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© 2001 American Society for Clinical Oncology Natural Killer/Natural Killer-Like T-Cell Lymphoma, CD56+, Presenting in the Skin: An Increasingly Recognized Entity With an Aggressive CourseFrom the Departments of Dermatology, Pathology, and Radiation Oncology, Stanford University School of Medicine, Stanford; and Departments of Pathology and Dermatology, University of California, San Francisco, CA. Address reprint requests to Serena Mraz-Gernhard, MD, Department of Dermatology, 900 Blake Wilbur Dr, W0069, Stanford, CA 94305; email: serenam{at}leland.stanford.edu
PURPOSE: To describe and identify the clinical and pathologic features of prognostic significance for natural killer (NK) and NK-like T-cell (NK/T-cell) lymphoma presenting in the skin. PATIENTS AND METHODS: This study was a retrospective review of 30 patients with CD56+ lymphomas initially presenting with cutaneous lesions, with analysis of clinical and histopathologic parameters.
RESULTS: The median survival for all patients was 15 months. Those with extracutaneous manifestations at presentation (11 patients) had a shorter median survival of 7.6 months as compared with those without extracutaneous involvement (17 patients), who had a more favorable median survival of 44.9 months (P = .0001). Age, gender, extent of cutaneous involvement, and initial response to therapy had no statistically significant effect on survival. Seven patients (24%) had detectable Epstein-Barr virus (EBV) within neoplastic cells. The patients with tumor cells that coexpress CD30 (seven patients) have not yet reached a median survival after 35 months of follow-up as compared with those with CD30- tumor cells (20 patients), who had a median survival of 9.6 months (P < .02). Routine histopathologic characteristics had no prognostic significance nor did the presence of CD3 CONCLUSION: NK/T-cell lymphoma is an aggressive neoplasm; however, a subset with a more favorable outcome is identified in this study. The presence of extracutaneous disease at presentation is the most important clinical variable and portends a poor prognosis. The extent of initial skin involvement does not reliably predict outcome. Patients from the United States with NK/T-cell lymphoma presenting in the skin have a low incidence of demonstrable EBV in their tumor cells. Patients with coexpression of CD30 in CD56 lymphomas tend to have a more favorable outcome.
NATURAL KILLER (NK) and NK-like T-cell (NK/T-cell) lymphoma is a rare entity of the hematolymphoid system originally recognized to involve the upper aerodigestive tract. Histologically, this type of lymphoma consists of neoplastic cells that exhibit a prominent angiocentric growth pattern and expression of the neural cell adhesion molecule, CD56.1 Other historical names for this entity include "midline lethal granuloma," "nasal NK lymphoma," and "angiocentric T-cell lymphoma." Nasal NK/T-cell lymphoma is most common in East Asian and South and Central American countries and is believed to be highly associated with Epstein-Barr virus (EBV).2-5 The disease is rapidly fatal in most instances. Over the past decade, NK/T-cell lymphomas were reported in other extranodal sites. The first reported case involved the gastrointestinal system.6 Chan et al7 reported 49 cases of extranasal NK/T-cell lymphoma and found skin involvement to be the most frequent site, affecting 14 (29%) of the patients in their series. Additional, predominantly smaller series of patients were subsequently published reporting this type of lymphoma involving the skin primarily.8-10 The largest series to date of patients with CD56+ lymphomas presenting with cutaneous involvement describes 12 cases.8 Although these lymphomas are all CD56+, some appear to be of NK cell origin, whereas others appear to be phenotypically and genotypically of T-cell origin.11 Although CD56+ lymphoproliferative disorders constitute a heterogeneous spectrum, the updated Revised European American Lymphoma and World Health Organization classification systems define criteria for the recognition of a distinct entity, termed "extranodal NK/T-cell lymphoma, nasal type."12 The Hong Kong workshop report classifies these as "nasal-type" NK and NK-like T-cell lymphomas.13 The literature on patients with primary cutaneous NK/T-cell lymphomas has been unclear, mostly because of the rarity of this lymphoma limiting access to large numbers of patients. We have observed that some of the previously unclassifiable primary cutaneous lymphomas that appear to have a more aggressive course express CD56. In this study, we describe the clinical and pathologic features of 30 patients with cutaneous NK/T-cell lymphomas presenting in the skin and focus on identification of clinical and pathologic features with prognostic significance.
