was detected by PCR analysis (V-γIV segment) (J). The small red peaks corresponded to internal size standards. The other 2 black peaks more than 270 bp represented amplification of the house-keeping gene (β-actin; internal control) (A, scanning power; B, low power; C, medium power; D, high power; E, F, H, I, DAB, low power; G, DAB, high power).
382
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
2.5.1.4. Stage, treatment, and follow-up. Because the tumor reached the subcutaneous tissue, a 6-mm punch biopsy for a complete removal was performed at the previous biopsy site to include subcutaneous tissue. Flow cytometry immunophenotypic studies of the peripheral blood failed to detect an aberrant T-cell population. This biopsy was negative for residual MF. She is being closely followed up with no additional treatment. 2.5.2. Discussion of GMF and GSS Ackerman and Flaxman [40] proposed the term granulomatous mycosis fungoides in 1970. Ackerman added the term granulomatous slack skin disease in 1978. The most common form of granulomatous cutaneous T-cell lymphoma is GMF [41]. This term is used for tumors with the histologic pattern of typical MF in which the histiocytic or granulomatous inflammation is prominent but without the preferential flexural skin involvement. Granulomatous MF is most frequently seen in adults, usually in the fifth to sixth decade, with the trunk representing the predilection site [41]. The clinical presentation of skin lesions in GMF is not indicative of the granulomatous histology. There is a dermal lymphohistiocytic infiltrate (diffuse, nodular, perivascular, or periadnexal) of small- to medium-sized lymphocytes associated with nonnecrotizing granulomas and/or multinucleated giant cells with numerous nuclei. A granuloma annular-like pattern can be seen in a small subset of patients. Epidermotropism can be seen. Loss of elastic fibers throughout the infiltrated areas is frequently seen, but lymphophaghocytosis and elastophagocytosis are less frequent than in GSS [41,42]. Granulomatous slack skin is an indolent and very rare form of MF (∼50 cases described). It is considered a distinct subtype of MF with characteristic clinical and histologic features [43]. Granulomatous slack skin is clinically characterized by large pendulous skin folds in flexural regions particularly the axilla and the groin [41]. It is most frequently seen in adults, usually in the fifth to sixth decade of life. Histologically, there is a dermal lymphohistiocytic infiltrate of small- to mediumsized lymphocytes associated with uniformly distributed giant cells with numerous nuclei (frequently more than 10 per cell) arranged in a wreath-like fashion [6,41]. Characteristically, there is minimal epidermotropism [6,41]. Giant cells show emperipolesis of small lymphocytes (lymphophagocytosis) or contain phagocytized elastic fibers (elastophagocytosis). Eosinophils and plasma cells are frequently seen. Infiltration of large veins in the subcutis by multinucleated giant cells and lymphocytes can be seen [6,41]. A Verhoeff–van Gieson stain (elastic stain) will confirm the destruction and loss of elastic fibers in the dermis and elastophagocytosis. Similar to classic MF, nearly all GSS cases have a CD3+, CD4+/CD8− immunophenotype and clonal TCR gene rearrangements [41,44]. The clinical
course of GSS is generally more indolent than MF. It is interesting that GSS has been described to be associated with other neoplasms including classic Hodgkin lymphoma in a rate higher than that seen in patients with classic MF [45-47]. There are clinical differences between GMF and GSS, but they also show overlapping histologic findings and thus cannot be discriminated by histologic examination alone [42]. Some studies found that the 5-year survival rate of GMF is worse than that of classic MF and similar to that of folliculotropic MF [41,48]. Similar to GSS, GMF also appears to be associated with a high risk for the development of second lymphoid neoplasm.
Fig. 10. (A-B) Hypopigmented and hyperpigmented areas with a reticulate appearance on the thigh and leg. (C-E) The recent skin biopsy from the left lateral thigh revealed compact and thick hyperkeratosis, acanthosis, and a thinned granular cell layer consistent with ichthyosis (C and D) and multifocal subtle atypical lymphocyte infiltrate in the epidermis (E). A mild perivascular lymphoid infiltrate and pigment incontinence were also noted (E) (C, scanning power; D, low power; E, high power).
