Cutaneous T Cell Lymphoma

Cutaneous T Cell Lymphoma

Introduction

Lymphoma is a type of cancer that begins in a lymphocyte. This disease is divided into two major categories: Hodgkin lymphoma and all other lymphomas (also referred to as non-Hodgkin lymphomas).

A lymphocyte is a type of white cell. Lymphocytes compose about 20 percent of the white cells in the blood. Most lymphocytes are found in the lymphatic system, the major part of the body's immune system. The lymphatic system consists of a network of organs, including the spleen, the lymph nodes (small bean-shaped structures located throughout the body), the lymphatic vessels and areas in the gastrointestinal tract.

The three main types of lymphocytes are: T lymphocytes, B lymphocytes and natural killer (NK) cells. These cells circulate throughout the body within the lymphatic vessels, suspended in a watery fluid called lymph. The lymphatic vessels ultimately empty into the bloodstream. Using the network of lymphatic vessels, lymphocytes are transported to

locations around the body where they are needed to respond to infectious organisms, especially bacteria, fungi or viruses. On contact with these infectious agents, T and B lymphocytes work in coordination to make antibodies. The antibodies coat the infectious agents, making them susceptible to ingestion and destruction by other white cells (called

neutrophils and monocytes). Also, NK cells can attack virus-infected cells and help to resolve viral infections.

Most lymphomas begin in a lymphocyte in a lymph node, when damage to cell DNA causes a cell change (mutation). The now abnormal cell divides, and subsequent cells grow in an uncontrolled way, forming a tumor. Additional tumors may grow in other lymph nodes or in tissues such as liver, lung and bone. Some lymphomas begin in other lymphatic structures or in organs, such as lymphoma of the stomach.

Cutaneous or skin lymphoma begins in a lymphocyte in the skin. Because the medical term for the skin is the cutaneous tissue or system, “cutaneous lymphoma” is the formal name for lymphoma of the skin. This disease may also be called “skin lymphoma.” The term “cutaneous lymphoma” or “skin lymphoma” actually describes a number of different disorders with various signs and symptoms, outcomes and treatment considerations. Most skin lymphoma begins in a T lymphocyte that has undergone a malignant change. This disease is called “cutaneous T-cell lymphoma” or CTCL. Older descriptive terms, such as “mycosis fungoides” and “Sézary syndrome,” are types of cutaneous lymphomas that are now also referred to as CTCL.

Mycosis fungoides (MF) is the most common type of CTCL. As a result, more is known

about it than other types of skin lymphomas. The name comes from the mushroom-like skin tumors noted in the first patient diagnosed. MF is usually a low-grade (slow-growing or indolent) lymphoma that primarily affects the skin. It often remains confined to the skin. In general the prognosis for MF is considered to be good. Most patients are diagnosed in early stages with skin involvement only, and the disease does not progress to the lymph nodes or internal organs. However, in a minority of cases MF does slowly progress. Sézary syndrome is a related, but more aggressive form of CTCL, with widespread skin effects and the presence of malignant lymphocytes in the blood. This condition is characterized by an extensive red rash and sometimes loss (sloughing) of the exterior layers of the skin. It was identified by the French dermatologist Sézary, who first reported that some people with this skin condition also had malignant lymphocytes in the blood.¹

Incidence/prevalence

The overall annual incidence of primary CTCL in the US in 1988 was 0·5–1·0 per 100 000 based on population data. However, the prevalence is much higher because most patients have low-grade disease and live long. Males and the black population are affected more commonly.2,3 The incidence has increased during the past two decades but this almost certainly reflects improved diagnosis of earlier stages and possibly better registration, particularly in the US.2

Aetiology

The underlying aetiology is unknown. There is evidence for inactivation of key tumour suppressor genes and TH2 cytokine production by tumour cells in mycosis fungoides/Sezary syndrome, but no disease-specific molecular abnormality has yet been identified. Primary CTCL must be distinguished from human T-lymphotropic virus type-1 (HTLV-I) associated adult T-cell leukaemia lymphoma (ATLL) in which skin involvement often closely mimics the clinicopathological features of mycosis fungoides/Sezary syndrome and may be the presenting feature.2

Mycosis Fungoides

Mycosis fungoides represents the most common type of cutaneous T-cell lymphoma. It is also a long-standing entity, having been described almost two centuries ago, in 1806, by the French dermatologist Alibert. Traditionally, it is divided into three clinical phases: patch, plaque and tumour stages. The clinical course can be protracted over years or decades. The term ‘mycosis fungoides’ should be restricted to the classic so-called ‘Alibert–Bazin’ type of the disease, characterized by the typical slow evolution and protracted  course. More aggressive entities (e.g. mycosis fungoides ‘a tumeur d’emblee’), characterized by an onset with plaques and tumours, an aggressive course and a bad prognosis, are better classified among the recently described group of cutaneous cytotoxic T- (NK/T-) cell lymphomas.

