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CME ARTICLE
Year : 2007  |  Volume : 52  |  Issue : 1  |  Page : 5-20
Mycosis fungoides: Current trends in diagnosis and management


Department of Dermatology, Ruby General Hospital, Kolkata, India

Correspondence Address:
Saumya Panda
Department of Dermatology, Ruby General Hospital, Kolkata
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.31918

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   Abstract 

Mycosis fungoides (MF) is the most common group of cutaneous T-cell lymphomas. It is a rare non-Hodgkin's lymphoma of mature, skin-homing, clonal, malignant T lymphocytes, usually observed in mid to late adulthood, that initially presents in the skin as patches, plaques, tumors, or generalized erythema (erythroderma) and can involve the lymph nodes and peripheral blood. Much progress has been made in recent years in understanding the origin of the malignant T cell in MF and the patho-physiology and immunology of the disease. This recent work has made a great impact on diagnosis, prognostication, and treatment. In this review, we survey the MF literature of the last decade and highlight the major trends.


Keywords: Cutaneous lymphoma, mycosis fungoides, Sezary syndrome, T lymphocytes


How to cite this article:
Panda S. Mycosis fungoides: Current trends in diagnosis and management. Indian J Dermatol 2007;52:5-20

How to cite this URL:
Panda S. Mycosis fungoides: Current trends in diagnosis and management. Indian J Dermatol [serial online] 2007 [cited 2017 Mar 27];52:5-20. Available from: http://www.e-ijd.org/text.asp?2007/52/1/5/31918



   Background Top


Mycosis fungoides (MF) may be defined as a rare indolent non-Hodgkin's lymphoma of a mature, skin-homing, clonal, malignant T lymphocytes [predominantly helper (CD4+) cells], usually observed in mid to late adulthood, that initially presents in the skin as patches, plaques, tumors, or generalized erythema (erythroderma) and can involve the lymph nodes and peripheral blood and other extracutaneous sites.[1],[2],[3] About 75% of cutaneous lymphomas belong to the group of T-cell lymphomas; cutaneous T-cell lymphomas (CTCL) account for two-thirds of cases of primary cutaneous lymphoma and, MF, which afflicts more than 50% of patients with CTCL, happens to be the most common of skin lymphomas. The incidence of MF is approximately 0.36 per 100,000 person-years in the United States.[4],[5] Global or country (India) - specific data are not available, but, according to literature, approximately 1000 new cases of CTCL are definitively diagnosed each year.[6]

Median age at diagnosis is 55-60 years, but MF may occur in children and adolescents as well.[7],[8],[9],[10],[11] Men are more commonly affected than women. Early lesions of MF may pose a significant diagnostic challenge to clinicians and dermato-pathologists. Many such patients need long-term follow-up and serial biopsies to make a definitive diagnosis. One of the reasons is that MF is one of the most difficult diagnoses to make in dermatopathology. The other reason is that mycosis fungoides is a great imitator and clinical diagnosis, particularly in the early stages, is extremely difficult.

Molecular cytogenetic tools including allelotyping and in vitro amplification of T-cell receptor-gamma gene rearrangement have been recently used to aid in the diagnosis of MF.[12],[13],[14] However, limitations exist with these tools as well because many inflammatory diseases, such as, lichen planus, pityriasis lichenoides, and pseudolymphoma, have also been shown to express clonality and early MF is not uncommonly polymerase chain reaction (PCR) negative for TCRG rearrangement. So all these investigational tools are simply adjuvants, and diagnosing MF ultimately depends on a holistic integration of clinical, histopathological, immunopathological, and molecular biological characteristics.[15]

As no shortcut to this painstaking process could have been evolved till now, the median timelag between onset of symptoms and diagnosis remains 4-6 years.[16] That is why, a proper approach to clinical diagnosis is necessary.


   Clinical Diagnosis Top


The clinical presentation of MF may be divided into classic, consistent, and atypical lesions. The classic morphology includes arcuate lesions, poikilodermatous patches, and plaques with atrophy; consistent lesions can present with erythema, papulosquamous lesions, alopecia, and hypopigmentation; atypical lesions include blisters, pustules, and digitate lesions.

Lesion distribution is also important in correctly diagnosing MF. Classic locations include the face, buttocks, intertriginous areas, and breasts; consistent locations include the trunk and proximal extremities; atypical locations are the distal extremities, the palms or soles and a single lesion anywhere on the body.[17] MF should be ruled out if a clinical eruption that is initially thought to be banal is refractory to treatment.

MF was so named by the French dermatologist Alibert in the 1800s due to the mushroom-like tumors that developed on the skin of a patient with advanced disease. The most common type of lesion of CTCL is the patch/plaque MF initially described by him. But the real challenge to the clinician is posed by the numerous rarer subtypes of MF, and the morphological mimicry MF of numerous benign dermatoses.


   Clinical Subtypes Top


Hypopigmented MF

It is a variant of patch stage or early plaque stage disease (grade 1). It is usually seen in dark-skinned patients and presents with hypopigmented, non-atrophic patches, and plaques. However, this variant has been described in a 12-year-old white girl.[8]

It is a rare clinical form of the disease, first described in 1978. Since then, only 100 odd cases have been documented. The other particularities of this form of MF are the age of early onset with a predominance of pediatric cases, biologically benign course, and common recurrences. Its course is indolent for several years and thus the source of delayed diagnosis. In one series, the mean latent period was 9.2 years.[18]

The differential diagnoses to be evoked are basically vitiligo, and achromate eczematides. The post-inflammatory depigmentation, frequent in black-skinned subjects, is only an eliminating diagnosis.[19]

Pagetoid reticulosis ( Woringer-Kolopp disease More Details)

It is an indolent, localized variant of MF that presents clinically with solitary or multiple erythematous, scaly, or verrucous plaques on acral skin.[20] The clinical course is characterized by slow growth and a more benign course than the classic MF.

