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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1483-1488 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.1374 Analysis of Primary CD30+ Cutaneous Lymphoproliferative Disease and Survival From the Surveillance, Epidemiology, and End Results Database
From the Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT; and the Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Corresponding author: Lynn D. Wilson, MD, MPH, Department of Therapeutic Radiology, Yale University School of Medicine, HRT 132, 333 Cedar St, New Haven, CT 06520; e-mail: lynn.wilson{at}yale.edu
Purpose Primary CD30+ cutaneous lymphoproliferative disease (PCLPD) is a spectrum of indolent cutaneous T-cell lymphomas. The primary intention of the analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database was to report epidemiologic information and overall survival of patients with PCLPD. Methods We investigated the SEER database from 1973 to 2004 and performed univariable and multivariable survival analysis. Results A total of 268 cases of PCLPD were recorded from 1973 to 2004. Median age at diagnosis was 61 years (range, 5 to 98 years). Among cases, 58% were male, and 42% female. Race distribution was 87% white, 7% black, and 4% Asian/Pacific Islander. A total of 157 patients had primary, localized PCLPD. For the total population (N = 268), overall survival at 3 years was 81% (95% CI, 74% to 87%). Population-matched relative survival at 3 years was 87% (SE, 3.6%). Disease-specific survival at 5 years was 92% (95% CI, 86% to 95%). Head and neck skin site predicted for inferior overall survival in patients with primary, localized PCLPD on univariable analysis (hazard ratio [HR] = 4.4; P = .008; 95% CI, 1.5 to 13.2), and was suggestive of decreased overall survival on multivariate analysis (HR = 3.0; P = .06; 95% CI, 0.95 to 9.7). Conclusion Localized PCLPDs are rare diseases with an excellent overall survival and occur more frequently in whites and in men. Head and neck skin primary site may be associated with poorer survival. Conclusions regarding subsets demonstrating association with survival should be taken with caution, given the small number of deaths analyzed.
Cutaneous lymphoma has an incidence of 1 in 100,000.1 Primary cutaneous T-cell lymphomas (CTCL) are T-cell lymphomas that have no evidence of extracutaneous involvement and occur with an overall age-adjusted incidence of 6.4 per million.2 The most common type of CTCL is mycosis fungoides (MF), and the second most common type of primary cutaneous lymphoma is primary CD30+ lymphoproliferative disease (PCLPD), which accounts for approximately 25% to 30% of all primary CTCL.3 PCLPD has been described as a spectrum of diseases, including primary cutaneous anaplastic large-cell lymphoma (PCALCL) and lymphomatoid papulosis (LyP).4 PCALCL is considered an indolent cutaneous lymphoma, and clinically presents as a solitary or localized group of nodules or tumors, although multifocality occurs in 20% of all patients. Extracutaneous spread, usually to regional lymph nodes, occurs in 10% of all patients. Lesions are usually greater than 1 cm in size, and are often ulcerated. Spontaneous partial or complete remission sometimes occurs, although less frequently than in LyP. PCALCL frequently relapses in skin, even after complete response to therapy.4 For a diagnosis of PCALCL, there should be no evidence or history of other lymphoproliferative disorders, such as LyP, MF, or other type of CTCL that may present as histologically similar entities. More than 75% of cells should stain positively for CD30+ antigen and will typically be anaplastic lymphoma kinase (ALK) negative.5 The prognosis for patients with primary PCALCL is thought to be generally favorable, with a more than 90% 10-year disease-related survival.4,6 Localized radiation has been described as the treatment of choice for localized PCALCL.4 LyP is on the other end of the PCLPD spectrum, and is also an indolent cutaneous lymphoid infiltration that can sometimes be distinguished from PCALCL on the basis of clinical features. LyP is more likely to be multifocal at presentation than