In the past, mycosis fungoides has been considered as an ‘incurable’, albeit slowly progressive disease, that inevitably ended with the death of the patient. Recently, an early

form of mycosis fungoides has been recognized, consisting of subtle patches of the disease. These patients have relatively mild stable disease, which questions the traditional

concept of the inevitability of disease progression until death. The aetiology of mycosis fungoides remains unknown. A genetic predisposition may have a role in some cases, and a familial occurrence of the disease has been reported in a few instances. Association with long-term exposure to various allergens has also been advocated, as well as exposure to environmental agents and association with chronic skin disorders and viral infections. Recently, seropositivity for cytomegalovirus (CMV) has been observed at unusually high frequencies in patients with mycosis fungoides, suggesting a role for this virus in the pathogenesis of the disease. In some countries, mycosis fungoides-like disorders are clearly associated with viral infections (human T-cell lymphotrophic virus I [HTLV-I]-associated adult T-cell lymphoma–leukaemia), but the search for viral particles in patients with mycosis fungoides has so far been unsuccessful. Genetic alterations have been identified mainly in late stages of the disease, and their importance for disease initiation is unclear.

Mycosis fungoides has been described in patients with other haematological disorders, especially lymphomatoid papulosis and Hodgkin lymphoma. In occasional patients, the same clone has been detected in mycosis fungoides and associated lymphomas, raising questions about a common origin of the diseases. In addition, patients with mycosis fungoides are at higher risk of developing a second (non-haematological) malignancy.

A staging classification system for mycosis fungoides was proposed in 1979 by the Mycosis Fungoides Cooperative Group (TNMB staging). This system takes into account the percentage of body area covered by lesions, and the presence of lymph node or visceral involvement. Although the presence of malignant circulating cells in the blood should be recorded for each patient, these data are not used for staging. More recently, a new staging classification for mycosis fungoides has been proposed in the World Health Organization (WHO) classification of haematopoietic neoplasms. Some centres specializing in the study and management of skin lymphomas do not utilize the TNM or WHO staging schemes, but classify mycosis fungoides according to the type of skin lesions (patches, plaques and tumours) and the presence or absence of large cell transformation and/or extracutaneous involvement. In this classify, stage I disease is confined to the skin and characterized morphologically by patches only. Survival is extremely long in these patients (usually decades), and nonaggressive treatments should be applied. Most patients in this stage die of unrelated causes. Patients with stage II in this classify also have disease limited to the skin, but characterized morphologically by the presence of plaques, tumours or erythroderma, or by large cell transformation histopathologically. The disease in these patients is inevitably progressive, and treatment should be more aggressive. Stage III patients have extracutaneous disease and should be managed with aggressive treatment options. Staging investigations are not necessary in early stage mycosis fungoides (patch stage). Patients with plaques, tumours or erythroderma should be screened for extracutaneous involvement (laboratory investigations, sonography of lymphnodes, computerized tomography (CT) scan of thorax and abdomen, bone marrow biopsy, examination of the peripheral blood). Although the presence of a monoclonal population of T lymphocytes within the peripheral blood has been observed by polymerase chain reaction (PCR) technique in  some patients with early mycosis fungoides, in many of these cases the clone was  different from that detected in the skin lesions. In addition, the prognostic value of the detection of monoclonality in the peripheral blood is unclear. It has been suggested that flow cytometry analysis is highly effective in demonstrating and quantifying small numbers of circulating tumour cells in patients with mycosis fungoides.⁴

Lesions of mycosis fungoides can be divided morphologically into patches, plaques and tumours. Itching is often a prominent symptom. Erythroderma may develop in the course of the disease, rendering distinction from Sézary syndrome difficult without a proper clinical history.^4,5,6,7

