Lack of c-kit (CD117) expression in CD30+ lymphomas and lymphomatoid papulosis.

c-Kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells and has been reported to be expressed in CD30+ lymphomas such as Hodgkin's disease and anaplastic large-cell lymphoma. Imatinib mesylate, a well-established inhibitor of bcr-abl tyrosine kinase, and currently used for the treatment of patients with chronic myeloid leukemia, also inhibits c-kit receptor kinase activity. In view of the possible use of imatinib as experimental therapy for patients with c-kit-positive tumors, we assessed c-kit expression in CD30+ cell lines and lymphomas. The cell lines were assessed using multiple methods (RT-PCR, flow cytometry, and Western blot). c-Kit expression was also immunohistochemically assessed in 168 CD30+ lymphomas including 87 classical Hodgkin's disease, 63 anaplastic large-cell lymphoma, and 15 cutaneous anaplastic large-cell lymphoma. We also studied 18 cases of lymphomatoid papulosis, a CD30+ lesion closely related to cutaneous anaplastic large-cell lymphoma. Neither c-kit mRNA nor protein was detected in any of the cell lines assessed. Furthermore, treatment with imatinib did not inhibit proliferation of cell lines in vitro. Using immunohistochemistry, only one of 183 (0.5%) lesions was positive for c-kit, the positive case being an ALK-negative anaplastic large-cell lymphoma. Our data demonstrate that expression of c-kit receptor is exceedingly rare among CD30+ lymphomas and lymphomatoid papulosis, suggesting that c-kit receptor is unlikely to be an appropriate target for therapeutic options such as imatinib in patients with these tumors.     

CD8+ lymphomatoid papulosis and its differential diagnosis

We describe 5 cases (4 males, 14-43 years old; 1 female, 61 years old) of primary cutaneous T-cell lymphoproliferative lesions expressing a CD8/granzyme/CD30-positive phenotype. Four cases were compatible with lymphomatoid papulosis (LyP) based on the clinical course, which was recurrent asymptomatic papular nodular lesions over years responding to methotrexate; granulomatous inflammation and lack of other inflammatory cell elements were characteristic. In 1 case, an initial erroneous diagnosis was made of aggressive epidermotropic CD8+ T-cell lymphoma. The fifth case in this series was first interpreted as representing primary cutaneous anaplastic large cell lymphoma but was later recategorized as primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma owing to the extent of extracutaneous dissemination, including testicular involvement and disease progression despite chemotherapeutic intervention. Although all cases of LyP showed sharp cytoplasmic membrane staining with perinuclear Golgi accentuation with CD30, the recategorized case of aggressive epidermotropic CD8 cytotoxic T-cell lymphoma manifested only a weak cytoplasmic staining pattern. CD8 LyP defines a distinctive entity with characteristic light microscopic and phenotypic findings and has a predilection for young males. CD30 expression can occur in other forms of CD8 lymphoproliferative disease unrelated to primary cutaneous anaplastic large cell lymphoma or LyP.     

Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders

CD30-positive T-cell lymphoproliferative disorders are classified as cutaneous (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) or systemic. As extent of disease dictates prognosis and treatment, patients with skin involvement need clinical staging to determine whether systemic lymphoma also is present. Similar processes may involve mucosal sites of the head and neck, constituting a spectrum that includes both neoplasms and reactive conditions (eg, traumatic ulcerative granuloma with stromal eosinophilia). However, no standard classification exists for mucosal CD30-positive T-cell lymphoproliferations. To improve our understanding of these processes, we identified 15 such patients and examined clinical presentation, treatment and outcome, morphology, phenotype using immunohistochemistry, and genetics using gene rearrangement studies and fluorescence in situ hybridization. The 15 patients (11 M, 4 F; mean age, 57 years) had disease involving the oral cavity/lip/tongue (9), orbit/conjunctiva (3) or nasal cavity/sinuses (3). Of 14 patients with staging data, 7 had mucosal disease only; 2 had mucocutaneous disease; and 5 had systemic anaplastic large cell lymphoma. Patients with mucosal or mucocutaneous disease only had a favorable prognosis and none developed systemic spread (follow-up, 4-93 months). Three of five patients with systemic disease died of lymphoma after 1-48 months. Morphologic and phenotypic features were similar regardless of extent of disease. One anaplastic lymphoma kinase-positive case was associated with systemic disease. Two cases had rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3, seen most frequently in primary cutaneous anaplastic large cell lymphoma. Our findings suggest mucosal CD30-positive T-cell lymphoproliferations share features with cutaneous CD30-positive T-cell lymphoproliferative disorders, and require clinical staging for stratification into primary and secondary types. Primary cases have clinicopathologic features closer to primary cutaneous disease than to systemic anaplastic large cell lymphoma, including indolent clinical behavior. Understanding the spectrum of mucosal CD30-positive T-cell lymphoproliferations is important to avoid possible overtreatment resulting from a diagnosis of overt T-cell lymphoma.     

