MATERIALS AND METHODS
A workshop of the EORTC Cutaneous Lymphoma Task Force was held on July 3–5, 1998, at the Study Center “I Cappuccini,” S. Miniato (Pisa, Italy). Cases were solicited on the following topics: 1) lymphomas in which tumor cells expressed at least one of the following molecules, namely, CD8, TIA-1, or CD56; 2) lymphoma showing features of subcutaneous or angiocentric lymphoma; and 3) lymphoma expressing the γ/δ phenotype. Sixty examples of primary cutaneous lymphoma exhibiting one the aforementioned features were provided.
During the workshop, there was a plenary discussion on the definition and differential diagnosis of cytotoxic and nonnasal NK/T-cell primary cutaneous lymphomas, but some gray areas still remained. To solve residual problems, a committee composed of 10 experienced dermatopathologists or hematopathologists (EB, MEK, DM, CJLMM, HKM-H, MP, NP, MS, JW, RW) was appointed. They met on January 16–18, 1999, at the Department of Human Pathology and Oncology, University of Florence Medical School, Florence, (Italy). This report summarizes the results of both the plenary and committee discussions. Forty-eight cases of appropriate immunophenotype were identified and included in the present study. Four of these cases have been included in previous studies on various lymphoma types.7–10
Clinical records and follow-up data through December 1999 were obtained from patients' charts. The principal parameters evaluated included age and gender, extent of disease, spontaneous regression, symptoms at presentation, bone marrow involvement, cutaneous recurrences, extracutaneous progression of disease, treatment, and follow-up duration (Table 1).
Table 1. Clinical Data and Follow-Up Information
|1||M/33||Plaques, nodules||Widespread||PUVA-PR||IFN-NR, TSEBI-NR, CT(CHOP)-NR||Skin, oral mucosa, and systemic involvement (sepsis)||DOD, 34|
|2||M/82||Nodules||Widespread||CT (COP) and RT-CR||CT (unspecified)||Skin and systemic involvement||DOD, 17|
|3||M/59||Plaques||Widespread||Topical nitrogen mustard-CR||CT (CHOP), RT, topical nitrogen mustard||Skin and systemic involvement||DOD, 28|
|4||M/74||Nodules||Lower limb||IFN and retinoids-PR||CT (CHOP)-PR||Skin and systemic involvement||DOD, 10|
|5||M/16||Patches, plaques||Widespread||PUVA-CR||N.A.||Skin||AWD, 24|
|6||M/30||Patches||Lower limb||PUVA-PR||Topical steroids-NR CT (miltefusine)-PR||Skin||AWD, 36|
|7||F/77||Plaques||Widespread||PUVA-PR||RT (TSEBI)-CR||Skin||AWD, 32|
|9||F/59||Patches, plaques||Widespread||PUVA-CR||PUVA-PR||Skin||AWD, 144|
|10||F/54||Subcutaneous nodules||Limbs||Systemic steroids-CR||CT(cyclophosphamide)-PR||Skin||AWD, 96|
|11||M/14||Subcutaneous nodules||Limbs, buttocks||CT (ACVBP)-CR||Nil||Nil||NED, 15|
|12||F/55||Subcutaneous nodules||Limbs||Nil (spontaneous remission)||Nil (spontaneous remission)||Skin||AWD, 60|
