Pityriasis rubra pilaris

ABSTRACT

Approximately 1,000 new cases of cutaneous Tell lymphoma are definitively diagnosed each year.

Mycosis fungoides and Sezary syndrome are the primary lymphomas In this group. Mycosis fungoides can begin in the patch, plaque, or tumor stage or in a combination. Less commonly, its initial presentation is erythrodermic. Because the Initial appearance of cutaneous T-cell lymphoma can be subtle and the histopathologic evidence nonspecific, the disease is commonly misdiagnosed as a common dermatologic condition such as chronic eczema. Misdiagnosis can severely affect treatment and prognosis. Clinicians must be able to recognize this disease and know when to include it in the differential diagnosis. This article provides an overview of cutaneous Tell lymphoma, discusses differential diagnoses, and outlines management considerations.

Cutaneous T-cell lymphoma (CTCL) is a malignant lymphoma that comprises a group of diseases typified by a proliferation of malignant T lymphocytes. The initial presentation is usually dermatologic. These lymphomas are of low grade and should not be confused with other dermatologic lymphomas such as B-cell lymphoma and adult T-cell leukemia/lymphoma.1 Staging and treatment are different for higher-grade lymphomas.

Cutaneous T cell lymphoma, represented primarily by mycosis fungoides (MF) and Sezary syndrome, has several other clinical variants (see Table 1). Although Louis Alibert described the first case of MF in 1806, the National Cancer Institute did not recommend adopting the term cutaneous T cell lymphoma until 1979.2

Cutaneous T cell lymphoma's initial presentation can be subtle. In many cases, the disease mimics common dermatologic conditions such as eczema and psoriasis, and in early stages, histopathologic studies may cloud rather than clarify the picture. According to one study, an accurate diagnosis takes an average of 6 years,z yet delayed diagnosis can affect treatment and prognosis.3

Although single and combined therapeutic drugs can produce prolonged remission, no systemic therapy provides a cure. However, the prognosis for stage IA is excellent.4 Limited early (patch stage) disease is more likely than later stages to respond to steroids.This stage also responds well to topical chemotherapy, psoralen-ultraviolet A (PUVA) treatment, and electron beam therapy, all of which can induce sustained therapeutic response. Early, accurate diagnosis is essential so that therapeutic intervention can begin promptly.

Once the clinician suspects CTCL or obtains confirmatory histopathologic, evidence, the patient should be referred to an oncologist or dermatologist who specializes in cutaneous oncology. Clinicians may continue to serve patients' primary care needs; therefore, they should be aware that disease dissemination can be manifested in any organ system, but this usually occurs in later stages (see Table 2).

Epidemiology

Because a definition of CTCL has not been broadly accepted, epidemiologic data must be viewed with caution. However, there is evidence that the incidence of CTCL has risen markedly.5 This finding is believed to reflect a true increase, not merely scientific advances that permit earlier detection.

Data for 1973 to 1978 show an average incidence of 0.3 cases of MF per 100,000 per year.b Approximately 1,000 new cases are definitively diagnosed in the United States annually. Although CTCL primarily affects older people, 12% of those diagnosed were younger than age 40. The disease occurs in twice as many men as women and is more common in blacks than in whites. No risk factors beyond age, race, and gender have been clearly established.

Clinical Manifestations

Cutaneous T cell lymphoma has four distinct phases: premycotic (patch), infiltrative (plaque), tumor, and erythrodermic (see Figure 1). The phases often overlap.

In the patch phase, CTCL may easily be mistaken for common dermatologic conditions such as chronic eczema and psoriasis (see Figure 2). Sezary syndrome, the erythrodermic, leukemic variant of CTCL, may be confused with such common skin conditions as allergic drug responses (see Figure 3), subacute systemic lupus erythematosus, and erythrodermic psoriasis. A patient's failure to respond to treatment for any of these conditions suggests a possible diagnosis of CTCL, especially in the presence of male sex, black race, or older age.

