Last revised 15 June 2009
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Table of contents
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: 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’s 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, review 728-745
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
Often peripheral blood and marrow involvement
Hypercalcemia in 50% during course of disease (28% at diagnosis); associated with increased osteoclastic activity
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)
bone marrow: may have increased osteoclastic activity without marrow involvement by lymphoma
Micro images: lymphoma (large arrow) with giardia (small arrows); cloverleaf-type cell
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
Aggressive NK cell leukemia involving bone marrow
Rare; Asian teenagers and young adults
May represent leukemic counterpart of extranodal NK/T cell lymphoma, nasal type, which usually lacks marrow involvement at diagnosis
Commonly involves blood, marrow, liver and spleen
Micro: large cells with moderate to abundant pale to slightly basophilic cytoplasm containing coarse azurophilic granules, regular nuclei with coarse chromatin and small nucleoli; may have hemophagocytic histiocytes
Positive stains: EBV
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
Usually T-cell origin and T-cell lineage, which can usually be proven by molecular studies, even if no T-cell antigen expression
Rarely 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)
Marrow involvement detected in 17% of cases without immunostains, rises to 35% with immunostains
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
bone marrow: varies from extensive involvement by tumor cells to only scattered cells that may be overlooked; anaplastic cells may mimic megakaryocytes; small cell variant may resemble normal marrow
Micro images: scalp lesion - A: H&E, B: CD30+, C: ALK1+; monomorphic variant - A: H&E, B: CD30+, C: ALK1+; endobronchial mass - A: CT scan, B: H&E, C: CD30+; associated with breast implant - A: H&E; B: silicone particles; C: CD43+; D: CD30+; CD99+ (figures 1D & 1E)
Positive stains: CD3, CD30 (cytoplasmic and Golgi staining), CD45, CD61; also CD2 or CD4, CD25, BNH9, factor VIII, 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%
Molecular images: FISH for NPM/ALK fusion product); translocation diagram
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)
Micro images: -5: H&E; 6-UCHL-1+; 7-CD30+; 8: EMA+
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
High incidence of marrow involvement, but difficult to identify without immunostains
Micro: mainly small cells with irregular nuclei
Usually arise in sinonasal area or skin
Case reports: arising in pancreas (Hum Path 2001;32:741)
Micro: perivascular and intravascular destructive infiltrates; also parenchymal necrosis
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
Marrow involvement in 90% in recent study (AJCP 2006;126:29)
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
bone marrow: focal or diffuse marrow involvement; focal lesions have indistinct margins; contain polymorphous infiltrate of lymphocytes, immunoblasts, plasma cells, histiocytes, eosinophils and neutrophils; often vascular proliferation with prominent endothelial cells and fibroblasts; perivascular clustering of neoplastic clear cells in 41%; variable epithelioid histiocytes; usually no amorphous PAS+ material (found in nodal lesions); uninvolved marrow may be hypercellular
Peripheral blood: reactive lymphocytes, immunoblasts, increased eosinophils
Positive stains: CD3, CD4, CD10 (but not in bone marrow), CD21; reticulin increased in involved areas; polyclonal immunoblasts and plasma cells
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
Micro images: 1: diffuse monotonous dermal infiltrate of medium sized cells; 2-cells resemble blasts with minimal cytoplasm and fine immature chromatin; 3-CD56+; 4-TdT+; 3-infiltration of ovary; 4-medium sized cells with blastic chromatin; 5-CD56+
infant in above case report - A-lymph node contains monomorphic medium sized cells with scant cytoplasm, round nuclei with finely granular cytoplasm, numerous mitotic figures; B-bone marrow biopsy shows hypercellular marrow with trilinear hematopoiesis and interstitial infiltrate of blastlike cells; C-peripheral blood smear post bone marrow transplant shows immature blasts with agranular cytoplasm, high N/C ratio and round nuclear contours; CD56+, CD43+, negative for CD45 and TdT; A-flow cytometry shows CD56+ and CD34 cells (upper left), no surface CD3 (upper right), cytoplasmic CD3 and no MPO (lower left), no CD13 or CD7 (lower right); B-karyotype shows unbalanced abnormalities of #11p, 15q and 18q
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
bone marrow: intrasinusoidal or interstitial patterns with expansion of sinusoids; lymphocytes may be blastic
Micro images: A/B-H&E of bone marrow; C-CD45RO+; D-splenic red pulp involvement; E-liver sinusoidal involvement; F-S100+
Positive stains: CD3, CD8 (61%), CD45RO, NK antigens (CD16-44%, CD56, CD57-40%), occasionally EBV
Molecular: T cell receptor rearrangements; also isochromosome 7q, trisomy 8
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
Case reports: no production of cytotoxic molecules (J Clin Pathol 2003;56:631)
Micro: lymphoid infiltrates in splenic red pulp, hepatic sinusoids and bone marrow sinuses
Intermediate sized tumor cells with scant to moderate clear 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
Micro images: liver and spleen; CD3 epsilon and TIA-1
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
Large granulated T cell lymphocytic leukemia of bone marrow
Uncommon
Modest lymphocytosis and often severe neutropenia; splenomegaly in 50%
May have rheumatoid factor and hypergammaglobulinemia
Case reports: donor origin after bone marrow transplant (AJCP 2003;120:626)
Peripheral blood: medium/large lymphocytes with abundant cytoplasm containing coarse azurophilic granules
Micro: interstitial involvement highlighted by CD8; may have occasional aggregates of B and T cells
Positive stains: CD3, CD8
Negative stains: CD4
Molecular: T cell receptor rearrangement
DD: reactive hyperplasia (no T cell receptor 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), with Hodgkin’s lymphoma (Mod Path 2001;14:91)
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
Micro images: mycosis fungoides and Hodgkin’s lymphoma
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 (mean survival 2 1/2 years)
“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), International Prognostic Index of 2 or more (Mod Path 2004;17:1097)
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); primary nodal presentation (J Clin Pathol 2005;58:443)
Micro: atypical lymphoid cells (large and small) with abundant cytoplasm, irregular nuclear borders and immunoblasts, with angiocentric and angioinvasive pattern; extensive necrosis and apoptosis
Micro images: various images; 1a-variably sized pleomorphic lymphoma cells; 1b-venous invasion (arrow); 1c-UCHL1+; 1d-EBER1+ by in situ hybridization; 2a-myocardium infiltrated by lymphoma cells; 2b-small normal appearing tumor cells without atypia; 2c-EBER1+ by in situ hybridization; lymphoma cells infiltrating and destroying vessel wall; case arising in lymph node #1; #2
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)
Molecular images: monoclonal proliferation of EBV infected cells
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)
Micro images: parotid mass - 1-cells have large vesicular nuclei and prominent nucleoli; 2A-CD3+; 2B-UCHL1+; 2C-TIA1+; 3-EBER ISH+