Patient Selection Patients with cutaneous NK/T-cell lymphomas were identified from the Stanford University and University of California, San Francisco, pathology databases. The databases were searched for cutaneous lymphomas, and those that satisfied histologic, immunophenotypic, and molecular criteria for the diagnosis of NK/T-cell lymphomas were further investigated clinically. Only the cases with initial clinical presentation of lymphoma in the skin were selected for this study, and include 30 patients. Consistent criteria were used in all cases and included the following: (1) examination of histologic features on hematoxylin and eosin (HE)–stained sections of skin biopsies; (2) immunophenotypic studies on paraffin sections including CD56, CD30, and CD3, among others; (3) in situ hybridization studies for the presence of EBV-specific RNA; and (4) T-cell receptor rearrangement studies. Detailed histologic and immunophenotypic features and molecular analysis of 17 of the patients have been previously described.8,14 The clinical parameters of these 17 patients, including treatment, clinical course, and follow-up, are expanded. In addition, complete clinicopathologic work-up of 13 new patients is added in the current study. Most patients had a staging evaluation after initial diagnosis that included a complete physical examination, complete blood count, and serum chemistries including lactate dehydrogenase (LDH), a bone marrow biopsy, and computed tomographic (CT) scans of the chest, abdomen, and pelvis. When clinically indicated, additional tests such as a lumbar puncture with cerebrospinal fluid examination were obtained on selected patients. Reasons for an incomplete staging evaluation include patient noncompliance with recommendations (one patient) and death occurring before completion of the staging evaluation (one patient). Patients with a history of extracutaneous CD56+ lymphoma before presenting with cutaneous lesions were excluded from the study, as were those with nasopharyngeal involvement at or before the time of presentation. These exclusion criteria were used with the goals of focusing on patients with a cutaneous presentation of their disease and avoiding overlap with the more well-described nasal region primary NK/T-cell lymphomas. Assessment of response was evaluated by follow-up clinical, radiologic, and tissue/cytology/serum laboratory studies as judged relevant by the treating clinician. For this study, the following definitions were used: (1) complete response (CR) is no evidence of residual disease, (2) partial response (PR) is at least a 50% reduction in the tumor burden from the onset of treatment, and (3) no response is less than 50% reduction in tumor burden or disease progression.15 Because of the aggressive nature of this disease and the small number of patients with a durable response (> 6 months), we opted to report the time to relapse rather than include a minimum of 6 months’ durability as part of the definition for a CR or PR.
Histology
Immunohistochemistry
In Situ Hybridization for EBV
Heteroduplex Analysis of T-Cell Receptor Gamma Gene Rearrangement
Survival and Statistical Analysis Actuarial survival curves were calculated from the date of diagnosis and were plotted according to the technique of Kaplan and Meier.18 Analysis of differences in actuarial survival curves was performed using the Gehan test.19,20 All P values correspond to two-sided significance tests.
Clinical Characteristics and Overall Survival An overall survival curve is shown in Fig 1 for all patients (n = 30). The median survival for patients with NK lymphoma presenting in the skin is 15 months. The median time of follow-up from diagnosis of NK lymphoma for all patients is 12 months, with a range of 1 to 61 months. The patient with the longest follow-up (61 months) is dead from disease.
General clinical characteristics of the patients studied are listed in Table 1. The median age at diagnosis is 50 years (range, 14 to 97 years). A predominance of male patients was observed, with a 3:2 ratio of male to female patients.