Mycosis Fungoides

In the patch phase, MF lesions are generally macular and up to several centimeters in size. The lesions usually appear on the trunk, thighs, buttocks, and upper arm but can emerge anywhere on the body Lesions typically resemble benign dermatologic conditions such as chronic eczema, superficial fungal infections, psoriasis, and drug reactions. The patches may appear singularly or in clusters and may or may not be pruritic. Their color may vary from faint pink to yellowish tan to dusky violet-red. The patient may exhibit superficial to mild scaling. The epidermis may appear atrophic.

The patch phase can evolve into the plaque phase over several months to years. In the plaque phase, patches become increasingly dense and more profoundly demarcated. The plaques are elevated, palpable, irregularly shaped, and darker red than patches.

Scaling and pruritus are common complaints in the plaque phase. Alopecia may occur in areas infiltrated by plaques. When plaques infiltrate the face, the patient may present a leonine appearance. Examination of mononuclear cells may reveal atypical cells such as pleomorphic or hyperchromatic convoluted nuclei. The plaque phase may be confused with Hodgkin's disease and other lymphomas.

In the next phase, the tumor phase, patients have aggressive disease for which the prognosis is usually poor. Tumors may arise from existing plaques or appear in previously unaffected areas. The tumors tend to appear on the face and in the axillae, groin, and other body folds but can occur anywhere. The inframammary area in women should be checked for tumor growth. Approximately 10% of initial symptoms are tumors; this condition is called mycosis fungoides d'emblee. The tumors tend to be reddish brown or purplish red with a smooth surface that is prone to ulceration.

Because the tumors can become large and frequently ulcerate, infection and sepsis can be a problem. Researchers have suggested that 50% of all CTCL deaths are caused by infections such as with Pseudomonas aeruginosa and Staphylococcus aureus.7

Local or generalized lymphadenopathy may occur in any phase, but it is common in the tumor phase and in patients with erythroderma. The presence of lymphadenopathy in any stage warrants immediate evaluation. The tumor phase may be confused with deep fungal infections, atypical mycobacterial infections, leukemic infiltrates, cutaneous B-cell lymphoma, and leprosy

Sezary Syndrome

Sezary syndrome is the erythrodermic, leukemic variant of CTCL. The malignant mature T cells circulate in the peripheral blood, populating the skin and lymph nodes. Mononuclear cell leukocytosis may occur in the peripheral blood. Patients exhibit generalized erythroderma and scaling, although some areas may have no involvement.

Other signs and symptoms include fissuring of the palms and soles, severe pruritus, alopecia, cutaneous pain, edema, lymphadenopathy, and hepatomegaly. Patients may complain of chills and poor temperature control caused by severe erythema and scaling. They may exhibit weight loss and may experience insomnia from severe pruritus.

The differential diagnosis for this CTCL variant includes any condition that causes generalized erythema such as allergic drug reactions, atopic and contact dermatitis, psoriasis, pityriasis rubra pilaris, and subacute cutaneous lupus erythematosus.

Diagnosis

Table 3 provides a general outline for diagnosing dermatologic conditions. The clinician should ask patients when they first noticed the onset of symptoms. If skin lesions are present, the clinician should ascertain whether they itch, burn, or hurt. The record should note whether the patient has ever had a skin disease and, if so, how it was treated and how the problem was resolved. The clinician should include a sexual history to preclude exposure to any sexually transmitted pathogen.

Other questions the clinician should ask include: Are you taking any new medications? Where were you born? Is there a history of skin disease in your family? Do you have any allergies or conditions such as asthma or hives? Have you had contact with chemicals or other hazardous materials? Have you traveled recently?

If the clinician suspects CTCL, the physical examination should focus on the skin for color changes and the presence of lesions. If lesions are present, the clinician should note their type, shape, arrangement, and distribution. The patient may have to be seen several times. At each visit, the evolution of lesions or skin changes should be noted.

