¹Department of Genetics & Molecular Medicine, School of Medicine King’s College, London, UK
²Skin Tumour Unit, St. John’s Institute of Dermatology, Guys and St. Thomas Hospital, London, UK

ABSTRACT

Cutaneous T-cell lymphomas are rare, distinct forms of non-Hodgkin’s lymphomas. Of which, mycosis fungoides (MF) and Sézary syndrome (SS) are two of the most common forms. Careful, clear classification and staging of these lymphomas allow dermatologists to commence appropriate therapy and allow correct prognostic stratification for those patients affected. Of note, patients with more advanced disease will require multi-disciplinary input in determining specialist therapy. Literature has been summarized into an outline for classification/staging of MF and SS with the aim to provide clinical dermatologists with a concise review.

Key Words:
CTCL, cutaneous T-cell lymphoma, mycosis fungoides, neoplasm staging, Sézary syndrome, therapy

Primary cutaneous lymphomas (PCL) are rare forms (2%) of non-Hodgkin’s lymphomas with an annual incidence of 0.3-1 per 100,000.¹ These lymphomas include both primary cutaneous T-cell (75%) and B-cell lymphomas defined by presentation at the time of diagnosis without any extracutaneous sites of disease.1 In 2005, the two classification systems for cutaneous T-cell lymphoma (CTCL), namely the World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC), were combined, providing distinct subtypes based on clinico-pathologic criteria (Table 1).^1,2

Mycosis fungoides (MF) represents the most common variant of CTCL³ and is characterized by a monoclonal proliferation of epidermotropic CD4+/CD45RO+ T-cells often with aberrant expression of mature T-cell antigens.^1,4 MF (Alibert-Bazin type) is characterized by the presence of polymorphic patches, plaques, and tumors.¹ Sézary syndrome (SS) is a rare CTCL variant closely related to MF and has classically been described as a triad of erythroderma, generalized lymphadenopathy and Sézary cells (atypical neoplastic T lymphocytes with hyperconvoluted cerebriform nuclei) in the skin, blood, and lymph nodes.^1,5,6 The WHO-EORTC system currently distinguishes SS as a separate entity from MF, but rare cases of SS preceded by typical MF have been described.^3,7

In this article, we will focus primarily on the evaluation and classification of these conditions and summarize the available therapies.

Evaluation

A confident diagnosis of MF can only be made from a combination of clinical and pathologic findings. Characteristic pathologic features include cytologically atypical lymphocytes with cerebriform nuclei (described above) either colonizing the basal layer of the epidermis (epidermotropism) or forming clusters of cells in the epidermis (Pautrier microabscesses) with or without a band of cytologically atypical cells in the upper dermis.^1,8,9 An algorithm for the diagnosis of early-stage MF has been suggested by the International Society of Cutaneous Lymphoma (ISCL), which includes clinico-pathological correlation and immunophenotypic and clonal T-cell receptor gene rearrangement studies, providing minimum criteria for diagnosis (Table 2).^2,8 For SS, ISCL recommends the presence of erythroderma and the demonstration of the same T-cell clone (using polymerase chain reaction [PCR] or Southern blot of the T-cell receptor [TCR] gene) in skin and blood plus one of the following: Sézary cell count >1000 cells/mm³; expanded CD4+ population with CD4/CD8 ratio >10; or loss of T-cell antigens (CD2, CD3, CD4, CD5 and CD7).¹ It must be appreciated that the diagnosis of early MF can be difficult and repeated biopsies may be required.^2,8 Careful clinico-pathological evaluation with a dermatologist and experienced pathologist in PCLs is recommended (Table 3).

Classification/Staging

The management of MF/SS is a stage-based approach derived from the TNM (tumor-node-metastasis) Classification of Malignant Tumours (Table 4). Patients with Stage IA, IB or IIA have an early stage disease compared to IIB (tumor), III (erythroderma), and IV (pathologically involved nodes – IVA; visceral involvement – IVB) have advanced-stage disease (Table 5).² Of note , there are two main classifications for lymph node involvement. The Dutch system defines atypical cells as cerebriform cells with a diameter >7.5 µm – increasing grade is associated with increased involvement of these cells.¹⁰ The second system, the National Cancer Institute and Veteran’s Administration Hospital (NCI-VA) classification focuses primarily on the number of cells within the paracortex of the lymph node and their subsequent effect on the structure of the node.¹¹

