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© 2001 American Society for Clinical Oncology Clinical Characteristics and Outcome of Patients With Extracutaneous Mycosis FungoidesFrom the Departments of Dermatology and Radiation Oncology, Stanford University School of Medicine, Stanford, CA. Address reprint requests to Youn H. Kim, MD, Associate Professor, Department of Dermatology, Stanford University Medical Center, 900 Blake Wilbur Dr, #W0069, Palo Alto, CA 94304; email: younkim{at}stanford.edu
PURPOSE: To identify prognostic factors predictive of outcome in patients with extracutaneous (stage IV) mycosis fungoides (MF) and to evaluate the risk of progression to extracutaneous disease by initial extent of skin involvement. PATIENTS AND METHODS: One hundred twelve patients with extracutaneous disease at presentation or with progression and 434 patients with initial cutaneous-only disease were identified. Actuarial survival curves were plotted according to the Kaplan-Meier technique. RESULTS: The median survival of all stage IV patients was 13 months from the date of first treatment for stage IV disease. Sex, race, age, extent of skin involvement, and peripheral blood Sezary cell involvement were not significant to survival outcome. Eleven patients (10%) had a complete response to therapy resulting in a significantly improved median survival compared with patients with a partial or no response (1.70 v 0.91 years, P = .047 and 1.70 v 0.57 years, P = .011, respectively). At 20 years from diagnosis, the risk for progression to 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. CONCLUSION: This was a larger scale study over a longer time period than had been completed previously on extracutaneous MF. Prognostic factors important in the cutaneous stages of disease are no longer significant once extracutaneous disease develops. Patients who had a more favorable response to therapy may have had a biologically less aggressive disease than their less fortunate counterparts. The risk of developing stage IV MF is highest in patients presenting with tumorous or erythrodermic skin disease and is lowest in patients with limited skin involvement.
MYCOSIS FUNGOIDES (MF) is a malignant lymphoproliferative T-cell disorder that is generally characterized by its initial presentation in the skin. Most commonly, early stages of disease consist of indolent, pruritic, scaly patches and plaques with or without erythroderma, which may progress to become the thickened cutaneous tumors whose mushroom-like appearance gives MF its name. Involvement of the lymph nodes or viscera occurs in the advanced stage, and the most commonly identified visceral sites are the lungs, spleen, and liver.1,2 Peripheral blood involvement by the atypical T cells with hyperconvoluted cerebriform nuclei can also occur, and these circulating cells are termed Sezary cells. The rate of disease progression is variable, and thus, it is possible for patients to have simultaneous expression of patches, plaques, and tumors in different areas of their skin and also to present initially with extracutaneous involvement.2-4 Previous studies of mycosis fungoides have shown that the most important indicators predictive of survival are the type and extent of skin involvement (T classification) and the presence of extracutaneous disease, whether it be lymph node (N2 or N3) or visceral (M1).4-10 Patients presenting with tumors (T3) or erythroderma (T4) generally have a worse long-term survival than patients presenting with either limited skin involvement (T1) or generalized patch or plaque disease (T2).4,11,12 Involvement of lymph nodes or viscera (stage IV) is associated with an even worse outcome. In this study, we reviewed the long-term clinical course of 112 patients with stage IV MF to evaluate prognostic factors that might be predictive of outcome. In addition, the risk of disease progression to stage IV disease as a function of initial T classification was evaluated in 434 patients who presented initially with disease limited to the skin.