Patch stage

Patches of mycosis fungoides are characterized by variably large, erythematous, finely scaling lesions with a predilection for the buttocks and other sun-protected areas . Loss of elastic fibres and atrophy of the epidermis may confer on the lesions a typical wrinkled appearance, and terms such as ‘parchment-like’ or ‘cigarette paper-like’ have been used to  describe them. Sometimes, these single patches have a yellowish hue, conferring a ‘xanthomatous’-like aspect to the lesions (xanthoerythroderma perstans). In early phases, a ‘digitate’ pattern can be observed (alone or in combination with larger patches; see also smallplaque parapsoriasis).^4,7,8

Plaque stage

Plaques of mycosis fungoides are characterized by infiltrated, scaling, reddish brown lesions. Typical patches are usually observed contiguous to plaques or at other sites on the body. Plaques of mycosis fungoides should be distinguished from flat tumours of the disease. Flat infiltrated lesions should be biopsied in order to allow histopathological examination and a precise classification of the lesions.^4,7,8

Tumour stage

In tumour-stage mycosis fungoides a combination of patches, plaques and tumours is usually found, but tumours may also be observed in the absence of other lesions. Tumours may be solitary or, more often, localized or generalized. Ulceration is common. In tumour-stage mycosis fungoides unusual sites of involvement may be observed, such as the mucosal regions. As oral and genital mucosae are frequently involved in cytotoxic T/NK-cell lymphomas, care should be taken to classify these cases correctly. Careful clinical history taking, re-evaluation of previous biopsies, and complete phenotypical and genotypical investigations are mandatory to make the diagnosis of mucosal involvement in mycosis fungoides.^4,7,8

Histopathology

Early lesions of mycosis fungoides reveal a patchy lichenoid or band-like infiltrate in an expanded papillary dermis. A psoriasiform hyperplasia of the epidermis may be seen , but in most cases the epidermis is normal. Small lymphocytes predominate, and atypical cells

can be observed only in a minority of cases. Epidermotropism of solitary lymphocytes is usually found, but Darier’s nests (Pautrier’s microabscesses) are rare. Useful diagnostic clues are the presence of epidermotropic lymphocytes with nuclei slightly larger than those of lymphocytes within the upper dermis and/or the presence of lymphocytes  aligned along the basal layer of the epidermis. Also useful is the presence of many intraepidermal lymphocytes in areas with scant spongiosis. In this context, it should be emphasized that in a few cases (approximately 5% of the total) epidermotropism may be missing. The papillary dermis shows a moderate to marked fibrosis with coarse bundles of collagen and a band-like or patchy lichenoid infiltrate of lymphocytes. Dermal oedema is usually not found. Unusual histopathological patterns of mycosis fungoides in early phases include the presence of a perivascular (as opposed to band-like) superficial infiltrate, prominent spongiosis simulating the picture of acute contact dermatitis, an interface dermatitis, sometimes with several necrotic keratinocytes, marked pigment incontinence with melanophages in the papillary dermis, prominent epidermal hyperplasia simulating the picture of lichen simplex chronicus and prominent extravasation of erythrocytes. A pattern characterized by a markedly flattened epidermis, a lichenoid infiltrate in the dermis and increased dilated vessels in the papillary dermis is the histopathological counterpart of poikilodermatous mycosis fungoides. Cytomorphologically, small pleomorphic (cerebriform) cells predominate. In some cases, plaques or flat tumours of mycosis fungoides may present with a predominantly interstitial infiltrate. This peculiar presentation can give rise to diagnostic problems, and has been designated ‘interstitial mycosis fungoides’. Immunohistology confirms that interstitial cells are T lymphocytes, thus being a helpful clue for the differential diagnosis with the interstitial variant of granuloma annulare. Intersitial mycosis fungoides is usually a manifestation of either the plaque or tumour stage of the disease. In tumours of mycosis fungoides, a dense nodular or diffuse infiltrate is found within the entire dermis, usually involving the subcutaneous fat. Epidermotropism may be lost. Flat tumours are characterized histopathologically by dense infiltrates confined to the superficial and mid parts of the dermis. Angiocentricity and/or angiodestruction can be observed in some cases. A peculiar histopathological presentation of mycosis fungoides characterized by marked involvement of hyperplastic sweat glands has been termed ‘syringotropic’ mycosis fungoides. In some of these cases, syringometaplasia can be observed. Involvement of the epidermis may be missing in syringotropic mycosis fungoides, thus creating problems in the histopathological diagnosis of this variant of the disease.^4,6,7