Peripheral T‐cell and NK‐cell lymphomas and their mimics; taking a step forward – report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology

Mature T‐cell and T/NK‐cell neoplasms are both uncommon and heterogeneous, among the broad category of non‐Hodgkin lymphomas. Owing to the lack of specific genetic alterations in the vast majority, most currently defined entities show overlapping morphological and immunophenotypic features, and therefore pose a challenge to the diagnostic pathologist. In the light of recent immunophenotypic, cytogenetic and molecular genetics advances in the field of T‐cell and T/NK‐cell lymphomas, the focus of the lymphoma workshop of the European Association for Haematopathology/Society for Hematopathology meeting in Lisbon, Portugal, in October 2012 was to refine existing diagnostic criteria and clarify the borders between overlapping entities. The panel reviewed over 200 submitted cases, which were grouped into five categories: (i) angioimmunoblastic T‐cell lymphoma and T‐follicular‐helper‐cell‐associated lymphomas; (ii) CD30‐positive T‐cell lymphomas/lymphoproliferative diseases; (iii) extranodal T‐cell and NK‐cell neoplasms; (iv) EBV‐associated T‐cell/NK‐cell lymphomas/lymphoproliferative diseases; and (v) peripheral T‐cell lymphoma, not otherwise specified, post‐transplant lymphoproliferative disorders, and mimics. This report summarizes the discussions and conclusions of the workshop, which question current diagnostic criteria and provide recommendations for refining existing classifications.     

Primary cutaneous CD30 positive T-cell lymphoproliferative disorders with aberrant expression of PAX5: report of three cases

Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B-cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs.     

CD30-positive T-cell lymphoproliferative disorder of the oral mucosa--an indolent lesion: report of 4 cases

Four cases of CD30-positive T-cell lymphoproliferative disorder (CD30+ LPD) of the oral mucosa are described. This article aims to draw attention to this entity and to emphasize its usual benign clinical behavior despite its resemblance to T-cell lymphoma. All the patients were adults. Three of the lesions were on the dorsal surface of the tongue and 1 affected the buccal mucosa. All biopsies showed a dense lymphoid infiltrate composed of CD30+ atypical T cells with a polymorphous infiltrate in the background, which included eosinophils. In 1 case, monoclonal T-cell expansion was detected by molecular techniques. Three cases tested for Epstein-Barr virus were all negative. It is concluded that primary CD30+ T-cell LPD of the oral mucosa can be regarded as the oral counterpart of cutaneous CD30+ LPD such as lymphomatoid papulosis or anaplastic large cell lymphoma. Recognition of the condition is important to avoid overtreatment.     

Primary CD30-positive cutaneous T-cell lymphomas and lymphomatoid papulosis frequently express cytotoxic proteins

