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T/NK cell disorders: general, WHO classification, adult T cell, anaplastic large cell, angiocentric T cell, angioimmunoblastic T cell, blastic NK, cutaneous alpha beta T cell lymphoma, cutaneous gamma delta T cell lymphoma, cytotoxic T cell lymphoma of skin, enteropathy type, epidermotropic CD8+ T cell lymphoma, hepatosplenic alpha/beta, hepatosplenic gamma/delta, indolent T cell proliferations, mycosis fungoides, NK cell large granular lymphocytic leukemia, NK/T cell lymphoma-nasal type, nodal CD8+ cytotoxic T cell, nonB nonT lymphoblastic, peripheral T cell lymphoma unspecified, pityriasis lichenoides, pre T cell lymphoblastic leukemia/lymphoma, primary cutaneous CD30 positive T cell lymphoproliferative disorders, primary effusion lymphoma, Sezary syndrome, subcutaneous panniculitis-like, T cell large granular lymphocytic leukemia, T cell prolymphocytic leukemia
Hodgkin lymphoma: general, classification, staging
follicular, lymphocyte depleted, lymphocyte predominant, lymphocyte rich classical, mixed cellularity, nodular sclerosis
Post-transplantation/other: general, WHO classification, plasmacytic hyperplasia, polymorphic B cell lymphoproliferative disorders, monomorphic B cell lymphoproliferative disorders, anaplastic large cell lymphoma, Burkitt, diffuse large B cell, Hodgkin, MALT, myeloma, NK/T cell disorders, graft versus host disease
AIDS associated lymphoproliferative disorders: general, anaplastic large cell, Burkitt/Burkitt-like, cutaneous lymphoma, diffuse large B cell, Hodgkin lymphoma, MALT, NK lymphoma-nasal type, peripheral T cell lymphoma, plasmablastic lymphoma, polymorphic B cell lymphoproliferative disorder, primary effusion lymphoma
Other: post-immunosuppressive therapy Hodgkin lymphoma, primary immune disorder associated, senile EBV+ lymphoproliferative disorders,
Go to Lymphoma-B cell and plasma cell neoplasms
(Lymph nodes (normal), Non-Hodgkin’s lymphoma (general), B cell disorders, Plasma cell neoplasms)
American Journal of Clinical Pathology (AJCP), Jan 1997 to Apr 2002 (no photos)
American Journal of Surgical Pathology (AJSP), Jan 1999 to July 2004
Archives of Pathology and Laboratory Medicine (Archives), Jan 1999 to July 2004
Human Pathology (Hum Path), Jan 2000 to June 2004
Modern Pathology (Mod Path), Jan 2001 to July 2004
Kjeldsberg, CR: Practical Diagnosis of Hematologic Disorders (3rd Edition); ASCP Press, 2000
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Please refer to these primary references for more detailed discussions
T/NK Cell disorders
15% of non-Hodgkin lymphomas in US/Western Europe; are usually aggressive with median survival of 10-30 months
Most T cell lymphomas are nodal; most NK cell lymphomas are extranodal
Must first establish that process is neoplastic
99% have diffuse lymphocytic infiltrate with numerous, evenly dispersed, ill-defined, small clusters of epithelioid histiocytes, but these may actually be Hodgkin lymphoma or lymphoplasmacytic lymphoma
Immunostaining or flow cytometry is useful for classification but usually cannot prove clonality, which requires T cell receptor rearrangement by PCR (can use paraffin)
Aberrant T cell phenotype (immunophenotypic clusters exhibiting altered expression of T-cell antigens relative to normal) usually implies clonality; most common aberrant values are for CD3, CD7, CD5; CD2 is most stable; for CD7, deletion is common (AJCP 2001;116:512)
Rarely express B cell markers CD20 and CD79a (Mod Path 2001;14:105)
NK markers are CD11b, CD11c, CD16, CD56, CD57 and polyclonal CD3 (detects CD3 epsilon)
Recommended immunostains include T cell markers (CD3, CD43, CD45RO) and B cell markers (CD20)
Peripheral T cell lymphomas are, by definition, composed of mature (not precursor) T cells; often misdiagnosed (Mod Path 2002;15:420)
