AJCP / Original Article
A Review of Survival in Mycosis Fungoides Robin T. Vollmer, MD From the VA and Duke University Medical Centers, Durham, NC. Key Words: Mycosis fungoides; Survival; Hazard function; Cutaneous T-cell lymphoma Am J Clin Pathol May 2014;141:706-711 DOI: 10.1309/AJCPH2PHXFCX3BOX
ABSTRACT Objectives: The objectives of this study are to review prior publications of survival for patients with mycosis fungoides (MF), to perform some analyses on the consolidated data, and then to consider the implications of the results. Methods: The data for this study comprise 18 survival curves derived from seven prior publications of long-term survival in relatively large series of patients with MF. Altogether, the study uses results from over 5,000 patients. To examine fatality, the study uses hazard functions derived from the survival curves. Results: The analyses demonstrate significant variability in survival between different groups who have studied MF, and the results document that for most patients the diagnosis of MF has little impact on fatality. Conclusions: Although MF is considered a cutaneous lymphoma, that is, a malignancy, it may be time to reconsider low stages of MF as precursors to malignancy analogous to the precursors to malignancies of other types or organs.
Mycosis fungoides (MF) is the most common primary lymphoma of the skin. Yet, MF is not common, and its histologic definition remains both elusive and controversial.1-5 Many investigators have thoroughly studied the histologic features of MF,3-16 finally achieving a consensus of sorts that emphasizes the importance of the following: MF cells’ cytology (modestly enlarged lymphocytes with dark convoluted nuclei and, for the most part, a high nuclear-to-cytoplasmic ratio), the presence of these cells in the epidermis (in basilar epidermal rows, scattered singly, or in Pautrier clusters), the clear halos that often surround these cells, their presence in the papillary dermis (where they are often appear interstitially among collagen fibers), and the limited changes typical for spongiotic or other dermatoses.1,3-5,15,17-20 Despite this consensus, benign nonlymphomatous mimics of MF confound the diagnosis.1-21 Controversy and uncertainty also mark outcomes of MF. For example, most patients with MF live for decades after the diagnosis and die of other causes, so deciding when they have died of complications of MF is not straightforward. In this setting, many investigators have studied and reported the most objective outcome of overall survival.22-27 Herein I review prior reports of survival in MF, reanalyze the data, and then examine the implications of the results.
Materials and Methods The data for this study comprise 18 survival curves derived from seven prior publications of survival in patients with MF.22-28 The years of publication spanned from 1988 through 2012. If a single institution published several 706 706
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© American Society for Clinical Pathology
AJCP / Original Article
❚Equation 1❚
t
S(t) = exp(–∫0 h dx) Because some of the results are given for specific T stages of MF, their definitions are summarized in ❚Table 2❚.32
Results Fit of Derived Hazard Functions to Observed Survival Curves Because most of the results rely on hazard functions derived from the survival curves and Equation 1, the first result shows how well these hazard functions provided survival probabilities that fit the original data. ❚Figure 1❚ is a plot of the observed values of S(t) on the x-axis vs values of S(t) derived from the hazard functions and Equation 1 on the y-axis. The line shows where perfect fits should occur, and the fact that the points are consistently close to the line implies that the derived hazard functions accurately reflect the observed survival probabilities. Altogether, the mean difference between observed and fitted survival probabilities was –1.1 × 10–4 (units of probability), with a median difference of 0 and a range of –.04 to .05. Overall Survival for MF ❚Figure 2❚ shows three survival plots for a total of 2,305 patients with MF of all stages and according to the three institutions that reported them: the Dutch group (Dutch Cutaneous Lymphoma Working Group registry),23 the UK group (ICARIS cutaneous lymphoma database in London, England),27 and the Stanford University group.25 The Dutch group did not contain cases of Sézary syndrome (SS), whereas 12% and 7%, respectively, of the UK and Stanford group patients had SS, so the better survival of the Dutch patients could in part © American Society for Clinical Pathology
❚Table 1❚ Study Data Useda Institution
Year
T Stage
No. of Patients
NCI 1988 T2 61 NCI 1988 T4 42 Dutch 1997 All 278 UCSF 1999 T1 174 UCSF 1999 T2 199 UCSF 1999 T3 47 UCSF 1999 T4 69 Stanford 2003 T1 159 Stanford 2003 T2 192 Stanford 2003 T3 96 Stanford 2003 T4 78 Stanford 2003 All 525 SEER 2011 All 1,815 UK 2012 All 1,502 MDA 2012 T1 522 MDA 2012 T2 395 MDA 2012 T3 136 MDA 2012 T4 188 Dutch, Dutch Cutaneous Lymphoma Working Group registry23; MDA, MD Anderson medical center27; NCI, National Cancer Institute22; SEER, Surveillance, Epidemiology, and End Results program28; Stanford, Stanford University25; UCSF, University of California, San Francisco24; UK, group of investigators associated with the ICARIS cutaneous lymphoma database in London, England.26 a The listed year is the year of publication.