is PCALCL, and presents as recurrent, self-healing papulonodular eruptions that often spontaneously resolve without treatment, over weeks to months after initial presentation.4 In addition to the histologic findings, clinical correlation is necessary for accurate diagnosis.6 The prognosis of patients with LyP is generally excellent, with a disease-related survival of 100% at 5 years.4 Unfortunately, 5% to 20% of LyP cases progress to or have concurrent systemic anaplastic large-cell lymphoma, MF, or Hodgkin's disease.4,7,8 Other lymphoproliferative diseases that involve the skin and express CD30 include systemic large-cell transformation of MF, systemic anaplastic large-cell lymphoma, cutaneous natural killer (NK)/T-cell lymphoma, primary cutaneous Hodgkin's disease, and cutaneous manifestation of systemic Hodgkin's disease. Secondary CD30+ lymphoproliferative disorders portend a worse outcome than does primary disease.4 The largest specific series of patients with secondary or primary CD30+ lymphoproliferative disorders described in the literature is provided by the Dutch Cutaneous Lymphoma Group,4 which reports on 219 patients diagnosed between 1983 and 1998. In that seminal report, 89 patients were noted to have "solitary" or "regional" disease. This series and others have reported a favorable 3- to 5-year prognosis for primary PCLPD (Table 1).
Diagnosis of cutaneous lymphomas is becoming increasingly sophisticated, with the use of multiple immunophenotyping stains and molecular markers.3 To provide a modern update and investigate the prognosis of patients with PCLPDs, we investigated a national population-based registry, the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database.
We investigated the entire SEER9 database from 1973 to 2004 and selected patients with PCLPD. Cases in the SEER database have histology and involved anatomic site recorded by the morphology and topography codes of the International Classification of Disease for Oncology, third edition (ICD-O-3).10 CD30+ lymphoproliferative disorders are coded with the ICD-O-3 morphology codes 9714 and 9718.11 Code 9718 is defined as "primary CD-30+ lymphoproliferative disorders" and included (but did not distinguish between) LyP and PCALCL. Code 9714 is defined as anaplastic large-cell lymphoma, both T-cell and null-cell type. To prevent analysis of patients with anaplastic large-cell lymphoma that was not primarily of skin origin, patients with ICD-O-3 morphology code 9714 were excluded. In addition, for analysis of localized, primary disease, patients with non–skin site disease were excluded from analysis. We investigated survival data, sex, age, race, skin site, extent of disease, nodal involvement, radiation usage, histology grade, surgery type and extent, and number and type of other malignancies. SEER recorded the extent of disease for Hodgkin's disease and non-Hodgkin's lymphoma of all sites (excluding MF and Sezary's disease) using terminology derived from the Ann Arbor staging system for Hodgkin's disease. Statistical analysis of factors influencing survival was performed on the cohort of all patients recorded in SEER as having PCLPD, and was then repeated for the subset of patients with localized and primary disease. Figure 1 outlines the inclusion process that was used to select cases with localized and primary disease for analysis.
For analysis of disease-specific survival (DSS), death by non-Hodgkin's lymphoma was considered to be caused by PCLPD. Survival relative to population matched US Census data was analyzed with SEER*Stat (NCI, Bethesda, MD). All other statistical analysis was performed with STATA/SE 9.2 (Stata Corp, College Station, TX). SEER does not record chemotherapy information or information about other medical interventions, including UV light treatment and topical therapy.
From 1973 to 2004, 268 cases of PCLPD were recorded in the SEER database, and patient characteristics are displayed in Table 2. Of those cases, 157 were of primary, localized disease. Median follow-up for all cases was 19 months (range, 1 to 94 months). Most cases (97.8%) were entered during or after the year 2000. There were no cases recorded before 1994.
