The spectrum of cutaneous lymphomas expressing CD56 has been heterogeneous with respect to clinical presentation and course, morphology and immunohistochemical phenotype, as well as the association with EBV infection. To classify these neoplasms more precisely, we evaluated the clinical and histological/immunophenotypical characteristics of a large series of CD56+ haematological cases (n
34) presenting in the skin. Based on the data obtained, we identified four groups which show significant differences in clinical behaviour and prognosis.
Despite their different cellular origin, CD56+ cases of haematodermic neoplasm/blastic NK‐cell lymphoma (group 1), of AML skin infiltration (group 2) and of extranodal NK/T‐cell lymphoma nasal type (group 3) are characterised by their extremely poor clinical outcome. This is in sharp contrast to the very favourable clinical outcome of patients with “classical” CD56+ primary cutaneous T‐cell lymphoma (group 4).
Haematodermic neoplasms (blastic NK‐cell lymphomas) (group 1) represent the largest group of our series (20/34, 56%), with a striking male dominance (15/20, 83%). Clinically, all patients experienced an aggressive clinical course regardless of whether they presented with localised or disseminated disease (median survival 12 months). This observation is in line with previous studies and is independent of the therapeutic regimens used.18,19
The origin of the CD4+/CD56+ tumour cells of the so‐called haematodermic neoplasms/blastic NK‐cell lymphomas is the subject of a longstanding debate. NK cell precursor, a myelomonocytic precursor or a mixed NK/myelomonocytic precursor have been proposed.20,21,22,24
Petrella et al
recently suggested a derivation from pDC, as indicated by expression of the interleukin‐3 receptor alpha subunit (CD123).25,26
Moreover, the same group also showed TCL1 expression in a larger series of CD4+/CD56+ haematodermic neoplasms, thus excluding NK cells as the origin of this entity.7
The pDC origin of CD4+/CD56+ haematodermic neoplasms was furthermore supported by Hallermann et al
and Urosevic et al
, who showed the co‐expression of CD123 and “blood dendritic cell antigen” (BDCA‐2) in nearly all investigated cases of cutaneous CD4+/CD56+ haematodermic neoplasm.27,28,29
BDCA‐2 is a C‐type lectin transmembrane glycoprotein that internalises antigen for presentation to T‐cells and is specifically expressed by human pDC.29
The investigation of a newly‐generated cell line (CAL‐1) derived from a blastic NK‐cell lymphoma revealed further convincing results for the pDC origin of this entity.30
The second group (4/34) of cutaneous CD56+ neoplasms represents cutaneous infiltrates of acute myelomonocytic leukaemia (AML), as evidenced by their additional expression of myelomonocytic markers such as CD33, CD68 and MPO.17
The morphological and clinical features are highly similar to the cases of blastic NK‐cell lymphoma of group 1. This includes the observation that allogenic bone marrow transplantation appears to be the most beneficial therapeutic option. These concordant features suggest a possible relation of both neoplasms, which is supported by the fact that in some cases, patients with haematodermic neoplasms/blastic NK cell lymphoma develop myeloid or myelomonocytic leukaemia as also shown in 2/20 patients of groups 1 and 2.31,32
Recently several studies have shown that CD56+ expression on AML tumour cells appears to be associated with a shorter period of complete remission and reduced survival as compared to CD56− cases.33,34
This is in harmony with the finding that CD56+ myeloid leukaemia displays more frequently an extramedullary involvement (skin, lymph node) at initial presentation, suggesting that CD56+ myeloid leukaemia might constitute a distinct biological and clinical disease entity.24,35,36
The third group (5/34) identified among the CD56+ cutaneous neoplasms consists of skin involvement of nasal type extranodal NK/T‐cell lymphoma. The clinical course of the five patients (80% men) resembled those in previous reports in that the development of skin lesions (fast‐growing tumour nodules) was most frequently followed by involvement of the nasopharyngeal region (40%) and lymph nodes (40%), with early dissemination to the bone marrow and liver (20%).37
Despite intensive combined chemotherapy, patients with cutaneous NK/T‐cell lymphoma have an extremely poor prognosis, as most patients die within several months after its onset as also shown in our patients, who died after a median survival of only 7 months.