|13||M/36||Subcutaneous nodules||Limbs||Topical steroids-CR||CT (CHOP, CDA, ara-C, others)-PR, RT (TSEBI)-PR||Skin and systemic involvement (hemophagocytic syndrome)||AWD, 24|
|14||M/53||Subcutaneous nodules||Limbs||Steroids and hydroxychlorokine-NR||CT (mitoxantrone, etoposide, vincristine, cyclophosphamide)-NR||Skin and systemic involvement (pancytopenia, sepsis)||DOD, 9|
|15||F/56||Subcutaneous nodules||Head, trunk, upper limb||Steroids-NR||CT (cyclophosphamide, CEOP)-NR||Skin and systemic involvement (pancytopenia, sepsis)||DOD, 24|
|16||M/10||Subcutaneous nodules||Trunk, upper limb||Steroids-NR||CT (cyclophosphamide, CEOP)-NR||Skin and systemic involvement (pancytopenia, sepsis)||DOD, 5|
|17||M/76||Subcutaneous nodules||Limbsa||N.A.||N.A.||Skin||AWD, 24|
|18||F/44||Subcutaneous nodules||Lower limb||CT (CHOP)-NR||CT (VIM2, ara-C)-NR||Skin and systemic involvement (liver and lung)||DOD, 17|
|19||F/8||Subcutaneous nodules||Trunk||Cyclosporine-PR||CT (unspecified)-NR||Skin and systemic involvement||DOD, 23|
|20||F/73||Subcutaneous nodules||Lower limb, buttocks||CT (CHOP)-PR||RT-PR, CT (methotrexate)-PR||Skin and systemic involvement (liver)||DOD, 12|
|21||F/33||Subcutaneous nodules||Limbs, buttocks||Steroids and retinoids-PR||N.A.||Skin and systemic symptoms (malaise, fatigue, and fever)||AWD, 12|
|23||F/27||Nodules||Head, trunk||Nil (spontaneous remission)||N.A.||N.A.||N.A.|
|24||F/43||Nodules||Upper limb||CT (CHOP)-CR||CT (unspecified)-PR||Skin,b||AWD, 10|
|25||M/71||Nodules||Trunk, limbs||CT (CHOP)-CR||CT (methotrexate)-CR||CNS||DOC (stroke), 3|
|26||M/60||Nodules||Head||CT (VICOP-B)-NR||CT (unspecified)-NR||Skin and systemic involvement (bone marrow)||DOD, 8|
|27||M/60||Papules, plaques||Widespread||CT (fludarabine)-CR||Nil||Nil||NED, 16|
|28||M/57||Plaques, nodules||Widespread||CT (unspecified)-PR||CT (unspecified)-PR||Skin||N.A.|
|29||F/47||Plaques||Head, lower limb||RT and CT (CHOP)-CR||IFN and CT (vincristine, chlorambucil)-PR||Skin and systemic involvement (lymph nodes, CNS)||DOD, 31|
|30||M/41||Plaques||Lower limba||RT-CR||Nil||Nil||NED, 44|
|31||M/38||Plaques, nodules||Widespread||Nil||CT (PROMACE-CYTABOM) and allogeneic BMT-CR||Skin and systemic involvement (bone marrow and blood)||DOD, 22|
|32||M/83||Plaques, nodules||Trunk||CT (mini-CEOP)-CR||CT (unspecified)-NR||Skin and systemic involvement (bone marrow and blood)bc||DOD, 10|
|33||M/80||Plaques, nodules||Head, trunk||CT (COP)-NR||CT (unspecified)-PR||Skin and systemic involvement (bone marrow)||DOD, 20|
|35||M/55||Plaques, nodules||Head, trunk||CT (MACOP-B)-CR||IFN, CT (chlorambucil), and steroids-NR, autologous BMT-CR||Skin and systemic involvement||N.A.|
|36||M/61||Plaques, nodules||Trunk, limbs||CT (CEOP)-CR||RT and CT (MACOP-B)-CR||Skin and systemic involvement (bone marrow, blood, and lymph nodes)||DOD, 37|
|37||M/58||Plaques, nodules||Widespread||CT (CHOP)-PR||CT (unspecified)-NR||Skin and systemic involvement (testis and bone marrow)||DOD, 16|
