Departments of 1 Dermatology; 2 Pathology, Leiden University Medical Center, Leiden; 3 Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
*Correspondence to: Dr M. Bekkenk, Department of Dermatology, B1-Q-93, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel: +31-71-526-2421; Fax: +31-71-524-8106; Email: m.w.bekkenk{at}lumc.nl
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Abstract |
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Patients and methods: The study group included 153 cases (23 new and 130 from the literature). According to the World Health Organization classification, the group included 15 nasal and 38 nasal-type natural killer (NK)/T-cell lymphomas, 63 blastic NK-cell lymphomas, 14 cutaneous CD30+ lymphoproliferations, 10 cases of myeloid leukemia, six cases of subcutaneous panniculitis-like T-cell lymphoma (SCPLTCL) and seven peripheral T-cell lymphomas, unspecified.
Results: In general, these CD56+ hematological neoplasms had a poor prognosis, with only 27% of patients alive after a median follow-up of 12 months. The median survival was 13 months. Nasal and nasal-type NK/T-cell lymphomas and CD56+ SCPLTCL had the worst prognosis, with a median survival of 5, 6 and 5 months, respectively. Only nasal-type NK/T-cell lymphomas presenting with only skin lesions had a somewhat better prognosis (median survival 27 months). In blastic NK-cell lymphomas (median survival 14 months), age 40 years, aggressive treatment with acute leukemia protocols and high TdT expression were associated with a more favorable prognosis. Striking similarities in histology, immunophenotype, clinical presentation and clinical behavior were found between blastic NK-cell lymphomas and CD56+ myeloid leukemias.
Conclusions: CD56+ hematological neoplasms presenting in the skin have a poor prognosis, except for primary cutaneous CD30+ lymphoproliferations. The striking similarities between blastic NK-cell lymphomas and CD56+ myeloid leukemias presenting in the skin provide a rationale to treat these patients with more aggressive regimens, rather than with CHOP(-like) regimens and radiotherapy, which have proven to be inadequate therapies for this neoplasm.
Key words: CD56, classification, cutaneous NK/T-cell lymphoma, leukemia, prognosis, treatment
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Introduction |
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These CD56+ T/NK-cell lymphomas preferentially present at extranodal sites, not uncommonly the skin, and almost without exception have an extremely poor prognosis. In the World Health Organization (WHO) classification, several groups of CD56+ lymphomas are distinguished, including extranodal NK/T-cell lymphoma (nasal/nasal type) and blastic NK-cell lymphoma [2]. Nasal NK/T-cell lymphoma, previously designated lethal midline granuloma, typically presents in the nasopharynx, and often shows an angiocentric growth pattern with prominent necrosis and vascular destruction. The neoplastic cells express cytotoxic proteins (TIA-1, granzyme B and perforin) in most cases. These lymphomas have been reported most frequently in Asia and Central and South America, and are almost without exception strongly associated with EpsteinBarr virus (EBV). Lymphomas with similar histology and phenotype arising at other extranodal sites are designated extranodal NK/T-cell lymphoma, nasal type.
Blastic NK-cell lymphoma most commonly presents in the skin, with or without concurrent extracutaneous disease. Histologically, these lymphomas are characterized by a diffuse monotonous infiltrate of medium-sized cells resembling lymphoblasts or myeloblasts. Characteristically, the neoplastic cells are positive for CD4 and CD56, and in some cases for TdT, but do not express surface CD3 and cytotoxic proteins, and are not associated with EBV. Recent studies showing that these blastic NK cell lymphomas express IL-3R (CD123) and an immunophenotype highly similar to that of plasmacytoid dendritic cells [3] argue against a NK-cell origin, which implies that the term blastic NK-cell lymphoma is inappropriate. CD4+, CD56+ hematodermic neoplasm [4
] and CD4+ CD56+ malignancy [5
] have been suggested as more appropriate terms. Notwithstanding, herein the World Health Organization (WHO) term blastic NK-cell lymphoma will further be used.
In addition to these three groups, cases of myeloid leukemia presenting primarily in the skin as well as other well-defined types of cutaneous T-cell lymphoma (CTCL), such as primary cutaneous CD30+ (anaplastic) large T-cell lymphomas, subcutaneous panniculitis-like T-cell lymphoma (SCPLTCL) and CD8+ epidermotropic CTCL, may show co-expression of CD56 in a proportion of cases.
