Dmitry V. Kazakov, Werner Kempf, and Günter Burg
Department of Dermatology, University Hospital, Zurich, Switzerland
Apart from the classical form of mycosis fungoides (MF), there are several variants of this disease with unusual or atypical clinical and/or histopathological features (Table 1).
Follicular MF has been given many names including folliculotropic MF, pilo-tropic MF, folliculocentric MF, and MF-associated follicular mucinosis (1-6). Some authors believe that the latter should be distinguished from folliculotropic MF, we think that folliculotropic MF and MF-associated follicular mucinosis belong to a spectrum of MF with a predilection for hair follicles. Clinically, the disease manifests itself as erythematous patches or plaques with follicular hyperkeratosis producing comedo-like plugs and often hair loss. The face and upper trunk are the sites of predilection (Fig. 1). Histologically, the disease is typified by dense lymphocytic infiltrates surrounding and infiltrating the hair follicles and sparing interfollicular skin
Table 1 Atypical Clinicopathological Forms of Mycosis Fungoides
(Fig. 2). The neoplastic cells are small to medium-sized cells with irregular nuclei. In some cases, Pautrier microabscesses can be seen within the follicular epithelium (Fig. 3). The follicles show cystic dilatation, cornified plugging, and, in some cases, mucin deposition. Since some patients experience an aggressive clinical course with large cell transformation and lymph node involvement, folliculotropic MF may carry a worse prognosis than classic MF (7,8). The exact cause of folliculotropism in folli-cular MF is not known. Changes in intercellular adhesion receptors may account for the phenomenon. In particular, the intercellular adhesion molecule-1 (ICAM-1) receptor has a high affinity for lymphocyte function associated antigen-1 (LFA-1) -positive cells, which are present in high numbers in MF (9). In one study, an increased expression of ICAM-1 was seen in follicular epithelial cells in association with folliculotropic LFA-1 lymphocytes, with concurrent decrease of ICAM-1 expression on epidermal keratinocytes (9).
Bullous MF is seen in elderly people (average age 66 years) and has no gender predominance (10). It is typified by flaccid or tense, often multiple or even generalized blisters appearing either on normal skin, on an erythematous base, or within typical plaques and tumors of MF (Fig. 4). The trunk and limbs are the site of predilection. Flaccid bullae can sometimes demonstrate a positive Nikolsky sign (11-14). If the bullae are accompanied by other typical lesions of MF or a patient has a previous history suggestive of MF, the diagnosis can be readily established. Otherwise, a patient with bullous MF may pose a diagnostic problem. Histologically, all the common features of MF are seen in the bullous variant (15). Blisters have been found to occur in various locations—subcorneal, intraepidermal, and subepidermal (Fig. 5). The exact mechanism of blister formation is not clear. Negative immunofluorescence studies (both direct and indirect) speak against an autoimmune
Figure 4 Patches and infiltrated plaques with central blistering. (From Burg G, ed. Cutaneous Lymphomas. Springer, 1983.)
process although acantholysis may be seen. The following explanations for bulla formation have been proposed (11). (1) An intraepidermal blister may appear as a result of confluence of Pautrier microabscesses. (2) A subepidermal blister may be caused by accumulation of neoplastic cells in the basal layer leading to loss of coherence between the basal keratinocytes and basal lamina. (3) Normal cohesion of keratino-cytes may be affected by the release of lymphokines by neoplastic cells. Bullous lesions in MF seem to indicate a poor prognosis, since almost 50% of patients have died within 1 year after the appearance of the blisters (13).
Granulomatous MF is another unusual subtype characterized by the histologi-cal presence of a granulomatous reaction. The latter can adopt several patterns, namely (1) sarcoidal pattern, (2) granuloma annulare-like pattern, and (3) granulomatous pattern with multinucleated giant cells (16-19). We regard granulomatous slack skin (see Chapter 23) to be a distinct variant of MF. In the sarcoidal pattern, naked epithelioid granulomas are the hallmarks. In the granuloma annulare-like variant, there is a dermal interstitial infiltrate of lymphocytes with rare histiocytes, producing a pattern which resembles the interstitial form of granuloma annulare or inflammatory morphea. Epidermotropic lymphocytes are present at least focally in all cases. Increased dermal mucin deposition can also be demonstrated. The presence of additional skin lesions with typical MF features and the detection of T cell clones enable one to distinguish this variant from granuloma annulare. The third pattern is typified, as its name implies, by the presence of multinucleated giant cells, usually of the foreign body type. Emperipolesis can be seen. This subtype differs from granu-lomatous slack skin by the absence of both giant cells with a peculiar and
Figure 6 Small nodules arising in a patch of MF, histologically displaying granulomatous features.
characteristic wreath-like arrangement of nuclei and of elastophagocytosis, although elastic fibers may be reduced in number.