Granulomatous slack skin syndrome

This entity was first described by Convit in 1973 and in 1978 Ackerman coined the term granulomatous slack skin syndrome (GSSS); LeBoit demonstrated in 1987 that this entity is a T-cell lymphoma by using molecular techniques.[21] The new World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas recognizes it as a formal variant of MF. This is a rare variant usually presenting with large circumscribed regions of slack skin and redundant skin folds accompanied by fibrotic bands. Histologically granulomatous T-cell infiltrate and loss of elastic fibers are the classic findings. The disease is often indolent, although rapid progression and transformation have been described.[22] The relationship between GSSS and other pre-existing or subsequent lymphoproliferative diseases (diagnosed in approximately 50% of the cases) warrant a life-long follow-up.[23]

Granulomatous MF

In MF, a 'granulomatous' variant is well-characterized. The lesions are pleomorphic: widespread erythematous scaly patches and plaques, red/purplish to brownish confluent plaques and ulcerated lesions with a purulent, hemorrhagic exudates and sharp elevated borders have been reported to coexist in the same patient.[24] Though this entity is entirely different from GSSS, in a patient presenting with inflammatory poikilodermatous lesions of loose skin on the upper arm, differentiation from the latter could not be successfully made even after T cell phenotyping.[25] Due to the multiplicity of clinical appearances, it has been suggested that this subtype be considered a primarily histopathological diagnosis in cases of 'unusual' granulomatous dermatitis with a prominent granulomatous reaction pattern in the presence of other histopathological characteristics of MF and suggestive T-cell phenotype and molecular genetics. A prominent granulomatous reaction is defined as the presence of a granulomatous component exceeding 25% of the dermal infiltrate.[26]

Folliculotropic MF

This was previously designated as MF-associated follicular mucinosis. Recent studies have shown that there is no difference in clinical presentation and behavior between cases of folliculotropic MF with or without associated follicular mucinosis. Accordingly, it has been agreed that the preferred term is that of folliculotropic MF. Follicular mucinosis is a chronic dermatosis involving the sebaceous glands and outer root sheaths. It is normally differentiated into a juvenile benign form and an adult form possibly associated with MF. Folliculotropic MF is characterized by erythematous, scaly plaques associated with lesional or perilesional comedo-like papules, plugged follicles or follicular papules from which gelatinous material sometimes can be expressed. Lesions most commonly appear on the head and neck and involvement of the scalp usually causes alopecia. The localized form of syringolymphoid hyperplasia with alopecia and anhidrosis (SLHA), characterized by scattered brownish papules forming a sharply demarcated erythematous patch lacking hairs and sweat production, is currently thought to be a syringotropic variant of mucinosis follicularis and thus, a facultative precursor of MF.[27] From the clinical point of view, the most relevant feature is the deeper localization of the neoplastic infiltrates and the reduced response to skin-targeted therapies and, consequently, a worse prognosis than classic MF.

Other rare clinical forms

MF has been reported to present as ichthyosiform lesions. This rare condition must be added to newly described forms of MF with epidermal hyperplasia such as keratosis lichenoides chronica-like MF and pilotropic MF.[28] It may also mimic reticular erythematous mucinosis,[29] Ofuji's papuloerythroderma (pruritic erythematous papules and extensive erythema sparing all skin folds),[30] centrifugal annular erythema,[31] pyoderma gangrenosum, hyperpigmentary disorders, toxic epidermal necrolyis syndrome (TENS)[32], and so on. Bullous forms of MF are extremely rare since they were first described by Kaposi in 1887. MF bullosa may be pleomorphic with coexistent palmoplantar dyshidrosis-like eruption.[33] Pediatric MF also has been reported to mimic inflammatory linear verrucous epidermal nevus (ILVEN).[34] Unilesional MF, a rare variant, may mimic Bowen's disease (squamous cell carcinoma in situ ).[35]


   MF at Unusual Sites Top


MF of the hands and soles (mycosis fungoides palmaris et plantaris, MFPP), characterized by hyperkeratotic patches or plaques confined to the palms and soles, is rare and easy to misdiagnose because of the clinical similarity to psoriasis, chronic eczematous dermatoses and dermatophytic infections.[36],[37] MF presenting with large, patchy pigmented tumors has been reported to occur all over the face and eyelids.[38] There is a report in the literature of a case of stage IVA MF/Sezary syndrome (SS) involving the vulva.[39]


   Associated Conditions Top


Among the frequent associations are some specific infections and other malignancies. Epstein-Barr virus (EBV) associated cutaneous B-cell lymphoproliferative disorder has been reported to occur with MF.[40] Dermatophytes can possibly trigger MF. Tinea pseudoimbricata (concentric, annular lesions secondary to Trichophyton rubrum) has been reported to occur concurrently with MF.[41] Likewise, recalcitrant tinea corporis has been reported as the presenting manifestation of patch-stage MF.[42] Among other opportunistic infections, herpes zoster is frequently found.[43]

Mycobacterium haemophilium , a non-tuberculous mycobacterium that was first described in 1978, is a pathogen that can cause an array of symptoms in immunocompromised patients, predominantly cutaneous. It has been reported in MF hosts from South-East Asia.[44] Pulmonary tuberculosis is also a common association; it might originate due to long-term corticosteroid therapy administered to some of the MF patients.[45]

The increased risk of second malignancies, including non-melanoma skin cancers, in patients with MF has been well-documented. There is also increased risk of malignant melanoma and dysplastic nevus syndrome.[46]