The ethnicity of the patients in the series follows an expected distribution from the United States. Most patients were born and raised in the United States. The exceptions are two patients from Asia, two from Mexico/Central America, and one from Puerto Rico. The duration of symptoms reported by the patient ranged from less than 1 month to 7 years, with a median duration of 4 months. Patient no. 22 had a previous diagnosis of mycosis fungoides (stage Ib) that had been diagnosed 3 years before his diagnosis of cutaneous NK/T-cell lymphoma. The original pathology was confirmed to be CD56- and had histologic and immunohistochemistry features typical of mycosis fungoides. The mycosis fungoides was in clinical remission at the time of the NK/T-cell lymphoma diagnosis. Patient no. 23 was pregnant at the time of diagnosis, but miscarried and then died soon thereafter. Patient no. 27 had a 6-year history of pancytopenia from unknown causes and had refused bone marrow biopsy examination before the diagnosis of cutaneous lymphoma. This patient, however, had no evidence of prior leukemia. Patient no. 13 had a history of a myeloproliferative disorder. Figure 2 shows the spectrum of clinical presentation of patients in our series. The majority (67%) presented with cutaneous involvement of more than one anatomic region. Two patients (7%) presented with more than one tumor/nodule or plaque confined to a single anatomic region and eight patients (27%) presented with a solitary tumor/nodule or plaque.
Most patients (70%) presented with cutaneous tumors or plaques on one or more extremity. Sixty-eight percent had cutaneous lesions on the trunk including two patients with breast masses (patient nos. 8 and 15). Only four (13%) had cutaneous involvement in the head or neck regions. Eighteen (60%) of the patients had no evidence of extracutaneous disease with initial staging evaluation. Four patients (13%) had lymph node involvement: two (patient nos. 24 and 30) had biopsy-confirmed lymph node involvement in the axillary, inguinal, and/or epitrochlear lymph node beds and two others (patient nos. 22 and 29) had mediastinal or paragastric lymph node involvement evidenced by CT scan. Patient no. 29 had autopsy confirmation of lymph node and visceral organ involvement. Four patients had involvement of visceral organs. The visceral sites were the liver (patient no. 29), the CNS (patient nos. 22 and 27), the adrenal gland (patient no. 22), and the bone with lytic lesions (patient no. 27).
Clinical Predictors of Survival The most important clinical factor predicting poor outcome among our patients is extracutaneous involvement in the bone marrow, visceral organs, and/or lymph nodes at the time of initial staging evaluation. Those patients found to have extracutaneous disease (11 patients) had a median survival of 7.6 months compared with 44.9 months for those with disease limited to the skin (17 patients, P = .0001) ( Fig 3). Patients younger than 50 years showed no statistically significant survival advantage over those older than 50 years (P = .2). Gender analysis likewise showed no survival difference (P = .4). Univariate analysis also showed no survival advantage for those presenting with a solitary cutaneous lesion or regional disease limited to a single cutaneous anatomic site (10 patients) compared with those presenting with multiple anatomic cutaneous sites (20 patients) of involvement (P = .4). Those with an initial CR to therapy (15 patients) had no statistically significant survival advantage over those who did not achieve a CR (10 patients) to initial therapy (P = .3).
Treatment and Clinical Response Table 2 lists the patients’ original site(s) of involvement, the initial treatment, initial response, duration of initial response, latest status, and follow-up duration. Treatment and clinical response varied. Nine of 11 patients with extracutaneous disease received chemotherapy as initial treatment. The other two had no treatment for reasons of noncompliance (one patient) and death before initiation of treatment (one patient).
The patients with disease limited to the skin had a more diverse profile of initial treatments. Ten (58%) received chemotherapy as primary treatment. Two (12%) received chemotherapy and local irradiation as adjuvant therapies after excision of a solitary lesion. Three (18%) had excision of a solitary lesion. Three (18%) had radiation alone. Four (24%) had radiation as adjuvant therapy, and one (patient no. 14) chose an unconventional therapy (intravenous vitamins). Two (patient nos. 8 and 21) died without a full staging evaluation and did not receive any treatment. The site(s) of initial recurrence of disease among those with a CR were varied. The majority of patients who relapsed recurred with a prominent cutaneous component (92%); however, many of these (58%) had concomitant extracutaneous disease progression. Only one patient had recurrence in extracutaneous sites alone.
