Lymphoma-non B cell

Last revised 27 May 2008

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Table of contents

Primary references

 

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)

 

Primary references

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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

General

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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)

 

WHO classification

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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)

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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

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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)

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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

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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

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Numerous histiocytes and small lymphocytes

Neoplastic cells tend to cluster around blood vessels

Positive stains: CD30, ALK

 

Neutrophil-rich cutaneous T cell

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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

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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

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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

 

Angiocentric T cell lymphoma

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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

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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+)

 

Blastic NK lymphoma

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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 contoursCD56+, 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

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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

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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

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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

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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

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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)