Examination of the palms and soles is important because fissuring and cracking, which are common, are painful and may serve as infection portals of entry. The oral cavity must be checked far lesions. All lymph nodes must be examined for lymphadenopathy, which can be an early sign of systemic manifestation of the disease.

Although hepatomegaly and splenomegaly are not generally present in early disease, their presence or absence should be noted. The stool must be checked for occult blood to determine a possible association with adenocarcinoma of the bowel.

Laboratory tests should include a complete blood count with a differential. Special attention should be focused on the absolute lymphocyte count; the patient may have lymphopenia or lymphocytosis. A complete chemistry battery, including liver and renal function tests, is warranted. An elevated lactate dehydrogenase level may indicate hepatic involvement or a significant tumor burden.

A skin biopsy is crucial. The gold standard for diagnosing CTCL is histologic proof from skin biopsy. Any patient with a chronic dermatosis that is refractory to treatment should undergo a biopsy every 3 months until a definitive diagnosis has been made. If a patient has a chronic dermatosis of a papulosquamous nature that is refractory to treatment, CTCL should be considered in the differential diagnosis. The patient should stop taking topical steroids for at least 1 month before a biopsy is performed because those drugs can mask CTCI;s histologic features.

Biopsy of CTCL shows evidence of atypical lymphoid cells or more definitively the presence of a Pautrier's microabscess in the epidermis. Southern blot analysis (immunogenotyping) may help detect a monoclonal T cell population in the infiltrated lesion.

Staging

Many staging systems have been developed for MF and Sezary syndrome.$ Tables 4 and 5 outline a possible protocol. The primary considerations are the extent of skin involvement and the presence of extracutaneous disease. The disease stage and aggressiveness and the patient's age, general health, and compliance with the prescribed regimen determine prognosis.

To determine prognosis, the patient is placed in one of three categories: good, intermediate, or poor. Patients with good prognosis have only patch or plaque involvement but no detectable blood or visceral involvement. Their median length of survival is more than 12 years.

Patients classified as having intermediate prognosis have a median survival of 5 years. They may have skin plaques, tumors, or erythroderma but no detectable blood, lymph node, or visceral involvement.

Patients who are at poor risk have advanced CTCL. Median survival rate is less than 40 months from the time of diagnosis. These patients have skin tumors, erythroderma, a high level of circulating Sezary cells, and lymph or visceral involvement or both. Therapy for advanced CTCL is associated with high morbidity and little longterm benefit. Untreated CTCL advances to systemic disease and death.

Treatment

Therapeutic options may be adjusted for disease stage. In the past, treatment beyond stage IA was considered primarily palliative. The goal of therapy was to keep the disease under control; however, recent combinations of biologic response modifiers have resulted in long-term remissions of advanced disease, sometimes lasting indef finitely. Far more choices are available for the treatment of early stages than for later stages.

Stages IA to IIA

The first two stages of CTCL, IA and IIA, may be treated with topical steroids, retinoids, PUVA therapy, extracorporeal photochemotherapy (photopheresis), single agent chemotherapy, interferon, electron beam radiation, or combination therapy.

Topical steroids. Topical steroids may induce remission in milder forms of CTCL by inhibiting the proliferative response of the malignant T cell. The steroids are available in a cream, ointment, or lotion at mild-, moderate-, high-, and super-high-potency.

The steroid's effects depend on its potency, the application site, the size of skin surface on which it is used, and the condition of the skin to which it is applied. Mildand moderate-potency topical steroids are usually applied to the affected areas twice a day; more potent strengths are usually applied once a day.

All topical steroids can cause dermal and epidermal atrophy, especially in patients with skin disease. Highpotency steroids may impair local host defenses against malignant T cells. Steroids can suppress the hypothalamicpituitary-adrenal axis. Therefore, patients who apply the higher-potency steroids to large surface areas should be monitored for adrenal suppression.

Because steroids are used to treat other dermatologic conditions, such as psoriasis, the drugs may be prescribed for an erroneously diagnosed disease. If the patient responds to the steroids, no further treatment may be needed despite the inaccurate diagnosis. If the patient does not respond to the steroids, a confirmatory biopsy is recommended. Additionally, fluorinated steroids should not be used on the face without first consulting a dermatologist or oncologist.