When granulomatous changes occur in patients with well-established MF later in the course of the disease, they do not pose any diagnostic problem (Fig. 6). When they are an early sign or when extensive granulomas obscure the underlying cutaneous lymphoma, the diagnosis may be a challenge. The prognostic and clinical significance of a granulomatous reaction in MF remains uncertain. Initially, a protective role was claimed for a granulomatous reaction. Later studies showed that granulomatous MF may have an aggressive course with rapid extracutaneous spread and death (20). A recent analysis of the literature revealed that nearly 40% of the reported patients with granulomatous MF died of the disease, and in half of them, death occurred within 5 years of the onset of the skin lesions (21). The exact cause of granuloma formation in MF is not clear but may be related to treatment with interferon-alpha in some instances.
Hypopigmented MF is often seen in young, dark-skinned patients of Indian or African-American origin who present with asymptomatic or slightly pruritic, non-scaly patches with irregular borders (Fig. 7) (22-28). In some instances, typical patches, plaques, or tumors may accompany the hypopigmented lesions. If this is not the case, MF is rarely suspected, as the differential diagnostic considerations may include pityriasis versicolor, pityriasis alba, vitiligo, leprosy, sarcoidosis, and postinflammatory hypopigmentation. The histological findings as well as clinical course and prognosis in hypopigmented MF are similar to those of classical patch-stage disease. The neoplastic cells in hypopigmented MF often express CD8 (29). The peculiar clinical changes may result from a decreased transfer of melano-
Figure 7 Sharply demarcated patches which are virtually depigmented and resemble vitiligo.
somes from melanocytes to keratinocytes and melanocyte degeneration as evidenced by electron microscopic studies (30,31).
A subset of patients with an otherwise typical clinical picture of MF may also develop poikilodermic lesions characterized by alternating hypo- and hyperpigmenta-tion, dryness, atrophy, and telangiectases (poikiloderma vasculare atrophicans [PVA]) (Fig. 8) (32-36). Frequently, these lesions develop slowly at the sites of pre-existing patches, usually in the areas where the skin is chronically rubbed by clothes, and are accompanied by otherwise typical patches and plaques of MF elsewhere. In some patients, the poikilodermic areas can predominate or even be the only finding. A biopsy from these areas will show histological findings similar to those seen in long-standing patch or plaque lesions. Additional pathological changes typical for poikiloderma include atrophy of the epidermis with flattening of rete
ridges, vacuolar alteration of the basal layer with loss of pigment, increased numbers of melanophages in the papillary and upper reticular dermis, and wide dilatation of superficial blood vessels containing erythrocytes (Fig. 9).
The poikilodermic variant of MF should be delineated from the hyperpigmen-ted subtype. The latter is characterized by diffuse macular hyperpigmentation as the only clinical feature, not associated with PVA or regression of pre-existing lesions (Fig. 10) (37,38). Lymphadenopathy can be present. Ultrastructural studies have demonstrated the presence of giant melanin granules in neoplastic cells, keratino-cytes, and Langerhans cells (37).
Patients with the pigmented purpura-like variant of MF present clinically with persistent pigmented purpuric dermatitis. On histological examination, there usually is a lichenoid band-like infiltrate composed mainly of small cerebriform lymphocytes accompanied by substantial numbers of siderophages and extravasated erythrocytes. The lymphocytes invade the epidermis with typical lining-up in the basal layer. The
majority of the cells are CD4+; some express CD8. Epidermal changes are variable but spongiosis and apoptosis are not seen. Clonal rearrangement can be demonstrated in a subset of cases. Close follow-up is crucial to distinguish between benign pigmented purpuric dermatoses and this type of MF (39-43).
Unilesional MF is typified by the presence of a single contiguous area of involvement covering less than 5% body surface area. The lesions are usually found on body regions typical for classical MF with breast, axilla, and buttocks being the most common sites (44). Pathological findings are identical to those seen in classical MF. Woringer-Kolopp is distinguished histologically from unilesional MF by the presence of marked hyperkeratosis, prominent pagetoid epidermotropism, and a pauci-cellular dermal infiltrate (44-46). Patients with unilesional MF demonstrate an excellent response to topical chemotherapy or irradiation.