   Differential Diagnosis Top


Several common benign skin disorders, including eczema, psoriasis, and contact dermatitis, closely resemble MF, rendering early diagnosis of the latter difficult. Among the infective dermatoses mimicking MF are secondary syphilis (particularly in HIV-1 positive patients),[47] disseminated coccidioidomycosis,[48] etc. History-taking is very important to rule out pseudolymphoma syndrome that is relatively rare but can lead to death if there are extensive skin lesions, severe hepatitis, agranulocytosis and neutropenia, particularly because it may mimic clinically and histologically MF to a great extent and thus may give rise to harmful effects if misdiagnosed and treated with chemotherapy. Anticonvulsants as a group (carbamazepine, phenytoin, phenobarbital and valproic acid) are the major offenders.[49] Of them, statistically speaking, carbamazepine-induced pseudo-MF is perhaps the largest category.[50],[51] Novel drugs like Gleevec, a protein tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia, melanoma and gastrointestinal stromal tumor, are also implicated.[52]

For therapeutic purpose, differentiating MF from other variants of CTCL is equally important. Close morphological similarity of MF is seen with hydroa-like CTCL, an unusual pediatric malignancy with an impressive cutaneous rash characterized by edema, blisters, ulcers, crusts and scars, resembling hydroa vacciniforme. It is seen mainly on face and sometimes on the extremities. It has a poor prognosis.[53] Similarly, pleomorphic small/medium-sized CTCL is a recently recognized rare type of CTCL, which is clinicopathologically different from MF.[54]

Staging

The clinician must attempt not only to make the diagnosis, but also to stage the extent of the disease once the diagnosis is made. Accurate staging is critical in determining the prognosis of those with MF. The tumor, node, metastasis, and blood stage needs to be documented and used to determine an overall stage from IA to IVB [Table - 1].

Extracutaneous MF

Extracutaneous MF (stage IV disease) may be sub-divided in two broad groups: Metastatic MF and Sezary syndrome.

Metastatic MF

Visceral involvement may be expected in an advanced stage of the disease. Metastasis can occur to almost all the organs, including the central nervous system.[55] Viscera are involved in one-half to three-quarters of patients suffering from this disease.[56] In possible meningeal or parenchymatous involvement of MF, atypical neurological or psychiatric symptoms may be dissociated from the evolution of the cutaneous lesions.[57] In a large scale study, it was found that at 20 years from diagnosis, the risk for progression for extracutaneous disease by initial extent of skin involvement was 0% for limited patch/ plaque, 10% for generalized patch / plaque, 35.5% for tumorous disease and 41% for erythrodermic involvement.[58]

Extracutaneous manifestation is more probable with subtypes having deeper T lymphocyte infiltrates like GSSS. In one such case, bilateral inguinal hernia and dislocation of great saphenous vein was reported due to very deep muscular infiltrate of neoplastic lymphocytes.[59]

Sezary syndrome

Patients with Sezary syndrome present with erythroderma, intense pruritus, peripheral lymphadenopathy, leathery infiltration and edema of the skin, hyperkeratosis of the palms and soles, hyper- or hypopigmentation, alopecia, temperature dysregulation caused by a compromised integument and abnormal hyperchromatic mononuclear cells in the skin and peripheral blood.[60] A triad of erythroderma, lymphadenopathy and the presence of neoplastic lymphocytes (Sezary cells) is classically described. Neoplastic lymphocytes in this variant are found in the blood-stream.[61]

The WHO-EORTC classification has recommended the criteria for the diagnosis of SS on the lines of the recent report from the International Society for Cutaneous Lymphomas (ISCL) on erythrodermic CTCL. Accordingly, a case of SS must demonstrate one or more of the following: an absolute Sezary cell count of at least 1000 cells/mm 3 ,[62] a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T cells and / or an aberrant loss or expansion of pan-T-cell markers evidenced by flow cytometry, increased lymphocyte counts with evidence of a T-cell clone in the blood by Southern blot or PCR techniques or a chromosomally abnormal T-cell clone. The WHO-EORTC acknowledge that SS is part of a broader spectrum of erythrodermic CTCL and that alternative staging systems for assessment of the degree of peripheral blood involvement in erythrodermic CTCL are needed. However, until the results of an ISCL study investigating the clinical validity of these proposals are available, demonstration of a T-cell clone (preferably of the same T-cell clone in skin and peripheral blood) in combination with one of the above-mentioned cytomorphological or immunophenotypical criteria are suggested as minimal criteria for the diagnosis of SS to exclude patients with benign inflammatory conditions simulating SS.

That even this new criteria is going to be challenged soon is indicated by the results of a study that performed immunoperoxidase staining of skin biopsies, as opposed to flow cytometry, and concluded that a CD4/CD8 ratio >10:1 on skin biopsy is not sufficiently specific to support a diagnosis of SS.[63]


   Initial Assessment of MF Top


Recently the guidelines and therapeutics subcommittee of the British Association of Dermatologists (BAD) and the UK Cutaneous Lymphoma Group (UKCLG) have jointly prepared an evidence-based guideline for the management of primary CTCL.[64] According to the BAD-UKCLG guidelines, the initial assessment should have the following components:

  • Multiple skin biopsies (ellipse rather than punch) are often required to confirm a diagnosis of MF.
  • Histology, immunophenotypic and preferably T-cell receptor (TCR) gene analysis should be performed on all tissue samples (ideally molecular studies require fresh tissue).
  • All patients (with the possible exception of early stage MF, stage IA) should ideally be reviewed by an appropriate multidisciplinary team (MDT) for confirmation of the diagnosis and to establish a management strategy. The MDT should include a dermatologist, a clinical or medical (hemato) oncologist and a dermatopathologist or pathologist with considerable experience of the diagnosis and management of primary CTCL.
  • Initial staging CT scans are required in all patients with the exception of those with early stages of MF (stage IA/IB).
  • At diagnosis, peripheral blood samples should be analyzed for total white cell, lymphocyte and Sezary cell counts, serum LDH, liver and renal function, lymphocyte subsets, CD4/CD8 ratios, HTLV-1 serology and, preferably TCR gene analysis.
  • Bone marrow aspirate or trephine biopsies are appropriate for those with late stages of MF (stage IIB or above).