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
NK/T cell lymphoma, NOS
Case reports: 5 year old girl with EBV negative angiocentric eyelid tumor with immature (CD16+/CD56-) phenotype that spontaneously resolved (Hum Path 2001;32:339); aggressive NK-like CD8+, CD56+, EBV+, T cell lymphoma in previously healthy, HIV-, West African man with erythematous skin nodules, generalized lymphadenopathy, hepatosplenomegaly who died of multiple organ failure (AJSP 2002;26:111)
Nodal CD8+ cytotoxic T cell lymphoma
Two groups: (a) poor prognosis - diffuse large cell type with massive necrosis, apoptosis, DIC or hemophagocytic syndrome; (b) better prognosis - diffuse medium or mixed cell type
Micro images: macrophages ingesting nuclear debris #1; #2 and large atypical cells; diffuse small to medium cleaved cells #1; #2; CD3+; CD8+; perforin+; granzyme B+; TIA1+; EBER1+ in situ hybridization
Positive stains: CD3, CD8, perforin, granzyme B, TIA1, EBV (EBER1 by ISH)
References: Mod Path 2002;15:1131
NonB, nonT lymphoblastic lymphoma
Includes CD7+ stem cell lymphoma (CD7+, CD4-, CD56-, CD33 variable), blastic NK lymphoma (CD56+, CD4-, CD33-, CD123-, CD7 variable, see above), myeloid/NK precursor leukemia (CD4-, CD7+, CD33+, CD56+), CD4+/CD56+ hematodermic malignancy (also CD33-, CD123+, CD7 variable)
May have poorer prognosis than T cell lymphoblastic lymphoma but comparable to B cell lymphoblastic lymphoma
CD7+ stem cell leukemia: CD7+ but no other lineage marker expressed; frequently presents with mediastinal mass and bone marrow invasion; may convert to AML
Negative stains: B cell markers (CD19, CD20 and CD79a), surface CD3
References: AJSP 2003;27:1366
Peripheral T cell lymphomas, unspecified
Among the most common nodal T cell lymphomas
Usually adults
Usually high stage (III/IV) with skin or lung involvement, generalized lymphadenopathy, B symptoms and often pruritus
More aggressive than most B cell lymphomas; 5 year survival of 25%
Includes lymphoepithelioid (Lennert) lymphoma and T zone lymphoma
May resemble marginal zone lymphoma morphologically (Mod Path 2002;15:420)
30-70% have marrow involvement at diagnosis
Case reports: limited to endometrium (AJCP 2001;115:561), T cell intravascular lymphoma predominantly involving kidneys in patient with AIDS (Hum Path 2003;34:950), CD15+/CD30+ tumor resembling Hodgkin’s lymphoma (AJSP 2003;27:1513)
Treatment: chemotherapy, autologous stem cell transplant
Micro: diffuse effacement by groups of atypical cells of variable sizes separated by delicate PAS+ connective tissue; cells often have clear cytoplasm, resemble Reed-Sternberg cells; may be accompanied by eosinophils, epithelioid histiocytes or granulomas; often marked vascularity
bone marrow: patterns are small lymphocytic, large cell/immunoblastic or mixed; diffuse or randomly distributed focal infiltrates of variable size with poorly demarcated margins that blend into remaining marrow; large cells have abundant amphophilic cytoplasm and prominent eosinophilic nucleoli resembling Reed-Sternberg cells or its mononuclear variants; small/medium sized cells have condensed chromatin with normal or irregular nuclear contours; often associated infiltrate of histiocytes, plasma cells, eosinophils and neutrophils; often epithelioid histiocytes, increased vascularity
Micro images: marginal zone features - lymph node: A-expansion of marginal zone; B-CD3+; C-small cells with abundant clear cytoplasm; D-small cells with abundant pale cytoplasm and round/mildly irregular nuclei;
Positive stains: CD2, CD3, variable CD4 and CD5; reticulin in marrow (increased fibers in neoplastic areas and extend into adjacent marrow)
Negative stains: CD1, TdT
Molecular: clonal rearrangements of T cell receptor; usually alpha-beta phenotype, no specific cytogenetic abnormalities
DD: Hodgkin’s lymphoma (classic Reed-Sternberg cells that are CD15+, CD30+, no atypia in lymphocytes), systemic mastocytosis (tryptase+), reactive lymphoid hyperplasia (usually no marked atypia, no T cell receptor clonality)
Variants
CD4- CD8- cutaneous T cell lymphoma
Mean age 53 years (range 19-77 years), no gender preference
Single or multiple cutaneous nodules; rapid multifocal cutaneous dissemination is common
Micro: dense infiltrate centered in mid-dermis, extending into subcutaneous tissue, consisting of small to intermediate lymphocytes with indistinct nucleoli, irregular nuclear contours; occasional periadnexal infiltration and epidermal ulceration (AJSP 2002;26:225)
Positive stains: CD3
Negative stains: CD4, CD8, CD30, TdT
Molecular: T cell receptor-delta expression
Follicular growth pattern
3 cases noted with follicular growth pattern in nodal peripheral T cell lymphomas (AJSP 2001;25:395)
Men 50-70 years with generalized lymphadenopathy, aggressive clinical course
Micro: follicles with abundant dendritic cells; tumor cells are small to medium size with clear cytoplasm, irregular cleaved or round nuclei
Positive stains: CD3, CD4, CD10, bcl6
Negative stains: CD8, CD57
Molecular: T cell receptor gene rearrangement
DD of follicular growth pattern: follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma with follicular colonization, some Hodgkin lymphoma
Lennert’s lymphoma
Also called lymphoepithelioid lymphoma
Tumor cells usually within lymph nodes
Mean survival 42 months
Micro: small to large clusters of reactive epithelioid histiocytes, some resembling Reed-Sternberg cells, plus variably sized T cells with destructive infiltration
Stains: CD3+, CD4 +/- (CD8 opposite), TIA1+, variable granzyme B, EBV- (AJSP 2000;24:1627)
Molecular: T cell receptor gene rearrangement
References: AJCP 1976;66:1
Perifollicular growth pattern
9 cases of T helper neoplasm with distinctive growth pattern (AJSP 2000;24:117)
Micro: prominent infiltration predominantly of marginal zones that partially distorts lymph node structure by medium-sized cells with clear cytoplasm and significant nuclear atypia
In the paracortical T-zone, marked proliferation of high endothelial venules; also plasmacytosis and capsular fibrosis
Stains: CD3+, CD4+, CD5+/-, CD8-, TIA1-
DD: marginal zone lymphoma, reactive changes
Reed-Sternberg-like cells
3 cases of nodal peripheral T-cell lymphoma with Reed-Sternberg-like cells (AJSP 1999;23:1233)
Micro: two cases with features of angioimmunoblastic T-cell lymphoma (AILT); large mononuclear and binucleated cells with prominent eosinophilic nucleoli and abundant cytoplasm resembling classic Reed-Sternberg cells and mononuclear variants
Stains: lymphoma cells - CD3, CD43, CD45RO, EBV negative
Reed-Sternberg-like cells - CD15+, CD30+, CD20+, EBV LMP+, EBER+, negative for T cell markers
DD: Hodgkin lymphoma
T zone lymphoma
Micro: interfollicular growth pattern with sparing of secondary lymphoid follicles
Papulosquamous disorder often considered a reactive dermatosis and classified with small plaque parapsoriasis (digitate dermatosis)
Considered by some a T cell lymphoproliferative lesion due to atypia and T cell clonality (Hum Path 2002;33:788)
Some patients develop large plaque parapsoriasis and mycosis fungoides
Mean age 40 years, 60% female
Micro: intraepithelial lymphocytes and Langerhans cells resembling Pautrier’s microabscesses, psoriasiform hyperplasia, dyskeratosis, parakeratosis; with persistent disease-also epidermal atrophy, dermal fibrosis, intraepidermal cerebriform cells
Positive stains: CD4+CD7- and CD8+CD7+ cells, CD8+ cells often CD56+
Precursor T cell lymphoblastic leukemia / lymphoblastic lymphoma
Teens and young men; 40% of childhood lymphomas and 15% of acute lymphoblastic leukemias