Immunophenotype

Mycosis fungoides is characterized by an infiltrate of α/β T helper memory lymphocytes (βF1+, CD3+, CD4+, CD5+, CD8–, CD45RO+). Only a minority of cases exhibit a T-cytotoxic (βF1+, CD3+, CD4–, CD5+, CD8+) or γ/δ (βF1–, CD3+, CD4–, CD5+, CD8+) lineage that show no clinical and/or prognostic differences. In these cases, correlation with the clinical features is crucial, in order to rule out skin involvement by aggressive cytotoxic lymphomas such as CD8+ epidermotropic T-cell lymphoma or γ/δ T-cell lymphoma. In late stages there may be a (partial) loss of pan-T-cell antigen expression. In

plaque and tumour lesions, neoplastic T cells may express the CD30 antigen. Recently, it has been suggested that a low CD8 : CD3 ratio in skin infiltrates supports the histopathological diagnosis of mycosis fungoides, but this finding should be confirmed by larger studies. Cytotoxic-associated markers such as TIA-1 and granzyme B are negative in mycosis fungoides, although occasionally in late stages of the disease some positivity may be observed. These cases should not be classified as cytotoxic lymphomas, but as tumour-stage mycosis fungoides with cytotoxic phenotypes. A similar phenotype may also be seen in early lesions of the rare γ/δ+ mycosis fungoides, which besides cytotoxic proteins also express CD56.⁴

Histopathological Differential Diagnosis

The histopathological diagnosis of early mycosis fungoides may be extremely difficult. In some instances, differentiation from inflammatory skin conditions (e.g. psoriasis, chronic contact dermatitis) may be impossible on histopathological grounds alone. In these cases, clinical correlation is crucial to make a definitive diagnosis. Immunohistological features are not distinctive, and are similar to those observed in many inflammatory skin conditions. Staining for CD3 or CD4 may help by highlighting epidermotropic T lymphocytes.⁴

Sézary syndrome

Sézary syndrome is characterized clinically by pruritic erythroderma, generalized lymphadenopathy and the presence of circulating malignant T lymphocytes (Sézary cells).^4,5 Other typical cutaneous changes include palmoplantar hyperkeratosis, alopecia and onychodystrophy. Differentiation from non-neoplastic erythroderma may be extremely difficult. The main causes of erythroderma, besides cutaneous T-cell lymphoma, are atopic dermatitis, psoriasis and drug reactions. Erythrodermic mycosis fungoides should be distinguished from true Sézary syndrome.

The presence of a monoclonal population of T lymphocytes within the peripheral blood has been recently proposed by the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Study Group, by the International Society for Cutaneous Lymphomas and by others as an important criterion for the diagnosis of Sézary syndrome. Other useful criteria include the presence of more than 1000 circulating Sézary cells/mm; an expanded CD4+ population in the peripheral blood resulting in a markedly increased CD4+ : CD8+ ratio (> 10); an increased population of CD4+ : CD7– cells in the peripheral blood; Sézary cells larger than 14 μm in diameter; and Sézary cells representing more than 20% of circulating lymphocytes.

Patients usually present with an abrupt onset of erythroderma, or with erythroderma preceded by itching and a nonspecific skin rash. Rarely, a classic Sézary syndrome may develop in patients with preceding mycosis fungoides; it has been suggested to classify these cases as ‘Sézary syndrome preceded by mycosis fungoides’, as it remains unclear whether the clinical features and prognosis are similar. The presence of neoplastic T cells within the peripheral blood alone should not prompt a diagnosis of Sézary syndrome unless all other main diagnostic criteria are met.

