Dermatology Online Journal

Mycosis fungoides stage IB progressing to cutaneous tumors
Emily Berger MD, Ahmet Altiner MD, Julie Chu MD, Rishi Patel MD, Scott Sanders MD, Jo-Ann Latkowski MD
Dermatology Online Journal 17 (10): 5

Department of Dermatology, New York University, New York, New York

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Abstract

A 44-year-old African American woman presented with well-demarcated, pruritic and intermittently painful plaques and subsequently a diagnosis of mycosis fungoides stage IB was made. Six months after diagnosis, cutaneous tumors developed despite treatment with narrow-band ultraviolet B phototherapy. The patient failed low-dose methotrexate treatment and is now slowly improving on combination therapy with subcutaneous interferon alfa and oral bexarotene. This patient demonstrates the progression of patch/plaque stage disease to cutaneous tumors. Her case highlights the use of interferon and combination therapies in more advanced mycosis fungoides and demonstrates potential difficulties encountered in treating skin of color.

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History

A 44-year-old African American woman with diabetes mellitus presented to the Dermatology Clinic at Bellevue Hospital Center with a one-year history of a pruritic and intermittently painful eruption on the buttocks, abdomen, and breasts. Her initial skin biopsy was not diagnostic, and treatment with topical glucocorticoids was not effective. Review of symptoms was negative. A second skin biopsy was performed. Narrow-band ultraviolet B (NB-UVB) phototherapy was initiated. Despite phototherapy, she developed eroded nodules on the neck, breasts, and abdomen. Low-dose, weekly oral methotrexate (maximum dose 12.5 mg) was added to her treatment regimen without clinical improvement and was discontinued after six months. Phototherapy also was discontinued, owing to repeated impetiginization of the eruption. Subcutaneous interferon alfa (IFNα) was initiated at a dose of 1.5 million units three times per week with improvement, but persistence of nodules. The IFNα dose was increased to 3 million units three times a week, and, most recently, oral bexarotene (375 mg daily) was added with continued improvement.

Physical examination

Figure 1	Figure 2

Well-demarcated, erythematous, and indurated plaques with scale were present on the abdomen, back, buttocks, and breasts. Eroded nodules were present on the posterior aspect of the neck and breasts.

Laboratory data

A complete blood count, serum chemistry profile, liver function tests, lipid profile, and thyroid function tests were normal. Lactase dehydrogenase was elevated at 317 U/L (range 110 to 225 U/L). Peripheral blood flow cytometry tests showed a small subpopulation (12% of the total) of atypical T cells that expressed CD2, CD3, and CD5 and that lacked CD7. The CD4/CD8 ratio was normal (1.81).

Histopathology

Figure 3

There is a dense, nodular, and band-like infiltrate predominantly of lymphocytes that fills the papillary and upper reticular dermis. Many lymphocytes have enlarged nuclei with irregular contours. Some atypical lymphocytes extend to the overlying epidermis as single units and small clusters with minimal associated spongiosis. Immunoperxidase studies show that the atypical lymphocytes are predominantly reactive for CD3, with preservation of CD5 reactivity and decreased expression of CD7. The atypical lymphocytes are not reactive for CD30.