❚Table 2❚ T Stages of Mycosis Fungoidesa Stage Description T1 Limited patches, papules, and/or plaques covering less than 10% of the skin surface T2 Patches, papules, or plaques covering 10% or more of the skin surface T3 One or more tumors 1 cm or larger in diameter T4 Confluence of erythema covering 80% or more of the skin surface a
From American Joint Committee on Cancer.32
Calculated Survival Probability
times, then data from just the latest publication were used. The midpoints of the year of diagnosis ranged from 1978 through 1996 (mean, 1986), and follow-up times ranged from 6.7 to 38 years (median, 20 years). Data from curves with fewer than 40 patients were not used, and there were no additional exclusion criteria. Altogether, the survival curves involved a total of 5,953 patients. Seventeen of the survival curves gave overall survival, and one provided relative survival, defined as the ratio of overall survival to the expected survival for matched patients from the population free of MF.29 Each survival curve was digitized to yield a list of survival probabilities at times from zero to the time of last follow-up, and the total number of such points was 328. ❚Table 1❚ summarizes the studies and data used.22-28 For ease of interpolation, further analysis, and plotting, hazard functions for these curves were derived as before.30,31 Specifically, if the survival probability at any time t is symbolized as S(t), then the hazard function h relates to S(t) through the following equation:
1.0 0.8 0.6 0.4 0.2 0.0 0.0
0.2
0.4
0.6
0.8
1.0
Observed Survival Probability
❚Figure 1❚ A plot of observed values of S(t) on the x-axis vs values of S(t) derived from the hazard functions and Equation 1 on the y-axis. The line shows where perfect fits should occur.
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1.0
1.0 Dutch UK
0.6
Stanford
0.4
0.8 Overall Survival
Overall Survival
0.8
Stanford and MDA
0.2
UCSF
0.6 0.4 0.2
0.0
0.0 0
2
4
6
8
10
0
2
4
Years
6
8
10
Years
❚Figure 2❚ Overall survival plots for mycosis fungoides reported in three studies from the Dutch group,23 the Stanford University group,25 and the UK group.27 In total, the number of patients used for these curves comprised 2,305.
❚Figure 3❚ Overall survival plots for a total of 855 patients with stage T1 mycosis fungoides according to the three institutions that reported them: the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27
be due to the lack of patients with SS. Nevertheless, 10-year survival for the UK and Stanford groups was 63% and 53%, respectively, a difference that was significant by the equality of proportions test (P = .0001, c2 = 16) but a difference not intuitively related to the percentage of patients with SS since the UK data included more, not fewer, patients with SS.
Overall Survival for Stage T4 MF ❚Figure 6❚ shows survival plots for a total of 377 patients with stage T4 MF according to the four institutions that reported them: the NCI,22 the UCSF group,24 the Stanford University group,25 and the MDA group.27 Survival at 10 years was significantly different between these groups (P = .0018, c2 test) and ranged from approximately 0.1% to 29%. Because the NCI had both the lowest survival and the lowest number of patients (n = 42), its data may represent an outlier. Furthermore, there was no significant difference
Overall Survival for Stage T2 MF ❚Figure 4❚ shows survival plots for a total of 847 patients with stage T2 MF according to the four institutions that reported them: National Cancer Institute (NCI),22 the UCSF group,24 the Stanford University group,25 and the MDA group.27 Survival at 10 years was significantly different for the patients from these four groups (P ~ 0, c2 test) and ranged from approximately 55% to 77% (weighted mean, 67%). Overall Survival for Stage T3 MF ❚Figure 5❚ shows survival plots for a total of 279 patients with stage T3 MF according to the three institutions that reported them: the UCSF group,24 the Stanford University group,25 and the MDA group.27 Survival at 10 years was significantly different for the patients from these three groups (P = .01, c2 test) and ranged from approximately 28% to 42% (weighted mean, 34%). 708 708
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1.0 MDA
Stanford
0.8 Overall Survival
Overall Survival for Stage T1 MF ❚Figure 3❚ shows survival plots for a total of 855 patients with stage T1 MF according to the three institutions that reported them: the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27 The 10-year survival among the three groups was the same at approximately 86% (P > 0.3, c2 test).
