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Primary cutaneous lymphomas - diagnostic problems

prof. dr hab. n. med. Joanna Maj PhD Alina Jankowska-Konsur

Department of Dermatology, Venereology and Allergology, Wroclaw Medical Uniwersity

Head of the clinic: prof. dr hab. n. med. Jacek Szepietowski

ABSTRACTPrimary cutaneous lymphomas – diagnostic problems

▶ KEY WORDS:primary cutaneous lymphomas, clinical picture, diagnosis

Primary cutaneous lymphomas comprise a group of heterogeneous lymphomas, initially developing in the skin. The diagnosis, especially of the early stages of the disease creates diagnostic dilem-ma for both dermatologists and pathologists. In this paper the authors presented clinical picture and problems concerning diagnosis of individual diseases.

INTRODUCTION

Primary cutaneous lymphomas (PCL) are a group of heterogeneous malignancies which origina-te from the lymphatic system. The incidence is 1/100 thousand cases per year. In the 1980s, mycosis fungoi-des (MF), sporadically Sézary syndrome (SS) and rarer B lymphomas were mainly recognized by dermatologists

in this group of diseases [1]. Currently, the development of molecular diagnostic methods and the improved hi-stological technique with immunophenotyping allowed for more frequent identification of other rare diseases in this group. An increase in the incidence of these pri-marily cutaneous lymphatic hyperplasia is another un-deniable fact. Despite advances in pharmacology, PCL is still a diagnostic and therapeutic problem.

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cal picture may be observed in Sézary syndrome. Spe-cial attention should be paid to patients diagnosed with multifocal and plaque parapsoriasis, as many studies confirm that the condition is de facto the initial stage of mycosis fungoides [3]. Suddenly appearing, persistent itching resistant to therapy is a symptom which should also alarm a doctor. Patients who have been histological-ly diagnosed with lymphomatoid papulosis (LyP), regar-dless of its subtype, require close monitoring. Although this lymphoma is prone to spontaneous resolution and does not require aggressive treatment, it can precede or coexist with Hodgkin's disease, mycosis fungoides or systemic large cell anaplastic lymphoma. Coexistence of LyP and chronic lymphocytic and myeloid leukaemia has also been reported. Skin lesions in PCL depend on the type of lymphoma. In the most common form, mycosis fungoides, we observe light pink or dark red erythema of various size, with slight peeling on the surface not always accompanied by itching. Then, there are infil-trative foci, often developing inside previously formed erythema (dark red colour predominates), poikiloder-mic foci (erythema with discoloration, decolouration or telangiectasia), eczema-like nodules and foci of various sizes or psoriatic-like lesions. Soft infiltrative plaque foci may occur on the scalp, leading to alopecia, which may be accompanied by similar, single lesions located on the upper parts of the torso. Such a picture is often found in the folliculotropic form of mycosis fungoides which is diagnosed based on the result of histological exami-nation. Also, any case of generalized dermatitis of the unknown aetiology should prompt the doctor to exclude PCL. On the other hand, the presence of tumours, often dark red or dark brown with a tendency to form ulcers, is a rare diagnostic problem because at this stage lympho-mas usually have a characteristic histological and immu-nophenotypic picture. Rare skin lesions observed in MF include seeded cysts, macular lesions, pustules, blisters, vesicles and anetodermic lesions.

AETIOLOGY The aetiology of PCL remains unknown. Howe-ver, more and more proponents suggest that the clonal expansion of T-helper lymphocytes in primary cutaneo-

Of course, the confirmation of hyperplasia by the pathomorphologist is the basis for making the diag-nosis of PCL and implementation of therapy [2]. Ho-wever, the clinical picture is equally important, because even a negative histological result should prompt the doctor to maintain the so-called oncological alertness. Many years of observations show that the initial histolo-gical picture of PCL may not be characteristic. The diag-noses we receive at the initial stages of this hyperplasia include: psoriasiform pattern or lichen planus pattern. Often, biopsies are performed repeatedly from various skin lesions, such as erythema, infiltrates or tumours. It is worth remembering that for about 2 weeks before collecting the material for histological examination we should not apply any steroid preparations to the skin. Specimens should not be taken from skin lesions in the seborrheic areas, because they statistically more often give a negative histopathological result. DIFFERENTIATION