Most relapses of nodal disease have similar histology, pattern of nodal involvement, immunophenotype (AJCP 2000;114:438)
Large B cells present in peripheral T cell disorders may be due to EBV (in immunodeficient patients) or represent clonal populations that develop into diffuse large B cell lymphoma (AJCP 2000;114:236, AJCP 2002;117:368)
Precursor T cell neoplasm:
Precursor T lymphoblastic leukemia/lymphoma
Mature (peripheral) T cell neoplasms:
T cell prolymphocytic leukemia
T cell large granular lymphocytic leukemia
Aggressive NK cell leukemia
Adult T cell leukemia/lymphoma
Extranodal NK/T cell lymphoma, nasal type
Enteropathy type T cell lymphoma
Hepatosplenic T cell lymphoma
Subcutaneous panniculitis like T cell lymphoma
Blastic NK cell lymphoma
Mycosis fungoides/Sezary syndrome
Angioimmunoblastic T cell lymphoma
Anaplastic large cell lymphoma
Peripheral T cell lymphoma, unspecified
Primary cutaneous CD-30+ T cell lymphoproliferative disorders
Primary cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
Borderline lesions
Adult T cell leukemia/lymphoma (HTLV-1 positive)
Most common where HTLV-1 virus (human T cell leukemia virus-1) is endemic (southwest Japan, Caribbean, southeast US, West Africa, South America)
Usually adults; patients have defects of cell-mediated immunity, are at risk for multiple opportunistic infections (Archives 2000;124:1241)
Occurs in 1-5% of HTLV-1+ patients;
Acquired from mother at birth, human milk, blood products or sexually transmitted; usually several decades before clinical features appear
Acute subtype: hepatosplenomegaly, generalized lymphadenopathy, bone marrow infiltration, skin lesions, high WBC count and lymphocytosis, hypercalcemia; median survival of less than 1 year despite aggressive chemotherapy
Lymphomatous subtype: prominent lymphadenopathy without significant peripheral blood involvement
Chronic subtype: increased WBC count, slight lymphadenopathy or hepatosplenomegaly
Smoldering subtype: few malignant cells in peripheral blood, may have slight lymphadenopathy, hepatosplenomegaly or marrow infiltrates
Note: chronic and smoldering subtypes may evolve into acute form
Note: HTLV-1 also causes tropical spastic paraparesis
Case reports: 32 year old man from West Africa (Archives 2003;127:636)
Micro: diffuse infiltrate of cells with multilobated nuclei (cloverleaf/flower cells), thick nuclear membranes and coarse chromatin, Reed-Sternberg like cells; cutaneous infiltrates are dermal or epidermotropic with Pautrier’s microabscesses (resembling mycosis fungoides)
Positive stains: CD2, CD3, CD4, CD5, CD25; rarely CD30+ but ALK-
Negative stains: CD7, CD8
Molecular: HTLV-1 provirus present in tumor cells; clonal T cell receptor rearrangement
Anaplastic large cell lymphoma (T and null-cell types)
Also called Ki-1 (CD30+) lymphoma
3% of adult and 10-30% of childhood non-Hodgkin lymphomas
T-cell origin and T-cell lineage can usually be proven by molecular studies, even if no T-cell antigen expression
Null cell types younger than T cell types (28 vs. 42 years, Hum Path 2002;33:146)
Moderately aggressive, may be curable; better prognosis than other peripheral T cell lymphomas with overall 5 year survival of 77%
Cutaneous forms described below under primary cutaneous CD30 positive T cell lymphoproliferative disorders
May be primary or a secondary transformation of another lymphoma
Usually nodal; nodal involvement often not contiguous, inguinal nodal involvement is more common than in Hodgkin lymphoma
Associated with HIV, mycosis fungoides; pulmonary inflammatory pseudotumors (Hum Path 2001;32:428), NOT EBV related (Hum Path 2004;35:455)
ALK positive tumors have longer 5 year survival (84% vs. 35%), younger age (median 19.5 years), are associated with TIA-1+ (AJSP 1999;23:1386); young age and ALK+ are favorable prognostic factors in CNS tumors (AJSP 2003;27:487)