Though it is difficult in Indian conditions to strictly adhere to these recommendations, these certainly provide the markers for standard of care. More recently it has been pointed out that (18) F- fluorodeoxyglucose (FDG) - positron emission tomography (PET) has higher diagnostic value than CT in the detection both of local disease and distant metastasis and, thus is more useful than the latter in initial staging and restaging following therapy.[65] The value of PCR in the assessment of TCR-gamma gene rearrangements and, thus, its role in the early diagnosis and evaluation of MF, wherever the facility is available, cannot be stressed more.[66]

In a very recent Irish study, however, it has been claimed that detailed investigations were unhelpful in early stage disease and only close clinical follow-up is essential to identify disease progression.[67] This echoes an earlier French study that investigated the correlations between clinical, histologic, blood, and skin PCR outcome in treated patients of MF and confirmed the frequent detection of a dominant gene rearrangement in peripheral blood in MF patients and showed that PCR may remain positive in lesional sites even when skin lesions are successfully treated.[68] Another large French study ( n =104) has strongly suggested that blood eosinophilia at baseline is a prognostic factor.[69]


   Histology, Immunohistochemistry and Molecular Genetics Top


MF is one of the most difficult diagnoses to make in dermatopathology, and therefore, histopathologic tissue examination is vital in making a correct diagnosis. Multiple features have been described. An intra-epidermal pattern criteria was discussed at the 64th Annual Meeting of the American Academy of Dermatology and is summarized in [Table - 2].[70]

The joint BAD/UKCLG guidelines have provided the following recommendations regarding histological diagnosis of MF:

  • The presence or absence of epidermotropism should be documented.
  • The depth of the infiltrate should be noted.
  • The morphology or cytology of the atypical cells and presence of large cell transformation, folliculotropism, syringotropism, granuloma formation, angiocentricity, and subcutaneous infiltration should be mentioned.
  • Immunophenotypic studies should be performed on paraffin-embedded sections and include the T-cell markers CD2, CD3, CD4, CD5, CD8, and the activation marker CD30. MF is characteristically CD7 negative. Additional markers such as p53 may have prognostic significance. Markers of cytotoxic function viz. TIA-1, the monocyte/macrophage marker CD68 and NK cell marker CD56 may be useful for specific MF variants.
  • Ideally all pathology results should be reviewed by a central panel.
  • The histology, after correlation with the clinical features, should be classified according to the integrated WHO - EORTC classificaoktion.


As for initial assessment, these BAD - UKCLG guidelines for histology set a benchmark for histopathological diagnosis of MF.

Among the newly diagnosed cell surface molecules, the natural killer receptor (NKR) p140 / KIR3DL2 normally expressed by NK and CD8+ T-cells was detected on the surface of CTCL cell lines, CouLS and Pno, as well as on freshly isolated CD4+ peripheral B lymphocytes (PBL) from SS patients. Furthermore, p140 marked in situ SS cells, distinguishing them from p140 negative tumor cells of patch/plaque MF. SC5 is another newly described activation-related intracellular inhibitory receptor expressed on the surface of a minor PBL subset. It was found that SC5 expression was significantly increased in SS cells and correlated to p140 expression.[71]

While analyzing the histology of CTCLs, relying overly upon any particular histological feature and ignoring other clinicopathological and phenotypic features may land the clinician at the wrong spot. For example, the presence of neoplastic T-lymphocytes forming a rim around the individual fat cells in the subcutaneous lobules, so-called 'rimming' of adipocytes, that is considered a characteristic morphologic feature of subcutaneous panniculitis-like T-cell lymphoma, has now also been identified in tumor stage MF.[72]

Among the newer serologically defined tumor-associated antigens, testis-specific protein 10 (TSGA 10) over-expression is consistently found in MF.[73]

An Egyptian study has found that normal skin (greater than 5 cm distal to any visible lesion) in patients with MF shows evidence of epidermotropism and superficial perivascular dermal infiltrate. This finding certainly raises questions regarding the credibility of the current staging classification of MF and suggests taking biopsies from normal skin before starting topical treatment. Similarly, during MF treatment, biopsies from cured lesions are recommended before starting withdrawal.[74]

Allelotyping studies have demonstrated allelic loss in more than half of MF/SS patients. Loss of heterozygosity was found on 9p, 10q, 17p and 1p with lower rates on 2p and 6q.

A dominant T-cell clone is detectable in the cutaneous lesions of 60% patients of MF. PCR gamma negativity (absence of clonality) is always associated with higher remission rate and thus should be always performed to assess prognosis.[75] The TCR gene rearrangement imprint is a stable and reliable tumor marker of MF. Keeping this in mind, the prognostic value of the finding of one-third of patients in complete clinical remission having a cutaneous molecular residual disease has to be freshly assessed.[76]

In consonance with its protean clinical manifestations and multidimensional histological characteristics, the cytokine profile of MF too cannot be put in a straitjacket. Though conventionally MF is described as a CD4+ epidermotropic tumor, newer variants are emerging. One such variant is clinically characterized by a patch-like pattern and hyperpigmentation. Histological analysis revealed a CD3+, CD8+ small-cell infiltrate showing a remarkable affinity to the dermoepidermal junctional zone. Clonality for the T-cell receptor gamma chain was detected by PCR followed by denaturing gradient gel electrophoresis. This non-aggressive clinical variant is now being considered to be a CD8+ MF variant.[77] The study of levels of concordance and reproducibility of histological diagnosis of MF, however, confirms the discriminating ability of the current classification criteria.[78]