For the cohort of all patients, median age at diagnosis was 61 years (range, 5 to 98 years). Among cases, 58% were male, and 42% female. Race distribution was 87% white, 7% black, and 4% Asian/Pacific Islander. Distribution of cases by skin site for the cohort of all patients was as follows: head and neck,18%; trunk, 17%; upper limb and shoulder, 21%; lower limb and hip, 21%; not specified, 22%; skin of overlapping regions, 1%. Three cases (1%) were coded in nonskin sites. Of these patients, 21% had surgery alone, 18% had radiation alone, and 16% had both radiation and surgery. As noted previously, SEER does not record chemotherapy data or other medical interventions. The CD30+ lymphoproliferative disease was the first malignancy recorded in SEER for 229 of 268 patients. Thirty-eight patients had two recorded malignancies, and 12 patients had three. Forty-four percent (118 of 268) of patients in the entire cohort received no cancer-directed surgery or radiation, whereas 34% (54 of 157) of patients with primary and localized disease received no recorded treatment. Eighteen percent (47 of 268) of patients in the entire cohort, and 18% (29 of 157) of patients with primary and localized disease received radiation alone. Sixteen percent (43 of 268) patients in the entire cohort and 23% (36 of 157) of patients with primary and localized disease received radiation in combination with cancer-directed surgery. For the cohort of all patients, overall survival at 3 years was 81% (95% CI, 74% to 87%; Table 3). Five-year overall survival was 68% (95% CI, 37% to 86%). Three- and 5-year DSS was 92% (95% CI, 86% to 95%). Thirty-eight deaths were detected in the cohort of all patients. Sixteen of these deaths were a result of non-Hodgkin's lymphoma.
For the cohort of all patients, stage I versus stage II to IV disease was not statistically predictive of improved survival (hazard ratio [HR] = 0.50; P = .10; 95% CI, 0.22 to 1.14). Stage IV versus I to III was also not predictive of worsened survival (HR = 0.86; P = .10; 95% CI, 0.88 to 4.7). On univariable analysis, head and neck skin site was statistically significant in the cohort of all patients in predicting for decreased survival (HR = 2.29; P = .02; 95% CI, 1.14 to 4.6). Age was also statistically significant in predicting for decreased survival. On multivariable survival analysis, there were no statistically significant predictors of survival, given the interaction between age and head and neck skin site. For patients with localized, primary PCLPD, overall survival at 3 years was 89% (95% CI, 81% to 94%). DSS at 3 years was 97% (95% CI, 90% to 99%). Population-matched relative survival at 3 years was 97% (SE 1.9%; Table 3). In the cohort of patients with only localized, primary disease, 14 deaths were detected, four of which were a result of non-Hodgkin's lymphoma. On univariable survival analysis of patients with localized and primary disease, increased age at diagnosis (HR = 1.05; P = .01; 95% CI, 1.01 to 1.09), head and neck skin site (HR = 4.4; P = .008; 95% CI, 1.5 to 13.2), and having received both radiation and surgery (HR = 3.9; P = .01; 95% CI, 1.3 to 11.7) significantly increased risk of death. On multivariate analysis, both age and head and neck skin site were suggestive of decreased survival, but only age remained significant by the standard of P < .05 (Table 4).