Discussion

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). There are four clinical presentations of MF: patches, plaques, tumors, and erythroderma. Cutaneous tumors in MF may represent progression from patches or plaques or may arise de novo as the initial manifestation of the disease. The rate of progression from patches to plaques to tumors varies. A retrospective study of 30 patients from Puerto Rico, which included patients with all stages of MF, noted that most patients with disease limited to the skin did not progress to more advanced disease with systemic involvement. Furthermore, if patients were to progress or even die from systemic involvement of lymphoma, then this was most likely to occur within the first three to five years of MF diagnosis [1]. Progression is a chronic occurrence that happens over months to years. In a 2007 study of 42 patients, 38 initially were diagnosed with patch stage MF. Twenty-seven of total patients with plaque stage subsequently progressed; 11 patients had tumor stage; six patients with lymph node involvement had visceral involvement; and 14 patients, all of whom were in tumor stage, eventually developed blastic transformation of tumor cells, which is a poor prognostic sign. The average duration of patch, plaque, and tumor stages was 7.2, 2.3, and 1.8 years, respectively [2]. A study of 100 Japanese patients with MF or Sézary syndrome highlights that prognosis worsens with increased stage at diagnosis [3]. Patients presenting with cutaneous tumors, in contrast to those with patches or plaques, have a poorer prognosis. In patients who develop skin tumors, prognosis is worst in those who develop histopathologic transformation in tumors, in which there are large malignant cells, mitoses, and, in some cases, new expression of CD30 on tumor cells [4].

Cutaneous tumors in MF have important implications for treatment. Most patients with patch/plaque MF are well-controlled with skin-directed therapies, such as topical glucocorticoids, topical chemotherapy, and phototherapy. If progression ensues (or tumors are present at outset) combination therapy with the above treatments plus local radiotherapy or systemic medication may be required. There are several options for systemic agents. The most relevant to our patient is cytokine therapy, e.g. interferon alpha (INFα) and systemic retinoids, e.g. bexarotene. Cytokine therapies are employed to enhance the host immune response against tumor cells. INFα is most commonly administered as low-dose therapy three times weekly for an extended time period (one year or longer). Dosing may be limited by side effects, which include flu-like illness or laboratory abnormalities (i.e., leukopenia or elevated liver enzymes) [5, 6]. INFα can be used as monotherapy or in combination therapy with phototherapy or oral retinoids [5].

Oral bexarotene, which is a synthetic retinoid, is a safe and effective treatment for MF and is most commonly employed in patients refractory to at least one other systemic treatment. In a retrospective chart review of 66 patients on bexarotene monotherapy or combination therapy, intention to treat response rate was 44 percent (where response rates were similar across stages) [7]. Bexarotene requires careful monitoring for thyroid function abnormalities and hyperlipidemia [5].

As our patient demonstrates, patients with skin of color are less likely to achieve complete clearance with phototherapy as compared with more lightly colored individuals, possibly because pigment impedes the penetration of ultraviolet light thus limiting potential lymphocytoxic effects [4]. As a result, therapeutic effects of phototherapy are greater in hypopigmented MF vs. pigmented MF. Phototherapy with psoralen plus ultraviolet A (PUVA) photochemotherapy is more effective than is NB-UVB phototherapy in MF patients with darker skin types [4]. Overall, progression in patients with skin of color may be difficult to halt with phototherapy and may require the addition of systemic therapies.

References

1. Berlingeri-Ramos A, et al. Disease evolution of patients with mycosis fungoides- a report of 30 cases. PRHSJ 2007;26:151 [PubMed]

2. Kamarashev J, et al. Mycosis fungoides-analysis of the duration of disease stages in patients who progress and the time point of high-grade transformation. Int J Dermatol 2007;46:930. [PubMed]

3. Suzuki S, et al. Prognosis of 100 patients with mycosis fungoides and Sezary syndrome. J Dermatol Sci 2010; 57: 37 [PubMed]

4. Hinds G, Heald P. Cutaneous T-cell lymphoma in skin of color. J Am Acad Dermatol 2009;60:359 [PubMed]

5. Marsden JR, Rajpar SF. Mycosis Fungoides. In: Treatment of Skin Disease: Comprehensive Therapeutic Strategies, 3rd edition. Lebwohl M, et al, eds. Elsevier Health Sciences, 2009:468

6. Lansigan F, Foss FM. Current and emerging treatment strategies for cutaneous T-cell lymphoma. Drugs 2010;70:273 [PubMed]

7. Abbott RA, et al. Bexarotene therapy for mycosis fungoides and Sezary syndrome. Br J Dermatol 2009;160:1299 [PubMed]

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