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CUTANEOUS LYMPHOMAS, MYCOSIS FUNGOIDES, AND PREMYCOTIC ERUPTIONS

Introduction, etiology, and pathogenesis

There are many types of cutaneous lymphoma, of which the most common are mycosis fungoides (MF) and other cutaneous T-cell lymphomas (CTCLs). All are rarethe incidence of new cases is less than five per million population per yearbut many patients have a long duration of disease, so the prevalence is higher. The cause of most is unknown, but a small proportion of cases are due to viral infections such as human T-cell leukemia virus (HTLV)-1. It is suggested that some may commence as a reactive process to antigen that persists, the reactive infiltrate eventually giving rise to malignant clones. Perhaps the best example that would appear to fit this concept is actinic reticuloid, a chronic photosensitivity disorder in which patients have both multiple contact allergies and abnormal responses to UV radiation but progress to have lymphoma-like histologic changes (Ch.17). An evolving process in CTCL itself is suggested by the progression that occurs from premycotic' eruptions to frank lymphoma in some patients, which may be accompanied by an increasing proportion of monoclonal cells, as demonstrated by T-cell receptor (TCR) gene rearrangement studies.

    The classification of skin lymphomas is a constantly altering area, due largely to advances in immunopathologic diagnosis. Factors involved in classification include the following.

    For this text, the emphasis will be on clinical patterns, as listed later. The current World Health Organization classification is felt to have some deficiencies from a dermatologic standpoint but is currently the most appropriate of the many classification systems; the main headings and some examples are given in Table 33.1.
    Cutaneous lymphomas are most often of T-cell type, CTCL; they usually present as one of the MF variants or as precursor premycotic eruptions, although some present as nodular forms. The commoner patterns have a CD4 T-cell infiltrate in the upper dermis, with invasion into the epidermis (epidermotropism'); this epidermal disruption is clinically manifest as scaling, which is therefore a common feature in CTCL. The progression is usually slow, and there may be a prolonged phase of essentially stable disease.
    By contrast, cutaneous B-cell lymphomas (CBCLs) present as one or several nodular or plaque lesions of relatively short duration. The infiltrating cells are usually in the deeper dermis, often with a perivascular pattern, and epidermal changes are not usually a feature clinically or pathologically. Concurrent lymphadenopathy and systemic symptoms may be apparent when the patient presents.

Premycotic and lymphoma-associated eruptions

There are various recognizable patterns of eruption that may be precursors to CTCL; the risk of progression differs depending on the type of eruption. Premycotic skin lesions, and other rashes that may sometimes be associated with or that may progress to lymphoma, include:

•	poikiloderma vasculare atrophicans,
•	pityriasis lichenoides,
•	parapsoriasis (including digitate dermatosis),
•	follicular mucinosis, and
•	lymphomatoid papulosis.

Poikiloderma vasculare atrophicans

This is characterized by patches of finely wrinkled atrophic skin with variable degrees of pigmentary mottling and telangiectasia (Figs 33.1). A mild inflammatory component may be a feature, causing itch; symptoms often improve during the summer months. The condition may run a prolonged and relatively non-progressive course, but a small proportion of patients develop CTCL.

Figure 33.1  Poikiloderma vasculare atrophicans. There is variable pigmentation and wrinkled atrophic change.

Pityriasis lichenoides

This condition exists as two forms, known as pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC). PLEVA is a disorder of children and young adults, which has acute onset and consists of rather vasculitic or acneiform papules and nodules that may be necrotic (Figs 33.2). PLC is a more subtle disorder of scattered tiny papules, which have a shiny surface scale known as a mica scale' (Figs 33.3and Figs 33.4). Although occasional cases of associated poikiloderma or MF have been reported, and some cases demonstrate low degrees of T-cell clonality in lesions, the risk of lymphoma would appear to be extremely small.

    The differential diagnosis varies between the two types as follows.

Parapsoriasis

Patients have scattered patches of mild erythema and scaling, usually of a pinkish brown color and with either mild itch or no symptoms (Figs 33.5 - 33.7). Covered sites such as the buttock are often the first area of involvement, and lesions are usually most prominent at sun-shielded areas, such as inner thighs, inner arms, and flanks. The conditin may improve or even resolve completely during the summer but gradually recur in winter.