UCSF 0.6
NCI
0.4 0.2 0.0 0
2
4
6
8
10
Years
❚Figure 4❚ Overall survival plots for a total of 847 patients with stage T2 mycosis fungoides according to the four institutions that reported them: National Cancer Institute (NCI)22; the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27 © American Society for Clinical Pathology
1.0
1.0
0.8
0.8 Overall Survival
Overall Survival
AJCP / Original Article
0.6 MDA
Stanford
0.4
UCSF
0.6
0.2
0.0
0.0 2
4
6
8
UCSF
0.4
0.2
0
MDA
Stanford NCI 0
10
2
4
between the 10-year survival probabilities for patients in the remaining three groups with T4 stage (P > .7, c2 test). The weighted 10-year survival for these last three groups was 27%. Consolidated values of overall survival at 10 years by T stage are summarized in ❚Table 3❚. Relative Survival for MF in the Surveillance, Epidemiology, and End Results Database Unlike the above sets of data, the Surveillance, Epidemiology, and End Results (SEER) data provide relative survival probabilities, that is, overall survival probability divided by the expected survival probability for a matched group from the MF-free population.29 ❚Figure 7❚ shows the survival curve derived from the SEER survival data on 1,815 patients with MF of all stages, and ❚Figure 8❚ shows the corresponding hazard function. The hazard function begins at 0, rises to a peak during the first 2 years after diagnosis, and then gradually declines to near 0 by 10 years. The fall in hazard at 10 years corresponds to a leveling of the survival curve after 10 years. Both curves indicate that after 10 years, the risk of death nearly equals that of the general population. In addition, the results suggest that approximately 19% of patients have a fatal form of MF and approximately 81% do not. Because academic centers have found that 15% of patients have the T4 stage and 28% have either the T3 or T4 stage, these results suggest that most with fatal MF have tumor stages higher than T1 or T2. Finally, the rise and fall in the hazard function implies that the timing of deaths in the few with fatal MF is skewed. For example, more than 50% of the observed deaths occur in the first 4 years after diagnosis, and an additional 40% occur over the next 6 years. © American Society for Clinical Pathology
8
10
❚Figure 6❚ Overall survival plots for a total of 377 patients with stage T4 mycosis fungoides according to the four institutions that reported them: National Cancer Institute (NCI)22; the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27
❚Table 3❚ Consolidated Values for 10-Year Overall Survival by T Stagea T Stage
Survival, %
No. of Patients
T1 86 855 T2 67 847 T3 34 279 T4b 27 335 a
The reported survival probability was calculated as a weighted mean, that is, a mean across the studies with results weighted by the number of patients in each of the studies. b For patients with T4 stage mycosis fungoides, the National Cancer Institute (NCI) data were not included because of the small number of cases and because the low survival for NCI data appeared to be an outlier.
1.0
Relative Survival
❚Figure 5❚ Overall survival plots for a total of 279 patients with stage T3 mycosis fungoides according to the three institutions that reported them: the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27
6 Years
Years
0.8 0.6 0.4 0.2 0.0 0
5
10
15
20
Years
❚Figure 7❚ A plot of relative survival probabilities vs time from diagnosis for 1,815 patients in the Surveillance, Epidemiology, and End Results data.
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Vollmer / Survival in Mycosis Fungoides
Relative Hazard
0.03
0.02
0.01
0.00 0
2
4
6
8
10
Years
❚Figure 8❚ The derived hazard function for relative survival of 1,815 patients in the Surveillance, Epidemiology, and End Results data set. The hazard function begins at 0, rises to a peak during the first 2 years after diagnosis, and then falls to near 0 by 10 years.