Histopathologic Characteristics
Histopathologic Predictors of Survival Routine histopathologic characteristics do not appear to be predictive of survival. All skin specimens in this series showed some degree of angiocentricity. Only a minority (seven patients) showed any epidermotropism. No correlation with outcome was demonstrated for either. The patients (seven patients) whose tumor cells revealed coexpression of CD30 had a more favorable survival. The median survival has not been attained for those with CD30+ tumor cells with 35-month of follow-up compared with the group with CD30- tumor cells (23 patients), who had a median survival of 9.6 months (P < .02) ( Fig 6). There was no survival difference between patients with CD3  + tumor cells (18 patients) and those with CD3- lymphomas (12 patients, P = .8). The minority of patients with EBV infection (seven patients) had no significant survival difference (P = .15) compared with those lacking evidence of EBV infection (20 patients). The majority of patients with the MDR gene (22 patients) similarly had no survival disadvantage (P = .4) compared with those without the gene (six patients).
NK/T-cell lymphoma of the nasopharyngeal cavity is probably known best for its rapidly fatal outcome. Over the past decade, the skin has been recognized as one of the most common sites of involvement outside of the nasopharynx.7 As opposed to the majority of cutaneous T-cell lymphoma such as mycosis fungoides and primary cutaneous anaplastic large-cell lymphoma that may have an indolent course, NK/T-cell lymphomas presenting with cutaneous manifestations have a greater propensity to involve the bone marrow, viscera, and lymph nodes, and have a poor prognosis. In our series of patients, all of whom presented to their physicians for evaluation of cutaneous lesions, 37% were found to be harboring extracutaneous disease at presentation. This subset had a significantly shorter median survival than those with cutaneous disease only. One third of our patients presented with solitary or localized regional cutaneous lesions. These patients fared no better overall than those presenting with more widespread or generalized cutaneous lesions. The tumor burden in the skin does not appear to be a reliable predictor of occult nodal, visceral, or bone marrow involvement. A complete initial staging evaluation including a bone marrow biopsy and CT scans of the chest, abdomen, and pelvis appears to provide important prognostic information for all presentations of cutaneous NK/T-cell lymphoma. Consistent with previous observations,7 our series of patients showed a male predominance. Although probably more common among men, gender does not appear to be a factor that affects survival in this disease. The median age in our series (50 years) is consistent with previous reports of patients with nasal and nasal-type NK/T-cell lymphomas out of Hong Kong7 (50 years), Japan21 (46.5 years), and France22 (43.5 years). Because of the limitations of a retrospective study and the number of patients in this series, we cannot draw any conclusions about what type of treatment is best. It is unclear from our data whether either the type or initial response to treatment affects survival with this disease. A trend toward increased survival was seen for those achieving a CR with initial treatment as opposed to those treated who did not achieve an initial CR; however, the difference did not reach statistical significance and may be attributable solely to confounding factors (eg, those without extracutaneous disease were more likely to achieve initial CR with therapy). Additional studies with larger numbers of patients are needed to clarify these issues. The majority of patients were found to have the MDR phenotype. The MDR phenotype has been studied in many cell lines and has shown resistance to multiple unrelated cytotoxic agents and has been suggested as a major mechanism of drug resistance in human cancer.23,24 Tumors manifesting this phenotype have at least the capability of resisting an effective response to therapy. Our data suggest that other factors play a role in the aggressive nature of NK/T-cell neoplasms because those that were MDR-negative had a survival curve that was as dismal as those with the phenotype. The median symptom duration was only 4 months; however, four patients reported cutaneous symptoms for 3 to 7 years before diagnosis. The time from onset of reported symptoms to diagnosis shows no clear relationship to outcome in our series. Only 26% of the 28 patients in our series had EBV-specific RNA demonstrated in the neoplastic cells. This result differs