Involvement of the palms and soles occurring at some time in the course of MF are seen in 11.5% of cases (47). A subset of MF patients [0.6%] present with lesions limited to or predominantly affecting the palms and/or soles, a condition referred to as mycosis fungoides palmaris et plantaris (47). Clinical variations include annular and hyperpigmented patches, plaques, hyperkeratotic lesions, vesicles, pustules, dyshidrotic lesions, verrucous changes, psoriasiform plaques, ulceration, and nail dystrophy (47-56). The lesions are either strictly confined to the palms and/or soles or may extend onto the feet, arms, and fingers. If these changes are not accompanied by typical MF lesions elsewhere on the body, the clinical diagnosis is usually challenging. The histological findings are usually compatible with typical MF, and demonstration of clonal rearrangement of TCR genes enable one to reach the correct diagnosis. Differential diagnostic considerations include mycotic infections, dyshi-drotic eczema, contact dermatitis, palmoplantar psoriasis, verrucae, hypertrophic lichen planus, and granuloma annulare. The course of this MF subtype is usually indolent. The disease remains confined to the initial area of involvement in most cases but extension of lesions to the limbs and trunk can occur, although no extra-cutaneous involvement has been reported. The relation of Woringer-Kolopp disease (unilesional pagetoid reticulosis) restricted to acral sites and hyperkeratotic cases of mycosis fungoides palmaris et plantaris has not yet been clarified.
Hyperkeratotic and verrucous changes may be found not only in MF palmaris et plantaris. Hyperkeratotic/verrucous MF manifests itself as hyperkeratotic and verrucous plaques which may or may not be accompanied by classical lesions or involvement of palms and soles (57,58).
The lesions of vegetating/papillomatous MF (sometimes this subtype is also referred to as acanthosis nigricans-like) arise in flexural areas (axillae, groins), neck, and breast (nipple, areolae) (59-61). They may resemble acanthosis nigricans or seborrheic keratosis, depending on their configuration, size, and color. Histologi-cally, there is papillomatosis, marked acanthosis which may have an appearance similar to that seen in seborrheic keratosis (interconnected rete ridges, horny pseudo-cysts), and a band-like/diffuse infiltrate of atypical lymphocytes (small convoluted or medium-sized blast-like).
Ichthyosiform MF is a rare subtype, which in a recent series represented 1.8% of MF cases (62). Clinically widespread ichthyosiform lesions are seen, often accompanied by comedo-like lesions and/or follicular keratotic papules. The ichthyosiform skin lesions favor the extremities, but the whole body surface may be involved. Pruritus is prominent and excoriations common. While the ichthyotic changes are usually the only manifestations of MF, the combination of classical MF and acquired ichthyosis (as a paraneoplastic phenomenon) has been documented (63,64). Histologically, the ichthyosiform areas demonstrate compact orthokeratosis, hypogranulosis, and a band-like epidermotropic infiltrate composed of small cerebriform lymphocytes, whereas a biopsy from the follicular papules will display cyst-like dilated ostia of hair follicle with cornified plugging and infiltration of the follicular epithelium by neoplastic cells. No deposition of mucin within the follicular epithelium is found. Oral retinoids, in combination with PUVA or UVA therapy, have been shown to be the most effective treatment for this subtype of MF.
Pustular MF is marked by pustular eruptions which may be limited to palmo-plantar areas or generalized. Histologically, there are intraepidermal spaces filled with a mixture of atypical lymphocytes, neutrophils, and eosinophils. The proportions of the above cell types is variable, and the inflammatory cells can outnumber the neoplastic ones (52-54,65).
In addition to all these well-established atypical forms of MF, there are anecdotal reports of the disease presenting as or mimicking keratosis lichenoides chron-ica, pityriasis lichenoides, and perioral dermatitis (66).
On very rare occasions, MF involves extracutaneous compartments such as oral cavity (tongue, oral mucosae), esophagus, breast, and eyes (Fig. 11). When this occurs before large cell transformation and spread to internal organs, one can speak of extracutaneous MF (67,68). Since typical lesions are also usually present, the diagnosis should be straightforward. In the oral cavity, both the tongue and mucosae may be affected. The incidence of tongue involvement in MF is estimated to be lower than 1%, with approximately 30 cases reported. It is a poor prognostic sign, since all reported patients have died within 3 years after the appearance of their oral lesions (13). Histopathologically, features typical for MF (epitheliotropic infiltrate composed of cerebriform cells) are demonstrable in extracutaneous lesions. In
advanced stages of the disease, an extracutaneous spread may occur with involvement of internal organs.
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