Usually presents as anterior mediastinal (thymic) mass with supradiaphragmatic lymphadenopathy and variable splenic, hepatic and bone marrow involvement (with leukemic phase); CNS involvement if untreated
Aggressive with 26% five year survival, but chemotherapy cures 60%
Defined as T-ALL if >25% lymphoblasts in marrow
Leukemia cases (pre T-acute lymphoblastic leukemia) often present with mediastinal mass in young adult males, with early blood and diffuse marrow involvement
Presence of extramedullary tumor without cytopenia is more compatible with diagnosis of lymphoma with marrow involvement than ALL
Case reports: coexisting Langerhans cell histiocytosis (Archives 2001;125:958)
Micro: similar to B-cell lymphoblastic leukemia/lymphoma; diffuse infiltrate of immature small/intermediate cells with scant cytoplasm, delicate chromatin, convoluted nuclear membrane, indistinct nucleoli; frequent mitotic figures; starry sky pattern produced by interspersed benign macrophages; often extensive pericapsular and soft tissue infiltrates
bone marrow: varies from scattered blasts to diffuse involvement; prominent mitotic activities
Micro images: 1-intermediate sized cells with scanty cytoplasm, finely dispersed chromatin and high mitotic rate; 2-infiltrating extranodal adipose tissue; CD10 (left) and TdT (right)
coexisting Langerhans cell histiocytosis - A-pale area on left-Langerhans cells; dark area on right-lymphoblastic lymphoma; B-lymphoblasts with scant cytoplasm, mildly irregular nuclear contours, immature chromatin, small nucleoli, frequent mitotic figures; C-Langerhans cells with nuclear grooves and scattered small lymphocytes; A-CD3+; B-CD79a; C-CD99+; D-TdT+; E-CD1a+; F-S100+ (lymphoblasts are positive for CD3, CD79a [unusual], CD99 and TdT; Langerhans cells are positive for CD1a and S100)
Positive stains: surface CD3, CD99, TdT; also CD7, variable expression of other T cell markers, CD10 (63%, Archives 2000;124:704), many tumors CD4+ and CD8+; occasional CD16, CD57 (NK markers)
Negative stains: CD19, CD20, HLA-DR
Molecular: t(1;14)(p32;q11): SCL (TAL1) and T cell receptor delta/alpha (15-30%)
t(10;14)(q24;q11): HOX11 and T cell receptor delta/alpha (7%)
Other rearrangements of 7q34 (TCR beta), TAL1, TCR delta/alpha, HOX11
DD: Burkitt lymphoma, granulocytic sarcoma, lymphoblastoid mantle cell lymphoma, CML blast crisis (Hum Path 2002;33:770)
Primary cutaneous CD30+ T cell lymphoproliferative disorders
Also called lymphomatoid papulosis
By definition, arises in skin with no known extracutaneous disease within 6 months of initial diagnosis
Self healing, recurrent, papular subcutaneous nodules less than 1 cm on extremities, trunk, face, genitals
Probably benign, but 10% associated with lymphoma (mycosis fungoides, Hodgkin lymphoma) and microscopically resembles lymphoma
Micro: large pleomorphic lymphoid cells with convoluted nuclei; some resemble Reed-Sternberg cells; also plasma cells and eosinophils
Positive stains: CD3, CD30 (strong)
Negative stains: CD15, EMA, ALK
Molecular: clonal rearrangement of T cell receptor in 60%; usually t(2,5) negative
DD: arthropod bites, nonneoplastic disorders (usually has atypical CD30+ cells but polyclonal for T cell receptor rearrangements and polyclonal or oligoclonal for B cell immunoglobulin rearrangements, AJSP 2003;27:912)
Possible mucosal variant in GI tract
Case report of 35 year old man with CD8+ T cells in oral mucosa, ileum, and colon that regressed spontaneously and recurred numerous times over 9-years without treatment (AJSP 2000;24:296)
Symptoms limited to occasional rectal bleeding and recurring painful oral ulcers
May represent T-cell lymphoproliferative process akin to mucosal lymphomatoid papulosis
Micro: small T cells with minimal architectural distortions and no extensive epitheliotropism
Molecular: PCR and sequencing analyses revealed that the identical T-cell clone was present for >9 years in different mucosal locations
Primary effusion lymphoma-T cell
Case report of 87 year old man, HHV8+, HIV- (Archives 2001;125:1246)
Micro images: A-immunoblastic or anaplastic cells; B-CD3+
Molecular images: PCR for T cell receptor; PCR for HHV8
Adults, usually men, with generalized exfoliative erythroderma, generalized lymphadenopathy (70%) and blood involvement by Sezary cells (resemble cells of mycosis fungoides)
Associated with monoclonal gammopathy and secondary neoplasms (carcinoma, other non-Hodgkin lymphomas)
Skin lesions rarely become tumor masses
Poor prognosis; better with categories LN 0-2 or Dutch classification I-II with negative T cell rearrangement by PCR
May transform to anaplastic large cell lymphoma with poor prognosis
NCI classification of lymph nodes:
LN-0: nonspecific reactive
LN-1: dermatopathic lymphadenopathy with scattered paracortical atypical lymphocytes
LN-2: dermatopathic lymphadenopathy with atypical lymphocytes singly or in clusters of 3-6 cells
LN-3: dermatopathic lymphadenopathy with atypical lymphocytes singly or in clusters of 15+ cells
LN-4: frank lymphoma with partial or complete effacement of lymph node
Dutch classification: categories I-II are dermatopathic lymphadenopathy based on size of cerebriform nuclei (category I: less than 7.5 microns); category III/IV are partial (III) or complete (IV) effacement by lymphoma
Micro: atypical lymphocytes (Sezary cells) are intermediate / large with basophilic cytoplasm, cerebriform nuclei, inconspicuous nucleoli; marrow usually normal
Peripheral blood: Romanowsky stained smears show large cells with slight cytoplasm containing PAS+, perinuclear vacuoles and large, cerebriform, hyperchromatic nuclei
Positive stains: CD2, CD3, CD4, CD5
Negative stains: CD8
Molecular: clonal rearrangement of T cell receptor, but no specific chromosomal abnormalities
Subcutaneous panniculitis-like T cell lymphoma
Subcutaneous nodules in extremities with associated hemophagocytic syndrome
80% female, median age 48 years, range 22-73 years
Course may be aggressive or indolent; estimated 5 year survival is 80%
CD56- cases (vs CD56+ cases): better prognosis (median survival 96 vs. 12 months), younger age, non-ulcerated nodules, subcutis vs. subcutis and dermis, medium sized vs. pleomorphic tumor cells, patchy vs. massive necrosis; negative for CD3 epsilon, CD8, TcRbetaF1, TIA1, CD95, Bax, caspase 3, p53 vs. positive for these markers in CD56+ cases (Hum Path 2004;35:231)
Micro: lesions confined to subcutis, monotonous infiltration of atypical pleomorphic lymphocytes surrounding fat lobules and infiltrating fibrous septae (resembling panniculitis); atypia varies from minimal to marked (more if CD56+); usually tumor necrosis, adipocyte rimming; variable vacuolated macrophages with lipid or nuclear debris, granulomatous reaction; no epidermal involvement; not primarily angiocentric
Micro images: small and large atypical lymphocytes rimming adipocytes; CD8+
Positive stains: CD3, CD43, Ki-67, perforin, granzyme B, alpha/beta type (see above for CD56+ vs. CD56- tumors)
Negative stains: CD30, EBV
Note: CD8 usually negative in CD56+ tumors and positive in CD56- tumors
Molecular: clonal rearrangement of T cell receptor
References: AJSP 2004;28:719, Mod Path 2002;15:625 (apoptosis and proliferation)
T cell immunoblastic lymphoma of bone marrow
33% have marrow involvement at diagnosis
T cell large granular lymphocytic leukemia
Mean 55 years old, no gender preference
Increase of large granular lymphocytes in peripheral blood, usually 2-20,000 per microliter, for > 6 months, with no known cause