The diagnosis of early MF is a persistent problem in clinical dermatology and here genotypic analysis comes in as a handy tool. A study comparing the different methods of detection of clonality in early skin lesions of MF and in the identification of silent extracutaneous involvement has found the nested PCR technique followed by polyacrylamide gel electrophoresis (PCR/PAGE technique) to be significantly more reliable and useful than Southern Blot analysis.[79]

Recently, cytotoxic proteins were found to be expressed by a subset of MF patients and these have been renamed as MF, cytotoxic immunophenotype variant.[80]

It has been pointed out that in spite of complex histological, immunophenotypic, and molecular genetic investigation of early CTCL, less than one-third of the patients remain unclassified. So, definite diagnosis of these cases could be based only on long-term follow-up and on the results of serial skin biopsies.[81]

In a recent Canadian study, T-plastin, a cytoplasmic protein regulating actin assembly and cellular motility, has been detected for the first time in Sezary cells using a global genomic screening tool, the modified representational difference analysis. This is the first time that T-plastin has been found on the hematopoietic cells. Therefore, T-plastin has the potential to be a Sezary cell-specific marker valuable for diagnosis of SS.[82]

The immunohistochemical staining for proliferating cell nuclear antigen (PCNA), which is a cofactor of DNA polymerase-delta and is essential for cell proliferation, has been observed to correlate well with labeling with Ki67, a nuclear protein expressed in cycling cells. It is postulated that PCNA labeling index (percentage of PCNA-positive cells) of skin is helpful in the early diagnosis of MF and distribution of PCNA-positive cells in the skin is additionally a marker for treatment resistance.[79]


   Prognosis Top


Prognosis in individual cases is important to know and assess as that has an important bearing on management. The joint BAD/UKCLG recommendations have the following evidence-based guidelines on the assessment of prognosis in MF/SS:

  • Prognosis in MF (and clinical variants) is related to age at presentation (worse if >60 years), to the stage of the disease and possibly to the presence of a peripheral blood T-cell clone; some MF variants (e.g., pagetoid reticulosis, poikilodermatous MF, hypopigmented MF, and GSSS) may have a better prognosis.
  • In Sezary syndrome the median survival is 32 months from diagnosis.[83]
  • Folliculotropic MF has a worse prognosis.


Overall prognosis of MF has improved during the past decades, possibly because of an increased proportion of cases being diagnosed at early stages.[84] At least within the first 10 years after diagnosis, disease progression and MF-related mortality occur in only a subset of patients generally presenting with advanced disease. The best survival is seen in female patients under 45 years of age without Sezary syndrome.


   Therapy Top


Appropriate therapy depends upon a variety of factors, including stage, the patient's overall health, the presence of symptoms and patient-specific issues such as cost of care and access to health care facilities. In general, therapies can be categorized into skin-directed (topical), phototherapy, and systemic treatments. To maximize response and minimize toxicity, these therapies are frequently used in combination. Unlike many other conventional lymphomas, MF, with the possible exception of the earliest stage, is not curable. At present, a stage-adjusted therapy is the best concept available,[85] since a pivotal study by Kaye et al . found that systemic chemotherapy offered no advantage over conventional conservative therapy in terms of overall and disease-free survival in patients with MF.[86] For these reasons, it is generally accepted that systemic chemotherapy, such as those commonly employed for visceral or nodal lymphoma, should be avoided except for advanced-stage disease. Fortunately, with most therapies, partial or complete remission is achievable; however, the majority of patients with MF require lifelong treatment and monitoring. In a US-UK joint study it was revealed that despite the differences in the two health care systems, in-patient therapy improves the quality of life and, thus, remains an important and effective therapeutic option of MF.[87]

The different therapeutic agents and their current place in the management of MF is reviewed below in the light of available evidence [Table - 3].


   Topical Therapy Top


Topical corticosteroids

High-potency class I to II topical steroids are frequently used first line to suppress inflammation and symptoms of itching. These agents are often useful as therapy for stage IA disease, but are mostly used in conjunction with other therapies for more advanced disease. Their clinical response is usually short-lived.[88]

Topical cytotoxic agents

Topical mechlorethamine (nitrogen mustard), 0.01% or 0.02%, either as an aqueous solution (in normal saline) or in an ointment base (emulsifying ointment), is effective for superficial disease with response rates of 51-80% for stage IA, 26-68% for IB and 61% for IIA disease.[89] The aqueous solution is relatively unstable and the ointment base, which is more irritant than the aqueous solution, can cause irritant or allergic dermatitis in sensitized individuals (35-58%), but its efficacy is similar. This product must not be used in pregnancy. Long-term follow-up results confirm its safety.[90] Mechlorethamine (CIM) therapy is a cost-effective and easily administered treatment for MF. The most common histological feature of patients with CIM is spongiotic dermatitis.[91]

Topical carmustine (BCNU) is an alternative topical chemotherapeutic agent in MF with similar efficacy to mechlorethamine as indicated by response rates of 86% in stage IA, 47% in stage IB and 55% in stage IIA patients.[92] Alternate day or daily treatment with 10 mg of BCNU in 60 mL of dilute alcohol (95%) or 20-40% BCNU ointment can be used. Hypersensitivity reactions occur less often (5-10%) than with mechlorethamine. All patients treated topically with BCNU should have regular monitoring of their full blood count; treatment is normally given for only a limited period, depending on the extent of the treated area (2-4 weeks for extensive areas), to avoid myelosuppression; maintenance therapy is contraindicated.