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
2.6. Ichthyosiform MF 2.6.1. Ichthyosis induced by MF 2.6.1.1. Clinical findings. This is a 54-year-old African American woman who has a long history of a skin rash since 1992, which started as an erythematous to brownish patch approximately the size of a palm on her right anterior thigh. She started triamcinolone cream in 1995 for a presumed diagnosis of psoriasis. In 1996, the rash worsened and spread down, covering the feet, up over her back, and into the stomach area. At that point, she was treated with oral steroids and triamcinolone. The rash continued to worsen; and a skin biopsy was obtained in October 1999, which revealed MF. At that time, she had multiple lymph node enlargement and erythematous macules and plaques with significant scale over about approximately 65% of her body surface area with sparing of the popliteal and antecubital fossa bilaterally and the palms and soles. Many of these areas have a reticulate appearance with alternating hyper- and hypopigmented areas. After extensive skin-directed treatment, she has relapsed with hypopigmented skin lesions on the posterior thighs and buttocks in 2004. In March 2010, she developed
383
also new hyperpigmented patches, mostly on the posterior trunk and posterior thigh and leg, as well as ichthyosis on the legs (Fig. 10A and B). 2.6.1.2. Pathologic findings. The initial skin biopsy from the abdomen performed in 2000 demonstrated an atypical lymphoid infiltrate present at the dermal-epidermal junction and in the superficial dermis surrounding blood vessels with multifocal epidermotropism. Immunohistochemical studies revealed that neoplastic cells were T-cells of a helper cell lineage, positive for CD4 and negative for CD8. In 2009, a skin biopsy from the left lateral thigh revealed compact and thick hyperkeratosis with a thinned granular cell layer consistent with ichthyosis (Fig. 10C and D) as well as a subtle epidermotropic atypical lymphoid infiltrate (Fig. 10E). 2.6.1.3. Molecular findings. not performed
Molecular tests were
2.6.1.4. Staging, treatment, and follow-up. The patient was diagnosed as having MF, stage IIA, and ichthyosis induced by MF. The patient has previously been treated with
Fig. 11. (A) Schematic diagram of the human TCR-γ locus on chromosome band 7p14 (above). Four sets of consensus Vγ and Jγ primer (bars) are used. Each Vγ family primer is end-labeled with a different fluorescent dye. Thus, if one of the segments of the VγI family is used in the gene rearrangement, the PCR products will be fluorescently labeled with corresponding dye and will show a specific color. If VγII, III, and IV are used, the PCR products will be fluorescently labeled with different colors and will show corresponding labeled dyes, respectively. Following PCR, amplified products are denatured and separated by highresolution capillary electrophoresis. Fluorescence data are analyzed. The PCR assay is performed for each case in duplicate, and only those cases with reproducible peaks in 2 determinations are considered clonal gene rearrangement. One dominant amplified clone (peak) is consistent with a monoallelic gene rearrangement, and 2 peaks are consistent with biallelic gene rearrangements. Three or more clonal gene rearrangements that are reproducible, distinct, and quantifiable above the polyclonal background characterize an oligoclonal pattern. Below. Two dominant TCR-γ gene rearrangement peaks of 231 and 239 bp (arrows) using the VγI primer. The other 2 black peaks more than 270 bp represent amplification of the house-keeping gene (β-actin; internal control). (B) Schematic diagram of the human TCR-β locus on chromosome band 7q34.