Patient Selection and Staging More than 600 patients with MF have been evaluated and treated in the Stanford Mycosis Fungoides Clinic since 1958. Diagnosis and staging of patients were completed after a comprehensive history and physical examination, complete blood cell count including peripheral blood smears for Sezary cells, general chemistry panel, chest x-ray, and skin biopsies. Clinically suspicious lymphadenopathy was evaluated by needle aspiration or by biopsy. Blind lymph node biopsies were not performed. Suspected visceral involvement was evaluated using imaging studies, by tissue biopsy and by bone marrow biopsy whenever possible. After the initial evaluation, all patients were staged according to the tumor-node-metastasis-blood categories ( Table 1) and overall staging classification system ( Table 2).13
One hundred twelve patients were identified as having stage IV MF (extracutaneous involvement) either on presentation (n = 37) to the clinic or with progression from an earlier stage (I to III) of disease (n = 75). Patient selection was limited to those patients who were untreated or who were seen at Stanford within 60 days of initiation of primary treatment for their stage IV disease. All 112 patients included in this study had their diagnosis established or confirmed in the Laboratory of Surgical Pathology in the Department of Pathology at Stanford University.4 For the risk of progression analysis, we reviewed 468 patients in our database who were seen within 6 months of their initial diagnosis and had their treatment managed in our clinic.
Response to Therapy Recently, the National Cancer Institute made recommendations for the standardization of response criteria for patients with non-Hodgkin’s lymphoma.14 Although the report details the criteria for response for involvement of lymph nodes, spleen and bone marrow, the criteria for response of skin lesions in cutaneous lymphomas were not well described. In this study, clinical response to treatment was evaluated primarily on the basis of physical examination, however, imaging studies or subsequent lymph node biopsies were also obtained from some patients. A complete response (CR) was defined as a complete clinical regression of all involved regions (both skin and extracutaneous sites). For the purposes of this study, a partial response was defined as any response that was less than complete, and no response was defined as no observable clinical response to therapy.
Statistical Analysis
Overall Survival The overall survival for the entire group of stage IV MF patients is shown in Fig 1. The median survival from the date of first treatment for extracutaneous disease was 13.0 months, and this ranged from 8 days in one patient to more than 235 months in another patient, who is currently without evidence of disease. Among 112 patients, 89 (79%) have died from disease, 10 (9%) have died from causes other than MF, and one has been lost to follow-up. Of the remaining 12 patients who are alive, six have active disease, and six (only 5% of all patients) are alive without disease.
Demographics and Survival The patient and disease characteristics of this patient population are listed in Table 3. The age range at presentation with stage IV disease was 19 to 85 years, with a median of 57.5 years. The male to female ratio was 1.2:1. There were 89 whites, 12 Latinos, eight African-Americans, and three Asians. Though there were slight differences in the median survivals when comparisons were made between patients younger than 58 years and patients older than 58 years, between males and females, and between whites and nonwhites, the differences in overall survivals were not found to be statistically significant (P = .98, P = .59, and P = .82, respectively).
Of the 112 patients identified, 78 patients had documented nodal disease only (stage IVA, median 1.15 years), whereas the remaining 34 patients had evidence of visceral involvement (stage IVB, median 0.90 years). The most common visceral sites of involvement were the lungs, the oral cavity and pharynx, and the CNS. The majority (n = 62, 55%) of stage IV patients had tumor stage disease (T3) at the time that extracutaneous disease was documented. Generalized patch or plaque (T2) involvement was seen in 16 patients (14%), erythroderma (T4) was seen in 34 patients (30%), and no patient with extracutaneous disease had limited skin involvement (T1). Neither the patient’s T classification at the time of stage IV diagnosis nor the patient’s type of extracutaneous involvement (nodal v visceral) was found to be predictive of a more favorable outcome. Presence of a Sezary cell count greater than 5% of total lymphocytes (B classification = 1) was seen in 29 patients, whereas the remaining 83 patients had a Sezary count less than or equal to 5% of total lymphocytes (B classification = 0). The B1 group of patients had a longer median survival than the B0 group of patients (median, 2.23 v 0.90 years, respectively), although this difference was not significant (P = .12).
T Classification and Risk of Progression
Response Rate, Survival, and Treatment Type Table 5 lists the response rates and median survivals for the 112 patients. Although a CR was obtained in only 11 patients (10%) compared with 70 patients (62%) who had a partial response and with 31 patients (28%) who had no response, a CR correlated with a significantly longer median survival (1.70 v 0.91 years, P = .047 and 1.70 v 0.57 years, P = .011, respectively). The likelihood of a CR of all lesions during the initial treatment for stage IV disease was similar in patients with either generalized plaque (T2) or tumor (T3) stage MF (19% and 13%, respectively), but unlikely in erythrodermic patients (T4, 0%).