ALK immunohistochemistry, FISH and RT-PCR results are comparable (AJSP 1999;23:1386)
Systemic: aggressive, involves bone marrow, bone, respiratory tract, GI, lymph nodes, skin; rarely lung
Cutaneous: indolent, affects adults, lesions may spontaneous regress; excellent prognosis; ALK negative
Case reports: endobronchial presentation in 17 year old girl (Archives 2003;127:e430), arising in silicon breast implant capsule (Archives 2003;127:e115), monomorphic variant arising in bone (Archives 2000;124:1339)
Micro: infiltration of interfollicular T zones and nodal sinuses by anaplastic, large cells with abundant cytoplasm, horseshoe, wreath-like or multiple nuclei, multiple nucleoli, perinuclear eosinophilic region and consistent expression of CD30/Ki-1; brisk mitotic activity
Cells resemble Reed-Sternberg cells, but prefer lymph node sinuses, may mimic metastatic carcinoma, behave differently than Hodgkin lymphoma (Mod Path 2001;14:219); vascular wall invasion is frequently seen in extranodal cases
Typically do not have a nodal architecture; monomorphic variant uncommon
Positive stains: CD3, CD30 (cytoplasmic and Golgi staining); also CD2 or CD4, CD25, BNH9, variable ALK; variable CD43, variable EMA, B cell markers in 10%, rarely CD13 (myelomonocytic marker, Archives 2000;124:1804)
“Small cell” and lymphohistiocytic variants are ALK1 positive, but cells are not large or anaplastic
Classify as null cell (all stains are negative) or T cell
Negative stains: CD15, CD20, CD79a, cytokeratin, bcl2, PAX5/BSAP
Molecular: t(2;5)(p23;q35): ALK and NPM (40-70%); translocation of anaplastic lymphoma kinase on #2 and nucleophosmin gene on #5; gene product present in nucleus and cytoplasm
t(1;2)(q25;p23): tropomyosin 3 and ALK
t(2;3)(p23;q21): ALK and TRK-fused gene (TFG)
inv(2) (p23;q35) ALK and ATIC
t(X;2)(q11-12;p23): MSN and ALK
t(2;17)(p23;q11-qter): ALK and clathrin heavy chain-like (CLTCL)
T cell receptor rearrangement seen in 60-90%
DD: pleomorphic carcinomas (keratin positive), Hodgkin lymphoma (lacks cohesive growth pattern, has few neoplastic cells, CD15+, PAX5/BSAP+, ALK-, EMA-), anaplastic diffuse large cell lymphoma (PAX5/BSAP+, usually CD20+, CD79a+), lymphomatoid granulomatosis (angiocentric, with a background of reactive lymphocytes and histiocytes, EBV+), nonneoplastic disorders with atypical CD30+ cells
Variants:
Hypocellular
Small cell types may have hypocellular, granulation tissue like appearance
Young patients with lymphadenopathy (AJSP 2000;24:1537)
Micro: lymphoid cells separated by edematous or fibromyxoid stroma with myofibroblast-like neoplastic cells forming short, sweeping fascicles and histiocytes; occasional large cells with atypical nuclei noted; perivascular cuffing of large cells
Positive stains: CD30+, ALK+
DD: inflammatory process
Lymphohistiocytic variant
Numerous histiocytes and small lymphocytes
Neoplastic cells tend to cluster around blood vessels
Positive stains: CD30, ALK
Neutrophil-rich cutaneous T cell
Associated with HIV
Case reports with scalp masses infiltrating dermis and subcutaneous tissue; CD3+, CD20-, CD30+, CD45RO+, ALK1-; marked neutrophilic infiltrate present in tumor, but no neutrophilia (AJCP 2000;114:478)
DD: abscess with atypical CD30+ cells (AJSP 2003;27:912)
Sarcomatoid
Rare, resembles sarcoma, anaplastic carcinoma, melanoma
Case report of 92 year woman with tumor in breast and axilla, CD30+, CD45+, UCHL-1 (CD45RO)+, ALK1 negative (Archives 2002;126:723)
Small cell
25% transform to classic anaplastic large cell lymphoma, usually associated with death within a year; necrosis may predict transformation (AJSP 1999;23:49)
Often systemic symptoms
Micro: mainly small cells with irregular nuclei
Usually arise in sinonasal area or skin
Micro: perivascular and intravascular destructive infiltrates; also parenchymal necrosis
References: Hum Path 2001;32:741