Discussion The variability found in the survival curves of Figures 2 to 6 and across several T stages for MF is likely due to uncontrolled factors, including referral patterns for the academic institutions involved as well as differences in prognostic factors such as patient age, patient sex, status of N and B stages, and status of patch vs plaque morphology in the primary lesions. Variability in the histopathologic diagnosis of MF must have added to these, because disagreements between pathologists about the diagnosis of MF are well documented.3,7,8,14,33,34 How to improve diagnostic agreement is not, however, clear. The International Society for Cutaneous Lymphomas has proposed an algorithm that combines clinical, histologic, molecular, and immunohistochemical (IHC) components.15 Yet, some have not found it helpful and even discovered that IHC stains offered limited help.2-5 For example, McCalmont recently wrote that “one cannot immunostain one’s way to a diagnosis of mycosis fungoides.”35 Despite these issues, the collected data illustrated in Figures 2 to 6 and in Table 2 emphasize how overall survival relates closely to T stage, how patients with stage T1 do well, and how most of those with shortened survival have higher T stages. Thus, if we see a skin biopsy specimen with histologic features of early MF, perhaps we should, as LeBoit2 suggests, question how much effort to put into diagnosing early MF and instead pursue further dialogue with dermatologists about the differential diagnosis as well as additional biopsies of persistent or plaque-like lesions. The survival results for patients in the SEER database are provocative for several reasons. The data comprise the largest number of patients and were collected over a relatively long and current period from 1988 through 2001. Because the 710 710
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SEER results use relative survival, the survival end point is most likely related to MF. Unlike the other data reported here, the SEER data reflect community practices broader than the academic centers for the other data. Regardless, the SEER survival data on MF suggest that most patients do not have a fatal disease. In summary, MF is classified as a lymphoma—that is, as a cancer—yet the survival results of more than 5,000 patients summarized here demonstrate that most with MF do not have a fatal disease. Perhaps a better way to think of early stages of MF is as precursors to, or markers of, cancer rather than cancer itself. In this regard, early MF may be similar to other precursors and markers such as dysplastic nevus, melanoma in situ, actinic keratoses, Bowen disease, dysplasias of the cervix, adenomas of the colon with high-grade dysplasia, and high-grade intraepithelial neoplasia of the prostate. For the most part, we embrace these diagnoses while recognizing that their pathologies do not imply a fatal form of cancer. Perhaps we should view early MF the same way. Address reprint requests to Dr Vollmer: Laboratory Medicine 113, VA Medical Center, 508 Fulton St, Durham, NC 27705; Robin. [email protected].
References 1. Glusac EJ. Of cells and architecture: new approaches to old criteria in mycosis fungoides. J Cutan Pathol. 2001;28:169173. 2. LeBoit PE. Simulators of cutaneous lymphoma: where should our efforts go? Am J Clin Pathol. 2013;139:414-417. 3. Florell SR, Cessna M, Lundell RB, et al. Usefulness (or lack thereof) of immunophenotyping in atypical cutaneous T-cell infiltrates. Am J Clin Pathol. 2006;125:727-736. 4. Ferrara G, Di Blasi A, Zalaudek I, et al. Regarding the algorithm for the diagnosis of early mycosis fungoides proposed by the International Society for Cutaneous Lymphomas: suggestions from a routine histopathology practice. J Cutan Pathol. 2007;35:549-553. 5. Furmanczyk PS, Wolgamot GM, Kussick SJ, et al. Diagnosis of mycosis fungoides with different algorithmic approaches. J Cutan Pathol. 2010;37:8-14. 6. Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Am J Dermatopathol. 1979;1:5-26. 7. Lefeber WP, Robinson JK, Clendenning WE, et al. Attempts to enhance light microscopic diagnosis of cutaneous T-cell lymphoma (mycosis fungoides). Arch Dermatol. 1981;117:408-411. 8. Nickoloff BJ. Light-microscopic assessment of 100 patients with patch/plaque-stage mycosis fungoides. Am J Dermatopathol. 1988;10:469-477. 9. King-Ismael D, Ackerman AB. Guttate parapsoriasis/digitate dermatosis (small plaque parapsoriasis) is mycosis fungoides. Am J Dermatopathol. 1992;14:518-530. 10. Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fungoides/Sézary syndrome (cutaneous T-cell lymphoma). Am J Surg Pathol. 1994;18:645-667. © American Society for Clinical Pathology