There has been only one randomized placebo controlled trial of topical peldesine cream (BCX-34, an inhibitor of the purine nucleoside phosphorylase enzyme) in MF, which showed no benefit compared with vehicle, emphasizing the difficulties in interpretation of uncontrolled studies of topical therapy in early stages of MF.[93]

Topical bexarotene gel

Recently, the US Federal Drug Administration (USFDA) for topical therapy has approved a novel retinoid, 1% targretin (bexarotene) gel, in stage I MF in patients who are resistant to or intolerant of other topical therapies.[94] Its exact mechanism of action is unclear. One proposed mechanism is regulation of abnormal T-cell proliferation.[95] Topical imiquimod

Imiquimod is a topical immune response modifier that binds to toll-like receptors 7 and 8 and induces alpha-interferon. Imiquimod 5% cream has been anecdotally reported to induce remission in PUVA-resistant plaque MF.[96]

Topical tacrolimus

Tacrolimus is an immunomodulatory macrolide that reduces the stimulating capacity toward T cells and has therefore been considered worth investigating as a treatment of MF. Topical tacrolimus has been related to an unknown effect with the risk for secondary malignancies including CTCL. Yet, there has been the odd anecdotal case report of patch stage MF being successfully treated with 0.1% tacrolimus ointment.[97]

Phototherapy

The clinical benefit of photochemotherapy [psoralen + ultraviolet A (PUVA)] was noted over 20 years ago and response rates of 79-88% in stage IA and 52-59% in stage IB disease have been reported.[99] Flexural sites ('sanctuary sites') often fail to respond and the duration of response varies. Maintenance therapy is rarely effective at preventing relapse.[100] There is no significant response in tumor (IIB) stage disease. Many patients will inevitably have a high total cumulative UVA dose and the risks of non-melanoma skin cancer are consequently increased for these patients. PUVA is an ideal therapy for patients with stage IB/IIA disease who are intolerant of or fail to respond to topical therapies. Efforts should be made to restrict the total PUVA dose to less than 200 treatment sessions or a total cumulative dose 1200 Jcm-[2]. Broadband and narrowband UVB and high-dose UVA1 phototherapy have also been used with benefit in MF.[101],[102],[103]

Current data allow no definitive conclusions as to whether NB UVB should be preferred to competing photo (chemo) therapeutic options, such as, UVA1 and psoralen - UVA regimes.[103]

On the heels of reports claiming beneficial response with 311 nm UVB, a 308 nm monochromatic excimer light, a new kind of xenon chloride lamp, has been claimed to be successful in stage IA MF. The total UVB dose ranged from 5 to 9.3 Jcm -2 . One-year follow-up has yielded no recurrence in another series.[104] Half of the patients experienced relapse in 30 months in an extended series.[105]

Photodynamic therapy

Photodynamic therapy acts by type II photo-oxidative reaction. It is being increasingly used for skin tumors including MF. The side effects are mild and transient. Newer photosensitizers like methyl aminolevulinate hold a lot of promise.[108]

Radiotherapy

MF is a very radiosensitive malignancy. Individual thick plaques, eroded plaques, or tumors can be treated successfully with low-dose superficial orthovoltage radiotherapy, often administered in several fractions (e.g., two or three fractions of 400 cGy at 80-120 kV). Large tumors may be treated by electrons, the choice of energy being dependent on tumor size and thickness. Whole body total skin electron beam (TSEB) therapy has been evaluated extensively in MF although it is not widely available. TSEB should be reserved for those who fail to respond to first and second line therapies.[107] Adverse effects of TSEB include temporary alopecia, telangiectasia, and skin malignancies. With the development of the modern linear accelerator, it has become possible to treat extended areas of the skin with accelerated electrons.[108] TSEBT is a technically difficult therapy for MF, but very effective, especially in stage IB and IIB. Complete long-term remission has been reported in patients of MF who had follicular mucinosis preceding their diagnosis.[109] Local radiotherapy, in contrast to TSEBT, result in long-term disease-free intervals and, possibly, cure in unilesional MF.[110] Similarly, patients with minimal stage IA MF may be managed effectively with local superficial radiation alone without adjuvant therapy. Distant failure is unusual and patients should receive a minimum surface dose of 20Gy, which offers excellent local control. Sequelae of therapy are minimal.[111] Topical nitrogen mustard (HN2) should be added as an adjuvant after a significantly symptomatic or extensive T2 MF shows a complete response to TSEBT. Patients with limited T3 disease may also be treated with HN2 and local radiotherapy to the tumors.[112]

Immunotherapy

Different forms of immunotherapy have been evaluated in MF with the intention of enhancing anti-tumor host immune responses by promoting the generation of cytotoxic T-cells and Th1 cytokine responses. Studies of a-interferon have shown overall response rates of 45-74%.[113] Various dosage schedules have been employed (3 MU ´ 3 week -1 to 36 MU day -1 ) and it appears that response rates are higher for larger doses.[114] Overall response rates are also higher in early (IB/IIA, 88%) compared to late (III/IV, 63%) stages of disease.[115]

Uncontrolled studies of combined PUVA and a-interferon (maximum tolerated dose 12 Mum -2 ´ 3 week -1 ) in MF and SS have shown overall response rates of 100% with 62% complete response rates.[116] This combination may also be useful in patients with resistant early-stage disease such as those with thick plaques and folliculotropic disease.