Angioimmunoblastic T cell lymphoma
Rare; called angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) if dysproteinemia present
Adults and elderly with generalized lymphadenopathy (~ 100%), bone marrow involvement (60-80%), hepatosplenomegaly (50-70%), skin rash (50%), pleuropulmonary involvement (40%), polyclonal hypergammaglobulinemia, fever, weight loss
May occur after penicillin/drug administration (27% of cases in one study)
Moderately aggressive; may respond to steroids, may progress to large T cell lymphoma
Error in initial diagnosis in >50% of cases
Case report of 67 year old woman with cutaneous trunk lesions with prominent granulomas (AJSP 2003;27:699)
Micro: effaced lymph nodes with preservation of subcapsular and trabecular sinuses; prominent arborizing endothelial venules with thickened, hyalinized PAS+ walls surrounded by CD21+ follicular dendritic cells and irregular homogenous eosinophilic material; burnt out germinal centers; aggregates of polymorphic large cells with clear/pale cytoplasm; variable eosinophils, plasma cells, histiocytes
Positive stains: CD3, CD4, CD10 (but not in bone marrow), CD21
Molecular: Clonal rearrangement of T cell receptor or IgH (75%), EBV+
DD: reactive lymphoid hyperplasia (may also have CD10+ T cells, Mod Path 2003;16:879)
References: AJSP 2004;28:54 (CD10+)
Some subtypes also called agranular CD4+ CD56+ hematodermic neoplasm
Very rare (< 60 cases reported through 2003)
Aggressive, with poor response to chemotherapy (some respond initially but recur, AJCP 2002;117:41)
Frequent skin invasion; usually disseminated at presentation
Usually ages 45+, but can affect all ages
Not associated with Epstein-Barr virus
Tumor cells may derive from plasmacytoid monocytes present in healthy volunteers, as both are CD4+ CD56+ CD43+ CD68+ HLA-DR+, negative for other markers (AJSP 2002;26:852)
Case reports: 31 year old woman with diabetes and 15 cm leg lesion (Archives 2003;127:e267), infant with multiple masses, no circulating blasts, negative marrow, resembled small round blue cell tumor; cytoplasmic CD3+, CD56+, CD34+, CD33+, MPO-, CD45-, CD7-, HLA-DR-, TdT- (Archives 2001;125:413)
Micro: diffuse monotonous infiltrate of lymphoblast-like cells (medium sized with fine chromatin) with NK cell lineage differentiation; skin cases usually involve entire dermis and may extend to subcutis but don’t involve epidermis; occasionally have single file pattern of infiltration; usually no coagulative necrosis, no angiocentric infiltrate
Positive stains: CD56, CD43, CD68, HLA-DR; variable CD4 and CD123; CD7, TdT, TIA1
Negative stains: CD3, CD19, CD20, CD33, EBV
Molecular: no T cell receptor rearrangement
DD: extranodal NK cell lymphoma, nasal type (cells not blastic), pre B/T lymphoblastic lymphoma (TdT+, CD56-, T cell receptor is rearranged), granulocytic sarcoma (may be CD56+, TIA-, usually evidence of myeloid disorders)
Cutaneous variant
85% male, median age 76 years, range 58-87 years
Skin lesions with blood or bone marrow involvement in 50%
Estimated 5 year survival is 0%
Gross: multiple bruise-like deep red plaques and tumors; 15% solitary; no ulceration
Micro: diffuse or nodular dermal involvement; subcutaneous infiltrate; grenz zone present; medium sized blast-type cells adjacent to adnexae, with variable rimming; no epidermal infiltrate, no tumor necrosis, no angiodestruction, no granulomas
Positive stains: CD4, CD43, CD56, HLA-DR, variable TdT
Negative stains: CD3, CD8, CD68, betaF1, TIA1, EBV
References: AJSP 2004;28:719
Cutaneous alpha/beta pleomorphic T cell lymphoma
Tumor of alpha/beta T helper lymphocytes, usually limited to skin, with expression of cytotoxic markers
No gender preference, median age 53 years, range 25-76 years
Estimated 5 year survival: 0%
Gross: solitary or multiple plaques or tumors