from previous studies of nasal NK/T-cell lymphomas and of extranasal NK/NK-like lymphomas reported from areas where both nasal NK/T-cell lymphomas and EBV infection rates are much higher in early childhood than in the United States.7,25 The likely reasons for the disparity are (1) the exclusion of patients with nasopharyngeal/upper airway disease at the time of presentation from our study and (2) the predominance of patients indigenous to the United States. The four patients in our series born in Vietnam, Laos, Guatemala, and Mexico—areas with a high incidence of early childhood infectivity of EBV26—all demonstrated EBV in their tumor specimens. Only 12% of the patients born in the United States were found to have EBV in their tumors. None of these patients had an underlying condition that would cause immunosuppression. Although patients with nasopharyngeal involvement at the time of presentation were excluded from this series, two patients developed recurrent disease after initial treatment that included involvement of the palate. The relevance of identifying EBV in neoplastic cells in some patients with the disease pertains to the virus having a possible pathogenic role. Our results show a low prevalence of EBV in patients with extranasopharyngeal NK/T-cell lymphoma and are consistent with a Japanese study21 that reported EBV in only three of nine patients with NK/T-cell lymphoma outside the upper and lower respiratory tract and corroborates the results from Natkunam et al,18 which showed five of 11 cases reactive for EBV. Also, our study provides evidence that EBV is not of prognostic significance for patients presenting with cutaneous NK/T-cell lymphoma.27 In addition to EBV, human T-cell lymphotropic virus type I has been reported in a few cases of cutaneous angiocentric lymphomas.28-30 To date, no conclusions have been reached regarding whether or not one or more types of virus plays a role in tumorigenesis for any or all aspects of this disease. Another aspect of this disease lacking clarity is the exact origin of the cell lineage of the neoplastic cells.21,31,32 Consistent with reports from others,22,33 the majority (18 patients), but not all, of the patients in our series had tumors that expressed CD3. Only a subset of these had detectable clonal TCR gene rearrangement by polymerase chain reaction analysis, evidence of T-cell origin. The evidence to date suggests that this disease process may derive from a common precursor cell that gives increase to NK- and T-cell lineage. Most striking from a pathologic/immunophenotypic standpoint is the survival advantage of patients whose CD56+ tumor cells coexpressed CD30 over those that were CD30-. The patients in our series that were CD30+ had skin involvement ranging from a solitary tumor nodule or plaque to a generalized distribution, but all lacked extracutaneous disease. Patients with primary cutaneous anaplastic large-cell lymphoma expressing CD30 also have a favorable prognosis.34 However, this observation should be interpreted with caution because the subset of patients with coexpression of CD30 in this series is small (seven patients). Further studies with larger numbers of patients and longer follow-up are needed before definitively concluding that coexpression of CD30 in NK/T-cell lymphomas presenting on the skin is a favorable prognostic indicator. In conclusion, NK/T-cell lymphoma presenting in the skin is generally an aggressive neoplasm. However, a subset of patients appear to have a more favorable outcome. Patients tend to have a worse prognosis if the disease is associated with extracutaneous involvement at presentation. With contemporary therapy, the disease is uniformly fatal when extracutaneous involvement is present. The extent of initial skin involvement, however, is not a reliable indicator of extracutaneous involvement or outcome. In contrast to findings from other countries where early infection with EBV is more common, patients from the United States with NK/T-cell lymphoma presenting in the skin have a very low incidence of demonstrable EBV in their tumor cells, and the presence of EBV does not have prognostic significance. In addition, MDR phenotype does not predict worse survival in our patients. Coexpression of CD30 on CD56+ tumor cells suggests a more favorable outcome; however, further studies are needed to confirm this finding.
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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
) gene rearrangement was performed as previously described.
/ß+ cells: New clues to their origin, specificity, and function. J Exp Med 182: 633-638, 1995