Other small pilot studies have shown that both interleukin (IL)-12 and g-interferon can produce clinical responses in MF but their therapeutic value remains to be established.[117],[118]

Ciclosporin has been used in MF, particularly in erythrodermic variants to relieve severe pruritus, but there is some evidence that treatment may actually cause rapid disease progression or large cell transformation and its use in MF is not recommended.[119]

Chemotherapy

MF and SS are relatively chemoresistant and responses are usually short lived. Chemotherapy should not be used in patients with early stage IA, IB, or IIA disease. However, treatment of stage IIB and IVA disease remains problematic. Individual tumors and effaced peripheral lymph nodes will respond to superficial radiotherapy and additional chemotherapy should be considered in patients with a good performance status [Eastern Cooperative Oncology Group (ECOG), 0-2, where 0 is 'fully active' and 4 is 'completely disabled']. Single agent chemotherapy, which has been shown to produce a clinical response in stage IIB-IVB disease, includes oral chlorambucil (4-6 cycles of 0.15-0.2 mg kg -1 for 2-4 weeks), methotrexate and etoposide and the intravenous use of the purine analogues 2-deoxycoformycin, 2-chlorodeoxyadenosine and fludarabine.[120] Recently, pegylated liposomal doxorubicin and gemcitabine have been used in MF.[121],[122] Pentostatin is another novel cytotoxic agent (a potent adenosine deaminase inhibitor) to be used in MF.[123] A phase II EORTC trial concluded that it is active in MF and SS. Due to its relatively specific lympholytic effect and its favorable toxicity spectrum, pentostatin might be especially useful for palliative treatment.[124]

Recent pilot studies assessing the use of TSEBT combined with high-dose conditioning chemotherapy before autologous stem cell transplantation in patients with stage IIB - IVA disease have shown good clinical responses, but there are no data available at present to indicate if this approach affects disease-free or overall survival.[125] Allogeneic stem cell or bone marrow transplantation has only been used in a few patients with encouraging results, but the associated mortality suggests that this approach is difficult to justify.[126] The latter has even been reported to induce remission in a case of refractory SS.[127] However, a graft-versus-lymphoma effect may be therapeutically important and the future assessment of non-myeloablative min-allografts in MF could be appropriate.

Monoclonal antibody therapy

Among the monoclonal antibodies to have shown some clinical response in mycosis fungoides are the following: a humanized chimeric anti-CD4 monoclonal antibody,[128] a radiolabeled anti-CD5 antibody,[129] alemtuzumab (anti-CD52)[130] and a fully humanized anti-CD4 antibody. At present none of these approaches are considered standard treatment.

Recently, denileukin diftitox, a DAB 389 -IL-2 fusion toxin has completed phase I / II studies. It is a recombinant fusion protein consisting of peptide sequences for the enzymatically active domain (389) of diphtheria toxin and the membrane translocation domain of IL-2 and can inhibit protein synthesis in tumor cells that express high levels of the IL-2 receptor, thereby resulting in cell death. Adverse effects include fever, chills, myalgia, nausea, and vomiting and a mild increase in transaminase levels. Acute hypersensitivity reactions occurred in 60%, invariably within 24 hours and during the initial infusion. A vascular leak syndrome characterized by hypotension, hypoalbuminaemia, and edema was defined retrospectively within the first 14 days of a given dose in 25% of patients. Myelosuppression is rare. Five percent of adverse reactions are severe or life threatening. This therapy is not likely to be appropriate for early-stage disease but may be useful in advanced disease.[131]

Novel retinoids

Acitretin and bexarotene are the two orally available retinoids used most commonly for treating MF. Bexarotene (Targretin) is a novel synthetic retinoid that selectively binds and activates the retinoid X receptor and has recently been approved in Europe for the treatment of advanced stages (IIB - IVB) of MF. It has been shown to promote apoptosis and inhibit cell proliferation. It is relatively selective and therefore should have little effect on the retinoid A receptor involved in cell differentiation. The most effective tolerated oral dose is 300 mg m -2 day -1 although responses improve with higher doses. Side effects are transient and generally mild but most patients require treatment for hyperlipidaemia and central (hypothalamic) hypothyroidism while on therapy. At the present time, oral bexarotene should only be prescribed for early stages of MF in the context of clinical trials.[132] It has been recommended to use early preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood to minimize the unavoidable side effects, followed by subsequent monitoring.[133] An early stage MF, refractory to PUVA-bath therapy alone, subsequently showed complete remission when bexarotene was added to PUVA-bath.[134]

Extracorporeal photochemotherapy

Extracorporeal photochemotherapy (ECP), also called photopheresis, is a type of pheresis in which aliquots of the patient's blood are removed, treated with a photosensitizing agent and subjected to ultraviolet A light. The treated cells are then re-infused into the patient. ECP is most effective for Sezary syndrome and erythrodermic MF.

The mechanism of action has not been fully elucidated. It is likely that photopheresis activates antigen presenting cells, so that tumor-related antigens are more readily presented to cytotoxic T-Cells.[135] That is why there have been claims that the CD8 count is critical in predicting whether patients will respond to ECP,[136] although others have provided evidence that the total baseline Sezary count is the only predictor of response.[137]

Photopheresis is an outpatient procedure that involves a 2-day treatment cycle repeated every 2 to 4 weeks for months or years, depending on individual response. The procedure lasts approximately 4 hours and is performed through a peripheral vein. Due to volume shifts during the treatment, cardiovascular instability is a relative contraindication.