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11. Smoller BR, Bishop K, Glusac E, et al. Reassessment of histologic parameters in the diagnosis of mycosis fungoides. Am J Surg Pathol. 1995;19:1423-1430. 12. Toro J, Sander CA, LeBoit PE. Persistent pigmented purpuric dermatitis and mycosis fungoides: simulant, precursor, or both? a study by light microscopy and molecular methods. Am J Dermatopathol. 1997;19:108-118. 13. Santucci M, Biggeri A, Feller AC, et al. Efficacy of histologic criteria for diagnosing early mycosis fungoides. Am J Surg Pathol. 2000;24:40-50. 14. 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;28:174-183. 15. Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53:1053-1063. 16. Massone C, Kodama K, Kerl H, et al. Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study of 745 biopsy specimens from 427 patients. Am J Surg Pathol. 2005;29:550-560. 17. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas: 2005: histological and molecular aspects. J Cutan Pathol. 2005;32:647-674. 18. Burg G, Kempf W, Smoller B, et al. Mycosis fungoides. In: LeBoit PE, Burg G, Weedon D, et al, eds. Pathology and Genetics of Skin Tumours. Lyon, France: IARC; 2006:169174. 19. Ralfkiaer E, Cerroni L, Sander CA, et al. Mycosis fungoides. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC; 2008:296-298. 20. Song SX, Willemze R, Swerdlow SH, et al. Mycosis fungoides: report of the 2011 Society for Hematopathology/ European Association for Haematopathology workshop. Am J Clin Pathol. 2013;139:466-490. 21. Sarantopoulos GP, Palla B, Said J, et al. Mimics of cutaneous lymphoma: report of the 2011 Society for Hematopathology/ European Association for Haematopathology workshop. Am J Clin Pathol. 2013;139:536-551. 22. Sausville EA, Eddy JL, Makuch RW, et al. Histopathologic staging at initial diagnosis of mycosis fungoides and the Sézary syndrome. Ann Intern Med. 1988;109:372-382. 23. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the cutaneous lymphoma study group of the European Organization for Research and Treatment of Cancer. Blood. 1997;90:354-371.
© American Society for Clinical Pathology
24. 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;40:418-425. 25. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome. Arch Dermatol. 2003;139:857-866. 26. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28:4730-4739. 27. Talpur R, Singh L, Daulat S, et al. Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009. Clin Cancer Res. 2012;18:5051-5060. 28. Clarke C, O’Malley C. Non-Hodgkin lymphoma. In: SEER Survival Monograph. 2011. seer.cancer.gov/publications/ survival/surv_nonhodgkin.pdf-2011-11-08. Accessed July 29, 2013. 29. Cho H, Howlader N, Mariotto AB, et al. Estimating Relative Survival for Cancer Patients From the SEER Program Using Expected Rates Based on Ederer I Versus Ederer II Method. Bethesda, MD: Surveillance Research Program, National Cancer Institute; 2011. Technical Report 2011-01. 30. Vollmer RT. The dynamics of death in prostate cancer. Am J Clin Pathol. 2012;137:957-962. 31. Vollmer RT. The dynamics of death in melanoma. J Cutan Pathol. 2012;39:1075-1082. 32. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:614. 33. Santucci M, Burg G, Feller AC. Interrater and intrarater reliability of histologic criteria in early cutaneous T-cell lymphoma. Dermatol Clin. 1994;12:323-327. 34. Yeh YA, Hudson AR, Prieto VG, et al. Reassessment of lymphocytic atypia in the diagnosis of mycosis fungoides. Mod Pathol. 2001;14:285-288. 35. McCalmont TH. Choose wisely. J Cutan Pathol. 2013;40:445446.
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A Review of Survival in Mycosis Fungoides Robin T. Vollmer, MD From the VA and Duke University Medical Centers, Durham, NC. Key Words: Mycosis fungoides; Survival; Hazard function; Cutaneous T-cell lymphoma Am J Clin Pathol May 2014;141:706-711 DOI: 10.1309/AJCPH2PHXFCX3BOX
ABSTRACT Objectives: The objectives of this study are to review prior publications of survival for patients with mycosis fungoides (MF), to perform some analyses on the consolidated data, and then to consider the implications of the results. Methods: The data for this study comprise 18 survival curves derived from seven prior publications of long-term survival in relatively large series of patients with MF. Altogether, the study uses results from over 5,000 patients. To examine fatality, the study uses hazard functions derived from the survival curves. Results: The analyses demonstrate significant variability in survival between different groups who have studied MF, and the results document that for most patients the diagnosis of MF has little impact on fatality. Conclusions: Although MF is considered a cutaneous lymphoma, that is, a malignancy, it may be time to reconsider low stages of MF as precursors to malignancy analogous to the precursors to malignancies of other types or organs.