384
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385
psoralen–UVA, interferon, total body surface electron beam, nitrogen mustard, triamcinolone, and tazarotene creams. She also was diagnosed with breast cancer in June 2009, and she completed 12 cycles of chemotherapy in December 2009. In the last follow-up (March 2010), she had few patches, mostly on the posterior trunk and posterior thigh and leg. She had also persistent ichthyosis on the lower legs. She is currently applying topical nitrogen mustard and triamcinolone. 2.6.2. Discussion of MF with ichthyosis There are a small number of reports documenting acquired ichthyosis associated with MF [49-52]. The patients have usually a fine scaling eruption resembling autosomal dominant ichthyosis vulgaris. The ichthyosis may be localized to the lower extremities or may have a widespread involvement [51]. Histologically, the features of ichthyosis (hyperkeratosis, acanthosis with a thinned granular cell layer) are superimposed upon MF. The immunophenotype is that of classic MF, and molecular studies usually confirm the presence of a monoclonal Tcell population [51,52]. In our case, the ichthyosis was not present at the time of the initial diagnosis of MF and was induced during the treatment of MF. 3. Role of TCR gene rearrangement for the diagnosis of MF Although epidermotropism and atypia of lymphocytes remain the morphologic hallmarks of MF, the presence of monoclonal T-cell population can support the diagnosis [10]. Polymerase chain reaction methods to assess clonality at the TCR-γ locus (Fig. 11A) have been widely used because of its high sensitivity and applicability to routinely processed skin biopsy specimens. In these analyses, the presence of a dominant amplified clone (peak) following electrophoresis of the PCR products is consistent with a monoallelic gene rearrangement. Two peaks are consistent with biallelic gene rearrangements (Fig. 11A, below). Three or more distinct and reproducible peaks above the polyclonal background characterize an oligoclonal pattern. Lack of distinct peaks indicates a polyclonal T-cell population. The TCR-γ PCR is a very sensitive test and detects more than 90% of T-cell neoplasm [53]. However, the simple configuration of TCR-γ locus (Fig. 11A) may give rise to “false”-positive results (pseudoclonality) and/or oligoclonal T-cell expansions in benign reactive conditions. In contrast, TCR-β PCR is a more specific test and less prone to false-positive results because of the larger numbers of V and J segments (Fig. 11B) than the TCR-γ locus but is less sensitive and technically more challenging. The presence of a prominent monoclonal TCR gene rearrangement detected by TCR-γ and/or TCR-β PCR supports the diagnosis of T-cell lymphoma [54]. However, nonneoplastic skin diseases including drug reactions, atopic dermatitis, allergic contact dermatitis, and psoriasis, just to name a few, can be associated with the presence of
small clones of T-cells; for this reason, it is important to emphasize again that the diagnosis of MF requires clinicopathologic correlation and cannot be established by molecular data alone. Reviewing the PCR results to see if the reported gene rearrangement is small or prominent may also help. On the other hand, a negative TCR-γ PCR test result does not exclude the diagnosis if the clinicopathologic findings are those of MF. In addition to diagnostic purposes, it is interesting to know that TCR-γ PCR analyses can be used for monitoring disease progression. We previously reported that if detection of the same clone is evident in more than one lesion or in a given patient over time, there is an increased risk of disease progression [55].
References [1] Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol 2007; 143:854-9. [2] Massone C, Kodama K, Kerl H, Cerroni L. Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol 2005;29: 550-60. [3] Nickoloff BJ. Light-microscopic assessment of 100 patients with patch/plaque-stage mycosis fungoides. Am J Dermatopathol 1988;10: 469-77. [4] Smoller BR, Bishop K, Glusac E, Kim YH, Hendrickson M. Reassessment of histologic parameters in the diagnosis of mycosis fungoides. Am J Surg Pathol 1995;19:1423-30. [5] Naraghi ZS, Seirafi H, Valikhani M, et al. Assessment of histologic criteria in the diagnosis of mycosis fungoides. Int J Dermatol 2003;42: 45-52. [6] Kinney MC, Jones D. Cutaneous T-cell and NK-cell lymphomas: the WHO-EORTC classification and the increasing recognition of specialized tumor types. Am J Clin Pathol 2007;127:670-86. [7] Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol 2004;18: 397-415. [8] Hodak E, David M, Maron L, et al. CD4/CD8 double-negative epidermotropic cutaneous T-cell lymphoma: an immunohistochemical variant of mycosis fungoides. J Am Acad Dermatol 2006;55:276-84. [9] Massone C, Crisman G, Kerl H, Cerroni L. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol 2008;159:881-6. [10] Krafft AE, Taubenberger JK, Sheng ZM, et al. Enhanced sensitivity with a novel TCRgamma PCR assay for clonality studies in 569 formalin-fixed, paraffin-embedded (FFPE) cases. Mol Diagn 1999;4: 119-33. [11] Dereure O, Levi E, Kadin ME. T-cell clonality in pityriasis lichenoides et varioliformis acuta: a heteroduplex analysis of 20 cases. Arch Dermatol 2000;136:1483-6. [12] Willemze R, Meijer CJ. Rationale of a new classification for the group of primary cutaneous lymphomas. Semin Cutan Med Surg 2000;19: 71-7. [13] Pope E, Weitzman S, Ngan B, et al. Mycosis fungoides in the pediatric population: report from an international Childhood Registry of Cutaneous Lymphoma. J Cutan Med Surg 14:1-6. [14] Ngo JT, Trotter MJ, Haber RM. Juvenile-onset hypopigmented mycosis fungoides mimicking vitiligo. J Cutan Med Surg 2009;13: 230-3.