Prognosis

The prognosis of MF/SS is primarily based on stage, particularly the extent/type of lesions and presence of extracutaneous disease,^1,2 emphasising the importance of thorough patient workup. Of note, MF/SS are thought as incurable diseases but the majority of patients with MF have an indolent disease course with 65-85% of patients being stage IA or IB at diagnosis.^2,12-14

Patients with stage IA disease have a median survival of more than 12 years and no decrease in survival when compared to an age-, sex- and race-match control population.^1,2,15-17 It is now appreciated that for patients with stage IB, the presence of plaques (T2b) is associated with a worse prognosis and increased risk of disease progression when compared to those with only patches (T2a).¹²

In contrast, patients with more advanced stage disease (stages IIB, III, IVA) have a median survival of 5 years and stage IVB patients have a median survival of 2.5 years.^{2,12,13,15,17} More specifically, patients with dermatopathic nodes (N1) also have a poorer survival when compared to those with no palpable nodes (N0). The presence of abnormal nodes with no histological confirmation (Nx) is also associated with mortality/poor outcome.¹⁴ A recent study also showed that patients with stage B0b (<5% Sézary cells with a T-cell clone) have a significantly worse overall and disease-specific survival with an increased risk of progression when compared to B0a (without a T-cell clone). A comparison study between stages B1 and B2 showed no significant difference in survival outcomes (Table 6).¹⁴

Treatment

Successful treatment of MF/SS requires appropriate classification/ staging, multi-disciplinary input and personalized patient therapy (including age, co-morbidities, and performance status).² Treatment should be focused on trying to induce sustained remission as measured by tumor burden.¹⁶ At present, there are no curative therapies and sometimes palliative options are the only appropriate therapeutic intervention18 with maintenance of a patient’s quality of life. The standard approach for early stage disease is skin-directed therapy including topical agents, phototherapy, and radiotherapy. Long-term durable remissions are rare. Total skin electron beam (TSEB) therapy and immunobiologics are key options for patients with disease that is resistant to skin-directed treatments. Patients in advanced disease stages often receive chemotherapy but responses are rarely sustained. Several novel agents such as fusion toxins (denileukin diftitox), bexarotene, and histone deacetylase (HDAC) inhibitors have received US FDA approval during the last few years and offer promising alternatives to chemotherapy. Similarly, data on antibodies such as alemtuzumab suggests significant and occasionally durable responses. Table 7 summarizes many of the available therapies.

Conclusion

Appropriate therapy for advanced stages of MF/SS can only be initiated based on a multi-disciplinary approach (including dermatologists, pathologists, and oncologists) to classification and staging. Accurate staging and work-up will allow appropriate therapy and prognostic details to be delivered to each individual patient.

References

1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May 15;105(10):3768-85.
2. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sezary syndrome. Blood. 2009 Nov 12;114(20):4337-53.
3. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 Sep 15;110(6):1713-22.
4. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005 Nov;32(10):647-74.
5. Wieselthier JS, Koh HK. Sezary syndrome: diagnosis, prognosis, and critical review of treatment options. J Am Acad Dermatol. 1990 Mar;22(3):381-401.
6. Akilov OE, Geskin L. Therapeutic advances in cutaneous T-cell lymphoma. Skin Therapy Lett. 2011 Feb;16(2):1-5.
7. Diwan AH, Prieto VG, Herling M, et al. Primary Sezary syndrome commonly shows low-grade cytologic atypia and an absence of epidermotropism. Am J Clin Pathol. 2005 Apr;123(4):510-5.
8. Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005 Dec;53(6):1053-63.
9. Guitart J, Kennedy J, Ronan S, et al. Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting. J Cutan Pathol. 2001 Apr;28(4):174-83.
10. Sausville EA, Worsham GF, Matthews MJ, et al. Histologic assessment of lymph nodes in mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system. Hum Pathol. 1985 Nov;16(11):1098-109.
11. Scheffer E, Meijer CJ, Van Vloten WA. Dermatopathic lymphadenopathy and lymph node involvement in mycosis fungoides. Cancer. 1980 Jan 1;45(1): 137-48.
12. Arulogun SO, Prince HM, Ng J, et al. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood. 2008 Oct 15;112(8):3082-7.
13. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003 Jul;139(7):857-66.
14. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010 Nov 1; 28(31):4730-9.
15. Zackheim HS, Amin S, Kashani-Sabet M, et al. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol. 1999 Mar;40(3):418-25.
16. van Doorn R, Van Haselen CW, van Voorst Vader PC, et al. Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients. Arch Dermatol. 2000 Apr;136(4):504-10.
17. Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood. 1996 Oct 1;88(7):2385-409.
18. Heald P, Latkowski J, Wilson L, et al. Successful therapy of cutaneous T-cell lymphoma. Expert Rev of Dermatol. 2008 Feb;3(1):99-110(12).
19. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer. 2006 May;42(8):1014-30.