|38||M/54||Plaques||Trunk, lower limb||Antibioticd||CT (CHOP)-CR||Skin and systemic involvement (CNS)||DOD, 17|
|41||M/63||Nodules||Limbs, trunk||Nil (spontaneous remission)||Nil||Skin||NED, 12|
|42||F/60||Nodules||Limbs, trunk||Steroids and clofazimine-PR||N.A.||Skin||AWD, 60|
|43||F/63||Plaques||Lower limb||RT and CT (cyclophosphamide)-CR||Nil||Nil||NED, 36|
|44||M/60||Nodules||Limbse||RT-NR,||CT (CDA, CHOP)-PR||Skin and systemic involvement (lymph nodes)||DOD, 18|
|45||F/38||Plaques, nodules||Trunk, limbsf||CT (unspecified)-CR|| ||Nil||N.A.|
|46||F/76||Plaques||Limbs||Nil (spontaneous remission)||RT-PR||Skin and systemic involvement (lymph nodes, soft tissues, CNS)||DOD, 11|
|47||M/77||Nodule||Head||Surgery and RT-CR||N.A.||Skin and systemic involvement (pharyngeal mass)||DOD, 11|
|48||M/39||Nodule||Lower limb||RT-CR||RT + CT (CHOP)-PR||Skin and systemic involvement (soft tissues and bone marrow)||DOD, 12|
The TIA-1 and CD56 status was determined immunohistochemically on paraffin sections using the antibodies TIA-1 (Coulter, Miami, FL) and 123C3 (Lab-Vision, Fremont, CA), respectively. In previous studies, other authors have shown that 123C3 reliably detects CD56 expression in lymphomas on paraffin-embedded tissues.5 Additional immunohistochemical data were provided by the source institutions. Epstein–Barr virus (EBV) infection was demonstrated using nonisotopic in situ hybridization for EBV-encoded small RNAs (EBERs) on paraffin-embedded material, as previously described,11 as well as by immunohistochemistry with antibodies against LMP-1 or by polymerase chain reaction (PCR). The DNA used for gene rearrangement studies was extracted from frozen or paraffin-embedded tumor tissue. T-cell receptor (TCR) gene rearrangement was evaluated by a PCR assay coupled with nondenaturing polyacrylamide gel electrophoresis according to a method previously described.12 Amplification of the TCR-γ chain locus V-J junctional region was performed by using oligonucleotide primers specific for J1/2 paired with V2a, V9, and V10. In some cases, DNA was digested with restriction endonuclease BamHI, EcoRI, or HindIII, subjected to electrophoresis on a 0.8% agarose gel, and transferred to a nitrocellulose filter for Southern analysis using hybridization with 32P-labeled DNA probes, according to standard protocols.13, 14 Rearrangements of the TCR and immunoglobulin genes were evaluated using probes that include a 1.0-kb germline Pst-EcoRI fragment containing the first region (Jδ1), the constant region of TCR-β gene (Cβ), the TCR-γ gene, and JH (heavy-chain joining region).15
The spectrum of cutaneous cytotoxic lymphomas was heterogenous with regard to clinical presentation, morphologic and immunophenotypic features, association with EBV, and clinical course. Taking into account these features, several categories were identified. Their salient features are summarized in Table 2, based on information from the current study and the literature.