AIMS: To analyse the relationship between expression of cytotoxic proteins, histopathology and the CD30 status in primary cutaneous T-cell disorders, we investigated the expression of TIA-1, granzyme B and perforin in CD30 negative and CD30 positive cutaneous T-cell lymphomas (CTCL) and lymphomatoid papulosis (LP). METHODS AND RESULTS: We studied 26 cases of CTCL and 12 cases of LP for the expression of TIA-1, granzyme B and perforin which are granule-associated proteins of cytotoxic lymphocytes involved in the mechanism of apoptosis. We showed that most cases (10/13) of CD30 negative pleomorphic lymphomas expressed cytotoxic proteins only in scattered, apparently reactive lymphocytes, the exception being one CD8+ CTCL and two gammadelta subcutaneous 'panniculitis-like' T-cell lymphomas. We also showed that at least one cytotoxic protein was expressed in a proportion of neoplastic cells in 77% (10/13) of CD30+ T-cell lymphomas (3/4 pleomorphic and 7/9 anaplastic) and in a proportion of atypical cells in 75% (9/12) of LP. CONCLUSIONS: Our findings show a strong correlation between the CD30 phenotype and the expression of cytotoxic proteins in primary CTCL. In addition, these results provide further evidence for an overlap between lymphomatoid papulosis and cutaneous CD30+ pleomorphic and anaplastic lymphomas. These entities, which belong to the spectrum of CD30 positive cutaneous T-cell lymphoproliferations, appear to be derived from cytotoxic cells.     

Aggressive cutaneous T-cell lymphomas

Cutaneous T cell lymphomas (CTCLs) are heterogeneous, with a prognosis determined in large part by combined clinical, histopathologic, and immunophenotypic features. They are classified under the WHO-EORTC classification of primary cutaneous lymphoma. Whether or not a patient diagnosed with CTCL will experience an aggressive course may not be completely predictable; however, certain subtypes have been proven to be associated with a poor response to therapy and/or short survival. These aggressive subtypes may be diagnosed by certain histologic, immunophenotypic, and clinical features; however, there are benign lymphoproliferative disorders (LPD), such as lymphomatoid papulosis (LyP) that present with biopsy findings that simulate an aggressive lymphoma. Moreover, some of the well-recognized aggressive lymphomas may rarely follow an indolent course, while otherwise indolent lymphomas may act aggressively. This review will focus on the non-mycosis fungoides (MF) aggressive subtypes, as well as potentially aggressive presentations of MF.     

Epstein-Barr virus-positive systemic NK/T-cell lymphomas in children: report of six cases

Rodríguez‐Pinilla S M, Barrionuevo C, García J, de los Ángeles M, Pajares R, Casavilca S, Montes J, Martínez A, Montes‐Moreno S, Sánchez L & Piris M Á
(2011) Histopathology  59 , 1183–1193
Epstein–Barr virus‐positive systemic NK/T‐cell lymphomas in children: report of six cases Aims: The World Health Organization lymphoma classification recognizes two different Epstein–Barr virus (EBV)‐positive T‐cell lymphoproliferative disorders of childhood: systemic EBV‐positive T‐cell lymphoproliferative disease of childhood, and hydroa vacciniforme‐like lymphoma, which is more prevalent in Asia and Latin America. The aim of this study was to characterize six cases of paediatric EBV‐positive peripheral T‐cell lymphoma with distinct features. Methods and results: All cases were male, with a median patient age of 9 years (range: 5–17 years). Most of them presented suddenly with fever, weight loss, hepatosplenomegaly, peripheral lymphadenopathy, and high lactate dehydrogenase (LDH) levels. Moreover, gut, lung or soft tissues of the abdominal wall were also affected in four cases. Partial to total replacement of the lymph node by pleomorphic infiltration of atypical neoplastic cells was found in all cases. Vasculitis and geographical areas of necrosis were seen in three and four cases, respectively. Neoplastic cells showed expression of EBV‐encoded RNA, T‐cell markers (CD2 and CD3), and cytotoxic markers (TIA1, granzyme‐B, and perforin). CD56 and T‐cell receptor ‐γ were expressed in one case each. TCR‐BF1, CD4, CD8 and anaplastic lymphoma kinase were negative. In all cases, the disease progressed rapidly, causing death of the patient, with a median survival of 7.1 months (range: 1–13 months). Conclusions: These cases probably represent a solid form of systemic EBV‐positive T‐cell lymphoproliferative disease of childhood, which requires identification and the development of appropriate therapy.     