J.H. Cho-Vega et al. / Annals of Diagnostic Pathology 14 (2010) 369–385 [15] Neuhaus IM, Ramos-Caro FA, Hassanein AM. Hypopigmented mycosis fungoides in childhood and adolescence. Pediatr Dermatol 2000;17:403-6. [16] El-Shabrawi-Caelen L, Cerroni L, Medeiros LJ, McCalmont TH. Hypopigmented mycosis fungoides: frequent expression of a CD8+ Tcell phenotype. Am J Surg Pathol 2002;26:450-7. [17] Werner B, Brown S, Ackerman AB. “Hypopigmented mycosis fungoides” is not always mycosis fungoides! Am J Dermatopathol 2005;27:56-67. [18] Wain EM, Orchard GE, Whittaker SJ, Spittle MSMF, Russell-Jones R. Outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study. Cancer 2003;98: 2282-90. [19] Lambroza E, Cohen SR, Phelps R, et al. Hypopigmented variant of mycosis fungoides: demography, histopathology, and treatment of seven cases. J Am Acad Dermatol 1995;32:987-93. [20] Singh ZN, Tretiakova MS, Shea CR, Petronic-Rosic VM. Decreased CD117 expression in hypopigmented mycosis fungoides correlates with hypomelanosis: lessons learned from vitiligo. Mod Pathol 2006; 19:1255-60. [21] Ardigo M, Borroni G, Muscardin L, Kerl H, Cerroni L. Hypopigmented mycosis fungoides in Caucasian patients: a clinicopathologic study of 7 cases. J Am Acad Dermatol 2003;49:264-70. [22] Petit T, Cribier B, Bagot M, Wechsler J. Inflammatory vitiligo-like macules that simulate hypopigmented mycosis fungoides. Eur J Dermatol 2003;13:410-2. [23] El-Darouti MA, Marzouk SA, Azzam O, et al. Vitiligo vs. hypopigmented mycosis fungoides (histopathological and immunohistochemical study, univariate analysis). Eur J Dermatol 2006;16: 17-22. [24] Volkenandt M, Soyer HP, Cerroni L, et al. Molecular detection of clone-specific DNA in hypopigmented lesions of a patient with early evolving mycosis fungoides. Br J Dermatol 1993; 128:423-8. [25] Gerami P, Guitart J. The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol 2007;31:1430-8. [26] Gerami P, Rosen S, Kuzel T, Boone SL, Guitart J. Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 2008;144:738-46. [27] 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;138:191-8. [28] Cerroni L, Fink-Puches R, Back 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. [29] Flaig MJ, Cerroni L, Schuhmann K, et al. Follicular mycosis fungoides. A histopathologic analysis of nine cases. J Cutan Pathol 2001;28:525-30. [30] Kossard S, White A, Killingsworth M. Basaloid folliculolymphoid hyperplasia with alopecia as an expression of mycosis fungoides (CTCL). J Cutan Pathol 1995;22:466-71. [31] Steffen C. Ketron-Goodman disease, Woringer-Kolopp disease, and pagetoid reticulosis. Am J Dermatopathol 2005;27:68-85. [32] Haghighi B, Smoller BR, LeBoit PE, et al. Pagetoid reticulosis (Woringer-Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study. Mod Pathol 2000;13:502-10. [33] Lee J, Viakhireva N, Cesca C, et al. Clinicopathologic features and treatment outcomes in Woringer-Kolopp disease. J Am Acad Dermatol 2008;59:706-12. [34] Oliver GF, Winkelmann RK. Unilesional mycosis fungoides: a distinct entity. J Am Acad Dermatol 1989;20:63-70. [35] Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma). A