Table 2. Summary of the Major Types of Cutaneous Lymphomas Expressing the Cytotoxic-Associated Marker TIA-1 and/or the Natural Killer Cell Marker CD56a
|Age||Middle-aged or elderly adults||Middle-aged or elderly adults||Middle-aged adults, children||Adults||Adults||Adults||Adult|
|Gender||M > F||M = F||F ≥ M||M > F||M > F||M||M|
|Clinical presentation||Patches, plaques, and nodules, often with hemorrhage and ulceration||As typical mycosis fungoides||Mimicking panniculitis: indurated, painful subcutaneous plaques or nodules, mostly located on the lower limbs, common ulceration of lesions and fever||Multiple cutaneous nodules commonly followed by systemic dissemination (upper aerodigestive tract, soft tissues, testis, and gastrointestinal tract); sometimes involvement of multiple extranodal sites at presentation||Multiple cutaneous papules, plaques, and nodules in noncontiguous skin sites||Disseminated plaques and nodules on the skin; sometimes systemic disease at presentation||Disseminated, cutaneous erythematous plaques|
|Histologic features||Lichenoid infiltrate composed of medium/large pleomorphic T cells, with linear and pagetoid epidermotropism, spongiosis, and blistering, variable numbers of necrotic keratinocytes at the dermal-epidermal junction.||As typical mycosis fungoides||Variably sized pleomorphic lymphocytes infiltrating subcutis in a lace-like fashion, with rimming of adipocytes by neoplastic cells; karyorrhexis and fat necrosis common; granulomatous reaction and erythrophagocytosis seldom observed; frequent dermal involvement in TCRδ1+ cases.||Proliferation of variably sized pleomorphic cells, with prominent angiocentricity, angiodestructive growth, and extensive necrosis.||Variably sized pleomorphic lymphocytes or, more rarely, monomorphic medium-large blasts in an “Indian file” or reticular pattern; angiocentric and/or angiodestructive features frequently observed, never prominent.||Monomorphous infiltrate composed of medium-large–sized cells infiltrating collagen bundles in an interstitial pattern||Intravascular accumulation of large atypical blast-like cells mixed with abundant fibrin|
|Most common immunophenotype||CD3+, CD4−, CD8+, CD45RA+, CD45RO−, TIA-1+, bcl-2+, MIB-1+(> 90%), CD56+/−, CD2−/+, CD5−/+, CD7+/−||CD3+, CD4−, CD8+/−, CD45RA+/−, CD45RO−/+, TIA-1+, CD56−/+, CD2+, CD5+||CD2+, CD3+, CD3ε+, CD45RO+, CD43+, TIA-1/perforin/GrB+, CD8+/−, CD4−/+, CD56+/−, CD5+/−, CD7−. γ/δ(TCRδ1+) > α/β(βF1+) (Europe), α/β(βF1+)>γ/δ(TCRδ 1+) (USA)||CD2+, CD3−, CD3ε+, CD4−, CD8−/+, CD45RO+, CD45RA−, TIA-1+, CD56+, CD57−, CD16−||CD4+, CD56+, bcl-2+, CD43+, CD3−, CD3ε+, CD8−, CD45RA+, CD45RO−, CD5−, CD2−/+, CD7−/+, βF1−, TCRδ1−, CD30−, CD57−/+, MIB-1+ (> 50%) TIA-1−/+, CD68+/−, CD34−||CD2−/+, CD3−, CD3ε+, CD4−, CD8−, CD45RO−, CD45RA+, CD56+, TIA-1−, GrB−, βF1−, TCRδ1−, TdT+/−||CD3ε+, CD56+, TIA-1+, GrB+, CD30+, MIB-1+ (100%), CD4−, CD8−, CD57−, CD68−, bcl-2−|
|TCR genes||Rearranged (TCRγ)||Rearranged||Rearranged||Germline||Germline||Germline||N.T.|
|Association with EBV||Absent||Absent||Absent||Present (> 90%)||Absent||Absent||?|
|Clinical behavior||Rapidly progressive dissemination (oral cavity, testis, lung, CNS, soft tissues; sparing of lymph nodes) and fatal outcome (mean survival time 32 mos)||As typical mycosis fungoides||Frequent dissemination of skin lesions and systemic spread to bone marrow, lung, liver, commonly accompanied by sepsis and hemophagocytic syndrome; more rarely, indolent course with spontaneous remission||Aggressive, with early dissemination; common recurrences despite initial response to chemotherapy||Aggressive, with rapid dissemination to bone marrow (leukemia +/−) and fatal outcome||Aggressive, with systemic involvement and death||CNS involvement and death|
|Treatment guidelines||Chemotherapy (purine analoges) with/without radiotherapy; allogeneic minitransplant (second line)||As typical MF (PUVA, topical chemotherapy)||Chemotherapy (CHOP-like or third-generation regimens, possibly followed by allogeneic BMT) with/without radiotherapy||Chemotherapy (CHOP-like or third-generation regimens), possibly followed by autologous or allogeneic BMT with/without radiotherapy; radiotherapy on isolated lesions.|