The TNM staging classification used for mycosis fungoides has also been adopted for Sézary syndrome. According to this system, Sézary syndrome is classified as stage III by definition.⁴

The histopathological features of skin lesions in Sézary syndrome are indistinguishable from those of mycosis fungoides. Often there is a psoriasiform spongiotic pattern with a variably dense band-like infiltrate of lymphocytes. Epidermotropism is usually less marked than in mycosis fungoides, but typical Darier’s nests ‘Pautrier’s collections’ may be observed. Cytomorphology reveals a predominance of small to medium-sized pleomorphic (cerebriform) lymphocytes, often referred to as ‘Sézary cells’. Differential diagnosis from mycosis fungoides can be achieved only by correlation of histopathological features with clinical ones. Histopathological variants of Sézary syndrome include the presence of a prominent granulomatous reaction, deposition of mucin within hair follicles (follicular mucinosis), or large cell transformation. Large cell transformation may be detected in skin lesions, lymph nodes, or both, and is indistinguishable from that occurring in advanced mycosis fungoides. The lymph nodes are characterized by monomorphous infiltrates of neoplastic cells, and reveal histopathological differences from lymph nodes involved by cells of mycosis fungoides, suggesting a pathogenetic difference between the two disease.⁴

Prognosis

Most cases of primary CTCL are not curable. Independent prognostic features in mycosis

fungoides include the cutaneous and lymph node stage of disease and age of onset (>60

years). The lymph node status and tumour burden within peripheral blood determine the

prognosis in Sezary syndrome. Serum lactate dehydrogenase and the thickness of the infiltrate in plaque-stage mycosis fungoides are also independent markers of prognosis. Multivariate analysis indicates that an initial complete response (CR) to various therapies is an independent favourable prognostic feature, particularly in early stages of disease. For mycosis fungoides, two staging systems are in regular use including a TNM (primary tumour, regional nodes, metastasis) system and a clinical staging specifically designed for CTCL. These staging systems can also be applied to Sezary syndrome, but neither system provides a quantitative method for assessing peripheral blood disease other than an additional B0 and B1 in the TNM system and this has prompted alternative approaches for Sezary syndrome. The 5- and 10-year overall survival (OS) in mycosis fungoides are 80% and 57%, respectively, with disease-specific survival (DSS) rates of 89% and 75% at 5 and 10 years respectively. Patients with very early stage disease (IA) are highly unlikely to die of their disease, with DSS rates of 100% and 97–98% at 5 and 10 years, respectively and risks of disease progression varying from 0% to 10% over 5–20 years.2,9

Treatment

Treatment for CTCL depends on the type and stage of the disease. Treatment options include phototherapy, radiation, topical therapy, systemic single-agent chemotherapy, combination chemotherapy and combined therapies. Patients with localized early-stage disease are usually treated with topical agents such as nitrogen mustard, skin-softening agents, anti-itch agents and gradual exposure to sunlight or ultraviolet light. Specific treatments include:

1. Topical nitrogen mustard

Nitrogen mustard or Mustargen® is a chemotherapeutic agent that is administered as an ointment, an aqueous solution or a liquid gel formulation. It is applied daily either to affected areas of skin or to all skin surfaces. People in the early stage of the disease respond best, but relapses are common after therapy is stopped.

2. Photochemotherapy

Psoralen is a drug that binds to the DNA in malignant cells. Patients take the drug by mouth and then are exposed to ultraviolet light to activate the drug, which damages the malignant cell DNA. This treatment often is referred to as PUVA, an acronym for Psoralen and Ultraviolet-A light. Treatment is usually given several times a week for one or two months, and less frequently thereafter. Maintenance treatment is usually continued for a year or more. Patients in the early phase of disease have the best response to treatment. Low-dose alpha-interferon, combined with PUVA therapy, has shown promising preliminary results for patients with early-stage disease. Narrow-band UVB, a form of phototherapy, is also used to treat patch-stage cutaneous lymphoma.^1,9,10

3. Electron beam radiation

Conventional radiation therapy penetrates the skin and reaches areas inside the body. Electron beam therapy can be applied to the entire skin surface without affecting internal organs. This type of radiation has been helpful for patients who have skin tumors. The tumors often heal after treatment and the dead tissue resolves, reducing the risk of infection. Treatment leads to complete clearing of lesions in several months without further treatment. Some patients appear to have longstanding regression of their skin lesions following this type of treatment.

4. Chemotherapy

Several combinations of chemotherapeutic agents have been used in patients with skin lymphoma, especially those with disease that involves the lymph nodes or other organs, or those with Sézary syndrome. Effective therapies include methotrexate, gemcitabine and liposomal anthracyclines. Other agents such as etoposide (VP-16), cyclophosphamide and pentostatin may also be used. The most commonly used drug combinations include cyclophosphamide, doxorubicin, vincristine and prednisone.This particular drug combination may also be used for those patients experiencing disease transformation or organ involvement. Chemotherapy has not been able to cure widespread skin lymphoma, and studies using chemotherapy combined with radiation therapy in patients with early stages of disease have not been very successful.