[36]
[37]
[38]
[39]
[40] [41]
[42]
[43] [44]
[45]
[46]
[47]
[48]
[49]
[50] [51] [52]
[53]
[54]
[55]
385
review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol 1994;18: 645-67. Berti E, Tomasini D, Vermeer MH, et al. Primary cutaneous CD8positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol 1999;155:483-92. Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T cell lymphoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol 1990;22:569-77. Gormley RH, Hess SD, Anand D, et al. Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. J Am Acad Dermatol 2009; 62:300-7. Heald PW, Glusac EJ. Unilesional cutaneous T-cell lymphoma: clinical features, therapy, and follow-up of 10 patients with a treatment-responsive mycosis fungoides variant. J Am Acad Dermatol 2000;42:283-5. Ackerman AB, Flaxman BA. Granulomatous mycosis fungoides. Br J Dermatol 1970;82:397-401. Kempf W, Ostheeren-Michaelis S, Paulli M, et al. Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC). Arch Dermatol 2008;144:1609-17. Metzler G, Schlagenhauff B, Krober SM, et al. Granulomatous mycosis fungoides: report of a case with some histopathologic features of granulomatous slack skin. Am J Dermatopathol 1999;21:156-60. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. Willemze R, Meijer CJ. Classification of cutaneous T-cell lymphoma: from Alibert to WHO-EORTC. J Cutan Pathol 2006;33(Suppl 1): 18-26. DeGregorio R, Fenske NA, Glass LF. Granulomatous slack skin: a possible precursor of Hodgkin's disease. J Am Acad Dermatol 1995; 33:1044-7. van Haselen CW, Toonstra J, van der Putte SJ, et al. Granulomatous slack skin. Report of three patients with an updated review of the literature. Dermatology 1998;196:382-91. Noto G, Pravata G, Miceli S, Arico M. Granulomatous slack skin: report of a case associated with Hodgkin's disease and a review of the literature. Br J Dermatol 1994;131:275-9. Papadavid E, Yu RC, Bunker C, Scoones D, Chu AC. Tumour progression in a patient with granulomatous mycosis fungoides. Br J Dermatol 1996;134:740-3. Kutting B, Metze D, Luger TA, Bonsmann G. Mycosis fungoides presenting as an acquired ichthyosis. J Am Acad Dermatol 1996;34: 887-9. Marzano AV, Borghi A, Facchetti M, Alessi E. Ichthyosiform mycosis fungoides. Dermatology 2002;204:124-9. Badawy E, D'Incan M, El Majjaoui S, et al. Ichthyosiform mycosis fungoides. Eur J Dermatol 2002;12:594-6. Eisman S, O'Toole EA, Jones A, Whittaker SJ. Granulomatous mycosis fungoides presenting as an acquired ichthyosis. Clin Exp Dermatol 2003;28:174-6. Vega F, Medeiros LJ, Jones D, et al. A novel four-color PCR assay to assess T-cell receptor gamma gene rearrangements in lymphoproliferative lesions. Am J Clin Pathol 2001;116:17-24. Wood GS, Tung RM, Haeffner AC, et al. Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/ Sezary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol 1994; 103:34-41. Vega F, Luthra R, Medeiros LJ, et al. Clonal heterogeneity in mycosis fungoides and its relationship to clinical course. Blood 2002;100: 3369-73.