Micro: dermal, subcutis and variable epidermal involvement with interface dermatitis and occasional grenz zone; pleomorphic tumor cells infiltrate adnexae with epidermal necrosis and rimming and variable tumor cell necrosis
Positive stains: CD3, betaF1, TIA1; variable CD2 and CD56
Negative stains: CD4, CD7, CD8, CD30, CD57, TdT, EBV
Cutaneous gamma/delta T cell lymphoma
Slight female predominance, mean 60 years, range 34-77 years
Usually limited to skin
Estimated 5 year survival: 0%
Gross: multiple plaques and tumors resembling disseminated pagetoid reticulosis
Micro: involvement of epidermis, dermis and subcutaneous tissue with interface dermatitis, no grenz zone; pleomorphic cells infiltrate adnexae with tumor cell necrosis, epidermal necrosis and rimming; occasional angiodestruction and granulomas
Positive stains: CD3, CD56, TIA1, variable CD2 and CD7
Negative stains: CD4 and CD8 (usually), CD30, CD57, betaF1, TdT, EBV
References: AJSP 2004;28:719
Cytotoxic T cell lymphoma of skin
Can be classified (5 year survival) as blastic NK cell lymphoma (0%), cutaneous alpha/beta pleomorphic T cell lymphoma (0%), cutaneous gamma/delta T cell lymphoma (0%), cutaneous medium/large pleomorphic T cell lymphoma NOS, epidermotropic CD8+ T cell lymphoma (0%), extranodal NK-T cell lymphoma-nasal type (0%), subcutaneous panniculitis-like T cell lymphoma (80%) (AJSP 2004;28:719)
Enteropathy type T cell lymphoma
Rare, aggressive disease associated with gluten-sensitive enteropathy
Typically affects jejunum (ulcers with possible perforation), stomach or colon
Lymphomas of small intestine may derive from various subsets of intestinal intraepithelial lymphocytes that are differentially activated by diverse antigenic stimuli
Case reports: 37 year old man with enteropathy but no celiac disease (Hum Path 2004;35:639), NK-like T cell lymphoma involving ileum but without celiac disease (Archives 2003;127:e142)
Micro: variably sized cells with abundant intraepithelial T cells; villous atrophy due to celiac disease may be present
Positive stains: CD3, CD7, CD103, cytotoxic proteins TIA-1, perforin, granzyme B; variable CD8
Negative stains: CD4, CD5, CD56 (usually)
Molecular: clonal rearrangement of T cell receptor, no specific cytogenetic abnormalities
DD: B cell lymphomas, histiocytic neoplasms, anaplastic carcinoma, melanoma
Epidermotropic CD8+ T cell lymphoma
Tumor of alpha/beta CD8+ cytotoxic T cells with predominant involvement of epidermis
80% male, median age 61 years, range 37-80 years
Estimated 5 year survival: 0%
Gross: multiple plaques and tumors similar to disseminated pagetoid reticulosis, ulceration common
Micro: involvement of epidermis, dermis (diffuse or nodular) and subcutaneous tissue; often interface dermatitis, usually no grenz zone; tumor cells are pleomorphic, near adnexae, with variable epidermal necrosis, rimming and tumor necrosis; no granulomas
Positive stains: CD3, CD8, betaF1, TIA1; variable CD2, CD4 and CD56
Negative stains: CD7, CD57, TdT, EBV
DD: mycosis fungoides
References: AJSP 2004;28:719
Hepatosplenic alpha-beta T cell lymphoma
Rare; <50 cases reported
Similar clinical presentation as hepatosplenic gamma-delta T cell lymphoma; also aggressive
79% female (although some reports indicate male predominance), wider age distribution than gamma-delta (some children, some age 50+ years)
Usually no significant nodal involvement
Peripheral blood involvement late in disease; may have blastic transformation
Case reports: 20 year old woman with S100+ tumor (Archives 2003;127:e119)
Micro: involves splenic red pulp, hepatic sinusoids and periportal areas, interstitial bone marrow; medium size tumor cells with scant-moderate cytoplasm, round-oval nuclei, inconspicuous nucleoli, occasionally irregular chromatin with nucleoli and abundant cytoplasm
Positive stains: CD3, CD8 (61%), CD45RO, NK antigens (CD16-44%, CD56, CD57-40%), occasionally EBV