¹ Skin Tumor Unit, St. John’s Institute of Dermatology, London, UK
² Division of Genetic & Molecular Medicine, King’s College School of Medicine, London, UK
³ Department of Medicine, University of Western Ontario, London, ON, Canada
⁴ Windsor Clinical Research Inc, Windsor, ON, Canada
⁵ Windsor Regional Hospital, Windsor, ON, Canada

Introduction

Acne is a common dermatological condition found in about 85% of adolescents and young adults.¹ Acne can have significant psychological, social or physical impacts. Many effective treatments are available to manage acne, but for best results, all therapeutic interventions require good patient adherence. Unfortunately, for a variety of reasons, the risk of poor adherence has been documented in around 50% of acne patients.²

Acne Overview

Acne is a chronic inflammatory skin disease characterized by four pathological processes, with treatments targeted at the various mechanisms felt to be responsible for its development:

1. Sebaceous hyper secretion – oral isotretinoin, antiandrogen oral contraceptives
2. Abnormal keratinization of the walls of the pilosebaceous unit – topical retinoids
3. Proliferation of Propionibacterum acnes – benzoyl peroxide, antibiotics
4. Inflammation – antibiotics, retinoids²

Measuring Acne Severity

• Severity of acne can be described objectively by the physician and subjectively by the patient.
• Mild acne is characterized by open and closed comedones (black and whiteheads, respectively) and few papulopustular lesions.
• Moderate acne includes papules, pustules, and no more than one nodule.
• Severe acne is widespread and includes all the lesions above. Even the presence of a few cysts or nodules can be indicative of severe acne.
• Acne on the trunk is more difficult to treat, thereby increasing the severity rating even if the lesion counts are modest.
• Scarring is very common and should be taken as an indication for aggressive therapy.Scarring may be produced even in mild acne.
• The objective severity of acne typically drives particular treatment rationales; although, the physician should include patient values and preferences to help guide therapeutic strategies.
• Furthermore, acne of any grade can be considered more severe if there is significant psychological upset.

Treatment Rationale

Acne treatment information usually starts at the patient’s local pharmacy or, increasingly, online. Skin cleansers, skin wipes, and lifestyle changes, which will be discussed below, are usually the first considerations for patients with acne. Typically, when the patient feels their acne is not improving or when it has breached the patient’s disease ‘threshold’ by becoming ‘too severe’, they might consult their family doctor or dermatologist. Many treatment options (Table 1) are available that target one or more of the pathological processes
described above. However, because of its multifactorial
pathogenesis, combination therapy is frequently prescribed.
The purpose of treatment is to improve the quality of life
for patients and to prevent long-term sequelae, particularly
scarring and psychological distress.

Optimizing Treatment Adherence

• In acne, as in many other disorders, adherence to treatment is essential for successful therapeutic results as well as improving outcomes.²
• The reasons attributable to the high rate of poor adherence can be categorized into patient factors, physician factors, treatment-related issues, and disease characteristics.
• Unfortunately, acne has a few unavoidable characteristics that can be difficult for patients to accept:²
  1. Clinical improvement is usually seen 6-8 weeks after treatment is started.
  2. There may be an initial flare-up of inflammation.
  3. Relapses are frequent and cures are not, causing treatment fatigue that may contribute to adherence difficulties.
• Many factors have an effect on adherence in acne treatment (Table 2).

In order to optimize adherence to treatment, the physician
first needs to quantify and measure compliance to therapy.
Many methods are available to assess adherence, although one quick, effective, and validated tool that can be used in
a clinical setting is called the ECOB (Elaboration d’un outil d’evaluation de l’observance des traitements medicamenteux)
questionnaire (Table 3). In this mini-questionnaire, adherence
is considered poor if at least one answer given is different from
the answers expected. If a physician suspects poor adherence,
it is important to gently investigate the reasons as to why
adherence is suboptimal.