Information on aggressive, CD8+, epidermotropic, cytotoxic T-cell lymphomas is very limited. Only sporadic cases of mycosis fungoides, pagetoid reticulosis, or other types of T-cell lymphomas expressing a CD8+, cytotoxic phenotype have been described.16–33 Even the EORTC classification in its current form does not include CD8+ cytotoxic T-cell lymphomas neither in a well defined nor provisional category.2 However, Berti et al.8 drew attention to these tumors and suggested that CD8+ cytotoxic T-cell lymphomas represent a distinctive type of cutaneous T-cell lymphoma with an aggressive clinical behavior.8 The results of our study confirmed those of Berti et al.8 concerning the distinctive clinical presentation and course, histology, and immunophenotypic features of neoplastic cells of this peculiar type of cutaneous T-cell lymphoma. In addition, we demonstrated that these cutaneous T-cell lymphomas also express the CD56 antigen, a finding not previously reported. The T-cell origin and the clonality of this neoplasm were confirmed by the rearrangement of the TCR-γ gene in the three cases investigated. The course of the disease is characterized by rapidly progressive dissemination and death, despite the use of aggressive multiagent chemotherapy regimens. It is noteworthy that the systemic spread did not involve the lymph nodes, but involved the oral cavity (one case), the soft tissues of the centrofacial region (one case), and unusual sites (lung, testis, or CNS) accompanied by sepsis in one case. This may be attributed to the CD56+ phenotype, which is associated with homing to extranodal sites.
Aggressive therapeutic modalities were ineffective in the management of these patients. Therefore, new strategies are needed. In this respect, two main points should be taken into account. First, the course of the disease is frequently associated with severe immunodeficiency. Therefore, neither TSEBI nor aggressive polychemotherapy regimens are likely to achieve long-standing clinical responses. When possible, an allogeneic minitransplant instead of autologous bone marrow transplantation may be suggested. Alternatively, the use of purine analogs devoid of high immunosuppressive capacity (like gemcitabine, which was used in aggressive cutaneous T-cell lymphoma cases34) may be proposed, possibly associated with local radiotherapy. Second, as suggested by Berti et al.,8 the putative Th1-like cytokine profile of these aggressive CD8+ cutaneous T-cell lymphoma should discourage treatments that increase Th1 responses (e.g., retinoids or interferon alpha). Extreme caution should be used for such regimens.
Concerning mycosis fungoides, the cytotoxic immunophenotype variant, these cases were characterized by the typical clinical evolution, histology, and course of mycosis fungoides. If there are immunophenotypic similarities with CD8+ aggressive lymphomas, cytotoxic mycosis fungoides has to be regarded as a phenotypic, and not a clinicopathologic, variant of mycosis fungoides and should be treated nonaggressively according to well established guidelines (PUVA, topical chemotherapy).
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL), currently included as a provisional entity in both the REAL classification35 and the EORTC classification2 for primary cutaneous lymphomas, has been incorporated as an entity in the WHO classification.2 The 12 cases in the current series exhibited the typical features as described in the more than 60 cases reported to date.36–59 In our series, two phenotypic subsets can be delineated: TCR-γ/δ+/CD56+ and α/β+/CD56−. In agreement with previous observations,58 these phenotypic subsets correlated with the presence or absence of dermal invasion. All but one case with dermal extension were γ/δ+/CD56+. Although a limited number of SPTCLs have been investigated for TCR expression, earlier studies from Europe and Eastern countries documented a prevalent γ/δ TCR expression similar to that found in the current, study.40, 46, 55, 60–62 American studies have emphasized that the majority of SPTCL cases expressed α/β TCRs.57, 58 We do not know the reasons for the discrepancy between the American and European/Eastern studies. In agreement with previous observations,39, 49 most cases have an aggressive clinical behavior. In a few cases, the course of the disease is indolent, with spontaneous remission of skin lesions and long periods of stable disease without associated systemic symptoms. Neither the age of the patients nor the aggressiveness of the initial treatment was related to the course of the disease. In agreement with previous observations,57 a correlation was found between the expression of TCR-γ/δ+/CD56+ phenotype by tumor cells and an aggressive course. Therefore, the presence of this peculiar immunophenotypic profile may be indicative of a dismal clinical course and may require aggressive therapeutic modalities (CHOP-like or third generation regimens, possibly followed by allogeneic bone marrow transplantation). Conversely, the finding of a TCR-α/β+/CD56− phenotype may be indicative of an indolent course and favor less aggressive treatments. However, further studies are needed to confirm whether the origin (α/β or γ/δ) and CD56 expression have a prognostic significance.