Formalin-resistant leukocyte surface antigens in the diagnosis of cutaneous malignant lymphomas

Immunophenotyping of routinely embedded lymphoma biopsies, increasingly used in nodal lymphomas, has not been systematically performed in cutaneous lymphomas. Eight monoclonal antibodies were tested directed against formalin resistant antigens (T cell biased: UCHL1, MT1; B cell biased: 4KB5, L26, Ki-B3; HLA-class II: CBL 120; activation antigens: Ber-H2; myeloid biased: Mac 387, M1) in cutaneous T (N = 29) and B (N = 10) cell lymphomas and pseudolymphomas (N = 9). UCHL1 and MT1 showed a high specificity and sensitivity. B cell-restricted antibodies L26 and 4KB5 showed the best sensitivity and specificity among the B cell-associated antibodies; Ki-B3 showed aberrant expression on T cells in some cases. Ber-H2 (CD30) was demonstrated in most cases of large cell anaplastic lymphoma and single cases of other lymphomas and lymphomatoid papulosis. Class II antigen expression, as determined by CBL 120, showed good specificity but low sensitivity, and antibodies directed against myeloid antigens did not react with tumor cells.     

A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders

Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ T-LPD) represent a spectrum encompassing lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL) and borderline lesions. They share the expression of CD30 as a common phenotypic marker. They differ however in their clinical presentation, the histological features and clinical course. Moreover, LyP and PcALCL show numerous clinical, histological and phenotypic variants. Overlapping features of LyP and pcALCL with themselves and with other cutaneous and systemic lymphomas emphasize the importance of careful clinicopathologic correlation and staging in the diagnosis of CD30+ T-LPD. Furthermore, an increasing number of inflammatory and infectious skin disorders harboring medium-sized to large CD30+ cells have to be considered in the differential diagnosis.Whereas the expression of CD30 in cutaneous CD30+ T-LPD stands for a favourable prognosis, its expression in other cutaneous and systemic lymphomas has a divergent impact. The assessment of CD30 expression does not only provide prognostic information, but is of potential therapeutic relevance as CD30 can serve as a therapeutic target.This review focuses on the clinicopathological and phenotypic spectrum of CD30+ T-LPD, its differential diagnoses and the role of CD30 as a diagnostic, prognostic and therapeutic marker.     

Therapeutic outcome of Epstein-Barr virus positive T/NK cell lymphoma in the upper aerodigestive tract

Expression of the natural killer (NK) cell antigen CD56 is uncommon in malignant lymphoma, but when it is, it is almost exclusively of the non-B cell lineage and show a preference for the nasal and nasopharyngeal region. T/NK cell lymphoma is known to be aggressive and refractory to treatment. It is highly associated with the Epstein-Barr Virus (EBV), but clinical investigations are rarely reported, that is until recently. We report here, on the clinical features and therapeutic outcomes of patients with T/NK cell lymphomas and its association with EBV. We reviewed fifty-four cases with peripheral T cell lymphomas in the upper aerodigestive tract between Jan. 1987 and Aug. 1998 from the Severance Hospital, Yonsei University College of Medicine. The diagnosis of T/NK cell lymphoma was made according to the expression of the NK cell markers, CD56 antigen and cytoplasmic CD3epsilon, in tumor specimens, by immunohistochemistry. Epstein-Barr early region (EBER) RNA was detected using in situ hybridization on paraffin-embedded sections. Among the 54 cases with malignant lymphomas occurring in the upper aerodigestive tract, 20 had T/NK cell lymphoma (37%). The primary sites of T/NK cell lymphomas were the nasal cavity, 12 cases (60%), the tonsils, 4 cases (20%), the nasopharynx, 2 cases (10%), and the oropharynx, 2 case (10%). There were no differences between the features, at diagnosis or therapeutic modalities for patients with T/NK cell lymphoma and non-T/NK cell lymphoma. The complete remission rate of T/NK cell lymphomas was lower than non-T/NK cell lymphomas (65% vs 85%, p=0.02). The overall survival of T/NK cell lymphomas was 13 months (1-74 month), which was significantly lower than non-T/NK cell lymphomas [60.6% with a median follow up of 22 months (1-101 month, p=0.02)]. Disease free survival of T/NK cell lymphomas was 22 months (4-66 month), significantly lower than non-T/NK cell lymphomas [73.8% with a median follow up of 22 months (2-95 month), p=0.04]. The overall survival rates for T/NK cell lymphomas were significantly lower than for EBV positive non-T/NK cell lymphomas (p=0.018). EBER RNA was detected in the paraffin-embedded tissue sections of all T/NK cell lymphomas, compared to only 17.6% (6 of 34 cases) for non- T/NK cell lymphomas. In conclusion, as patients with T/NK cell lymphomas showed poor clinical outcomes, and a high association with EBV positivity, clinical trials with more investigational therapeutic strategies, and further research into the relationship of EBV infection with pathogenesis of T/NK cell lymphoma is warranted.     