Retinoids. Retinoids are vitamin A compounds found in dietary animal and vegetable sources such as fish liver oils and yellow and green leafy vegetables. Acitretin (Soriatane) is the commercially available synthetic form of retinoid.

Retinoids have immunomodulatory and anti-inflammatory effects. They help control cell proliferative capacity and differentiation. Benefits last only as long as the patient takes the drug. Adverse effects, which are related to dose and identical to those for toxic reaction to vitamin A, include myalgias, alopecia, visual changes, hyperlipidemia, elevated liver function tests, and cardiovascular thrombotic events. Because of the teratogenic activity of these drugs, women of childbearing age should be instructed not to become pregnant while taking them.

PUVA therapy. The patient undergoing PUVA therapy takes a psoralen compound before being exposed to ultraviolet A (UA) light. The radiation has no direct ef fect on the lymph nodes or viscera. The usual initial treatment regimen is three times a week for 3 months or until the disease goes into remission or until treatment fails. In the case of remission, the patient is slowly tapered off treatment. Adverse effects include pruritus, sebostasis, nausea, cataracts, and photocarcinogenesis.

Extracorporeal photochemotherapy (photopheresis). Photopheresis is a form of pheresis therapy that is used to treat CTCL's systemic manifestations for palliation. Patients generally receive two treatments every 3 to 4 weeks. Treatment involves the extracorporeal exposure of 2 % to 5 % of peripheral blood leukocytes to a psoralen compound and WA irradiation. The treated cells are then returned to the patient.

Photopheresis's exact mechanism of action is unknown. The DNA of the leukocytes absorbs the psoralen. After UVA exposure, a cross-linking of the DNA occurs, causing those cells to be altered. This alteration induces the increased production of biologic response modifiers such as tumor necrosis factor alpha and interleukins 1 and 6. Photopheresis is safe and effective and exerts therapeutic effects in the erythrodermic and late stages of disease 9,10

Single agent chemotherapy. Single agent chemotherapy can be given either topically or systemically with alkylating drugs that produce breaks in the DNA, such as mechlorethamine (Mustargen) and carmustine (BiCNU, Gliadel). Protective gloves should be worn when topically applying chemotherapeutic drugs. Before the application, the patient should undergo a test application to determine if an irritant response will occur. Neither of these chemotherapeutic drugs should be applied to the genitals or areas that are easily irritated, such as the eyelids.

Because mechlorethamine is not as easily absorbed systemically as carmustine, the former can be used twice a day. Treatment fails when no response occurs after a 12- to 14-week trial period. The patient is given a rest period to prevent bone marrow suppression, which is more likely to occur with the more readily absorbed carmustine. Either drug may be restarted later with a higher dose or in combination with another drug.

Among the systemic drugs that are used to treat CTCL are antimetabolites that inhibit the synthesis of nucleic acids. Examples include the folate antagonist methotrexate and the enzyme inhibitor S-fluorouracil (Adrucil, Efudex, Fluoroplex). Although all of these drugs produce some response, evidence does not favor one in particular.11

Interferon. Interferons are glycoproteins that have numerous immunomodulatory, antiproliferative, and antiviral effects. The two types, I and II, are divided into three classes: alfa and beta (type I) and gamma (type II). Interferon alfa (Alferon N, Intron A, Roferon-A) and interferon gamma (Actimmune) are usually used to treat CTCL.

The dosage and treatment schedule should be individualized.12 Interferon's most common adverse effects are flulike signs and symptoms such as myalgias and lowgrade fever. The drugs can also cause serious adverse ef fects such as depression, heart failure, retinal bleeding, and diabetes.

Electron beam radiation. This form of therapy is considered if the disease is refractory to treatment or progresses to stage II or IIA. The dosage of the beam depends on the lesions' thickness. Generally, only a small dose is required because CTCL plaques and tumors tend to be highly sensitive to irradiation. Usually only the areas that have plaques or tumors are exposed to the beam and irradiated; however, the entire body can be treated.

