Last revised 27 May 2008
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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)