These CD56+ (cutaneous) hematological neoplasms are an extremely difficult group, for both pathologists and clinicians. For pathologists, correct classification of these lymphomas is difficult, expensive and time-consuming, since it requires application of several complimentary techniques such as extensive phenotyping, EBV analysis and T-cell receptor (TCR) gene rearrangement studies. It is therefore important to know whether such a detailed analysis is useful from a therapeutic or prognostic point of view. Clinicians are confronted with an aggressive clinical behavior and a fatal outcome often within 1 year after diagnosis, and may consider more intensive therapies, as in acute leukemias, as initial therapy. Whether patients presenting with only localized skin lesions have a somewhat better prognosis and require another therapeutic approach is uncertain. It is also not known whether coexpression of CD56 in well-defined types of CTCL is associated with a less favorable prognosis, and should be treated more aggressively.
In an attempt to answer some of these questions and to better define these different subgroups, we evaluated the clinicopathological and immunophenotypical data of a large group of CD56+ hematological neoplasms presenting in the skin, including 23 new cases and 130 cases from the literature.
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Materials and methods |
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Review of literature
Our literature search focused on reports of CD56+ hematological neoplasms with (i) skin lesions at presentation, (ii) a follow-up of at least 12 months unless prior death to lymphoma, and (iii) sufficient immunophenotypical data to allow categorization according to the WHO classification [2].
A Medline survey using skin and CD56 in the PubMed search engine including papers up to 1 December 2002 revealed 87 English papers containing patients with a cutaneous CD56-positive lymphoma/leukemia. Fifty-seven papers included CD56+ hematological neoplasms with skin lesions at first presentation, which had been designated variously as nasal(-type) NK/T-cell lymphoma, NK/T-cell lymphoma, angiocentric lymphoma, blastic NK-cell lymphoma, lymphoblastic NK-cell lymphoma, NK-cell leukemia/lymphoma, CD4+/CD56+ (hematodermic) lymphoma, CD30+/CD56+ lymphoma, myeloid leukemia, granulocytic sarcoma, cytotoxic T-cell lymphoma, SCPLTCL, lymphomatoid papulosis and (primary cutaneous) CD30+ (anaplastic) lymphoma [3, 7
62
].
A total of 130 cases met all three criteria mentioned above. Using the WHO classification [2], these cases from literature included: 14 nasal NK/T-cell lymphomas {references: [8
, 15
, 24
] (two cases), [28
, 34
] (two cases), [35
, 37
, 53
, 56
] (two cases), [60
]}, 36 extranodal NK/T-cell lymphomas, nasal type {references: [7
, 9
] (two cases), [16
] (three cases), [14
, 18
, 26
] (three cases), [30
, 34
] (two cases), [35
] (two cases), [38
, 41
] (four cases), [44
] (three cases), [45
] (two cases), [46
] (three cases), [49
, 53
] (two cases), [55
, 56
, 57
, 62
]}, 52 blastic NK-cell lymphomas {references: [3
] (13 cases), [9
] (three cases), [13
, 19
, 20
, 21
] (15 cases), [27
, 30
, 33
] (three cases), [32
, 33
, 35
] (two cases), [41
] (two cases), [45
] (three cases), [50
, 58
, 61
] (two cases)}, 12 cutaneous CD30+ lymphoproliferations {references: [10
, 16
, 23
, 31
, 43
, 45
, 46
] (four cases), [48
, 56
]}, seven cases of acute myeloid leukemia (AML) (references: [9
, 22
, 31
, 42
, 43
, 44
, 50
]), five cases of SCPLTCL {references: [25
, 39
] (two cases), [51
] (two cases)}, and four peripheral T-cell lymphoma, unspecified (all with co-expression of CD56; references: [41
, 47
, 56
, 59
]).
Statistical analysis
Comparison between different subgroups of patients were performed using the 2 of Fisher's exact test for categorical variables (cross-table) or the MannWhitney test for continuous variables. Survival duration was calculated from time of diagnosis to date of death or censoring. Overall survival rates were estimated using the method of Kaplan and Meier [63
]. For overall survival analysis, deaths were taken into account whatever the cause; disease-specific analysis was not performed because only one case died from an unrelated cause.
