Case 8 -

Nasal/Nasal Type NK/T-cell Lymphoma Marsha C. Kinney and Steven H. Swerdlow

Clinical History 43 year old female with one year history of skin lesions. Biopsy of paranasal sinus. Diagnosis: Nasal/Nasal Type NK/T-cell Lymphoma Case 8 - Figure 1 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy. Large areas of necrosis are present in the soft tissue. Case 8 - Figure 2 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy. Higher magnification reveals infiltration and destruction of a vessel by large, dysplastic tumor cells with hyperchromatic nuclei. Case 8 - Figure 3 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy, paraffin immunoperoxidase, antibody Beta-F1. The tumor cells lack expression of T cell receptor beta chain. A small reactive lymphocyte is positive. Case 8 - Figure 4 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy, paraffin immunoperoxidase, antibody T1A-1. Tumor cells express the cytolytic granule protein TIA-1. Immunophenotype: CD45+, cytoplasmic CD3+, CD45RO+, CD43+, CD4-, CD8-, bF1-, TCRd-1-, CD56-, TIA-1+, CD30+/-, EBER- Natural killer cell neoplasms are rare. [168a] The prototype is the nasal/nasal type NK/T-cell lymphoma occurring in the nose/paranasal sinus, skin and soft tissue, and other extracutaneous sites. Discussion of Case 8: Clinical and pathologic features of nasal/nasal type NK/T-cell lymphoma Cutaneous nasal type NK/T-cell lymphoma and its differential The complicated world of NK-cell neoplasms--an overview General characteristics of nasal/nasal type NK/T-cell lymphoma: [1, 168, 169, 170, 171, 172, 173, 174] Distinct clinicopathologic entity highly associated with EBV Angiocentric/angiodestructive growth pattern and zonal necrosis Predilection for the nasal/paranasal sinuses and less frequently the skin, gastrointestinal tract, testis, female genital tract, kidney, and upper respiratory tract, and rarely the eye/orbit [174] Designation "nasal-type" is used for lymphomas with these histologic features arising at extranasal sites Roughly 10-20% of these lymphomas involve both the skin and nasal area as demonstrated in case 8 NK>>T-cell phenotype, particularly in the Far East, Central and South America, and in Native Americans Clinical features of nasal NK/T-cell lymphoma: [175, 176, 177, 178, 179] Wide age range; median 45-50 years (range 14-78 years) with most patients in the fifth to seventh decade [176, 177, 178] Males> females in most series (M:F = 0.7-4.0) Obstruction, bloody discharge, facial swelling, pain; rarely visual disturbances Destructive nasal or midline facial tumor (lethal midline granuloma; polymorphic reticulosis); may have destruction of the palate, orbital swelling and edema 80%-90% have stage I/II disease; less than 20% have regional node involvement; 5 year overall survival is 30%-40% [177, 179, 179a] Treatment consists of radiation with or without chemotherapy or autologuous stem cell transplantation [175, 177, 179a, 179b] Recurs locally or at other extranodal sites Hemophagocytic syndrome occurs in 8%-12% [176, 179, 180] Marrow involvement in <10% at presentation; requires immunohistochemistry for CD56 (CD56 also stains plasma cells and osteoblasts) or EBER-ISH to detect, and is predictive of early death. An additional 10-20% develop marrow involvement during the course of their disease [181] Histologic features of nasal/nasal type NK/T- cell lymphoma: Broad cytologic spectrum with a mixture of small, medium or large cells; many tumors have a predominance of large dysplastic cells with hyperchromatic or vesicular chromatin* Admixed inflammatory cells may be prominent Zonal necrosis; although not required for the diagnosis, angiocentricity and angiodestruction are seen in most (>60%), but not all cases * Lesions with smaller cells and less cytologic atypia are difficult to diagnose; they were