Tips to Improve Adherence ³

• An open empathetic approach can help establish trust
• Dedicated appointments for acne counseling – either nurse or doctor led
• Patient education about etiology, prevalence, and myths associated with acne
• Provide written information (i.e., handouts/leaflets) or online resources on acne, and also on their specific treatments, including expectations
• Address nonadherence promptly
• If current treatment is unsatisfactory, be willing to modify
• Recommend simplified treatment and skin care regimes, including an appropriate moisturizer and mild, gentle cleanser, to suit the patients needs²

Non-drug Interventions and Recommendations

Dispel common acne myths:

• Acne is due to being dirty
  • Hourly washing does not make a difference
• Acne is due to ‘hormonal imbalance’
  • Hormonal levels are normal in the majority of acne patients
• Acne is related to sexual behaviour
  There is no proven association with the level of sexual activity⁴

Topical treatment considerations that can encourage adherence:

• Using medication on sites that are easily accessible (face and upper trunk)
• Keeping the regimen simple and quick to use
• Selecting therapies with cosmetic acceptability
• Minimizing factors that produce irritation of the skin; many anti-acne topicals are irritating
• Applying the topicals on the entire acne-prone area to prevent new acne lesions is fundamental, rather than on existing acne lesions only
• Using short contact application (e.g., cleaning off after a few minutes to a few hours is useful at the start of a new topical regiment); introducing longer contact time as tolerated
• Avoiding application just before bedtime may reduce the additive irritant occlusive effect of a pillow
• Using aqueous-based topicals, thereby avoiding irritants such as alcohol
• Explaining that visible improvement may take several weeks or months, and an initial flare of acne can occur

Moisturizers and Cleansers

An essential component of acne skin care management with
positive effects on adherence is the appropriate selection and
use of moisturizers and cleansers.² Physicians can provide
information on key ingredients and suitable formulations to
assist patients in making informed decisions.

• Recommend aqueous moisturizers that are noncomedogenic, with minimal allergenic ingredients (e.g., fragrance and preservatives), and compatible with the chosen therapeutic regimen.
• Regular use of mild cleansers is an important aspect of optimal acne management. Routine cleansing is not only an essential part of basic hygiene, but it also removes dirt, sweat, bacteria, and exfoliated cells, preparing the skin to receive topical medications and improving drug absorption.
• Routine cleansing may enhance antimicrobial activity and decrease the chances of infection.
• Care must be taken to minimize any further disruption of the skin barrier during cleansing. The use of improper techniques and unsuitable cleansing agents can irritate or exacerbate existing lesions.
  • The use of anionic detergents (i.e., soaps) can alter the pH of skin, resulting in increased skin sensitivity.
  • Cleansers containing the surfactant sodium lauryl sulfate (SLS) can be irritating and further disrupt the skin barrier.⁵
  • Avoid the use of soaps, foams, and mechanical cleansers (e.g., beads, brushes, and scrubs ), which can inadvertently damage intercellular lipids, leading to further impairment of the barrier function and cause dry skin.
• Cleansers that are suitable for acne-prone skin are generally based on mild synthetic surfactants that minimize barrier disturbances.
  • Non-ionic surface-acting agents (e.g., silicone and polysorbate) are less likely to cause irritation and are formulated to the same pH as the skin (5.5).
  • Silicone surfactants (e.g., dimethicone) are effective at eliminating surface debris without completely stripping away protective oils.
  • Emollients contained in cleansers can minimize barrier damage by emulsifying dirt and oil for easy removal, while at the same time replacing lipids that are lost during the washing.⁶
• With the use of a mild cleanser, washing should be done twice daily.

Conclusion

Achieving adherence in acne patients often represents an
ongoing challenge. In order to realize therapeutic objectives,
pharmacologic initiatives must be accompanied by patient
education. Time devoted to counseling patients on avoiding
aggravating factors, medication use, and the importance
of maintaining proper skin care routines can contribute to
increased adherence. Finally, efforts aimed at early detection
and mitigation of poor treatment follow-through signs will
improve the outcome of therapeutic strategies.

References

1. Tan JKL. Skin Therapy Lett Pharm 4(2):1-3 (2009 Jul-Aug).
2. Dreno B, et al. Int J Dermatol 49(4):448-56 (2010 Apr).
3. Vender RB. Skin Therapy Lett FP 4(2):1-3 (2008 May).
4. Graham-Brown R, et al. Lecture Notes Dermatology 9th Edition (2007).
5. Tsang M, et al. Br J Dermatol 163(5):954-8 (2010 Nov).
6. Cork MJ. J Dermatolog Treat 8(Suppl 1):S7-13 (1997).