Prognostic factors in the different subgroups were evaluated by overall survival univariate and multivariate analyses using a Cox proportional hazards model. Factors significant at the 0.1 level in univariate analysis were included in a stepwise regression multivariate analysis.
The following parameters were analyzed: clinical prognostic factors including gender, age, extent of cutaneous, and extracutaneous disease and therapy; histological factors including cell size, angiocentricity, expression of cytotoxic proteins and expression of several immunohistochemical markers, in particular CD30 and TdT, expression of EBV and the presence of clonal T-cell rearrangement, if performed or described.
For statistical analysis the software package for social sciences (SPSS 10.0; SPSS, Chicago, IL, USA) was used.
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Results |
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Nasal NK/T-cell lymphoma (n=15)
This group consisted of 10 males and five females with a median age of 58 years (range 1990). All cases presented with lesions in the nasopharyngeal area combined with skin lesions either on the trunk and/or extremities (14 cases) or a tumor on the nose (one case), whereas other sites were affected infrequently (see Table 4). Initial treatment, mostly multiagent chemotherapy (73%), resulted in a complete remission in only three cases. All cases died of lymphoma. This was the group with the worst prognosis; the median survival was only 5 months, and 2-year survival was not reached (Table 4
). Two cases were of T-cell origin as proven by TCR and CD3 expression on frozen tissue sections.
Nasal-type NK/T-cell lymphoma (n=38)
This group included 19 males, 15 females and four cases with unknown gender. The median age at diagnosis was 50 years (range 1679). Fifteen of 38 cases presented with only skin lesions. Treatment mostly consisted of multiagent chemotherapy (n=26; 68%) and resulted in a complete remission in 10 of 40 cases. Only three cases did not relapse, and 29 of 38 (76%) died of lymphoma. The prognosis was poor, with a median survival of only 6 months (95% CI 210) and a 2-year survival of 28% (see Table 4). Four cases were of T-cell origin as proven by TCR analysis.
Univariant analysis showed that only presentation with skin-limited disease (P=0.006) and presentation with localized as opposed to multifocal skin lesions (P=0.05) were associated with a significantly better prognosis. In multivariant analysis, only presentation with skin-limited disease was significantly related to better survival (P=0.03; relative risk 2.7; 95% CI 1.16.4). The median survival of patients presenting with skin-limited disease was 27 months (95% CI 945) compared with 4 months (95% CI 35) for patients presenting with both cutaneous and extracutaneous disease (see Figure 1).
|
Blastic NK-cell lymphoma (n=63)
This group consisted of 41 male and 20 female cases (male:female ratio 2:1); two cases were of unknown gender. The median age at diagnosis was 67 years (range 889); 13 cases were <40 years old. A strikingly high percentage of patients had bone marrow involvement: 46% at presentation and 72% during the course of the disease (see Table 3). Initial treatment consisted of multiagent chemotherapy in the majority of patients (70%). Most patients had received CHOP or CHOP-like regimens (56%), whereas only eight patients had been treated more aggressively with schemes used in acute leukemias followed by autologous or allogeneic bone marrow or stem-cell transplantation. Six of these eight patients are alive, and although the follow-up is mostly short (median 25 months; range 640), they proved to have a significant better prognosis when compared with all other cases (P=0.01) and compared with cases that received adriamycin-containing chemotherapy (P=0.04). The prognosis of these lymphomas was poor, with a median survival of 14 months, and 2- and 5-year overall survivals of 33% and 6%, respectively (see Table 4
). Patients presenting with only skin lesions (median survival 21 months; 95% CI 1428) had a better prognosis than patients presenting with both cutaneous and extracutaneous disease (median survival 12 months; 95% CI 1014) (see Figure 2
).