Skin lesions that should prompt a doctor to diagnose or observe for PCL include: - eczema resistant to classic anti-histamine or local glucocorticoid therapy, - erythematous plaques with foci slightly peeling on the surface, often located on the lateral parts of the torso, thighs, inner surfaces of the upper limbs (plaque parapsoriasis), - recurrent scabies without the presence of Sar-coptes scabiei in the microscopic or dermatoscopic exa-mination, - long-term atopic dermatitis in the form of erythroderma resistant to treatment, - lichen ruber pilaris resistant to treatment, - poikilodermic foci located in the armpits, groins and on the buttocks (poikilodermic parapsoria-sis). Sporadically, vitiligo-like foci may be the first skin lesions, also in children. In mycosis fungoides a sig-nificant increase in serum IgE is common, unfortunately some physicians misunderstand this result and make the diagnosis of atopic dermatitis. Similarly, the presence of healthy skin areas in erythroderma is usually associated with lichen ruber pilaris. However, a very similar clini-

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ma and the same T cell clone in the skin and peripheral blood (cloning test of the T cell receptor using PCR or Southern blot method) [10]. The MF sub-types vary in terms of prognosis and include the folliculotropic form (quite aggressive, with severe itching), granulomatous slack skin and pagetoid reticulosis. Skin lesions in page-toid reticulosis are very often mistakenly initially regar-ded as psoriasis eruptions, because in fact they are single dark red erythemas with keratosis on the surface, mainly on the limbs. The term of primary cutaneous CD30+ lym- phoproliferative diseases was also introduced. They include lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma CD30+ (c-ALCL) [11]. It should be noted that these proliferations – the second most common primary cutaneous T-cell lymphomas – have a tendency to relapse, but also to spontaneous re-missions. It is true that spontaneous regression of erup-tions in LyP is more frequent, but the phenomenon is also observed in 20% of c-ALCL. Therefore, therapeu-tic decisions should be made very carefully. C-ALCL also requires monitoring for the systemic form of the lymphoma, as therapy and prognosis differ. The current CTCL classification also includes three new rare types of lymphomas. Primary cutaneous follicle centre lymphoma is the most common among primary cutaneous B-cell lymphomas (PBCL) [12]. The disease affects mainly adults around 51 years old. The clinical picture is domi-nated by blue-red nodules, infiltrates and tumours, ra-rely ulcerative lesions, located mainly on the head, neck and torso. There is no organ or nodal progression. The prognosis is very good, the 5-year survival is 95%. Pri-mary cutaneous marginal zone lymphoma (PCMZL) is another B-cell lymphoma characterized by good pro-gnosis, i.e. the 5-year survival – 100%. The pathogene-sis of the disease focuses on the role of chronic antige-nic stimulation and the relationship with the Borrelia burgdorferi infection. Recent studies indicate the role of the factors mentioned above. The skin lesions include blue-red nodules, infiltrates and tumours, located on the limbs and torso. Primary cutaneous DLBCL, leg type is a hyperplasia in which dissemination of lymphoma cells to internal organs is quite common. The disease more often affects women, in older age, and – as the name im-

us T-cell lymphomas is due to chronic antigenic stimu-lation. Medications (hydrochlorothiazide) or infections may play a role in the development of the most common lymphoma, mycosis fungoides. An increased incidence of T-cell receptor (TCR) monoclonal rearrangements has been described, as well as a more advanced stage of the disease diagnosed in the group of patients with MF tre-ated for hypertension with hydrochlorothiazide compa-red to those not receiving this drug [3]. 28.8% of patients who discontinued the therapy with hydrochlorothiazide showed complete or partial remission of skin lesions in the course of MF. However, there is still debate as to whe-ther hydrochlorothiazide is a medicine that promotes the development of lymphoma or whether the lesions should be classified as pseudo-lymphoma. A role of human T-lymphotropic virus type 1 (HTLV-1) is also well documented in the development of lymphoma/T-cell leukaemia in adults [7]. It is also believed that the state of immunosuppression, e.g. after bone marrow transplantation, may predispose to the development of CTCL. Rare reports on the familial su-sceptibility to MF, as well as finding specific deletions in HLA class II antigens may suggest, at least in some cases, the genetic background of the disease [5,6]. A role of Borrelia burgdorferi infection is also emphasized in. low-grade B-cell lymphoma. The impact of environmen-tal factors (occupational exposure, smoking, pesticides, sun exposure, halogenated aromatic hydrocarbons, e.g. benzene) has not been sufficiently documented [8].