previously considered of indeterminate malignancy and called "polymorphic reticulosis." [1, 182] Note: angiocentricity is defined as "a preferential concentration of tumor cells around and within blood vessels, with infiltration and destruction of the blood vessel wall." Perivascular pattern of infiltration is not sufficient. [168] Immunophenotypic features of nasal NK/T-cell lymphomas: Approximately 80% are NK-cells; 10%-30% are T-cell, with gd> ab type [170, 171, 172, 177, 183] Cytoplasmic CD3+/-; surface CD3- in NK-cell types; CD2+/-; CD4-CD8+>CD4-CD8-; CD45RO+/-; CD43+/- Cytolytic phenotype: TIA-1+, perforin+, granzyme B+ [184, 185] CD56+ in 50-90% [176, 178, 183] EBV+ in majority of cases; CD56- cases are often EBV- [170, 171, 172, 178, 186] CD30+ in ~20% Aberrant BCL-10 expression is seen in tumor cell nuclei (normal NK-cells express BCL-10 in their cytoplasm.) [186a] This is not due to mutations in the BCL-10 gene. [186b] Note: 35%-55% percent of nasal tumors overall have a B-cell phenotype. [176, 179] Lymphomas involving the sinuses without nasal lymphoma are predominantly diffuse large B-cell lymphomas, whereas lymphomas involving the nasal cavity alone are NK/T- cell lymphomas. [176] Note: In the absence of CD56 a diagnosis of nasal or nasal type NK/T-cell lymphoma should not be made unless EBV or cytotoxic molecule expression is present; otherwise, the diagnosis should be peripheral T-cell lymphoma unspecified (WHO Classification). Note: Rarely Herpes simplex virus (HSV) of the nasopharynx may simulate nasal NK/T-cell lymphoma. The presences of giant cells with "ground glass" nuclei, immunoreactivitiy for HSV rather than EBV, polyclonal CD4+ T-cell nature of the infiltrate, and lack of angioinvasion and destruction are distinguishing features. [186c] Pathogenesis of nasal/nasal type T/NK-cell lymphoma: Cytogenetics/Molecular Genetics: [187, 188, 188a, 189, 189a, 189b, 189c, 189d]   Few cytogenetic studies have been performed   del 6q is the most common   Other lesions include iso (6p), iso (1q), 11q, 13q abnormalities [187]   Comparative genomic hybridization also confirmed loss of 1p and loss of material on 16p and 17p consistent with loss of p53 in some cases; additional abnormalities include losses at 1p, 12q and gains at 2q, 13q, and 10q [188, 188a]   Molecular studies have implicated abnormalities of tumor suppressor gene function (p53, p21,etc) as being important in the pathogenesis of NK-cell tumors [189a, 189b, 189c]   FAS gene mutations have been detected in 50% of nasal NK/T-cell lymphoma suggesting resistance to apoptosis may be important in its pathogenesis [189d] Epstein Barr virus:   EBV is present in the majority of cases and has been demonstrated to be clonal in some [190, 191]   EBNA-1 mutations arising in vivo suggest that nonrandom distribution of EBV subtypes highlights a role for EBV in lymphomagenesis [192] Multifactorial causes of tissue necrosis:   angioinvasion and angiodestruction   cytotoxic effector molecules released from NK/ T-cell lymphoma cells (perforin and Fas/FasL cytotoxic pathways) [184, 185]   cytokine production such as TNF-alpha. Cutaneous nasal type NK/T-cell lymphoma [193, 194, 195, 196, 197, 198, 199, 200] Older patients (median age 52-66 years, range 19-76 years) Males<females Single or multiple purple nodules, often ulcerated [196] Multiple sites; lower extremities>upper extremities>trunk>face Nodules, plaques, or tumors that can be generalized or regional>solitary 25%-50% show other organ involvement including gastrointestinal tract, testis, breast, nasal (~10-20% involve both), less frequently liver, spleen, marrow, lymph node, salivary gland Pleomorphic small, medium or large cells Angiodestruction and angioinvasion; zonal necrosis Dermal and subcutaneous (often lobular pattern) involvement; NK/T-cell lymphomas with subcutaneous