Mycosis fungoides (MF) is the most common primary lymphoma of the skin. Yet, MF is not common, and its histologic definition remains both elusive and controversial.1-5 Many investigators have thoroughly studied the histologic features of MF,3-16 finally achieving a consensus of sorts that emphasizes the importance of the following: MF cells’ cytology (modestly enlarged lymphocytes with dark convoluted nuclei and, for the most part, a high nuclear-to-cytoplasmic ratio), the presence of these cells in the epidermis (in basilar epidermal rows, scattered singly, or in Pautrier clusters), the clear halos that often surround these cells, their presence in the papillary dermis (where they are often appear interstitially among collagen fibers), and the limited changes typical for spongiotic or other dermatoses.1,3-5,15,17-20 Despite this consensus, benign nonlymphomatous mimics of MF confound the diagnosis.1-21 Controversy and uncertainty also mark outcomes of MF. For example, most patients with MF live for decades after the diagnosis and die of other causes, so deciding when they have died of complications of MF is not straightforward. In this setting, many investigators have studied and reported the most objective outcome of overall survival.22-27 Herein I review prior reports of survival in MF, reanalyze the data, and then examine the implications of the results.
Materials and Methods The data for this study comprise 18 survival curves derived from seven prior publications of survival in patients with MF.22-28 The years of publication spanned from 1988 through 2012. If a single institution published several 706 706
Am J Clin Pathol 2014;141:706-711 DOI: 10.1309/AJCPH2PHXFCX3BOX
© American Society for Clinical Pathology
AJCP / Original Article
❚Equation 1❚
t
S(t) = exp(–∫0 h dx) Because some of the results are given for specific T stages of MF, their definitions are summarized in ❚Table 2❚.32
Results Fit of Derived Hazard Functions to Observed Survival Curves Because most of the results rely on hazard functions derived from the survival curves and Equation 1, the first result shows how well these hazard functions provided survival probabilities that fit the original data. ❚Figure 1❚ is a plot of the observed values of S(t) on the x-axis vs values of S(t) derived from the hazard functions and Equation 1 on the y-axis. The line shows where perfect fits should occur, and the fact that the points are consistently close to the line implies that the derived hazard functions accurately reflect the observed survival probabilities. Altogether, the mean difference between observed and fitted survival probabilities was –1.1 × 10–4 (units of probability), with a median difference of 0 and a range of –.04 to .05. Overall Survival for MF ❚Figure 2❚ shows three survival plots for a total of 2,305 patients with MF of all stages and according to the three institutions that reported them: the Dutch group (Dutch Cutaneous Lymphoma Working Group registry),23 the UK group (ICARIS cutaneous lymphoma database in London, England),27 and the Stanford University group.25 The Dutch group did not contain cases of Sézary syndrome (SS), whereas 12% and 7%, respectively, of the UK and Stanford group patients had SS, so the better survival of the Dutch patients could in part © American Society for Clinical Pathology
❚Table 1❚ Study Data Useda Institution
Year
T Stage
No. of Patients
NCI 1988 T2 61 NCI 1988 T4 42 Dutch 1997 All 278 UCSF 1999 T1 174 UCSF 1999 T2 199 UCSF 1999 T3 47 UCSF 1999 T4 69 Stanford 2003 T1 159 Stanford 2003 T2 192 Stanford 2003 T3 96 Stanford 2003 T4 78 Stanford 2003 All 525 SEER 2011 All 1,815 UK 2012 All 1,502 MDA 2012 T1 522 MDA 2012 T2 395 MDA 2012 T3 136 MDA 2012 T4 188 Dutch, Dutch Cutaneous Lymphoma Working Group registry23; MDA, MD Anderson medical center27; NCI, National Cancer Institute22; SEER, Surveillance, Epidemiology, and End Results program28; Stanford, Stanford University25; UCSF, University of California, San Francisco24; UK, group of investigators associated with the ICARIS cutaneous lymphoma database in London, England.26 a The listed year is the year of publication.