Molecular: T cell receptor rearrangements, some with isochromosome 7q
References: AJSP 2001;25:285, AJSP 2001;25:970, AJSP 2000;24:1027, AJSP 2000;24:459
Hepatosplenic gamma-delta T cell lymphoma
Very rare, <100 cases reported
Hepatosplenomegaly, B symptoms, moderate anemia, marked thrombocytopenia, no lymphadenopathy
Young adults, 86% males
Often associated with renal transplant recipients (AJCP 2001;116:41, AJCP 2000;113:487, Hum Path 2002;33:253)
Aggressive, most die within 2 years
Micro: lymphoid infiltrates in splenic red pulp, hepatic sinusoids and bone marrow sinuses
Intermediate sized tumor cells with scant to moderate cytoplasm, round/oval nuclei, slightly dispersed chromatin, inconspicuous nucleoli
Bone marrow aspirate smears contain malignant cells resembling blasts, occasionally with fine cytoplasmic granules; display sinusoidal pattern in core biopsies
Positive stains: CD2, CD3, CD7, CD56 or 57, TIA-1, Fas Ligand
Negative stains: CD4, CD5, variable CD8, TCR alpha beta
Molecular: isochromosome 7q, trisomy 8; T cell receptor gamma gene rearrangements (AJCP 2001;116:410)
Positive for gamma-delta T cell receptor, negative for alpha-beta T cell receptor
Indolent T-lymphoblastic proliferations
Rare, often in tonsils and oropharynx
In tonsils, may arise from TdT positive cells that participate in lymphopoiesis (AJCP 2001;116:12)
Case reports: involvement of oropharynx in myasthenia gravis patient with multiple local recurrences over 11 years without systemic dissemination (AJSP 2001;25:411), recurrent upper aerodigestive tract masses over 16 years, treated by excision, no chemotherapy or radiation therapy (AJSP 1999;23:977)
Positive stains: TdT, CD1, CD3, CD4 and CD8
Negative stains: cytokeratin
Molecular: no rearrangement
Also called cutaneous T cell lymphoma (not a good type since nonspecific as to histological type)
Mycosis fungoides and Sezary syndrome are different manifestations of cutaneous T cell lymphoid neoplasms
Adults with multiple skin lesions, progressing from a scaly rash to patches to plaques to tumors
Often misdiagnosed as psoriasis
Indolent (median survival 8 years) but may progress to Sezary syndrome (see below)
Spreads to lymph nodes and bone marrow; 25% have peripheral blood involvement resembling Sezary syndrome
Transformation to large T cell lymphoma occurs occasionally as a terminal event; may be associated with hyperdiploidy
Can screen for Mycosis fungoides or Sezary syndrome in peripheral blood using flow cytometry for CD26 negative or dim expression; tumor cells also have increased CD4/CD8 ratio and lower CD4 surface expression (AJCP 2001;115:885); also CD8:CD3 ratio < 25% in epidermal component of lymphocytic infiltrate is supportive (Mod Path 2003;16:857)
Treatment: phototherapy or chemotherapy, topical therapy, radiotherapy
Case reports: lesions only in skin appendages of sun damaged skin (Hum Path 2003;34:1216)
Micro: T cells (small and large) in epidermis and upper dermis with cerebriform nuclei (marked infolding of nuclear membrane), Pautrier microabscesses in epidermis; minimal papillary dermal fibrosis, may have granulomas
Positive stains: CD2, CD3 (dim), CD4, CD5
Negative stains: CD7, CD8
Molecular: clonal rearrangement of T cell receptor, but no specific chromosomal abnormalities
DD: Woringer-Kolopp disease (pagetoid reticulosis); T cell cutaneous proliferative disorder with intraepidermal infiltrate of cells with cerebriform nuclei; solitary erythematosquamous patch with slow evolution; spongiotic dermatitis (also atypical lymphocytes in epidermis/dermis)
References: AJSP 2000;24:40 (criteria for diagnosis); AJSP 2002;26:1259 (prominent granulomatous reaction), AJCP 2000;114:467 (diminished CD3 staining)
Hypopigmented variant
Hypopigmentation occurs in the absence of classic lesions of mycosis fungoides