Also peripheral lymphocytosis and splenomegaly, neutropenia, anemia; may have autoimmune disease (rheumatoid arthritis); often have recurrent infections due to neutropenia
Indolent course; death is uncommon
Treatment: either none, or cyclosporine A with methotrexate; splenectomy for splenomegaly
Case reports: CD56+ / CD4+ cases (AJCP 2001;116:168), primary CNS tumor (AJSP 2003;27:682), 85 year old woman with rheumatoid arthritis and lymphocytosis (Archives 2003;127:e51), 41 year old Chinese man with chronic anemia, red cell aplasia and lymphocytosis (Archives 2002;126:1549)
Micro: splenic, liver and variable bone marrow infiltration by cells with variable blue cytoplasm and azurophilic granules, round/oval nuclei, condensed chromatin, occasionally irregular, indistinct nucleoli; no/rare mitosis; no/rare necrosis
Positive stains: CD2, CD3, CD8, TIA-1, variable CD16, variable CD57
Negative stains: CD4, CD5, CD7, CD25, variable CD56
Molecular: T cell receptor rearrangement (alpha/beta more common than gamma/delta)
EM: granules have parallel tubular arrays
DD: NK large granular lymphocyte leukemia (CD3-, CD16+, acute clinical course over a few weeks)
References: Hum Path 2003;34:322
T cell prolymphocytic leukemia
Rare; may initially be indolent, but enters aggressive phase after median 33 months; usually not curable
Presents with high WBC count (75% were >100K)t and cutaneous (27%) or mucosal disease; also lymphadenopathy (53%), hepatomegaly (40%), splenomegaly (73%), CNS involvement, anemia and thrombocytopenia
Case reports: small cell variant with t(3;22) (Archives 2005;129:1164)
Micro: cells are small to medium sized lymphocytes with abundant basophilic, nongranular cytoplasm, atypical nuclei, prominent nucleoli; diffuse involvement of splenic red and white pulp; paracortical involvement of lymph nodes; skin involvement is usually perivascular or periadnexal
small cell variant - small cells with indistinct nucleoli; 19% of cases
Micro images: various images #1; #2; #3; small cell variant-scant cytoplasm, condensed chromatin; shows TCR beta gene rearrangement
Positive stains: CD2, CD3, CD5, CD7, CD4 (60%)
Negative stains: TdT, CD1a
Molecular: clonal rearrangements of T cell receptor beta and gamma genes; 75% show inv 14(q11;q32) (affects T cell receptor) or other chromosome 14 translocations; translocations of TCL-1 gene at 14q32.1; #8 abnormalities in 70%; MTCP-1 gene at Xq28; also ATM gene at 11q23, 12p13-
DD: T-CLL (may represent small cell variant of T-PLL),
Hodgkin lymphoma
Arises in a single node or chain of nodes, spreads characteristically to anatomically contiguous nodes to spleen to liver to marrow to extra-nodal
Composed of occasional Reed-Sternberg (RS) cells (<5% of tumor mass) or its variants (lacunar cells or lymphocytic and histiocytic cells) in a background of reactive lymphocytes, eosinophils, granulocytes and histiocytes
8,000 new cases/year in US
Common malignancy of young adults (mean age 32); also occurs after age 50; 75% are curable
Developing countries: early peak occurs in childhood; for children younger than 10 years, may be related to EBV infection; higher incidence of mixed cellularity subtype (Archives 2003;127:1325)
HIV patients have increased incidence, usually higher stage
5 year survival: Stage 1 or 2a-90%, Stage 4-60%
Patients have increased risk of second cancers (breast cancer in women treated with radiation during adolescence, solid tumors after radiation, AML and myelodysplasia after chemotherapy); also pulmonary fibrosis and accelerated atherosclerosis
Symptoms: painless enlargement of lymph nodes
Rarely involves mesenteric nodes and Waldeyer ring, rarely is extranodal
Pain in lymph nodes may occur with alcohol consumption (paraneoplastic symptom)
Most patients have cutaneous anergy that persists even after treatment
B symptoms: fever, night sweats, weight loss (10% of body weight), pruritis (by some authors); associated with stage 3 or 4, mixed cellularity and lymphocyte depletion types
Pathophysiology: RS cell is clonal proliferation of post-germinal center derived B cell
For nodular lymphocyte predominance Hodgkin lymphoma, RS cell is derived from antigen-selected germinal center B cells with productive rearrangements of the IgH gene
For “classic” Hodgkin lymphoma, RS cell is derived from germinal center B cells with “crippling” mutations of IgH variable region segment; associated with Epstein-Barr virus infection (in ~ 30%), which may prevent these cells from undergoing apoptosis
RS cells probably secrete cytokines to recruit reactive cells; IL-5 attracts eosinophils, which produce TGF-beta (transforming growth factor-beta) which causes fibrosis
Expression of FasL in most RS cells plus loss of FasL expression in the follicular dendritic cell cluster of the germinal center (FDC), suggests a disturbed FDC microenvironment may contribute to its pathogenesis (AJSP 2001;25:388)
Post-bone marrow transplant: recurrences showed increased sclerosis, but are otherwise similar (AJCP 1997;107:74)
Case reports: with nemaline myopathy after radiotherapy (Hum Path 2003;34:816), apparent T cell origin derived from CD30+ cutaneous leg lymphoma (Hum Path 2001;32:1269), primary tumor in terminal ileum in Crohn’s patient (Archives 2001;125:424), with mycosis fungoides (Mod Path 2001;14:91)
Composite lymphomas: with follicular lymphoma (Archives 2000;124:1376), with mantle cell lymphoma (AJSP 2003;27:1577), with diffuse large B cell lymphoma (AJCP 2006;126:222)
Gross: fleshy lymph node; cannot distinguish Hodgkin vs. non-Hodgkin lymphoma
Gross images: fleshy lymph node; liver with multifocal involvement
Micro: RS cell classically is large (15-45 microns) with abundant amphophilic cytoplasm; binucleate or bilobed; 2 halves are mirror images; may have single/multiple multilobate nucleoli or large, inclusion like, owl-eyed eosinophilic nucleoli (5-7 microns) surrounded by clear halo; thick nuclear membrane
L & H (lymphocyte and histiocytic) cells: polypoid nuclei resemble popcorn kernels; seen in lymphocyte predominant/rich types; have moderately abundant cytoplasm, inconspicuous nucleoli, occasional noncaseating granulomas, vascular invasion
Mononuclear RS variant: single round or oblong nucleus with large inclusion like nucleoli
Micro images: A-atypical lymphocytes in terminal ileum; B-Reed-Sternberg cells and variants; C-CD15+; D-CD30+; E: Fascin+; F-EBV mRNA+ by ISH; composite lymphoma with 1-Reed Sternberg cells and 2-lambda restriction in follicular lymphoma; EBV+ by ISH (figures A-B)
Positive stains: Epstein Barr virus (40-60% of mixed cellularity and nodular sclerosing, but not lymphocyte predominant/rich); see also individual subtypes; CD20 (33%), CD79a (10%), rarely CD138
Negative stains: ALK, TIA1, CD3, CD45 (may have focal globular cytoplasmic staining)
Molecular: RS cell is aneuploid, but has no consistent cytogenetic abnormalities; tumor necrosis factor receptor associated factors 1 & 2 are characteristic in RS cells (Mod Path 2000;13:1324)
DD: infectious mononucleosis (particularly in children/young adults); peripheral T cell lymphoma (expresses T cell markers but may be CD15+, CD30+ (AJSP 2003;27:1513), anaplastic (Ki-1) large cell lymphoma (positive for ALK1, t(2,5), EMA, TIA1, AJSP 2001;25:297), non-Hodgkin lymphoma (particularly if disease in Waldeyer’s ring, skin, GI tract)
References: Mod Path 2003;16:1141 (B cell marker expression)
Bone marrow involvement
Incidence of marrow involvement overall and Stage IV
Nodular lymphocyte predominant: 1%, 3%
Classic - lymphocyte rich: 1%, ?
Classic - nodular sclerosis: 3%, 37%
Classic - mixed cellularity: 10%, 49%
Classic - lymphocyte depletion: 50%, ?