CURRENT CLASSIFICATION

The WHO-EORTC classification, which was modified in 2005 and 2008 and is currently in force, dis-tinguished MF from Sézary syndrome requiring aggres-sive treatment from the beginning. Thus the view that SS is the erythrodermic form of mycosis fungoides is in fact out of date. According to the International Society for Cutaneous Lymphomas (ISCL), the diagnosis of SS sho-uld be based on the determination of an absolute Sézary cell count of at  least 1000/mm3 in peripheral blood, or an increase in the population size of CD4+ lymphocy-tes (CD4+/CD8+ ratio > 10) alternatively, the loss of one or part of the T  lymphocyte antigens (CD2, CD3, CD4, CD5) [9], as well as the presence of erythroder-

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plies – the skin lesions, i.e. blue-red nodules and tumours are located mainly on the limbs, but eruptions can also occur apart from the limbs. As in all primary cutaneous lymphomas, the diagnosis is made based on the histopa-thological picture and immunophenotyping.

DIAGNOSTICS As 10% or more of the skin surface covered by the same eruptions, e.g. infiltrates, changes the stage of the disease, a clinical examination is very important to make diagnosis of lymphomas, including a precise de-scription of skin lesions and their extent. On the other hand, the presence of ulceration in MF along with other eruptions is an unfavourable prognostic factor. At the stage of tumour, a diameter of the largest tumour, size and number of eruptions should be given. The evaluation of the lymph nodes is another important diagnostic component; suspicious nodes are hard, 1.5 cm or more in diameter, irregular, not shifted in relation to the ground. The diagnosis of a lymphoma variant is ba-sed on a biopsy with immunophenotyping. We  should collect several specimens at the same time, if possible, avoiding seborrheic areas. Approximately 2-4 weeks be-

fore the collection of specimens, general medications, e.g. immunosuppressants ought to be discontinued, and steroid preparations should not be applied to the skin. During the course of the disease, a biopsy of the lesions should be repeated (possible transformation into a more aggressive lymphoma). Other necessary diagno-stic methods which should be repeated every few mon-ths (depending on the stage of the disease and response to therapy) include immunophenotyping with the use of flow cytometry from peripheral blood, imaging exa-minations: ultrasound of the abdomen and lymph nodes, a plain X-ray of the chest, and in special cases compu-ted tomography or magnetic resonance imaging (MRI). The exception to this rule is the early (stage I) of MF, in which peripheral blood immunophenotyping or MRI is not recommended. Routine complete blood count, platelet counts and microscopic smear should be done in all patients; in addition, hepatic enzyme activity, LDH, beta-2-microglobulin concentration and other parame-ters, depending on the patient's condition. The expression of T and B cell markers is im-portant in the diagnosis of primary cutaneous lympho-mas. It is assessed both in immunophenotyping of the biopsy specimen and in the blood. The examination evaluates the expression of T cell antigens (CD2, CD3,

Fig. 1. Infiltrative lesion in the course of Mycosis fungoides

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CD26 antigens indicates a more aggressive course of MF and SS [13].

SUMMARY

▶ Before choosing the therapy, we must determine the stage of the disease. Although in the most common forms of CTCL prognosis is good, long-term remissions or recovery are rare. Therefore, effective palliative care is the main goal of the management [12]. A method that gives effective remission with the least toxicity is the gold standard.

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CD4, CD5, CD7, CD8, CD26, CD45 RO, CD30) and B cells antigens (CD19, CD20). The loss of CD7 and

Adres do korespondencji:

Joanna Maj Katedra i Klinika Dermatologii, Wenerologii i Alergologiiul. Chałubińskiego 1, 50-368 Wrocław Poland/Polska