Figure 33.2  Pityriasis lichenoides et varioliformis acuta: inflammatory papules and nodules on the trunk of a young man, with some ulceration and crusting. The clinical and microscopic appearances are alarming, but many cases resolve spontaneously without further problems.

    Numerous different patterns have been described, of which three are probably most significant as recognizable entities.

     The differential diagnosis includes the following.

Figure 33.3 Pityriasis lichenoides chronica. Multiple lesions on the leg (a) and close view, demonstrating the typical shiny émica scaleé (b).

Figure 33.4  Pityriasis lichenoides chronica. A persistent case in which histology of lesions suggested early follicular mycosis fungoides.

Figure 33.5  Parapsoriasis showing long parallel bands on the flanks, the pattern known as digitate dermatosis. This has a benign course.

Follicular mucinosis

This condition is characterized by a mucinous degeneration of hair follicles, and presents as sharply circumscribed areas of alopecia (also known as alopecia mucinosa) with variable degrees of scaling, erythema, and induration (Figs 33.8 - 33.10). It may occur as an isolated entity (especially small lesions on the face and neck); in lesions of discoid lupus erythematosus, sarcoidosis, or lichen simplex; or associated with MF, lymphomas, or leukemias. In young adults, the process is usually primary, but association with lymphomas is more likely (1020%) if the age of onset is over 40 years. Occasionally, mucin can be squeezed from the plaques (Figs 33.8), but the diagnosis is made pathologically, as it is important to examine the nature of the infiltrate.

Figure 33.6  Small plaque type of parapsoriasis. This may often recur annually in the autumn and winter, and improve in sunlight during the summer.

Figure 33.7  Large plaque type of parapsoriasis, which may be a precursor of mycosis fungoides.

Figure 33.8  Follicular mucinosis. A slightly tumid plaque that, when squeezed, may express mucin.

Figure 33.9  (a) Follicular mucinosis on the scalp. The head and neck are a common area for this condition. (b) Follicular mucinosis showing alopecia of the eyebrows.

Lymphomatoid papulosis

This is a condition in which patients develop one or several red nodules with a predilection for the extremities, although they can be generalized (Fig 33.11 - 33.13). They may be clinically alarming, as they can grow rapidly, and some become necrotic, but even untreated they self-heal over a period of several weeks (up to about 2 months). Also of concern is the fact that they have histologic features suggestive of lymphoma. The course is quite variable: the presentation may be frequent recurrent crops of lesions or just consist of solitary nodules at intervals of several years. Other premycotic eruptions such as parapsoriasis may coexist, and the condition may precede (or sometimes follow) a frank CTCL or Hodgkin disease. Lymphomatoid papulosis lesions vary pathologically, resembling CD30 + lymphoma, MF nodules, or Hodgkin disease. The very variable course makes it difficult to estimate the risk of progression to CTCL, but it occurs only in a minority; when it does occur, the T-cell clone in the two conditions is the same.
    Treatment, depending on the size of the nodule(s), is generally with topical or intralesional steroids; radiotherapy has been used for isolated lesions. For those with frequent crops of lesions, PUVA can be very helpful; methotrexate and bexarotene have also been used.

Figure 33.10  Follicular mucinosis of the back, manifest as a sharply defined disk of hair loss with otherwise unremarkable clinically detectable skin change.

Figure 33.11  Lymphomatoid papulosis showing reddish brown plaques occurring on a background of parapsoriasis, a common combination.

Figure 33.12  Lymphomatoid papulosis showing more aggressive nodular lesions on the digits, with central necrosis. These typically grow rapidly and take several weeks to resolve.

Figure 33.13  An ulcerated nodule of lymphomatoid papulosis on the arm. This lesion resembled a squamous cell carcinoma, and occurred in a patient with a 20-year history of intermittent self-resolving lesions, raising the question of self-healing keratoacanthomas (see Ch. 32). Note the nearby old scars of previous lesions. However, he also had intermittent self-healing lymphadenopathy, the histology of the lesion shown was lymphomatoid papulosis, and he later developed systemic lymphoma.