The most common adverse effects are generalized erythema, alopecia (usually reversible), and an inability to sweat for 6 to 12 months, followed by chronically dry skin. Patients have an increased risk for secondary skin cancers.13

Combination therapy. Various forms of combination therapy can successfully treat CTCL. PUVA therapy may be combined with mechlorethamine, retinoids, or an interferon. Interferon may be combined with retinoids or photopheresis.

Stage IIB

Three treatment options are available for stage IIB disease. The first option is combination therapy of mechlorethamine and PWA therapy, interferon, retinoids, and photopheresis. These drugs may be given together or in some combination. The second option is multidrug systemic chemotherapy consisting, for example, of chlorambucil (Leukeran), cyclophosphamide (Cytoxan, Neosar), and prednisone (Deltasone, Meticorten, Panasol-S). The third option is radiation therapy with local field or electron beam.

Stage III or Sezary Syndrome

Options for this advanced stage include photopheresis, systemic chemotherapy, total skin electron beam irradiation, and combination therapy with interferon, retinoids, photopheresis, and electron beam.

Stages IVA and IVB

Multidrug chemotherapy is used for the final stages of CTCL.

ACKNOWLEDGMENT

The author thanks Alain Rook, MD, Professor of Dermatology; Marilyn Watkins, RN, CS, MSN, of the Occupational Health Department; and William Witmer, BS, photographer for the Dermatology Department, all at the University of Pennsylvania Medical Center, Philadelphia.

REFERENCES

1. Nagatani T, Miyazawa M, Matsuzaki T, et al.: Comparative study of cutaneous T-cell lymphoma and adult T cell leukemia/lymphoma. Semin Dermatol 1994;13(3):216-22.

2. Koh HK, Charif M, Weinstock MLA: Epidemiology and clinical manifestations of cutaneous T-cell lymphoma. Hematol/Oncol Clin North Atn 1991;9(5):943-60.

3. Heald PAL; Edelson RL: Lymphomas, pseudolymphomas, and related conditions. In: Fitzpatrick TB, Eisen AZ, 'olff K, et al., eds: Dermatology in general medicine. New York, NY: McGraw-Hill; 1993:1285-307.

4. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage LA (limited patch and plaque) mycosis fungoides. Arch Dermatol 1996;132:1309-13.

5. Weinstock MA: Epidemiology of mycosis fungoides. Semin Dermatol 1994;13(3):154-59.

6. Weinstock MA, Horn JW: Mycosis fungoides in the United States: Increasing incidence and descriptive epidemiology. JAMA 1988;260:42-46.

7. Lorincz AL: Cutaneous T-cell lymphoma (mycosis fungoides). Lancet 1996;347:871-76.

8. Foss FM, Sausville EA: Prognosis and staging of cutaneous T-cell lymphoma. Hematol/Oncol Clin North Am 1995;9(5):1011-19.

9. Gottlieb SL, Wolfe JT, Fox FE, et al.: Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: A 10-year experience at a single institution. J Am Acad Dermatol 1996;35(6):946-57.

10. Duvic M, Hester JP, Lemak NA: Photopheresis therapy for cutaneous T cell lymphoma. J Am Acad Dermatol 1996;35(4):573-79.

11. Bunn PA, Hoffman SJ, Norris D, et al.: Systemic therapy of cutaneous Tcell lymphomas (mycosis fungoides and the Sezary syndrome). Ann Intern Med 1994;121(8):592-602.

12. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol/Onocol Clin North Am 1995;9(5):1089-107.

13. Zackheim HS: Treatment of cutaneous T-cell lymphoma. Semin Dermatol 1994;13(3):207-15.

ABOUT THE AUTHOR

William H. Macey, RN, CS, MSN, is a photopheresis staff nurse, Department of Dermatology, University of Pennsylvania Medical Center, Philadelphia.

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