panniculitis-like involvement have been reported, primarily in patients of Asian descent. [200, 200a] CD56+ (60%-100%), TIA-1+, ~30% CD30+ EBV+/- (some report ~15%-33% of cases EBV+ [95, 96, 196, 198, 201] ,others report 90%-100% EBV+ [197, 198, 199] , EBV appears to be less often positive in T-cell cases) [202]; EBV negative cases have a better prognosis and some are reported to show spontaneous regression [95] Cell of origin variable; 20%-50% are T-cell in origin [196, 197, 198] t(3;17) reported in one T-cell case [203] Note: Rare cases of indolent NK-cell panniculitis with transformation at 12 years to large cell, aggressive tumor have been reported. [204] Note: Patients with lymphomatoid granulomatosis (angiocentric lymphomas in the lung, often with a EBV+ B-cell phenotype) have cutaneous lesions in 20%-30% of cases; [205, 206] only a small percentage of skin lesions have clonal IgH rearrangements and EBV expression. [207] Table 13. Comparison of Nasal NK/T-cell Lymphoma and Cutaneous Nasal-type NK/T-cell Lymphoma Parameter Nasal NK/T-cell Lymphoma Cutaneous Nasal-type NK/T-cell Lymphoma Sex M>F F>M Median age 45-50 years 52-66 years Other sites of disease <20% 25%-50% T-cell phenotype 10%-30% 20%-50% CD56 expression 50%-90% 60%-100% CD30 expression ~20% ~30% EBV ~80-100% ~15-40%* Prognosis Aggressive, 5 year survival~ 30%-40% ~75% alive at a median followup of 63 mos in one series; may have regression; 95 lack of EBV is more favorable with less systemic disease * some series report higher incidence [197, 199] The complicated world of NK-cell neoplasms--an overview: Similar to T-cell neoplasms, NK-cell neoplasms can be subclassified according to the stage of maturation and clinical characteristics of the tumor. [168a, 208, 209] Table 14. Classification of NK-cell Neoplasms Immature Mature Myeloid/NK-cell precursor acute leukemia Leukemia: -Indolent LGL leukemia [61, 210, 211, 212, 212a, 212b] -Aggressive NK-cell leukemia * Blastic NK-cell lymphoma# Nasal/nasal type NK/T-cell lymphoma LGL = Large granular lymphocyte * Recently characterized as aggressive NK-cell leukemia to emphasize the predominance of the leukemic manifestations [213] # Recent studies have presented evidence that most cases described as "blastic NK-cell lymphoma" likely represent tumors arising from plasmacytoid dendritic cells rather than NK-cells (see "Blastic NK-cell Lymphoma" below). [213a, 213b, 213c, 213d, 213e] Table 15. General Comparison of Immature and Mature NK-cell Neoplasms Immature Mature Blastic morphology Small, medium or large lymphocytes Azurophilic granules inconspicuous or absent Azurophilic granules present TIA-1 usually negative TIA-1 + Lacks killer activity in vitro Has killer activity in vitro EBV- EBV+ In the normal developmental pathway of NK-cells, pre NK-cellsexpress CD161 (C-type lectin), immature NK-cells express CD161 and CD56, and mature NK-cells express CD161, CD56, and CD94 (C-type lectin). [213g] The immature NK-cell neoplasms are difficult to categorize and include "blastic NK cell lymphoma" and myeloid/NK cell precursor acute leukemia. There is overlap of these neoplasms with CD56+ AML and dendritic cell precursors. "Blastic NK-cell Lymphoma" * [209, 213a, 213b, 213c, 213d, 213e, 214, 215, 216] Older patients, median 52-69 years (range 4-86 years) with multiple pigmented or erythematous plaques; approximately 15% occur in children Frequent marrow involvement (50%-87%); some progress to overt leukemia; cytopenias in ~90%, predominantly thrombocytopenia and anemia Extramedullary disease in 100%: skin lesions (60%-80%); adenopathy (~50-60%); hepatosplenomegaly (~15%; splenomegaly more frequent); mediastinum (20%) Superficial and deep dermal and subcutaneous involvement (diffuse, not lobular) Blastic appearance (loose chromatin, cytoplasmic vacuoles along the cytoplasmic