Initial biopsy in lymphocyte depletion subtype may be bone marrow biopsy
Marrow involvement associated with B symptoms, bulky disease, disease above and below diaphragm, AIDS (40%), no large mediastinal mass
Subtype should not be based on marrow exam, because fibrosis is common
Diagnosis requires presence of Reed-Sternberg cells; may need serial sections
Micro: 70% have diffuse involvement; classic Reed-Sternberg cells with cellular background of small lymphocytes, neutrophils, plasma cells, histiocytes or mononuclear Reed-Sternberg variants with a diagnosis in other specimens; may have necrosis, particularly post-therapy; variable granulomas; fibrosis by itself is only suspicious for involvement
Positiv e stains: CD15, CD30
DD: megakaryocytes, follicular center cell lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, parvovirus B19 infection (large erythroid precursors with marked erythroid hypoplasia)
Colon
Case report at Archives 2000;124:1824
Rare, may present as inflammatory bowel disease
WHO classification (same as REAL)
Nodular lymphocyte predominant Hodgkin lymphoma
Classical Hodgkin lymphoma
Nodular sclerosis Hodgkin lymphoma
Mixed cellularity Hodgkin lymphoma
Lymphocyte-rich classical Hodgkin lymphoma
Lymphocyte depleted Hodgkin lymphoma
Lukes-Butler classification as modified at Rye Conference (used prior to WHO/REAL)
Lymphocyte predominant
Nodular sclerosing
Mixed cellularity
Lymphocyte depleted
Important in determining therapy since Hodgkin lymphoma spreads in an orderly fashion
Cotswald Modification of Ann Arbor staging classification, J Clinical Oncol 1989;7:1630
1: 1 lymph node region or organ, 1E similar
2: 2 lymph node regions, same side of diaphragm, 2E similar
3: both sides of diaphragm
3-1: with or without splenic hilar, celiac or portal nodes
3-2: with para-aortic, iliac or mesenteric nodes
4: disseminated
E = single extranodal site, contiguous or proximal to a known nodal site
S = spleen
A = absence of B symptoms, B = presence of significant fever, night sweats, >= 10% unexplained weight loss, pruritis
X = bulky disease (1/3 the width of the mediastinum or >10 cm)
Not a standard histologic type
Similar to nodular lymphocyte predominant Hodgkin lymphoma, but has follicles with germinal centers, classic Reed-Sternberg cells and relative absence of histiocytes (AJCP 2002;117:29)
Common nodal sites: neck, axilla, groin
Micro: follicles with small, eccentric germinal centers and expanded mantle zones containing classic Reed-Sternberg cells; reactive germinal centers common
Positive stains (Reed-Sternberg cells): CD15, CD30, fascin, occasionally CD20; surrounded by CD3 epsilon rosettes
Lymphocyte depleted Hodgkin lymphoma
Rare in US and Europe; older men (median age late 50’s) with disseminated disease or patients with HIV or in developing countries
Most cases are actually anaplastic lymphomas or syncytial variant of Hodgkin lymphoma
90% have subdiaphragmatic disease or organomegaly; marrow involvement common (54%); 50% have peripheral adenopathy
Median survival 25 months (one study)
Frequent B symptoms
Micro: either diffuse fibrosis or reticular forms
diffuse fibrosis type - complete effacement of nodal architecture by abundant disorderly connective tissue with PAS+ fibrinoid material and hypocellular background; rare Reed-Sternberg cells
reticular form - no disorderly connective tissue, numerous bizarre Reed-Sternberg cells, often in sheets, with few lymphocytes
bone marrow - rare Reed-Sternberg cells with amorphous, nonbirefringent eosinophilic background material andinflammatory infiltrate; multiple sections/levels often required; uninvolved marrow is normocellular with increased eosinophils (AJSP 1986;10:219)
Positive stains for Reed-Sternberg cells: CD15, CD30
Negative stains for Reed-Sternberg cells: CD45
DD: nodular sclerosis-syncytial type, anaplastic large cell lymphoma [CD2+, CD3+, CD45+, t(2;5)], diffuse large cell lymphoma
Nodular lymphocyte predominant Hodgkin’s lymphoma
5% of all cases
Usually nodular; existence of diffuse subtype is controversial
Usually young men with cervical or axillary adenopathy; rarely mediastinal or bone marrow involvement; often long history of localized disease
L & H cells may have follicular B cell origin, as they have identical IgH gene rearrangements and have Vh segments with somatic hypermutation, seen in follicular B cells
3-5% transform to diffuse large B cell lymphoma
Usually stage I/II, excellent prognosis (10 year survival of 80%)
May be associated with progressive transformation of germinal centers (large germinal centers with blurred border between mantle zones and germinal centers with progressive infiltration by small lymphocytes)
Poor prognostic factors: bone marrow involvement is associated with aggressive disease (AJSP 2004;28:489), diffuse T cell rich pattern may be associated with recurrence
Case reports: with gamma heavy-chain disease (Archives 2001;125:803)
Micro: usually total replacement of nodal architecture by expansive vague nodules of sparse, relatively large tumor cells (lymphocytic or histiocytic / L&H) with multilobulated or round nucleus, thin nuclear membrane, finely granular chromatin, and variable small nucleoli; mixed with numerous small B lymphocytes, epithelioid histiocytes, CD21+ dendritic reticulum cells; scant eosinophils, plasma cells or fibrosis; no/rare classic Reed-Sternberg cells; post-capillary venules may be prominent; also prominent sclerosis (20%), small germinal centers (15%); no granulomas; may have rim of normal lympho node; diffuse cases have background of reactive T cells
Patterns (usually mixed): classic B cell rich nodular, serpiginous/interconnected nodular, nodular with prominent L&H cells, T cell rich nodular, diffuse with T cell rich background, diffuse (moth eaten) B cell rich
bone marrow: 3% of cases; involvement by large B cells (<10% of all cases) in background of T cells and histiocytes.