|
CD56+ myeloid leukemia first presenting in the skin (n=10)
This group included seven males and three females with a median age of 54 years (range 294). Seven of 10 cases presented simultaneously with skin lesions and bone marrow and/or blood involvement. The other three cases presented with only skin lesions, but developed frank leukemia after 312 months. According to the WHO classification, all cases were classified into the broad category of AML not otherwise categorized. When further subdivided, three cases of acute monoblastic and monocytic leukemia (FAB M5a/b) and three cases of acute myelomonocytic leukemia (FAB M4) could be distinguished. Four cases presented with only skin lesions, and would be designated as myeloid sarcoma; after the involvement of the bone marrow all four of these cases could be classified as acute monoblastic and monocytic leukemia (FAB M5). Four cases had been published as blastic NK-cell lymphoma, but were reclassified as AML because of the expression of CD33 and other myeloid markers. Initial treatment, including CHOP-like courses in three cases and AML schemes in four cases, resulted in complete remissions in six of 10 cases. The prognosis was poor, with a median survival of 6 months and a 2-year survival of 20% (see Table 4).
Comparison between blastic NK cutaneous CD56+ myeloid leukemia
In view of recent reports that blastic NK and a proportion of myeloid leukemias presenting in the skin are possibly derived from precursor plasmacytoid dendritic cells type 2 [3, 64
66
], we compared the 63 cases diagnosed as blastic NK with the 10 CD56+ myeloid leukemias. Striking similarities between both groups were noted in histology and immunophenotype, including expression of CD34, CD68 and TdT (but with the exception of CD33, myeloperoxidase and lysozyme, used as exclusion criteria for blastic NK). Clinical presentation, including the percentage of bone marrow involvement at presentation (46% versus 60%), response to therapy and prognosis were also very similar (see Table 4
and Figure 3
).
|
Initial therapy consisted of multiagent chemotherapy in six of 14 cases, whereas five cases were not treated at all. Three cases died, two within 2 months due to side-effects of chemotherapy and one of unrelated disease. The median survival was not reached; the 2- and 5-year survivals were 75% and 56%, respectively.
Subcutaneous panniculitis-like T-cell lymphoma (n=6)
This group consisted of three males and three females with a median age of 50 years (range 1256). Two cases presented with only skin lesions, whereas three cases had concurrent involvement of lymph nodes. Chemotherapy resulted in a complete remission in only one of six patients, and all but one died of lymphoma. The median survival was only 5 months (95% CI 19); the 2-year survival was 33% (see Table 4). The only patient still alive had an alpha/beta phenotype, whereas the five patients who died had a gamma/delta phenotype.
Peripheral T-cell lymphoma not otherwise specified (n=7)
This group consisted of two males, four females and one case with unknown gender. The median age was 67 years (range 2875). All cases presented with only skin lesions. This was a heterogeneous group, including four epidermotropic CD8+ CTCL [67], two CD30 large primary cutaneous T-cell lymphomas [6
] and one large granular NK/T-cell leukemia with skin localizations. Initial treatment resulted in a complete remission in four cases, but all but one patient relapsed. Four of seven patients died of lymphoma. The median survival was 66 months (95% CI 32100); the 2- and 5-year survivals were 83% and 56%, respectively.
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Discussion |
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Comparison between blastic NK-cell lymphomas and CD56+ myeloid leukemias presenting in the skin showed striking similarities in histology, immunophenotype, clinical presentation, including the percentage of bone marrow involvement at presentation (46% compared with 60%), and prognosis. In addition, in a recent workshop of the EORTC Cutaneous Lymphoma Study Group on cutaneous CD56+ lymphomas, the great similarities between both groups were noted (Muche et al., unpublished data). These observations suggest a possible relationship between both conditions. In addition, the development of AML in patients with blastic NK-cell lymphoma has been reported [31].
Recent studies demonstrated that blastic NK-cell lymphomas express markers typical of plasmacytoid dendritic cells, in particular the IL-3R alpha chain (CD123) and the lymphoid protooncogene TCL1 [64]. Expression of CD123 has also been reported in a proportion of myeloid leukemias presenting in the skin [3
, 65
]. These findings argue against a NK-cell origin and suggest that the term blastic NK-cell lymphoma is inappropriate. CD4+, CD56+ hematodermic neoplasm [4
] and CD4+ CD56+ malignancy [5
] have been suggested as more appropriate terms for this condition.