Diagnostic approach to T- and NK-cell lymphoproliferative disorders in the gastrointestinal tract

Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.     

Primary natural killer/T-cell lymphomas of the oral cavity are aggressive neoplasms

Thirty-four cases of primary non-Hodgkin’s lymphoma of the oral cavity were investigated for their clinical findings, histopathological features, immunophenotypes and association with Epstein-Barr virus (EBV). Four cases (12%) were natural killer/T-cell lymphomas, 3 (9%) were T-cell lymphomas and 27 (79%) were B-cell lymphomas. Compared with T- and B-cell lymphomas, NK/T-cell lymphomas had a male predominance (M:F 4:0), and most presented as ulceration of the palate and/or maxillary gingiva. Histologically, the lesions showed diffuse infiltration of medium-sized or large lymphoid tumour cells. Angiocentricity and/or angioinvasion were found in all 4 cases. The immunophenotypes of the NK/T-cell lymphomas were CD3+, CD43+, CD45RO+, CD56+ and TIA-1+. EBV was detected in 2 NK/T-cell lymphomas by in situ hybridization (ISH) and polymerase chain reaction (PCR) methods, and was not detected in T- and B-cell lymphomas. The survival rate of patients with NK/T-cell lymphoma was zero, but the survival rates for patients with T-cell and B-cell lymphomas were 67% and 38%, respectively. It appears that NK/T-cell lymphomas of the oral cavity have a predilection for originating in the palate and maxillary gingiva and are aggressive neoplasms. EBV positivity might be associated with more aggressive behaviour. Received: 21 January 1999 / Accepted: 14 April 1999     

Primary Cutaneous CD8-Positive Epidermotropic Cytotoxic T Cell Lymphomas : A Distinct Clinicopathological Entity with an Aggressive Clinical Behavior

Cutaneous T cell lymphomas (CTCL) generally have the phenotype of CD3+, CD4+, CD45RO+ memory T cells. CTCL expressing a CD8+ T cell phenotype are extremely rare and ill-defined. To elucidate whether these CD8+ CTCL represent a distinct disease entity, the clinical, histological, and immunophenotypical features of 17 CD8+ CTCL were reviewed. None of the 17 cases expressed markers characteristic of natural killer cells or gamma/delta T cells. Nine of 17 cases showed the characteristic clinical and histological features as well as clinical behavior of well defined types of CTCL, such as mycosis fungoides (2 cases), pagetoid reticulosis (2 cases), lymphomatoid papulosis (2 cases), and CD30+ large T cell lymphoma (2 cases), all of which usually express a CD4+ T cell phenotype, and 1 case of subcutaneous panniculitis-like T cell lymphoma. The other 8 cases formed a homogeneous group showing a distinctive set of clinicopathological and immunophenotypical features, not consistent with that of other well defined types of CTCL. Clinical characteristics included presentation with generalized patches, plaques, papulonodules, and tumors mimicking disseminated pagetoid reticulosis; metastatic spread to unusual sites, such as the lung, testis, central nervous system, and oral cavity, but not to the lymph nodes; and an aggressive course (median survival, 32 months). Histologically, these lymphomas were characterized by band-like infiltrates consisting of pleomorphic T cells or immunoblasts, showing a diffuse infiltration of an acanthotic epidermis with variable degrees of spongiosis, intraepidermal blistering, and necrosis. The neoplastic cells showed a high Ki-67 proliferation index and expression of CD3, CD8, CD7, CD45RA, betaF1, and TIA-1 markers, whereas CD2 and CD5 were frequently lost. Expression of TIA-1 pointed out that these lymphomas are derived from a cytotoxic T cell subset. The results of this and other studies reviewed herein suggest that these strongly epidermotropic primary cutaneous CD8+ cytotoxic T cell lymphomas represent a distinct type of CTCL with an aggressive clinical behavior.