No correlation between treatment type and clinical response could be made because the number of patients in each treatment category was small, and treatments were selected based on the extent of disease and practice patterns at the time of treatment. When specific treatment types were grouped into broad categories, patients who received systemic treatment only (n = 30), systemic and topical therapy (n = 31), or regional and topical treatments (n = 19) were found to have CR rates of 6.7%, 6.4%, and 21.0%, respectively (Table 5). Of the remaining 32 patients, seven had regional therapy only, three had systemic and regional therapy, 20 had topical only therapy, and two had a combined systemic, regional, and topical therapy as their first treatment regimen for stage IV disease. The median survival of patients who had systemic and topical regimens after documentation of stage IV disease was about half (0.67 years) of that for patients who received systemic only (1.19 years, P = .078) or regional and topical (1.22 years, P = .123) regimens, although none of the three treatment groups conferred any advantage for long-term survival.
Large-scale studies of mycosis fungoides have identified several prognostic factors predicting for a worse survival. These include advanced age,18,19 African-American race,19 more extensive skin involvement (T classification),6,18,20 and the presence of visceral or nodal disease.5-7,18,20,21 For the most part, the studies have focused on the earlier stages of disease with cutaneous-only involvement (stages I to III) and less so on patients with extracutaneous disease (stage IV). Our current review of extracutaneous mycosis fungoides in 112 patients is a much larger scale study over a longer time period than has been completed previously. We have confirmed many of the earlier findings by previous investigators, and we have made some interesting observations about this unique patient population. The recent paper of Diamandidou et al18 analyzing prognostic factors in 115 patients with MF (only 21 of whom had extracutaneous disease) reported that the median survival of patients with stage IV disease was approximately 2.5 years. Of these 21 patients, the majority had nodal involvement, the rest had bone marrow disease, and none had solid organ involvement.18 In our study of 112 patients with extracutaneous disease, 78 of whom had nodal involvement and the remainder had visceral disease, we observed a median survival of only 1.1 years. This was similar to our prior observation in a smaller group of patients.22 The very poor survival in the presence of extracutaneous disease was independent of whether the involved sites were nodal (stage IVA) or visceral (stage IVB), although slight differences did exist (1.15 years v 0.90 years, respectively). When prognostic factors were examined in patients for whom extracutaneous involvement with MF had already been diagnosed (stage IV), we observed that neither advanced age, African-American race, sex, advanced skin stage, nor the presence of Sezary cells in the peripheral blood was associated with a significantly worse survival. Another critical finding of our study supports the observation that the probability of developing extracutaneous disease correlates strongly with the extent of skin involvement at presentation (T classification). Those patients with limited patch or plaque lesions are unlikely to progress to extracutaneous disease when they are treated for their skin disease, whereas patients with generalized lesions are more likely (10% at 20 years), and patients with tumorous or erythrodermic involvement are most likely (35.5% and 41%, respectively). These findings are consistent with earlier reports that the risk of progression to extracutaneous mycosis fungoides is higher in patients with more advanced skin manifestations of the disease at presentation.4,12 The randomized trial of 103 patients with all stages of MF reported by Kaye et al,23 from the National Cancer Institute in 1989, demonstrated that the early use of combined therapies of electron-beam radiation and parenteral chemotherapy resulted in higher CR rates compared with treatment with conservative sequential topical therapies; however, this did not result in significant improvements in either disease-free or overall survival.23 In our study of 112 patients with stage IV MF, we observed that only a small number of patients (10%) were able to achieve a CR with the first treatment regimen after their extracutaneous disease diagnosis, however this was associated with significant improvement in survival. Unfortunately, because of selection of patient treatments and the small number of patients in each group, we are unable to identify a particular effective regimen. The variation in outcome for different treatments may simply reflect patient selection. In summary, our results suggest that prognostic factors, such as advanced age, African-American race, and advanced skin stage, found to be important in the early stages (I to III) of mycosis fungoides, are no longer significant to the overall survival once extracutaneous disease develops. These patients have a poor outcome, with a median survival of 13 months from the time of their first treatment for stage IV disease. The risk of developing extracutaneous mycosis fungoides is highest in patients who initially present with tumorous and erythrodermic skin disease and the risk is lowest in patients with limited skin involvement. This observation is important for patient management discussions. Finally, although the likelihood of obtaining a CR to the initial therapy after stage IV diagnosis is relatively small, those patients who are able to achieve complete resolution of their disease have a significantly improved overall survival when compared with patients who achieve a partial or no response. Although this may be because of more limited manifestations of extracutaneous disease in those patients, we could demonstrate no change, for example, in patients with stage IVA (nodal) versus stage IVB (visceral) disease. Clearly, given these poor outcome data, all patients with stage IV mycosis fungoides should be considered candidates for clinical trials testing novel approaches to therapy.