5. Other drug therapies

Skin lymphomas are covered under the U.S. Orphan Drug Act (1983). The Orphan Drug Act provides incentives to induce sponsors to develop and manufacture drugs that otherwise might not be profitable because of their small potential market. Since 1983, more than 200 drugs and biological products for rare diseases have been brought to market, compared with 10 such products in the decade prior to 1983.

6. Photopheresis

This procedure, also called ECP for “extracorporeal phototherapy,” is a form of chemotherapy that requires removal of blood through a vein and isolation of the white cells, which includes circulating CTCL cells. The removed cells are treated with a drug, 8-methoxsalen (UVADEX®), which sensitizes the cells to ultraviolet light. An external source of ultraviolet A (UVA) rays is used to irradiate the cells, which are  then returned to the patient through a vein. The ultraviolet light acting on 8-methoxsalen damages DNA of the CTCL cells. The procedure must be repeated multiple times to gain the full effect. It is believed that the effect is more extensive than killing removed CTCL cells. It has been postulated that it involves a reaction of normal immune cells against the UV light-damaged lymphoma cells. Thus, there may also be an immune component because more CTCL cells are destroyed than the number irradiated in the procedures. Photopheresis is most often used for advanced stages of CTCL with signs of circulating CTCL cells in the blood. It is often combined with other therapies. Photopheresis is also being studied in clinical trials for early-stage disease.

7. Supportive therapy

The itching that accompanies the skin lesions can be difficult to control. Antihistamines, particularly Benadryl® or Atarax®, may relieve itching to someextent. However, the major side effect of these drugs is drowsiness. Also, patients may develop a resistance (tolerance) to the effectiveness of the drugs and require larger doses. Application of skin softeners or steroid ointments may also help relieve itching. Antibiotics are given if lesions become infected. Patients with long-standing, troublesome symptoms may require treatment for depression or insomnia.^1,7,9,11,12

  

References

1.   cutaneus T Cell Lymphoma. Available at: www.leukemia-lymphoma.org/attachments/.../br_1163608564.pdf.

2.            Williams H. Bigby M. Diepgen T. Herxheimer A. Naldi L. Rzany B. Evidence Based Dermatology: Primary Cutaneus T cell Lymphoma. BMJ. London. 2003 : 344-345.

3.            Twenty-Year Trends in the Reported Incidence of Mycosis Fungoides and Associated Mortality. Available at: www.ajph.org/cgi/content/abstract/89/8/1240.

4.            Cerroni L. Gatter K. Kerl H. An Illustrated Guide to Skin Lymphoma: Cutaneus T Cell Lymphoma. Blackwell Publishing Ltd. USA. Second Edition. 2004: 7-21.

5.            Kumar V, Abbas A.K, Fausto N. Pathologic Basis of Disease: Mycosis Fungoides. Elsevier Saunders. Philadelphia. 2005: 685.

6.            Raphael R. Strayer D.S. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. Lippincott Williams & Wilkins. Philadephia. 2008: 921.

7.            Pillsbury D.M. Shelley W.B. Kligman A.M. Dermatology: The Lymphoma. W.B.Saunders Company. Philadelphia. 1960: 1089-1093.

8.            Girardi M. Heald P.W. Wilson L.D. The Pathogenesis of Mycosis Fungoides. NEJM. Volume 350: 1978-1988.

9.            Suarez Varela M.M.M. Cutaneus T Cell Lymphoma. CRC Press. 2005: 1-32.

10.        The Addition of Interferon Gamma to Oral Bexarotene Therapy With Photopheresis for Sézary Syndrome. Available at: http://archderm.ama-assn.org/cgi/content/extract/141/9/1176.

11.        Bickers D. Henry W.Lim. Margolis D. Weinstock M. The Burden of Skin Disease. The Lewin Group Ltd. Washington. 2004: 29-31.

12.        Classification and Treatment of Rare and Aggressive Types of Peripheral T-Cell/Natural Killer-Cell Lymphomas of the Skin. Available at: www.moffitt.org/moffittapps/ccj/v14n2/pdf/112.pdf.