Figure 33.14 (a - c) Mycosis fungoides (MF). The appearance of late patch- or early plaque-stage disease is clinically characteristic. The disks and ovals of varying shades of red-brown, apparently superimposed on each other, are typical of MF.

Mycosis fungoides and cutaneous T-cell lymphoma

Introduction

Mycosis fungoides is the most common CTCL (Fig 33.14-33.20) and generally has an indolent course. The cellular infiltrate is upper dermal, invades the epidermis (epidermotropism), forms intraepidermal collections of atypical lymphocytes (Pautrier microabscesses), and consists mainly of CD4+ T cells. Variants include Sézary syndrome, pagetoid reticulosis, CD8+ MF, and granulomatous and lichenoid forms. The granulomatous histologic variant needs to be distinguished from a rare but clinically striking indolent CTCL known as granulomatous slack skin, which affects flexural areas to produce lax, pendulous folds of skin.

Figure 33.15  Mycosis fungoides (MF). This shows a more subtle appearance of patch-stage MF.

Figure 33.16  Mycosis fungoides (MF). Annular lesions such as this are relatively common in MF.

Figure 33.17  Mycosis fungoides. This shows rather more papular lesions.

Figure 33.18  Mycosis fungoides. This shows more inflammatory, bright-red lesions.

Clinical aspects of mycosis fungoides

Mycosis fungoides rarely presents at sites other than the skin, but cutaneous lesions may occur at unusual sites either in isolation or associated with typical skin lesions. Thus it may affect skin sites such as palms and soles (Figs 33.20), or internal sites such as lung or larynx. Rarely, a small, solitary patch of MF may occur with no progression to more widespread disease. Occasional patients present with tumor-stage lesions (tumeur d'emblée, Figs 33.21). Patients may present with erythroderma, many of whom will have Sézary syndrome with atypical circulating lymphocytes (discussed later).

Figure 33.19  Mycosis fungoides, nodular stage, on the chest (the previous partial mastectomy was for breast cancer, so metastases had to be excluded). These lesions were treated with local radiotherapy.

Figure 33.20  Mycosis fungoides (MF) may affect the soles of the foot or palms of the hands. This is a particular diagnostic problem if it occurs in isolation, as it may resemble a chronic dermatitis, although ulcerated areas also occur. In patients with known MF, especially those on chemotherapy, tinea pedis secondary to immunosuppression should be excluded.

Figure 33.21  Mycosis fungoides. An annular tumeur d'emblée lesion was the initial feature. .

Sézary syndrome

Sézary syndrome is characterized by erythroderma (Figs 33.22), scaling, edema, itch, and circulating atypical lymphoid cells (Sézary cells) that have large cerebriform nuclei. The condition may arise de novo or by progression from MF, and is variably aggressive. Such patients have greater than 1000 atypical lymphocytes/mm3 in blood. Monoclonal gammopathy is also increased in frequency in Sézary syndrome.
    The main difficulty in patients with erythroderma without a preceding firm diagnosis is distinguishing those with Sézary syndrome from those with benign causes of erythroderma, as Sézary cells are often present in any erythrodermic process. In benign causes of erythroderma, the Sézary cell count is usually less than 400 cells/mm3, or less than 5% of total white blood cells. Immunophenotyping of the cells in the skin infiltrate may also be useful in difficult cases; for example, Sézary cells may occur in erythrodermic actinic reticuloid, but the predominant cell type in such cases is CD8+ T cells rather than the CD4+ cells of erythrodermic CTCL. A pre-Sézary' syndrome has also been described for patients with erythroderma of unknown cause, Sézary cell counts of less than 1000 cells/mm3, and a chronic course that may progress to MF eventually.

Pagetoid reticulosis (WoringerKolopp disease)

This is a particular morphologic variant of a solitary plaque type of MF, which usually affects the foot or distal limb, and which is clinically psoriasiform or crusted. Common clinical differential diagnoses are eczema, psoriasis, and tinea pedis. It may be both clinically and histologically difficult to distinguish from Bowen disease, but has the usual T-cell immunostaining of MF.