Increasing attention has been given to the clinicopathologic spectrum of the CD56+ lymphomas, possibly due to the availability of a paraffin section-reactive CD56 antibody, which has greatly facilitated the recognition and further characterization of these rare tumors.4–5, 63–69 CD56+ lymphomas show a polymorphous clinical presentation, a wide morphologic spectrum, and a variable immunophenotypic profile. For this reason, there is much confusion and little consensus regarding the best nomenclature for these tumors. A review of the literature on this topic shows that similar cases have been designated with different terms, such as “aggressive natural killer cell leukemia/lymphoma”,70, 71 “large granular lymphocytic lymphoma”,72, 73 “angiocentric T-cell lymphoma”,74 “CD56+ T-”cell lymphoma,”75, 76 “natural killer cell lymphoma” and “CD56 angiocentric lymphoma”.78 A comprehensive study provided a more complete picture of these rare neoplasms and better clarified the clinicopathologic spectrum of these uncommon tumors.5 In the current study, we focused on NK and NK-like lymphomas with primary presentation of disease in the skin. It should be noted that many of our cases had histologic/immunophenotypic patterns that were difficult to assign unambiguously to one or another of the existing categories. In addition, this preliminary review gave us reason to doubt that histopathologic features by themselves were invariably specific. That is, we frequently found it impossible to unequivocally classify single cases on morphologic grounds alone.
The three cases of NK/T-cell lymphoma, nasal type, showed the characteristic morphology (dermal proliferation of small to medium pleomorphic cells, with prominent angiocentricity and angiodestructive growth as well as extensive necrosis), immunophenotype (CD3−, CD3ε+, CD56+, CD45RO+, TIA-1+, TCRs−), and association with EBV, as previously described.4, 5, 79 In addition, in the only patient with available follow-up information, the development of skin lesions was rapidly followed by involvement of the frontal paranasal sinuses and nasal cavity, in agreement with the highly aggressive clinical behavior reported in previous studies.4, 5 An extensive immunohistochemical study on frozen section also showed an NK CD2+/CD94+/NKp46+ phenotype.
Clinically, in the group of CD4+ NK cell lymphomas, a striking male preponderance was observed, in agreement with previous observations.5, 67 Histopathologically, these cases showed a dermal infiltrate of variably sized pleomorphic cells or monomorphic, medium to large blasts. The neoplastic cells showed an Indian file or reticular pattern of infiltration. The angiocentric/angiodestructive features, although often observed, were never prominent as in the nasal type NK/T-cell lymphoma. The immunophenotype was CD3ε+/−, CD4+, CD43+, CD45RA+/−, CD56+, CD68+/−, CD123/IL3Rα+, CD3−, CD57−, TCRs−, TIA-1−, EBER− and LMP-1−, resembling the immunophenotypic profile described by Petrella et al.6 as “CD4+, CD56+ cutaneous lymphomas.” Possible examples were published by others.7, 80, 81 Therefore, we preferred to retain this terminology instead of using the one proposed by the WHO classification (blastic NK-cell lymphoma).