The overlapping clinical, histological and immunophenotypical features of blastic NK-cell lymphoma and CD56+ myeloid leukemias presenting in the skin provide also a rationale to treat these patients with more aggressive regimens used in myeloid leukemias, rather than with convential CHOP(-like) regimens, which is in line with the results of recent studies [5, 61
].
Nasal and nasal-type NK/T-cell lymphomas together represented the second largest group in this study (55 of 157 cases; 35%). In cases with a true T-cell phenotype as defined by expression of surface CD3 and/or the presence of a clonal TCR gene rearrangement, which express cytotoxic proteins, but no EBV, it is an arbitrary decision whether a diagnosis of nasal type NK/T-cell lymphoma or peripheral T-cell lymphoma NOS should be made. In this study, such EBV-negative cases were classified as peripheral T-cell lymphomas, not otherwise specified. Angiocentricity proved not to be very helpful in distinguishing the two groups, because this feature was observed in all groups investigated in this study (see Table 3). Nasal and nasal-type NK/T-cell lymphomas showed many similarities (see Table 4
). No difference in survival was found between nasal NK/T-cell lymphomas presenting with concurrent cutaneous disease and nasal type NK/T-cell lymphomas presenting with cutaneous and extracutaneous disease (median survival 5 and 4 months, respectively). Nasal-type NK/T-cell lymphomas presenting with skin-limited disease had a somewhat better prognosis, which is consistent with the results of previous studies in primary cutaneous angiocentric lymphomas [68
] (see Figure 1
). The poor survival data in these nasal(-type) NK/T-cell lymphomas also indicate that current standard regimensgenerally doxorubicin-based chemotherapyare insufficient in these cases, and that other approaches should be investigated.
Apart from the entities discussed above, other types of CTCL can occasionally show co-expression of CD56. Within the group of CD56+ SCPLTCL, five of six cases appeared to have a gamma/delta phenotype. These gamma/delta-positive cases are often not confined to the subcutis, but may extend into the dermis [69]. In such cases differentiation between SCPLTCL and nasal-type NK/T-cell lymphomas extending into the subcutis may be difficult [15
]. It is noteworthy that both groups have a similar poor prognosis, and do not respond sufficiently to CHOP(-like) therapy. The only patient with a CD56+ SCPLTCL still alive in this study had an alpha/beta T-cell phenotype. This observation is consistent with the results of other studies indicating that SCPLTCL with an alpha/beta phenotype have a much better prognosis than cases with a gamma/delta phenotype, and that the two groups should be considered separately [51
, 70
].
Previous studies in systemic CD30+ anaplastic large-cell lymphoma suggested that expression of CD56 is associated with a less favorable prognosis [71]. The favorable prognosis of the patients with a primary cutaneous CD30+ lymphoma and LyP included in this study suggests that CD56 expression does not affect clinical behavior and outcome in the group of primary cutaneous CD30+ lymphoproliferations. Similarly, the four cases with an epidermotropic CD8+ CTCL with co-expression of CD56 did not differ clinically from CD56 cases, as described previously [67
].
Classification of lymphomas that are defined primarily by phenotype, such as these CD30+ lymphomas and CD8+ CTCL, and which at the same time express CD56, may be difficult. This problem is well illustrated by the eight CD30+/CD56+ lymphomas in the study by Mraz-Gernhard et al. [41]. In that study, on NK/NK-like T-cell lymphoma primarily defined by the presence of CD56 expression, it was found that cases which co-express CD30 had a much better prognosis than CD30 cases. Seven of eight cases are alive and well after initial treatment, and did not relapse. It seems that these patients have a clinical presentation and course similar to that observed in primary cutaneous CD30 + CTCL [10
, 72
]. Although EBV-expression was noted in three out of eight cases, one wonders why at least some of the cases were not simply classified as primary cutaneous CD30+ CTCL with co-expression of CD56. Therefore, studies on larger numbers of patients with co-expression of CD30 and CD56 are necessary. If it is confirmed that primary cutaneous CD30+ CTCL with co-expression of CD56 do not have a separate clinical behavior from CD56 cases, cases with localized disease can be better treated with radiotherapy than with multiagent chemotherapy.
Received for publication October 28, 2003. Revision received February 27, 2004. Accepted for publication February 27, 2004.
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