❚Table 2❚ T Stages of Mycosis Fungoidesa Stage Description T1 Limited patches, papules, and/or plaques covering less than 10% of the skin surface T2 Patches, papules, or plaques covering 10% or more of the skin surface T3 One or more tumors 1 cm or larger in diameter T4 Confluence of erythema covering 80% or more of the skin surface a
From American Joint Committee on Cancer.32
Calculated Survival Probability
times, then data from just the latest publication were used. The midpoints of the year of diagnosis ranged from 1978 through 1996 (mean, 1986), and follow-up times ranged from 6.7 to 38 years (median, 20 years). Data from curves with fewer than 40 patients were not used, and there were no additional exclusion criteria. Altogether, the survival curves involved a total of 5,953 patients. Seventeen of the survival curves gave overall survival, and one provided relative survival, defined as the ratio of overall survival to the expected survival for matched patients from the population free of MF.29 Each survival curve was digitized to yield a list of survival probabilities at times from zero to the time of last follow-up, and the total number of such points was 328. ❚Table 1❚ summarizes the studies and data used.22-28 For ease of interpolation, further analysis, and plotting, hazard functions for these curves were derived as before.30,31 Specifically, if the survival probability at any time t is symbolized as S(t), then the hazard function h relates to S(t) through the following equation:
1.0 0.8 0.6 0.4 0.2 0.0 0.0
0.2
0.4
0.6
0.8
1.0
Observed Survival Probability
❚Figure 1❚ A plot of observed values of S(t) on the x-axis vs values of S(t) derived from the hazard functions and Equation 1 on the y-axis. The line shows where perfect fits should occur.
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Am J Clin Pathol 2014;141:706-711 DOI: 10.1309/AJCPH2PHXFCX3BOX
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1.0
1.0 Dutch UK
0.6
Stanford
0.4
0.8 Overall Survival
Overall Survival
0.8
Stanford and MDA
0.2
UCSF
0.6 0.4 0.2
0.0
0.0 0
2
4
6
8
10
0
2
4
Years
6
8
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❚Figure 2❚ Overall survival plots for mycosis fungoides reported in three studies from the Dutch group,23 the Stanford University group,25 and the UK group.27 In total, the number of patients used for these curves comprised 2,305.
❚Figure 3❚ Overall survival plots for a total of 855 patients with stage T1 mycosis fungoides according to the three institutions that reported them: the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27
be due to the lack of patients with SS. Nevertheless, 10-year survival for the UK and Stanford groups was 63% and 53%, respectively, a difference that was significant by the equality of proportions test (P = .0001, c2 = 16) but a difference not intuitively related to the percentage of patients with SS since the UK data included more, not fewer, patients with SS.
Overall Survival for Stage T4 MF ❚Figure 6❚ shows survival plots for a total of 377 patients with stage T4 MF according to the four institutions that reported them: the NCI,22 the UCSF group,24 the Stanford University group,25 and the MDA group.27 Survival at 10 years was significantly different between these groups (P = .0018, c2 test) and ranged from approximately 0.1% to 29%. Because the NCI had both the lowest survival and the lowest number of patients (n = 42), its data may represent an outlier. Furthermore, there was no significant difference
Overall Survival for Stage T2 MF ❚Figure 4❚ shows survival plots for a total of 847 patients with stage T2 MF according to the four institutions that reported them: National Cancer Institute (NCI),22 the UCSF group,24 the Stanford University group,25 and the MDA group.27 Survival at 10 years was significantly different for the patients from these four groups (P ~ 0, c2 test) and ranged from approximately 55% to 77% (weighted mean, 67%). Overall Survival for Stage T3 MF ❚Figure 5❚ shows survival plots for a total of 279 patients with stage T3 MF according to the three institutions that reported them: the UCSF group,24 the Stanford University group,25 and the MDA group.27 Survival at 10 years was significantly different for the patients from these three groups (P = .01, c2 test) and ranged from approximately 28% to 42% (weighted mean, 34%). 708 708
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Overall Survival for Stage T1 MF ❚Figure 3❚ shows survival plots for a total of 855 patients with stage T1 MF according to the three institutions that reported them: the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27 The 10-year survival among the three groups was the same at approximately 86% (P > 0.3, c2 test).