Recent findings suggest that co-incubation of these cells prior to re-infusion allows far more efficient phagocytosis and processing of apoptotic malignant T cells by the newly formed dendritic cells (DC). Moreover, such a co-incubation step permits the direct external manipulation of this system and the design of strategies to augment the production of tumor-loaded DCs. These considerations have led to the development of 'transimmunization', so named because it causes transfer of tumor antigens to newly formed dendritic cells capable of initiating immunization against the tumor cells, as the replacement technology for ECP.[138]

Experimental therapies

A new category of agents, namely histone deacytelase inhibitors, is being tested in ongoing clinical trials. Examples are depsipeptide and vorinostat. These agents modulate gene expression. Human monoclonal antibodies, such as zanolimumab (anti-CD4), also fall into the category of drugs under trial. Another novel group of agents being currently evaluated are NF-kappa B inhibitors.[139] There have been uncontrolled reports of various agents, including intra-arterial isolated limb infusion of melphalan in the disease confined to one limb,[140] topical tazarotene, topical methotrexate, etc.[141] Early clinical trials have indicated that IL-12 may prove maximally effective in combination with additional cytokines such as interferon alfa-2b or IL-2.[142]


   Future Directions in Therapeutics Research Top


Immunotherapy is widely held to be the future of CTCL therapeutics. The prerequisite for immunological therapy is the knowledge of tumor-specific antigens. The most successful strategies for discovery of new tumor antigens include the cytotoxic T-cell approach using either genetic or biochemical tools or synthetic peptide libraries leading to so-called mimotopes. A second strategy utilizes antibodies for screening recombinant libraries: either monoclonal anti-bodies generated against tumor cells or the so-called SEREX approach using antibodies of the patient's serum. Especially the antibody-based strategies have led to several new antigens expressed in MF. Finally, already known tumor antigens are being evaluated as possible targets for cutaneous lymphomas. A growing list of tumor antigens can be summarized for MF, which include cTAGE-1, SCP-1, GBP-TA, several mimotopes, SC5, LAGE-1, and NY-ESO-1, as well as the GAGE and MAGE-A groups.[143]

This area of defining novel strategies for identifying tumor antigens and evaluating them as possible therapeutic targets is a burgeoning area of MF and CTCL research.

The role of neuropeptides, such as, neurotensin, in the growth and chemotaxis capacity of CTCL cells is another interesting area of research. Malignant T cells express neurotensin receptors on their cell membrane. Functional results have indicated that neurotensin inhibits the proliferation of tumor cells in response to exogenous IL-2. It has been suggested that neurotensin in skin can play a role in the disease by locally limiting the growth of tumor cells in response to cytokines and by enhancing their chemotactic capacity.[144] This discovery certainly has enormous potential in drug development in the future.

Matrix metalloproteinase (MMP) expression and production are associated with advanced stage tumor and contribute to tumor progression, invasion, and metastases. In patients with MF, the expression of MMP-2 (gelatinase A), and MMP-9 (gelatinase B) mRNA was significantly upregulated with advancing stage. Besides MF cells, the mRNAs were expressed by some stromal cell populations, suggesting that these cells cooperate in the process of tumor invasion. These studies identify the MMPs as an important class of proteinases involved in the extracellular matrix degradation by MF and suggest that MMP inhibitors may lead to important new treatment for its control.[145]


   Practical Issues Top


The inflammation and abnormal scaling, flaking, and cracking of the upper layers of the skin in patients with MF leads to considerable itching and discomfort. This can be controlled with the following general measures:[148]

  • Showering or bathing in warm, not hot, water
  • Use of mild cleansers
  • Oatmeal bath soaks
  • Avoid rubbing skin with washcloth or sponge, use only hands
  • Immediately after showering, apply moisturizer such as petroleum jelly
  • Use a humidifier during winter; an inexpensive alternative is to put a shallow pan of water near a heating source.


If the itching becomes severe oral anti-histamines are needed. Because MF patients have an impaired epidermal barrier, they are particularly susceptible to secondary skin infection. Staph. aureus is the commonest bacterial pathogen and when present should be treated aggressively to prevent systemic infection. To prevent such systemic spread of infection, that is major cause of death in MF, ulcers in advanced stage should be managed with active colloidal hydrogel topically.[147]

Other than systemic antibiotics, two kinds of infections are particularly important to consider in our clinical setting: fungal infections and tuberculosis. Mycosis in these patients, whether superficial or deep, whether primarily cutaneous or cutaneous manifestation of fungaemia, has to be treated with systemic agents, viz, amphotericin B, fluconazole, itraconazole, voriconazole, caspofungin, etc.[148] Tuberculosis, that is ubiquitous in this country, has to be recognized early and treated appropriately to avoid fatal outcome.

Summary

MF is an indolent CD4+ non-Hodgkin epidermotropic lymphoma and the commonest type of CTCL. While classically MF presents with erythematous patches, plaques, and tumors, multiple clinical variants, some with characteristic histologic patterns, have been described in the literature. It is very difficult to make a diagnosis of early MF. Thus, the clinician must be vigilant and be prepared to take a holistic view of the clinical, histological, immunophenotypic, and molecular genetic evidence to reach a proper diagnosis and accurate staging and classification.

The few randomized studies in MF carried out so far clearly indicate that in early stage skin directed therapy is most appropriate. Long-term cure may be achieved in localized disease, but patients with multi-focal early stage disease, as present in most cases, are only likely to achieve a short-term clinical response with recurrent disease for many years and, in the majority of cases, a normal life expectancy. Therefore, potentially toxic and aggressive therapies ought to be avoided.

In contrast, patients with later stages of disease have a poor prognosis and the absence of large well-designed RCTs at present is reflected by a lack of consensus regarding treatment. MF is a very radiosensitive tumor and both superficial radiotherapy and TSEBT are invaluable for all patients at later stages. All the different therapies taken together have an overall response rate of approximately 30% and complete response rate around 10%. Chemotherapy, single and multi agent, has a typically short-lived response (median duration 35-41 months). So, none of these therapies so far have had any significant effect on disease outcome. It is also critical to ensure that the individual patient's quality of life is considered when therapeutic options are discussed and that patient expectations are realistic. Palliative care should be considered in all patients with resistant late-stage disease and those with poor performance status (ECOG > 2)[156].

 
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