Positive stains for L&H cells: CD45; bcl6, monotypic light chain expression; variable CD20 within nodules, variable CD79a, variable EMA
Note: rosettes contain bcl6+ and CD57+ cells, as do some T cell rich B cell large cell lymphomas (AJSP 2000;24:1068)
Negative stains for L&H cells: CD3, CD15, CD30, EBV
DD: progressive transformation of germinal centers (well circumscribed nodules of confluent sheets of CD20+, CD45RA+ small cells with scattered T cells, fewer T cell rosettes than nodular LP HD, AJSP 1999;23:27), nodular paracortical hyperplasia, classic Hodgkin lymphoma, SLL/CLL, follicular lymphoma, diffuse large B cell lymphoma [either (a) bcl6- large cells with few CD57+ small cells and no significant bcl6+ CD57+ cells OR (b) bcl6+ large cells with numerous CD57+ and bcl6+ CD57+ cells, similar to lymphocyte predominance Hodgkin lymphoma]
References: AJSP 2003;27:1346 (microscopic patterns)
Lymphocyte-rich classic Hodgkin lymphoma
3% of all cases; usually men (median age 43 years) with stage 1 or 2 disease and no B symptoms
Excellent prognosis
Micro: classic or mononuclear Reed-Sternberg cells with background of B cells; rarely eosinophils or other inflammatory cells; no L & H cells
Positive stains for Reed-Sternberg cells: CD15, CD30
Negative stains for Reed-Sternberg cells: CD20, CD45
DD: nodular lymphocyte predominance Hodgkin lymphoma, follicular lymphoma, mantle cell lymphoma, reactive hyperplasia
Mixed cellularity Hodgkin lymphoma
25% of all cases; 50% present as stage 3 or 4 with abdominal lymph nodal or splenic involvement
Usually men, biphasic age peaks (young adults, adults > 55)
Good prognosis
Case reports: involvement of distal esophagus, stomach, proximal ileal anastomosis of post-gastric bypass patient for morbid obesity (Archives 2002;126:1534)
Micro: diffuse effacement of lymph node by frequent mononuclear and classic RS cells accompanied by large number of eosinophils, plasma cells and atypical mononuclear cells, otherwise similar to nodular sclerosis; occasionally resembles lymphocyte poor Hodgkin lymphoma with few macrophages, plasma cells, eosinophils; may have interfollicular growth pattern, prominent granulomatous reactions
Micro images: stomach/ileal tumor - 1-GE junction with polymorphous lymphocytic infiltrate; 2A/2B-Reed-Sternberg cells and variants; 3A-CD15+; 3B-CD30+; 3C-CD45 negative; H&E; LMP1
Virtual slides: lymph node
Positive stains for Reed-Sternberg cells: CD15, CD30
DD: diffuse large B cell lymphoma, T cell lymphoma (Lennert’s lymphoma), anaplastic large cell lymphoma, infectious mononucleosis or other viral adenitis, angioimmunoblastic lymphadenopathy
Nodular sclerosis Hodgkin lymphoma
65% of all cases; 2/3 have stage 1 or 2 disease; frequently involves mediastinal, lower cervical or supraclavicular lymph nodes; also lung
Usually young adults
Excellent prognosis
Case reports: 54 year old immunocompetent patient with superficial occipital lobe infiltrate; EBV+ Reed-Sternberg cells (AJSP 1999;23:477), 4 year old girl with juvenile rheumatoid arthritis treated with methotrexate and cyclosporine who developed EBV+ Hodgkin lymphoma and Legionella pneumophilia infection (Hum Path 2000;31:253), 40 year old man with ear tumor (Archives 2003;127:E101), 21 year old woman with lung tumor (Archives 2003;127:e49)
Gross: lymph node
Micro: well defined birefringent fibrous bands of acellular collagen divide cellular areas into nodules; frequent lacunar cells, occasional classic RS cells; background of T cells, eosinophils, macrophages, plasma cells; variable necrosis; mitoses uncommon; typically confined within capsule; occasional foamy macrophages; early disease involves paracortical T cell zones; syncytial variant (see below)
lacunar cells: delicate folded or multilobate nuclei, surrounded by abundant pale cytoplasm often disrupted or retracted during cutting of sections with formalin fixation (but not B5 or Zenkers), leaving a lacune (empty hole)
Micro images: bands of collagen #1; #2; lacunar cells with perinuclear halo; classic Reed-Sternberg cells with bilobed mirror-image nuclei, prominent nucleoli and abundant amphophilic cytoplasm
lung tumor - 1A/1B-dense consolidation; 2A/2B-atypical large multinucleated cells; 3-CD15+; 4-CD30+
Virtual slides: nodular sclerosis #1, #2
Positive stains for Reed-Sternberg cells: CD15, CD30; also fascin, vimentin
Negative stains for Reed-Sternberg cells: B cell markers (CD19, CD20), T cell markers (CD3, CD4, CD5), CD34, CD45, EMA
DD: anaplastic large cell lymphoma (T cell markers+, CD15-, EMA+, CD45+), mediastinal large B cell lymphoma, metastatic carcinoma, melanoma, seminoma
Syncytial variant
Rare; typical histologic and immunohistochemistry features of nodular sclerosing Hodgkin lymphoma plus cohesive aggregates of atypical mononuclear RS cells
DD: anaplastic large cell lymphoma, thymoma, germ cell tumors, carcinoma, melanoma, non-Hodgkin lymphoma
Post-transplantation lymphoproliferative disorders
Post-transplant lymphoproliferative disorders (PTLD) - general
Associated with intense immunosuppression that accompanies solid organ and bone marrow transplantation
95% are B cell, 5% are T cell
Affects 5% of these patients (10% of children, 3% of adults), who have 50:1 relative risk for non-Hodgkin B cell lymphoma
Usually occurs in extranodal sites (CNS, lung, small bowel)
85% are Epstein-Barr virus (EBV) related; infection occurs shortly after transplantation
SV 40 detected in 13% of cases, restricted to malignant cells (Hum Path 2006;37:1130)
Note: AIDS associated lymphoproliferative disorders are similar
Common in heart or heart/lung recipients (5-10%), rare in bone marrow transplant patients (<1%)
In lung transplant patients, lung usually involved, occurs median 7 months after transplant (vs. 41 months for other organs), short survival (Mod Path 2002;15:647)
Associated with cyclosporin A and OKT3 immunosuppression
Determine clonality by flow cytometry in addition to genotypic studies (AJCP 2002;117:24)
Pathophysiology: EBV infects lymphocytes (usually from host; subclinical or infectious mononucleosis), which immortalizes B cells; immunosuppressed patients are unable to mount the usual T cell cytotoxicity, causing plasmacytic and polyclonal lymphocytic proliferation; monoclonal populations may emerge, and with mutations, cause malignancy
Tumors of donor origin may be more indolent than of recipient origin (Mod Path 2000;13:1180)
Symptoms: mononucleosis-like, GI symptoms or systemic
Treatment: stop immunosuppressive therapy; give acyclovir or interferon-alpha; use chemotherapy for polymorphic or monomorphic disorders
Case reports: EBV associated lymphoma in placental villi of fetal origin (AJSP 1999;23:595), following nonmyeloablative allogeneic stem cell transplant (AJSP 2004;28:794); EBV+ peripheral T cell lymphoma composed of CD4+ cells in 15 year old liver transplant patient (AJSP 2004;28:967)
Micro: plasmacytic hyperplasia, polymorphic proliferation or monomorphic proliferation; usually B cell proliferations; may resemble rejection
Micro images: EBV+ tumor cells in transplant patient; EBV+ diffuse large B cell lymphoma and Burkitt lymphoma; EBER using chromogenic in situ hybridization
Flow cytometry: often negative for CD20 and surface immunoglobulin light chain negative (Archives 2004;128:181)
Flow cytometry images: 1-most CD19+ cases are CD20-; 2-negative for kappa or lambda
Variant associated with fludarabine treatment
Arises in patients with B-CLL or splenic marginal zone lymphoma treated with fludarabine
Treatment was excision, nothing (regressed spontaneously), chemotherapy or antiviral therapy
Tumors were clonally distinct from initial B cell tumor
Micro: resembles post-transplant lymphoproliferative disorder, polymorphic cells with geographic necrosis and some CD20+ Reed-Sternberg like cells
References: AJSP 2002;26:630
WHO Classification of post-transplant lymphoproliferative disorders
1. Early lesions
a. Reactive plasmacytic hyperplasia