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❚Figure 4❚ Overall survival plots for a total of 847 patients with stage T2 mycosis fungoides according to the four institutions that reported them: National Cancer Institute (NCI)22; the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27 © American Society for Clinical Pathology
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between the 10-year survival probabilities for patients in the remaining three groups with T4 stage (P > .7, c2 test). The weighted 10-year survival for these last three groups was 27%. Consolidated values of overall survival at 10 years by T stage are summarized in ❚Table 3❚. Relative Survival for MF in the Surveillance, Epidemiology, and End Results Database Unlike the above sets of data, the Surveillance, Epidemiology, and End Results (SEER) data provide relative survival probabilities, that is, overall survival probability divided by the expected survival probability for a matched group from the MF-free population.29 ❚Figure 7❚ shows the survival curve derived from the SEER survival data on 1,815 patients with MF of all stages, and ❚Figure 8❚ shows the corresponding hazard function. The hazard function begins at 0, rises to a peak during the first 2 years after diagnosis, and then gradually declines to near 0 by 10 years. The fall in hazard at 10 years corresponds to a leveling of the survival curve after 10 years. Both curves indicate that after 10 years, the risk of death nearly equals that of the general population. In addition, the results suggest that approximately 19% of patients have a fatal form of MF and approximately 81% do not. Because academic centers have found that 15% of patients have the T4 stage and 28% have either the T3 or T4 stage, these results suggest that most with fatal MF have tumor stages higher than T1 or T2. Finally, the rise and fall in the hazard function implies that the timing of deaths in the few with fatal MF is skewed. For example, more than 50% of the observed deaths occur in the first 4 years after diagnosis, and an additional 40% occur over the next 6 years. © American Society for Clinical Pathology
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❚Table 3❚ Consolidated Values for 10-Year Overall Survival by T Stagea T Stage
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The reported survival probability was calculated as a weighted mean, that is, a mean across the studies with results weighted by the number of patients in each of the studies. b For patients with T4 stage mycosis fungoides, the National Cancer Institute (NCI) data were not included because of the small number of cases and because the low survival for NCI data appeared to be an outlier.
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❚Figure 5❚ Overall survival plots for a total of 279 patients with stage T3 mycosis fungoides according to the three institutions that reported them: the University of California, San Francisco (UCSF) group24; the Stanford University group25; and the MD Anderson (MDA) group.27
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❚Figure 7❚ A plot of relative survival probabilities vs time from diagnosis for 1,815 patients in the Surveillance, Epidemiology, and End Results data.
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❚Figure 8❚ The derived hazard function for relative survival of 1,815 patients in the Surveillance, Epidemiology, and End Results data set. The hazard function begins at 0, rises to a peak during the first 2 years after diagnosis, and then falls to near 0 by 10 years.
Discussion The variability found in the survival curves of Figures 2 to 6 and across several T stages for MF is likely due to uncontrolled factors, including referral patterns for the academic institutions involved as well as differences in prognostic factors such as patient age, patient sex, status of N and B stages, and status of patch vs plaque morphology in the primary lesions. Variability in the histopathologic diagnosis of MF must have added to these, because disagreements between pathologists about the diagnosis of MF are well documented.3,7,8,14,33,34 How to improve diagnostic agreement is not, however, clear. The International Society for Cutaneous Lymphomas has proposed an algorithm that combines clinical, histologic, molecular, and immunohistochemical (IHC) components.15 Yet, some have not found it helpful and even discovered that IHC stains offered limited help.2-5 For example, McCalmont recently wrote that “one cannot immunostain one’s way to a diagnosis of mycosis fungoides.”35 Despite these issues, the collected data illustrated in Figures 2 to 6 and in Table 2 emphasize how overall survival relates closely to T stage, how patients with stage T1 do well, and how most of those with shortened survival have higher T stages. Thus, if we see a skin biopsy specimen with histologic features of early MF, perhaps we should, as LeBoit2 suggests, question how much effort to put into diagnosing early MF and instead pursue further dialogue with dermatologists about the differential diagnosis as well as additional biopsies of persistent or plaque-like lesions. The survival results for patients in the SEER database are provocative for several reasons. The data comprise the largest number of patients and were collected over a relatively long and current period from 1988 through 2001. Because the 710 710
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SEER results use relative survival, the survival end point is most likely related to MF. Unlike the other data reported here, the SEER data reflect community practices broader than the academic centers for the other data. Regardless, the SEER survival data on MF suggest that most patients do not have a fatal disease. In summary, MF is classified as a lymphoma—that is, as a cancer—yet the survival results of more than 5,000 patients summarized here demonstrate that most with MF do not have a fatal disease. Perhaps a better way to think of early stages of MF is as precursors to, or markers of, cancer rather than cancer itself. In this regard, early MF may be similar to other precursors and markers such as dysplastic nevus, melanoma in situ, actinic keratoses, Bowen disease, dysplasias of the cervix, adenomas of the colon with high-grade dysplasia, and high-grade intraepithelial neoplasia of the prostate. For the most part, we embrace these diagnoses while recognizing that their pathologies do not imply a fatal form of cancer. Perhaps we should view early MF the same way. Address reprint requests to Dr Vollmer: Laboratory Medicine 113, VA Medical Center, 508 Fulton St, Durham, NC 27705; Robin. [email protected].
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