Similarities and differences have been noted in histologic and morphologic data contained in SEER (which is based on the ICD-O-3 classification), and the classifications contained in the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification of cutaneous lymphomas.11 In addition, although the reliability of a proper diagnosis and subtype classification of non-Hodgkin's lymphoma within SEER are excellent overall, the level of agreement between expert review and recorded SEER data can vary depending on non-Hodgkin's lymphoma subtype.12 Because of these difficulties, we undertook careful selection of cases from the SEER database to analyze only cases that were clearly recorded as PCLPD for descriptive analysis. Therefore, although both ICD-O-3 morphology codes 9714 and 9718 potentially encode for CD30+ lymphoproliferative disease, only those patients coded with the morphology code 9718 were included for descriptive analysis. It is possible that some cases of PCALCL were not analyzed as a result of our decision to exclude the code 9714. Nonetheless, our sample size is still large compared with prior studies, and valid hypotheses can still be generated. For survival analysis, we analyzed the entire cohort, and then applied even more stringent standards (Fig 1) and selected only those patients with localized disease for reanalysis. In clinical practice, patients with CD30+ lymphoproliferative disease with general involvement of the skin are more likely to have lymphomatoid papulosis,7 and therefore this selection process likely weighed our sample population more heavily towards PCALCL. On the basis of a recent survey of the CD30+ lymphoproliferative disease in the literature,6 solitary primary PCLPD without lymph node involvement is CALCL 100% of the time. Solitary and regional primary PCLPD without lymph node involvement is still CALCL 68.8% (201 of 292) of the time. Also, we hypothesize that patients with lymphomatoid papulosis, who have a regressing course of disease, would be less likely to be reported to the local cancer registrar, and therefore less likely to be included in our observational population. Therefore, we believe that our results and conclusions remain valid for a cohort of localized PCLPD that is likely predominantly CALCL, and that these conclusions remain clinically important and valuable for reporting. CD30+ lymphoproliferative diseases are uncommon malignancies that have been reported retrospectively in the literature. Our analysis of the SEER database confirms the previously noted relative male predominance of disease, and reveals a relative white predominance in disease incidence within the US population. Our median age of diagnosis (61 years; range, 5 to 98 years) is slightly older than the previously reported median ages for primary CALCL (50 to 60 years) and significantly older (one-sample t test P < .001) than the previously reported median ages for LyP (40 to 45.5 years).3,6,13,14 This, too, indicates that our sample was weighted more heavily with PCALCL cases than with LyP cases. The large range in age of our population is also consistent with previous reports that have indicated CD30+ lymphoproliferative disease occurring in the pediatric15 and elderly13 populations. Although the SEER database has been previously shown to have a relatively higher incidence for CTCL in blacks,2 we have noted an increased prevalence in whites relative to other demographic groups specifically for PCLPD that has not been previously reported. Previous analysis of the SEER database by other investigators have noted a white predominance to "T-cell/NK-cell lymphoid neoplasms not otherwise specified," which included PCLPD, but did not separate PCLPD as a distinct entity.16 Five-year overall survival for all patients (68%; 95% CI, 37% to 86%) has wide 95% CIs because of a relative lack of 5-year follow-up recorded in the database. This reported overall survival is lower than previously noted by other investigators (Table 1) and may be a result of the spurious inclusion of patients with secondary CD30+ lymphoproliferative disease under the ICD-O-3 morphology code 9718. However, our reported DSS and US population matched relative survival for patients with PCLPD and also for those with localized, primary disease alone, confirms the relatively indolent nature of this disease group. This population-based study is limited by the well-understood problems associated with any retrospective investigation. SEER is also limited by the inability to independently verify the reported diagnoses, by ambiguities