membrane; pseudopods); lack of angioinvasion/angiodestruction and necrosis Cytoplasmic granules absent or inconspicuous in 75% CD2-/+, surface CD3-, CD4+, CD5-/+, CD7+ (72%), CD33-/+ (weak), CD56+, CD57-, CD16-/+ (<10%+), CD36+, CD38+, CD68+(90%), CD71+, CD117-, CD123+ (IL-3 receptor a-chain), TdT+/- (some cases TdT+ by immunohistochemistry; TdT- by flow cytometry), TIA-1-/+; CD34-/+ (<10%+); [209] some T cell cases have been reported ; [196] some reports suggest possible monocytic differentiation; [216] but, cells are alpha-napthyl butyrate esterase - and CD14- [217] EBV negative [96, 196, 209] Aggressive course; the complete response rate is 78% with multiagent chemo- therapy, but most relapse in <2 yrs (bone marrow, skin, CNS) with a poor outcome Complex chromosomal abnormalities have been reported including abnormalities of 3, 5 (5q-), 7,13(del 13), 6q, del 12p, del 9, del 15, and +1, +9, +19, +Y [209, 213c, 217] * Although an extensive discussion is beyond the scope of this handout and course, recent evidence suggests that most cases described as "blastic NK-cell lymphoma" are tumors of plasmacytoid dendritic cells (also formerly called plasmacytoid monocytes or plasmacytoid T-cells) rather than a true NK-cell. [213a, 213b, 213c, 213d, 213e] The plasmacytoid dendritic cell (pDC) is a lymphoid dendritic cell precursor. pDC and the proposed normal counterpart of "blastic NK-cell lymphoma" (also called CD4+CD56+ hematodermic neoplasm and more recently early pDC leukemia/lymphoma [213d]) express comparable levels of CD4, CD43, CD68, CD123 (IL-3 receptor a chain), and CXCR3 but usually lack more lineage specific markers (CD13, CD33, surface CD3). [213a, 213b] The CD56+ tumor cells also express chemokine receptors (CCR5, CXCR1), integrins (CD11a, CD49e) and adhesion (CD56, CD62L, CD162) or activation (CD5, CD101) antigens and they likely represent an activated form of the pDC. CD123bright+ expression can be used to distinguish this neoplasm from other lymphomas. However, CD123bright+ expression may be seen in CMML and a subset of AML; the lack of MPO, CD13, CD14, CD15, and CD33 is useful in distinguishing this CD4+CD56+ neoplasm. CD2, CD7, CD38, CD36, CD4SRA may also be positive in pDC tumors [213d]. Newly described markers of pDC include BDCA-2+, BDCA-4+. [213d] A recent study by Karube et al, 2003, has described a small number of patients with blastic tumors that involved lymph nodes and the mediastinum. [213f] Their phenotype (CD7+CD4-CD123-CD56+TdT+CD68-CD33-CD34-) is different from myeloid/NK-cell precursor acute leukemia and of pDC tumors discussed above. These cases may truly represent tumors of immature, but committed, NK-cells. Note: References 213d and 213e, by Jacob et al., provide an excellent review of this difficult area. Table 16. Differential diagnosis of CD56+ Skin Lesions Lymphoma Subcutaneous Involvement Cell of Origin Granules EBV CD4 Other Sites gd- SCPTCL8 Lobular* T Not reported -/+ -/+ Infrequent "Blastic NK-cell lymphoma" Diffuse NK No - + Marrow Nasal type NK/T-cell lymphoma Lobular/diffuse NK or T Yes -/+ - Other extranodal sites ∞ Most CD56+ SCPTCL have a gd T-cell phenotype * More dermal involvement than ab type but is patchy (perivascular and periadnexal) Note: Some cutaneous ALCL may be CD56+ Myeloid/NK-cell precursor acute leukemia: [209] Median age 46 years (range 19-79 years) Male>female Marrow and blood involvement (80%-100%) Extramedullary disease in 87%: lymph node (73%); mediastinum (20%); hepatosplenomegaly (<10%); skin (~10%) CD2+, surface CD3-, CD4-/+, CD5-/+, CD7+, CD10-, CD11b+, CD11c+, CD13+ and/or CD33+, myeloperoxidase -/+, CD56+, CD16-, CD57-, CD34+, HLA-DR+/-, TdT-/+ (negative by flow cytometry; some positivity by immunohistochemistry) FAB-M0 morphology (no azurophilic granules); however more extramedullary disease than usually