Usually affects young people with dark complexions with childhood onset; otherwise similar history, prognosis and histology of classic form, although most were CD8+ (classic forms are CD8-, AJSP 2002;26:450)
Micro: similar to classic form
Natural killer cell large granular lymphocytic leukemia
Asian young adults with fever, hepatosplenomegaly, lymphadenopathy
Highly aggressive clinical course
Rarely CD56 and CD4 positive with blastic features, initial skin involvement and aggressive behavior (AJCP 2001;116:168)
Micro: peripheral blood demonstrates large cells with abundant blue cytoplasm, azurophilic granules
Positive stains: CD2, CD16, CD56, TIA-1, variable CD8, may be positive with polyclonal CD3
Negative stains: CD3 (surface), CD4
Molecular: no T cell receptor rearrangement; EBV particles often present
NK/T cell lymphoma, nasal and nasal-type
Also called angiocentric lymphoma, polymorphic reticulosis, lethal midline granuloma
Rare; adults, often Chinese (in US, of Asian/Hispanic descent, AJSP 2000;24:1511), with destructive sinonasal or midline facial tumors and hemophagocytic syndromes, EBV+, poor prognosis
“Non-nasal” NK lymphomas are similar; often in GI tract, skin, testis
Marrow involvement: infrequent at diagnosis, associated with early death, diagnose with EBER in-situ hybridization, AJCP 2001;115:266
In US, paranasal sinus lymphomas are often diffuse large B cell type, EBV- in one study, AJSP 1999;23:1356
Gynecologic tumors are rare (Archives 2000; 124:1510)
Poor prognostic factors: p53 missense mutations; also high LDH, large cell immunoblastoid polymorphous histology (Hum Path 2004;35:86)
Case reports: 37 year old man with enteropathy but no celiac disease (Hum Path 2004;35:639); post-treatment residual lymphoma resembling normal lymphocyte infiltration, but monoclonal by in-situ hybridization for EBV RNA (Archives 2002;126:602); 81 year old Japanese man with orbital tumor and metastases to lungs and heart (Hum Path 2003;34:290); 66 year old Korean man with testicular tumor (Archives 2002;126:1527);
Micro: Atypical lymphoid cells (large and small) with abundant cytoplasm, irregular nuclear borders and immunoblasts, with angiocentric and angioinvasive pattern; extensive necrosis and apoptosis
Positive stains: CD3 (cytoplasmic, not membranous, in 56%), CD56 (67-100%), cytotoxic granular markers TIA1, granzyme, EBER (96%); also CD2, CD5, CD7, CD4 or CD8 (20%), CD30 (focal), CD43 (96%), perforin (35%), LMP-1 (48%), p53 (56%)
Negative stains: CD16 (positive on histiocytes only), CD20, CD57, ALK-1
Molecular: Usually clonal EBV material (100%), but only rarely T cell receptor rearrangements (7%); may have 6q- or trisomy 7 (nonspecific changes)
DD: HSV infection of nasopharynx (CD56+, but HSV+, no angioinvasion or angiodestruction, EBV-, polyclonal; Mod Path 2003;16:166)
Cutaneous variant
Rare, uneven EBV expression; mean survival 15 months from diagnosis (AJSP 1999;23:571)
Median age 57, range 43-84 years
Usually limited to skin, but may subsequently involve oral and nasal mucosa
Gross: multiple patches, plaques or nodules resembling mycosis fungoides
Micro: variable epidermal involvement; nodular or diffuse dermal involvement; subcutaneous involvement; variable grenz zone and interface dermatitis; tumor cells are pleomorphic, affecting adnexae, with variable rimming, tumor necrosis and angiodestruction
Positive stains: CD3epison, TIA1; variable CD2, CD3, CD8, CD45RO, CD56
Negative stains: CD4, CD7, CD57, betaF1, TdT
References: AJSP 2004;28:719
HIV associated
Case report of 42 year old man with AIDS, parotid and hepatic masses (Archives 2002;126:738)
Positive stains: CD3, UCHL-1, EBV latent membrane protein or EBER, TIA1
Flow cytometry: CD2, CD3, CD7 (dim), CD8, CD56; negative for CD5
Molecular: T cell receptor gamma gene monoclonal rearrangement, EBV RNA and HIV RNA by ISH