in the coding of cases caused by differences between the ICD-O-3 classification, and the WHO-EORTC classification for cutaneous lymphomas.2,3 The SEER database is also limited in its inability to distinguish between LyP and PCALCL, two different clinicopathologic entities. PCALCL is usually treated with radiation, whereas LyP is usually observed. LyP also tends to present with involvement of multiple regions of the skin, whereas PCALCL is often a localized lesion or group of lesions. Therefore, in selecting for patients with localized, primary disease for statistical analysis, patients included were likely predominantly patients with PCALCL. The survival of patients with LyP differs from that for patients with PCALCL, with the 5-year overall survival for LyP of 98% to 100%4,6,13,14 and the 5-year overall survival for PCALCL ranging from 83% to 100%.4,13,14 Secondary cutaneous CD30+ T-cell lymphoma, defined as cutaneous CD30+ large T-cell lymphoma with concurrent or prior extracutaneous disease at time of skin presentation, has a much worse survival compared with primary disease, with 5-year survival estimates of 24% after the development of skin lesions.4 Interestingly, for all patients and for patients with localized and primary disease, head and neck skin site seems to suggest a worse prognosis. This observation has not been previously noted in the literature for either PCALCL or LyP. Our observation of inferior prognosis for patients with PCALCL of the head and neck could be a result of multiple factors, including a hesitancy to incorporate higher doses of radiation given the proximity of the skin of the neck to critical structures as an example. Our institutional data indicate that 40 Gy administered in 2-Gy fractions is a dose that causes complete remission and excellent local control.17 Physicians may be hesitant to irradiate the head and neck to 40 Gy for what they perceive as an indolent lymphoma. Identification of worse prognosis for certain areas of the skin has precedence in cutaneous B-cell lymphoma, where cutaneous large-cell lymphoma–leg type portends a worse prognosis and is a distinct histopathologic entity in comparison to other cutaneous B-cell lymphomas.5,18,19 In addition, the observed suggestion of worse prognosis for patients with head and neck lymphomas could also be possibly a result of misclassification of aggressive extranodal natural killer/T-cell nasal-type lymphoma (EN-NK/T-NT), which can arise in the skin.20 Survival of patients with EN-NK/T-NT is poor, with median survival of less than 12 months.3 Although we took care to exclude patients with null-cell or NK- cell histology, and EN-NK/T-NT has a unique ICD-O-3 morphology code (9719) that should ideally distinguish EN-NK/T-NT from PCLPD, EN-NK/T-NT can have variable expression of CD30 and could possibly have been misclassified. Although the features of EN-NK/T-NT are well defined, cases that differ in one or more features can be difficult to differentiate from extranodal peripheral T-cell lymphomas.20 EN-NK/T-NT can disseminate to the skin and can also arise in the skin without involving the classic nasal location.21,22 This possible misclassification may have skewed results and caused our cohort of PCLPD patients with head and neck skin site to seem to have a worse survival compared with other skin sites. Although EN-NK/T-NT is usually seen in Asian populations and other populations with endemic Epstein-Barr virus infection,22 and the relative numbers of Asian patients in our cohort is low, possibly indicating that few, if any cases of EN-NK/T-NK were misclassified as PCLPD, only a few contaminating cases are needed to explain our findings. Localized PCLPDs are rare and indolent diseases with excellent overall survival. There is a predominance of disease in whites according to SEER data. Localized, primary PCLPD has a better overall prognosis than does the entire cohort of PCLPD, which includes those with more widespread disease. In patients with localized, primary PCLPD, head and neck skin site seems to suggest a worse survival. Conclusions regarding subsets with improved or decreased survival should be taken with caution, however, given the small number of deaths analyzed. There are previously reported series revealing different survival and outcomes on the basis of geographic skin site of disease for other cutaneous lymphomas. Our observation of a potentially inferior survival for patients with head and neck skin PCLPD merits further investigation.
The author(s) indicated no potential conflicts of interest.