Funding provided by the Stanford Medical Student Scholars Program.
1. Epstein EH, Levin DL, Croft JD, et al: Mycosis fungoides, survival, prognostic features, response to therapy, and autopsy findings. Medicine 15: 61-72, 1972 2. Bunn PA, Huberman MS, Whang-Peng J, et al: Prospective staging evaluation of patients with cutaneous T-cell lymphomas: Demonstration of a high frequency of extracutaneous dissemination. Ann Intern Med 93: 223-230, 1980 3. Weiss LM, Hu E, Wood GS, et al: Clonal rearrangement of T-cell receptor genes in mycosis fungoides and dermatopathic lymphadenopathy. N Engl J Med 313: 539-544, 1985[Abstract] 4. Kim YH, Hoppe RT: Mycosis fungoides and the Sezary syndrome. Semin Oncology 26: 276-289, 1999[Medline] 5. Green SB, Byar DP, Lamberg SI: Prognostic variables in mycosis fungoides. Cancer 47: 2671-2677, 1981[Medline] 6. Lamberg SI, Green SB, Byar DP, et al: Clinical staging for cutaneous T-cell lymphoma. Ann Intern Med 100: 187-192, 1984 7. Sausville EA, Eddy JL, Makuch RW, et al: Histopathologic staging at initial diagnosis of mycosis fungoides and the Sezary syndrome: Definition of three distinctive prognostic groups. Ann Intern Med 109: 373-382, 1988 8. Weinstock MA, Horm JW: Population-based estimate of survival and determinants of prognosis in patients with mycosis fungoides. Cancer 62: 1658-1661, 1988[Medline]
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Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17: 1244-1253, 1999 15. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
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Gehan E: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 203-223, 1965 17. Cox D, Snell E: Analysis of Binary Data. London, England, Chapman & Hall, 1989 18. Diamandidou E, Colome M, Fayad L, et al: Prognostic factor analysis in mycosis fungoides/Sezary syndrome. J Am Acad Derm 40: 914-924, 1999[Medline] 19. Weinstock MA, Reynes JF: The changing survival of patients with mycosis fungoides: A population-based assessment of trends in the United States. Cancer 85: 208-212, 1999[Medline] 20. Fuks ZY, Bagshaw MA, Farber EM: Prognostic signs and the management of mycosis fungoides. Cancer 32: 1385-1395, 1973[Medline] 21. Vonderheid EC, Diamond LW, Van Volten WA, et al: Lymph node classification systems in cutaneous T-cell lymphoma: Evidence for the utility of the working formulation of non-Hodgkin’s lymphoma for clinical usage. Cancer 73: 207-218, 1994[Medline] 22. Merlo CJ, Hoppe RT, Abel E, et al: Extracutaneous mycosis fungoides. Cancer 60: 397-402, 1987[Medline] 23. Kaye F, Bunn PJ, Steinberg S, et al: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321: 1784-1790, 1989[Abstract] Submitted May 31, 2000; accepted October 3, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