seen in AML EBV- Responds to AML therapy Poor prognosis Cytogentics: multiple abnormalities most commonly involving 3p (p21-p36) Note: CD56 can be expressed in acute myeloid leukemia in 13-41% of acute myeloid leukemias. [218, 219, 220, 221] Scott et al. [220] described a myeloid/NK-cell acute leukemia whose morphologic features most resembled microgranular APL. Compared to the myeloid/NK-cell precursor acute leukemia there was: more expression of CD13 and less expression of CD34 and HLA-DR; the white blood count was higher; extramedullary disease was less common; there was a better prognosis; and chromosome abnormalities included t(11;17), del 17q25, and +8. [209] Note: Other small round blue cells tumors such as lymphoblastic lymphoma/T-ALL [62, 222, 223] and primitive neuroectodermal tumors, neuroblastoma, and rhabdomyosarcoma can express CD56 [223a]; Incorporation of markers such as neuron specific enolase, CD99 (detected by antibody 0-13), desmin, and a -sarcomeric actin, HHF35 are useful; O-13 is not lineage specific and can be seen in ALL/LBL and "blastic NK-cell lymphoma". [223a] Aggressive NK-cell leukemia: [197, 213, 224, 225, 226, 227] Young to middle-aged adults, some children [228] Systemic disease with generalized adenopathy, hepatosplenomegaly, atypical large granular lymphocytes in the blood; may have generalized adenopathy and minimal or no involvement of the peripheral blood Patchy or minimal involvement of the marrow compared to other leukemias Monotonous cytologic appearance, lymphocytes vary from mature-looking large granular lymphocytes to large cells with finer chromatin and more prominent nucleoli Sinusoidal pattern of infiltration of nodes; massive necrosis and apoptosis may be prominent; angioinvasion may be present; portal tracts and sinuses of the liver; splenic red and white pulp Phenotype: CD2+, surface CD3-, CD5-, CD56+, CD57-, CD16-/+, CD33-, TIA-1+, granzyme B+ EBV+ /- [209, 225] Chromosome abnormalities include;   Deletions of 6q16-q27, 11q22-q25, 17p13 by comparative genomic hybridization, similar to nasal/nasal type NK/T cell lymphoma [229]   recurring 8p21- pter rearrangements and 8p23 translocations [230] Often associated with systemic hemophagocytosis Very aggressive clinical course; median survival < 2 mos except in children where survival is longer [226, 227, 230] Note: Rare cases of agranular, EBV- NK-cell leukemia/lymphoma have been described [231, 232] Differential Diagnosis:   Chronic indolent T-LGL: CD3+. CD4-, CD8+, CD16+, CD57+, CD56-, TCR+; often associated with rheumatologic disease [212]   Chronic, indolent NK- LGL: CD3-, variable expression of CD4 and CD8 (usually CD8+ or CD4-CD8-), CD56+, EBV-, TCR-, CD16+/-, CD57+/- lack fever, hepatosplenomegaly, and lymphadenopathy; no association with rheumatoid arthritis Table 17. Differentiation of CD56+ Neoplasms with Blastic Features Feature Blastic NK-cell Lymphoma Aggressive NK-cell Leukemia Myeloid/NK-cell Precursor Leukemia* Marrow Involvement ++ Minimal or patchy ++ Skin ++ rare ~10% LN + ++ ++ Hepatosplenomegaly ~15% + <10% EBV - +/- - Cytoplasmic Granules -/+ + - * 13% - 41% of AML are CD56+ And finally in summary: Many extranodal lymphomas involve the skin; they can be differentiated by characteristic features: Cutaneous T/NK-cell Neoplasms Strong CD30 Expression Zonal Necrosis Angiodestruction Predominantly Subcutaneous Blastic ALCL Nasal/Nasal type NK/T-cell lymphoma SCPTCL "Blastic NK-celllymphoma/leukemia* * Must rule out AML Cutaneous lymphomas with a cytotoxic or NK-cell phenotype are as yet, with some exceptions, poorly understood, and there is a lack of consensus as to their classification. The WHO classification and EORTC classification of primary cutaneous lymphomas [124] did not include several of these disorders. 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