Fig 33.22  Sézary syndrome, showing dermatitis-like scaling and erythroderma. This occurred rapidly in a previously well patient, and responded to low-dose chlorambucil.

Differential diagnosis of mycosis fungoides

The main diagnostic difficulty is in cases evolving from a premycotic eruption, in which pathologic features of MF may be subtle. Many lymphocytic infiltrates will contain some morphologically atypical lymphocytes, and common disorders such as eczema may include some exocytosis of lymphocytes into the epidermis; the diagnosis involves interpretation of the degree of abnormality combined with immunopathologic stains, molecular genetic analysis, and clinicopathologic correlation. In some patients, a series of sequential biopsies may be required over a period of time to establish a diagnosis.
     Clinical differential diagnoses of patch- or plaque-stage disease include the following.  

•	Premycotic eruptionsespecially large plaque parapsoriasis and lymphomatoid papulosis.
•	Benign dermatosesespecially eczema of various types (usually if vague and extensive in morphology); also psoriasis, fungal infection, or sarcoidosis (especially if there are annular lesions). Less commonly, the pattern may be lichenoid.
•	Drug eruptionsespecially if the pattern is eczematous or erythrodermic.

    In nodular disease, there are numerous differential diagnoses, but this pattern usually evolves from patch- or plaque-stage MF, so there are usually plaques as well as nodules concurrently (purely nodular disease is more suggestive of B-cell lymphoma).

    Any cause of erythroderma (see Ch.7) may need to be considered in Sézary syndrome.
    Sarcoidosis is a potentially important differential, as there is an association between sarcoidosis and cutaneous lymphomas, presumably due to the immune disturbance that occurs in sarcoidosis.

PRACTICE POINTS

Treatment of premycotic eruptions and cutaneous T-cell

lymphoma

The premycotic eruptions are generally treated with emollients, topical steroids, phototherapy, or PUVA photochemotherapy, depending on severity. Intralesional steroid injections or radiotherapy may be used to treat thicker nodules or other localized premalignant lesions, such as resistant plaques of follicular mucinosis, although localized radiotherapy is more commonly used for nodular forms of T-cell lymphoma (Figs 33.23).
    Treatment of MF varies considerably, as the disease itself may vary from a mild and slowly progressive disorder through to a rapidly evolving and potentially fatal disease. Although MF is probably a systemic lymphoma with epidermotropism, topical treatments (skin-directed therapy) may give excellent control in less advanced disease. Therapeutic options therefore vary according to the pattern, taking into account both the extent and the thickness of lesions.

Figure 33.23  A localized nodule of T-cell lymphoma on the scalp. This pattern is more typically seen in B-cell lymphomas. Treatment was with radiotherapy

Figure 33.24 (a) B-cell lymphoma. Lesions are typically smooth, purplish-colored plaques or nodules, either solitary as in (a) or multiple as in (b).

Figureure 33.24 (b) B-cell lymphoma. Lesions are typically smooth, purplish-colored plaques or nodules, either solitary as in (a) or multiple as in (b). (Panel b courtesy of Dr. L. Barco.)

Figure 33.25  B-cell lymphoma on the thigh. An annular morphology is not uncommon.

Figure 33.26   This elderly patient had multiple tumor nodules on the trunk, this large mass in the groin crease, and huge axillary lymph node enlargement. Histology confirmed a B-cell lymphoma, which responded rapidly to radiotherapy.

Figure 33.27  Massive lymphedema due to a rapidly enlarging groin lymph node affected by lymphoma. In this case, the lymphoma was not previously diagnosed, and referral was as a case of cellulitis; in fact, the erythema is typical of acute eczema occurring secondary to the rapid swelling of the leg.

Figure 33.28  Nodules of inflammatory non-Hodgkin lymphoma in the skin, associated with profound paraneoplastic acquired ichthyosis causing an asteatotic eczema pattern.