b. Infectious mononucleosis-like lesions
2. Polymorphic PTLD
3. Monomorphic PTLD (use WHO classification of lymphoma)
B-cell neoplasms
a. Diffuse large B-cell lymphoma (immunoblastic, centroblastic, anaplastic)
b. Burkitt/Burkitt-like lymphoma
c. Plasma cell myeloma
d. Plasmacytoma-like lesions
T-cell neoplasms
a. Peripheral T-cell lymphoma not otherwise specified
b. Other types
4. Hodgkin lymphoma and Hodgkin lymphoma-like lesions
WHO classification system is helpful for disease management (Archives 2006;130:1649)
Post-transplant plasmacytic hyperplasia
Usually early in post-transplant period
More common in children and young adults
Polyclonal lymphoid cells, secondary to multiple EBV infection events, usually no oncogene or tumor suppressor gene alterations
Case report of plasmacytic malignancy 6 years after plasmacytic hyperplasia (Archives 2002;126:351)
Sites: oropharynx or regional lymph nodes
Treatment: no treatment or reduction in immunosuppression
Micro: plasma cells and plasmacytoid lymphocytes with intact nodal architecture; occasional immunoblasts, but without atypia
Positive stains: EBV EBER+
Molecular: polyclonal
Molecular images: EBV in-situ hybridization
Post-transplant polymorphic B cell lymphoproliferative disorders
Either hyperplasias or lymphomas
Usually monoclonal with single form of EBV, but usually no oncogene or tumor suppressor gene alterations
Genotypic studies and flow cytometry are complementary in defining a clonal process (AJCP 2002;117:24)
Hyperplasias: single cell necrosis but no atypical lymphoid cells
Lymphomas: geographic necrosis and large atypical mononuclear cells resembling Reed-Sternberg cells
Sites: extranodal (GI, lung) or nodal
Treatment: may be reversible with reduced immunosuppressive therapy; possibly antiviral therapy; may progress to monomorphic lymphomas
Micro: diffuse effacement of lymph node by heterogeneous cells (small, round and centroblast-like lymphocytes, immunoblasts, plasma cells); variable necrosis and atypia
Micro images: polymorphous infiltrate (figure 1); centrocytes, centroblast-like cells and plasma cells
Positive stains: B and T cells, EBV-LMP
Negative stains: no light chain restriction
DD: rejection (EBER negative or minimally positive)
Post-transplant monomorphic B cell lymphoproliferative disorders
Usually high grade neoplasms with a single form of EBV, often with mutations in oncogenes or tumor suppressor genes (N-ras, p53, c-myc)
Genotypic studies (PCR) and flow cytometry are complementary in defining a clonal process (AJCP 2002;117:24)
Resembles other diffuse large B cell lymphomas; also Burkitt lymphoma, plasmacytic neoplasms, T cell lymphomas
Immunoblastic lymphoma: diffuse, uniform population of neoplastic cells with prominent nucleoli
Multiple myeloma: atypical plasma cells
Treatment: controversial; reduction in immunosuppression, followed by chemotherapy or radiation therapy in nonresponders
Specific subtypes
Post-transplant anaplastic large cell lymphoma
Case reports: 14 year old boy with EBV+ anaplastic large T cell lymphoma at 14 years after cardiac transplant (AJSP 2004;28:410), 68 year old woman with EBV- tumor post heart and liver transplant (Archives 2003;127:349)
Micro images: gastric tumor post heart and liver transplant - A-pleomorphic cells with moderate cytoplasm, irregular nuclei and prominent nucleoli; B-CD30+; C-CD5+ (faint); D-CD43+; E-CD20 negative; F-ALK+
Post-transplant Burkitt lymphoma
5 cases reported (4 men, 1 woman, mean 35 years old, AJSP 2003;27:818)
Interval averaged 4.5 years
Presents with high stage disease with generalized lymphadenopathy and bone marrow involvement
Treatment: Rituximab or combination chemotherapy led to complete remission
Micro: Burkitt or Burkitt-like morphology with monomorphic intermediate sized tumor cells with a small rim of basophilic cytoplasm, round nuclei and multiple small nuclei, also many tingible-body macrophages giving a typical starry sky pattern; touch preparations show deeply basophilic cytoplasm with numerous vacuoles; atypical (Burkitt-like) cases have more variability in size and shape
Molecular: c-myc rearrangement, EBV
Post-transplant diffuse large B cell lymphoma
Common histologic type of post-transplant monomorphic lymphoma
Case reports: 61 year old post liver transplantation (Archives 2003;127:248)
Micro
images: 1-CT
with multiple liver lesions; 2-diffuse liver involvement by large cells with
prominent nucleoli; 3-CD20+; 4-EBV+; pleomorphic
atypical lymphoid cells; CD20+
Post-transplant histiocytic sarcoma
Micro images: cells with large, irregular nuclei (figure 3)
Positive stains: CD68, granzyme B
Post-transplant Hodgkin’s lymphoma
Micro: mixed infiltrate of plasma cells, lymphocytes and eosinophils mixed with Reed-Sternberg or like cells
Positive stains: Reed-Sternberg cells - EBV EBER1 by ISH, CD15, CD30, fascin
Negative stains: CD45
Molecular: no immunoglobulin gene rearrangements
Post-transplant Hodgkin’s lymphoma-like lymphoproliferative disorder
Very rare
Cases to date involve males, often teenagers
Similar to Hodgkin’s lymphoma, but with atypical phenotype
Nodal or extranodal
Appears to be a type of B cell post-transplant lymphoproliferative disorder (Archives 2006;130:558)
Treatment: reduce immunosuppression, variable chemotherapy or radiation therapy
Micro: small to medium lymphoid cells mixed with Reed-Sternberg like cells (large, mono- bi or multinucleated); also histiocytes, plasma cells and rare eosinophils
Micro images: Reed-Sternberg like-cells are CD30+ (inset), but also CD45+ and CD15- (figure 4)
Positive stains: Reed-Sternberg like cells - CD45, CD20, CD79a, EBER; variable CD30; lymphoid cells are B/T cells and often EBER+
Negative expression: CD15
Molecular: immunoglobulin gene rearrangements
Post-transplant MALT-type extranodal marginal zone lymphomas
Rare, 5 cases reported at AJSP 2000;24:100
Mean age 51 years (range, 48-63 years); after heart, liver, kidney transplants; involves stomach (H. pylori+) and parotid gland
Occurs a mean 7 years post-transplant
All tumors reported above were low-grade MALT, EBV negative, non-aggressive
Rare; 3 cases reported resemble conventional myeloma (Mod Path 2004;17:389)
Micro images: Fig 1a: bone fracture site with plasma cells; 1b/1c: bone marrow biopsy (inset is light chain immunostains); 1d: bone marrow (left) and liver (right) showing polymorphic lymphoplasmacytic infiltrate (inset is EBER ISH of bone marrow); plasmacytoma-like PTLD with mature and occasional atypical plasma cells
Post-transplant NK/T cell lymphoproliferative disorders
Rare, <100 cases reported; most post-transplant lymphoproliferative disorders are B cell origin
20% are associated with Epstein-Barr virus
Case reports of extranodal NK/T cell lymphoma, nasal-type: hypopharynx in renal transplant recipient (Hum Path 2001;32:1264), EBV+ tumor in breast in heart transplant patient (Mod Path 2004;17:125)
Micro: angiocentric growth of medium to large lymphoid cells with necrosis
Micro images: breast tumor after heart transplant - a: angiocentric infiltration; b: angiodestructive with mitotic figures and apoptotic bodies; c: CD2+; d: CD56+; e: p53+; f: EBER 1-2 ISH
Post-transplant T cell lymphoma of bone marrow
Case reports: T-cell large granular lymphocytosis (AJCP 2005;123:196)
Micro: focal or extensive interstitial involvement of large cells with abundant cytoplasm and prominent nucleoli; cellular debris prominent; reduced normal hematopoiesis; may be difficult to identify without special stains
Positive stains: CD2, CD3
Graft versus Host Disease (GVHD)
Clinical: Common complication of allogeneic bone marrow transplantation seen in 20-50% of HLA identical and 70% of nonidentical / unrelated recipients
Causes 1/3 of bone marrow transplant deaths
Acute GVHD: within 100 days of transplant; affects skin, GI tract, liver
Skin – maculopapular rash of palms, soles, trunk, later entire body; may progress to bullous patches and desquamation