The expression of CD4, CD56, CD68, and CD123 and the negativity of NKp46 and CD94 (in seven cases tested), the striking male preponderance, and the subsequent rapid spread to bone marrow, with or without leukemic evolution, raise doubts concerning the origin/differentiation of tumor cells and the relationship of this entity with other NK/T-cell lymphomas and leukemias.4, 5, 70, 82–85 The CD4+/CD68+/CD123+ phenotype was mainly expressed by immature monocytic and dendritic cell precursors. The cases belonging to this group, although primary cutaneous at presentation according to the EORTC definition2 and characterized by initial response to the treatment with aggressive polychemotherapy, experienced rapid spread to the bone marrow, with or without leukemia, and death notwithstanding aggressive second-line treatments including bone marrow transplantation. We recommend aggressive polychemotherapy possibly followed by autologous or heterologous bone marrow transplantation in patients presenting with disseminated cutaneous diseases and local radiotherapy and close follow-up in patients who present with single, isolated skin lesions.
The patient with blastoid NK cell lymphoma presented with the clinical symptoms (extranodal disease at diagnosis, histopathologic features (monomorphous proliferation of medium to large cells in a retiform pattern reminiscent of leukemia), immunophenotypic profile (CD3−, CD4−, CD8−, CD56+, βF1−, TCRδ1−), the lack of association with EBV, and the aggressive clinical course recently described by Chan et al.5 as typical of this entity. For this reason, and because of the lack of CD4 expression, we believe that this case is phenotypically different from CD4+NK-like lymphoma. Therefore, we retained the original terminology instead of using the one proposed by the WHO classification, which lumps the two categories under the heading “blastic NK cell lymphoma.” However, because few cases of blastoid NK cell lymphoma have been reported, the proper nosology of these rare cases and their relationship with other types of NK/T-cell lymphomas/leukemias remain to be determined. In particular, it cannot be excluded that both blastoid NK cell lymphoma and CD4+/CD56+ primary cutaneous lymphoma partly overlap with or may be identical to the entity called blastic NK cell lymphoma according to the WHO classification.1
The only case of intravascular, NK-like lymphoma had such a distinctive morphoimmunophenotypic profile that it deserves a separate category. We preferred to use NK-like instead of NK cell because we were not able to investigate the TCR gene status. On histopathologic examination, our case exhibited the typical intravascular accumulation of large atypical cells, which dilated and occluded the vascular lumina and were associated with fibrinous thrombi.86 To the best of our knowledge, this is the first case reported of an intravascular NK-like lymphoma. In fact, most of the previously described cases showed a B-cell phenotype and a concurrent predilection for lung and skin,87, 88 whereas fewer reported cases of T-cell–derived cases showed a clear-cut predilection for the skin.88–100 The current case characterized by complete remission after initial aggressive polychemotherapy (CHOP), metastasis to the CNS, and death 17 months after diagnosis, has to be considered exceptional as that putatively histiocytic variant reported.101
The group of cytotoxic, peripheral T-cell lymphomas by Snowden et al. represented a hodgepodge of cases that did not have unifying features and were lumped together because they did not conform to any of the other categories. These cases were composed of pleomorphic lymphocytes of variable size or blast-like cells with the features of pleomorphic small to medium-sized cutaneous T-cell lymphoma or large cell cutaneous T-cell lymphoma, CD30−, or large cell cutaneous T-cell lymphoma CD30+/lymphomatoid papulosis according to the EORTC classification. Although the small number of cases does not us allow to draw definite conclusions, it seems that the cytotoxic phenotype does not significantly affect the clinical evolution and prognosis of the single entities, similarly to cytotoxic mycosis fungoides.
In conclusion, primary cutaneous lymphomas expressing the cytotoxic granule-associated protein (TIA-1) and/or the NK cell marker (CD56) include distinct groups of diseases, both clinically and biologically. Our objective was to clarify the clinical, morphologic, and phenotypic features of these distinct categories, which are often characterized by a highly aggressive behavior. Because the finding of a cytotoxic phenotype often has prognostic significance, the routine use of cytotoxic markers in the diagnosis and classification of cutaneous lymphomas should be expanded.