Cutaneous B-cell lymphoma

Cutaneous B-cell lymphoma usually presents as several deep dermal nodules, often with annular morphology (Figs 33.24 - 33.27). Many are slowly progressive and remain localized to skin, in which case local treatment with potent topical steroids, intralesional steroids, or radiotherapy may be appropriate. However, patients with extensive skin involvement, lymphadenopathy, or other systemic involvement may require chemotherapy. Hence investigations such as blood counts, chest radiography, computed tomography scan or ultrasound of abdomen, and bone marrow aspirate and biopsy are required. Some types of CBCL may be suspected from the clinical pattern and course (such as Crosti indolent lymphoma of the dorsum), but all require histologic assessment and immunophenotyping for a firm diagnosis.
    Skin involvement may also occur as a secondary effect in primary systemic B-cell lymphomas such as B-cell chronic lymphocytic leukemia or B-cell lymphoblastic lymphoma, and may occur in 1020% of such patients; in such cases, the prognosis is poor and treatment is systemic chemotherapy. Monoclonal antibodies such as rituximab (anti-CD20) have an increasing role.

Other lymphomas and related conditions

Hodgkin disease

Hodgkin disease may directly affect the skin in about 25% of patients. It is both associated with and confused with lymphomatoid papulosis. There are also several cases of patients who have had MF and Hodgkin disease. Cutaneous Hodgkin disease lesions are usually firm nodules or plaques, which may ulcerate.
    Non-Hodgkin lymphoma and Hodgkin disease may also indirectly affect the skin in several ways; itch and acquired ichthyosis (Figs 33.28) are both common, and sweating may occur. Cutaneous infections and drug eruptions may occur during treatment; some patients appear to develop recalcitrant warts for some years despite hematologic remission.

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis is rare. It may present with cutaneous nodules or ulcers due to a large-vessel necrotizing vasculitis, but often progresses with involvement of lymph nodes and behavior of a frank lymphoma (Figs 33.29).

Plasmacytoma

Plasmacytoma is a nodule of malignant plasma cells that may occur in various extramedullary organs, including the skin (Fig 33.30). It usually occurs when there is advanced myeloma, but may rarely be the presenting feature of this disorder. IgD myeloma may be overrepresented in the skin.

Figure 33.29  Lymphomatoid granulomatosis. Two rather non-specific nodules are apparent. Some lesions may be more inflamed and necrotic than this. (Courtesy of Michael O. Murphy, M.D.)

Figure 33.30  Plasmacytoma on the temple in a patient who presented with renal failure secondary to advanced multiple myeloma of IgG  l type. Multiple smaller skin lesions of extramedullary plasmacytoma were present on the trunk and limbs.

Figure 33.31  Leukemia cutis. Semiconfluent brownish lesions affecting the lower abdomen, with a rather intertriginous appearance. (Courtesy of Michael O. Murphy, M.D.)

Figure 33.32  Leukemic deposits on the trunk. These tend to be more purple or brown compared with lymphoma deposits, which are usually more flesh-colored.

Figure 33.33  Leukemia cells. Multiple nodules of the skin in acute myelomonocytic leukemia.

Figure 33.34  Leukemia cells. Hemorrhagic nodule of the tongue in chronic myelomonocytic leukemia.

Figure 33.35  Angiosarcoma of the forehead and temple region. These lesions are often flat, purplish, spreading lesions, which may be ignored for long periods.

Leukemia cutis and skin lesions associated with leukemia
Skin lesions may occur for several reasons in patients with leukemia (Table 33.3). Several of these are discussed in other chapters.
    Leukemia cutis may involve skin or mucosal surfaces; lesions may be papules, plaques, or nodules, but may also present as (sometimes palpable) ecchymoses or ulcerated areas (Figs 33.31 - 33.34). More chronic purplish-colored lesions occur in chronic myelomonocytic leukemia; oral lesions are common. Most leukemia cutis lesions are not specific to particular types of leukemia, but large greenish-colored nodules, known as chloromas, may occur in acute myeloid leukemia (the green color is due to myeloperoxidase enzymes in the leukemic cells, the same chemicals that impart a green color to pus in wounds).

Figure 33.36  Angiosarcoma of the leg. This patient did not have lymphedema, but the prognosis for this type of sarcoma is still poor.

Figure 33.37 ´Classic´ pattern Kaposi sarcoma on the foot of a young man. Older patients are more commonly affected.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.