Conception and design: James B. Yu, Rachel C. Blitzblau, Roy H. Decker, Lynn D. Wilson Administrative support: James B. Yu Collection and assembly of data: James B. Yu, Lynn D. Wilson Data analysis and interpretation: James B. Yu, Rachel C. Blitzblau, Roy H. Decker, Douglas M. Housman, Lynn D. Wilson Manuscript writing: James B. Yu, Rachel C. Blitzblau, Roy H. Decker, Douglas M. Housman, Lynn D. Wilson Final approval of manuscript: James B. Yu, Rachel C. Blitzblau, Roy H. Decker, Douglas M. Housman, Lynn D. Wilson
Presented at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 28–November 1, 2007, Los Angeles, CA, and was published in abstract form by the International Journal for Radiation Oncology, Biology, and Physics. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Groves FD, Linet MS, Travis LB, et al: Cancer surveillance series: Non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 92:1240-1251, 2000 2. Criscione VD, Weinstock MA: Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol 143:854-859, 2007 3. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 4. Bekkenk MW, Geelen FAMJ, van Voorst Vader PC, et al: Primary and secondary cutaneous CD30+ lymphoproliferative disorders: A report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 95:3653-3661, 2000 5. Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders: A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28:973-980, 1993[Medline] 6. Liu HL, Hoppe RT, Kohler S, et al: CD30+ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 49:1049-1058, 2003[CrossRef][Medline] 7. Beljaards RC, Willemze R: The prognosis of patients with lymphomatoid papulosis associated with malignant lymphomas. Br J Dermatol 126:596-602, 1992[Medline] 8. Wang HH, Myers T, Lach LJ, et al: Increased risk of lymphoid and nonlymphoid malignancies in patients with lymphomatoid papulosis. Cancer 86:1240-1245, 1999[CrossRef][Medline] 9. Surveillance, Epidemiology, and End Results (SEER) Program Limited-Use Data (1973-2004), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, based on the November 2006 submission. National Cancer Institute, Bethesda, MD, 2007 10. Fritz A, Percy C, Jack A, et al (eds): International Classification of Diseases for Oncology (ed 3). Geneva, Switzerland, WHO, 2000 11. Dores GM, Anderson WF, Devesa SS: Cutaneous lymphomas reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results program: Applying the new WHO-European Organisation for Research and Treatment of Cancer classification system. J Clin Oncol 23:7246-7248, 2005 12. Clarke CA, Glaser SL, Dorfman RF, et al: Expert review of non-Hodgkin's lymphomas in a population-based cancer registry: Reliability of diagnosis and subtype classifications. Cancer Epidemiol Biomarkers Prev 13:138-143, 2004 13. Paulli M, Berti E, Rosso R, et al: CD30/Ki-1-positive lymphoproliferative disorders of the skin: Clinicopathologic correlation and statistical analysis of 86 cases—A multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol 13:1343-1354, 1995[Abstract] 14. Vergier B, Beylot-Barry M, Pulford K, et al: Statistical evaluation of diagnostic and prognostic features of CD30 cutaneous lymphoproliferative disorders: A clinicopathologic study of 65 cases. Am J Surg Pathol 22:1192-1202, 1998[CrossRef][Medline] 15. Tomaszewski MM, Moad JC, Lupton GP: Primary cutaneous Ki-1 (CD30) positive anaplastic large cell lymphoma in childhood. J am Acad Dermatol 40:857-861, 1999[CrossRef][Medline] 16. Morton LM, Wang SS, Devesa SS, et al: Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 107:265-276, 2006 17. Yu JB, McNiff JM, Lund MW, et al: Treatment of primary cutaneous CD30+ anaplastic large cell lymphoma with radiation therapy. Int J Radiat Oncol Biol Phys [Epub ahead of print November 23, 2007] 18. Vermeer MH, Geelen FAMJ, van Haselen CW, et al: Primary cutaneous large B-cell lymphomas of the legs: A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis—Dutch Cutaneous Lymphoma Working Group. Arch Dermatol 132:1304-1308, 1996 19. Smith BD, Smith GL, Cooper DL, et al: The Cutaneous B-cell Lymphoma Prognostic Index: A novel prognostic index derived from a population-based registry. J Clin Oncol 23:3390-3395, 2005 20. Hasserjian RP, Harris NL: NK-Cell lymphomas and leukemias. A spectrum of tumors with variable manifestations and immunophenotype. Am J Clin Pathol 127:860-868, 2007 21. Bekkenk MW, Jansen PM, Meijer CJLM, et al: CD56+ hematological neoplasms presenting in the skin: A retrospective analysis of 23 new cases and 130 cases from the literature. Ann Oncol 15:1097-1108, 2004 22. Chan JK, Sin VC, Wong KF, et al: Nonnasal lymphoma expressing the natural killer cell marker CD56: A clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 89:4501-4513, 1997 Submitted August 23, 2007; accepted December 12, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