According to the WHO classification, extranodal NK/T‐cell lymphoma is nearly always associated with EBV infection, irrespective of the ethnic origin of the patients, suggesting a pathogenic role for the virus.17,38,39,40,41,42
However, we could not detect an EBV infection of tumour cells in 25% of the cases. This is in agreement with a recent series of primary cutaneous NK/T‐cell lymphomas of Asian and Caucasian patients, which were EBV‐negative in most cases (17/52, 33%).48,49,50
Interestingly, the histological features of extranodal NK/T‐cell lymphomas are indistinguishable among the various sites of involvement.
The cellular origin of the CD4+/CD56+ cells in extranodal NK/T‐cell lymphoma has not been completely clarified. In the majority of extranodal NK/T‐cell lymphomas, T‐cell receptor genes are in germline configuration, consistent with a natural killer cell origin.43,44,45,46,47
Conversely, clonal TCR‐receptor gene rearrangement as evidence for a T‐cell origin could be detected in nearly 30% of the investigated cases of cutaneous extranodal NK/T‐cell lymphoma.48,49,50
The evidence to date suggests that the postulated counterparts of extranodal NK/T‐cell lymphoma are probably both cell types, activated NK cells and cytotoxic T lymphocytes, indicating a close relationship to the precursor cell. However, the presence or absence of EBV or TCR rearrangement in extranodal NK/T cell lymphomas seems to have no prognostic significance.
The fourth group (5/34) represents cutaneous neoplasms with a co‐expression of the CD56 molecule but not included in the other groups. All cases of group 4 were cutaneous T‐cell lymphomas (CTCL) such as lymphomatoid papulosis (n
2), CD8+ subcutaneous panniculitis‐like T‐cell lymphoma with an alpha/beta‐phenotype (n
2) and mycosis fungoides (n
1). However, besides the typical histological/immunohistochemical and molecular features for these lymphomas, an atypical CD56 expression of the tumour cells was detectable.5
The most striking feature of the cases of group 4 is their excellent clinical outcome (all patients alive: follow‐up time median 62 months) when compared to the clinical course of the CD56+ cases of the other three groups. Considering the heterogeneity and small number of patients in group 4, our results suggests that the expression of CD56 cannot be regarded as a general marker for adverse prognosis identifying the need to discriminate among the patients suffering from CD56+ neoplasms. However, cases previously termed as subcutaneous panniculitis T‐cell lymphoma with a gamma/delta phenotype are now described in the recent WHO–EORTC classification as cutaneous gamma/delta‐T cell lymphoma and should be distinguished from subcutaneous panniculitis like T‐cell lymphoma. Most patients with a cutaneous gamma/delta‐T cell lymphoma have an aggressive disease and are resistant to multiagent chemotherapy and/or radiation therapy, showing a median survival of only 15 months.5
- Cutaneous lymphomas expressing CD56, a neural cell adhesion molecule, are characterised in most cases by a highly aggressive clinical course and poor prognosis.
- Aggressive types of CD56‐positive neoplasms of the skin are represented by haematodermic neoplasm, skin infiltration as the first manifestation of CD56+ acute myeloid leukaemia, and nasal‐type extranodal NK/T‐cell lymphoma.
- Cutaneous T‐cell lymphoma (CTCL), for example panniculitis like T‐cell lymphoma, may also show expression of the CD56 molecule, which is not associated with an aggressive clinical course.
- Therefore, it is clinically very important to separate CD56+ CTCL from the remaining CD56+ haematological disorders.
In conclusion, our findings indicate that CD56+ cutaneous lymphoproliferative disorders comprise a spectrum of different entities with specific clinical and biological features preferentially occurring in men (26/34, 76%). Most of these entities are associated with an aggressive clinical course and poor outcome with a median survival time of only 7–12 months. However, CD56 expression by itself is not a prognostic marker since several types of “classical CTCL” cases may also show a co‐expression of CD56. The extreme prognostic difference among the patients with cutaneous CD56+ neoplasms requires a precise diagnostic evaluation in order to identify those patients who presumably benefit from bone marrow transplantation. Because of the rarity of the diseases described in this study and the small number of patients, especially in groups 2–4, multicentre trials should be initiated to determine the most appropriate treatment strategies.