GI – diarrhea (profuse, bloody), nausea, abdominal pain
Liver – elevated liver function tests, nausea, vomiting
Also oral GVHD with xerostomia
Chronic GVHD: after 200 days of transplant; autoimmune-like symptoms, wasting, recurrent infections, prolonged immunodeficiency
Pathophysiology: due to donor T cytotoxic (CD8+) T cells introduced with bone marrow cells as bystanders that attack recipient tissue
Donor T cells recognize host HLA antigens, proliferate and secrete Interleukin-2 and then other cytokines including tumor necrosis factor, IL-1 and interferon, causing tissue damage
Treatment: increased immunosuppression, irradiation (treatment opposite that of post-transplant lymphoproliferative disease)
Micro:
Skin: Lerner et al, Transplant Proc 1974;6:367
Grade 0: no definite evidence of GVHD
Grade 1: vacuolar degeneration of basal epithelial cells or acanthocytes
Grade 2: also dyskeratosis, apoptosis of keratinocytes (eosinophilic bodies) surrounded by lymphocytes,
spongiosis, edema of overlying epithelium
Grade 3: also splitting and degeneration of acanthocytes and basal cells, causing cleft formation and
separation of dermoepidermal junction
Grade 4: sloughing of overlying epithelium
Rectum:
Early: flatting/atrophy of mucosa, degeneration and loss of crypts; occasional apoptotic bodies surrounded by lymphocytes
Late: mucosal sloughing
Salivary glands:
Grade 1: abnormal mononuclear infiltrates with or without ductal epithelial necrosis
Grade 2: also obliteration of ducts
DD: chemotherapy effect, drug reaction, infection
AIDS associated
AIDS associated lymphoproliferative disorders - general
Occurs in 4-10% of AIDS patients, 100x expected rates of non-Hodgkin lymphoma (Hum Path 2002;33:392)
Conversely, 10% of non-Hodgkin lymphomas in US/Europe are AIDS related
Usually extranodal, aggressive, poor outcome
Three categories: more specific to HIV+ patients (primary effusion lymphoma, plasmablastic lymphoma, primary CNS), common in HIV- patients (Burkitt lymphoma, diffuse large B-cell lymphoma, extranodal marginal zone B-cell lymphoma of MALT type, rare peripheral T-cell lymphoma, classic Hodgkin lymphoma) and occurring in other immunodeficiency states (polymorphic B cell lymphoma)
Most common subtypes are primary CNS and diffuse large B cell lymphoma; highly active retroviral therapy has reduced incidence of primary CNS lymphoma and Burkitt lymphoma
Micro: diffuse, pleomorphic, high-grade B cells; frequent mitotic figures, increased cellular debris, necrosis common
AIDS associated anaplastic large cell lymphoma
Case report of ALK negative tumor in brain of 46 year old man with AIDS (Archives 2004;128:324)
Micro images: 1-MRI of 3 cm occipital lobe lesion; 2-large anaplastic cells in perivascular pattern; 3-CD43+; 4-CD30+; 5-rearrangement of T cell receptor gamma gene (patient-lane 7, positive control-lanes 12 and 13, negative control-lane 14); 6-extra ALK signals by ISH
AIDS associated Burkitt and Burkitt like lymphoma
Features of Burkitt lymphoma or Burkitt like lymphoma
AIDS associated cutaneous lymphoma
Presents as solitary nodule/tumor in severely immunocompromised patients with low CD4 count
Death due to immunosuppression, not spread of lymphoma (AJSP 1999;23:1208)
Types: diffuse large B cell lymphoma, CD30+ T cell lymphoma, mycosis fungoides, anaplastic large cell lymphoma (ALK negative)
HHV8 negative
Treatment: avoid aggressive immunosuppression
AIDS associated diffuse large B cell lymphoma
Associated with end stage HIV, severe combined immunodeficiency, bone marrow transplantation, solid organ transplantation, EBV infection
May regress with restoration of T cell immunity
AIDS associated Hodgkin lymphoma
Frequently involves bone marrow; occasionally only involves bone marrow
Median survival 4 months (range, 2-118 months) in bone marrow only cases
Micro: Reed-Sternberg cells present
Micro images: A: focal involvement; B: diffuse involvement; C: Reed-Sternberg cells; D: CD15+, CD30+, Oct2 negative, EBER+
References: Mod Path 2002;15:1273
Primary pulmonary lymphomas are rarer than secondary spread to lungs
Usually in HIV+ children, rare in adults
Case report in adult with coexisting aspergilloma (Archives 2000;124:1506)
AIDS associated NK lymphoma, nasal type
Case reports: EBV+, HIV+ patient (Archives 2001;125:660), mediastinal mass (Archives 2000;124:304)
Gross/micro images: 1A-anterior
mediastinal mass; 1B-lymphoid cells with zonal necrosis, angiocentric and
angiodestructive infiltration; 1C-polymorphitc atypical lymphoid cells with
moderate eosinophilic cytoplasm, irregular nuclei, occasional Reed-Sternberg
like cells; CD3+;
granzyme+; TIA1+; a-large areas of tumor necrosis; b-medium to large
cells; c-CD94+; d-EBER-1+ in situ hybridization
AIDS associated peripheral T cell lymphoma
Less common than B cell lymphoma
Case reports: intravascular T cell lymphoma in appendix (Archives 1999;123:335), two cases with Touton-like tumor giant cells and mononuclear large lymphoma cells (AJSP 1999;23:519)
Micro images: 1A-lymphoma cells in submucosal vessels; B-intravascular large lymphoma cells with prominent nucleoli and occasional mitotic figures; CD3+
Positive stains: CD3, CD4, CD5, CD30, CD43, CD45 RO
Negative stains: B cell markers
Molecular: T cell receptor gamma chain gene rearrangement
AIDS associated plasmablastic lymphoma
See under Lymphomas - B cell and plasma cell neoplasms
AIDS associated polymorphic B cell lymphoproliferative disorders
Rare; indolent if benign, aggressive if high grade
Morphologically similar to post-transplant lymphoproliferative disorders
Arise in lymph nodes, lungs, other sites
EBV may play a role in pathogenesis
Case reports: EBV+, CNS lymphoma in a child with AIDS (Archives 1999;123:83)
Micro: diffuse growth of polymorphic lymphocytes with variable plasmacytic differentiation, atypia and atypical immunoblasts; numerous mitoses, extensive necrosis and architectural distortion
Positive stains: EBV (60%)
Molecular images: clonal B cell population (may be faint, indicating a small population of clonal cells)
References: AJSP 1999;23:560, Hum Path 2002;33:392, AJSP 2003;27:293
AIDS associated primary effusion lymphoma
See under Lymphomas - B cell and plasma cell neoplasms
Other
Post-immunosuppressive therapy: Hodgkin lymphoma
Rare; 4 cases of primary GI Hodgkin lymphoma reported at mean 4 years post-immunosuppressive therapy for Crohn’s disease and myasthenia gravis (AJSP 2000 ;24:66)
Post-transplant cases usually associated with >500 EBV genome copies per 100K lymphocytes (Archives 2001;125:1480)
Case reports: post-renal transplant (Archives 2001;125:1480), Reed-Sternberg like cells (University of Pittsburgh)
Micro images: 1-classic Reed-Sternberg cell; 2-EBER by in situ hybridization in bone marrow biopsy
Molecular: one case associated with polyclonal Reed-Sternberg cells, early stage disease and apparent cure by surgical resection, suggesting EBV-driven proliferation
Primary immune disorder associated
Usually extranodal
Varies from polymorphous proliferation of lymphoid cells to diverse lymphomas, usually B cell lineage
Usually EBV+
Senile EBV positive lymphoproliferative disorders
Defined as EBV+ but with no predisposing immunodeficiency, HIV-, age 60+ years
82% had extranodal involvement
Classified as polymorphic lymphoproliferative disorder (polymorphous and inflammatory background) or large cell lymphoma subtype (diffuse proliferative lesions of large lymphoid cells)
Analogous to immunodeficiency associated B cell lymphoproliferative disorders, but without underlying immunodeficiency diseases
Often aggressive disease (particularly with large cell lymphoma subtype)
Micro: variable centroblasts, immunoblasts and Reed-Sternberg like giant cells, often necrosis, often angiocentric
Positive stains: CD20, CD79a, EBV (LMP1 or EBNA2)
Negative stains: CD5, CD10
References: AJSP 2003;27:16 (Japanese patients)
End of Lymphomas - non B cell chapter
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