Non-Hodgkin lymphoma (differentiating types of NHL)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[3], Kamal Akbar, M.D.[4]

Non-Hodgkin lymphoma (differentiating types of NHL)

Differentiating different types of Non-Hodgkin lymphoma. Gold standard for differentiation different types of Non-Hodgkin lymphoma is biopsy.

Disease		Etiology	Clinical manifestations						Paraclinical findings		Associated findings
									Lab findings
			Symptoms				Signs		Immunochemistry	Histopathology
			Constitutional symptoms	Rash	Abdominal pain	Diarrhea	Mass	Other
Hodgkin's Lymphoma		Activation of (NF-kB) Mutations in JAK-STAT pathway NF-kB leads to activation of many genes like: (ICAM-1) gene GM-CSF gene IL-6 gene IKBA gene Gain of function mutation of the MAP3K14 gene	Fever (Pel-Ebstein fever): persistent temperature >38°C (>100.4°F) Drenching night sweats Unexplained weight loss >10% of total body weight within the past 6 months	-	±	-	Painless lymphadenopathy with a rubbery consistency. Mostly above the diaphram	Pruritus Pain in lymph nodes after drinking alcohol Skin blushing or flushing Bone pain	Nodular lymphocyte predominant CD19+ CD20+ CD22+ CD15- CD30 Classical Hodgkin's lymphoma CD15+ CD30+ CD20- CD45-	Effacement of the lymph node architecture by Reed-Sternberg cells . Reed-Sternberg cell is a large often bi-nucleated cells with prominent nucleoli and an unusual immuno phenotype.	EBV infection
Non-Hodgkin's Lymphoma (B Cell Lymphoma)
Diffuse large B cell lymphoma		Mature B-cell Lymphoma 8q24/MYC translocations Hypermutated immunoglobulin genes Mutation of BCL6, MYC, PAX5, PIM1, RhoH /TTFn, TP53 genes Translocations involving c-MYC, BCL6, and IgH gene.	Fever Night sweats Weight loss	-	+	+	Painless rapidly enlarging lymph nodes	Extranodal involvement of GI tract, lungs, and CNS	CD20 CD3 CD5 CD45 CD10 BCL-2 BCl-6 MYC IRF-4/ MUM-1 Ki-67	Centroblastic Medium-to-large-sized lymphocytes Monomorphic Immunoblastic > 90% immunoblasts Trapezoid shaped large lymphoid cells with significant basophilic cytoplasm Anaplastic Very large cells with a round, oval, or polygonal shape that may resemble Reed-Sternberg cells	_
Mantle cell lymphoma		Mature B-cell lymphoma CD5 positive antigen in pre germinal center of B-cell Chromosomal translocation at t(11:14)	Fatigue Night sweats Weight Loss	–	+	+	Palpable masses in skin, breast, and salivary glands Generalized lymphadenopathy	Extranodal involvement of GI tract, lungs, and CNS Mental retardation	CD5+ B-cell antigen positive Overexpression of Cyclin D1	Germinal centers filled by small-to-medium atypical lymphocytes Nodular appearance	Abdominal distention
B-lymphoblastic leukemia/lymphoma		Precursor B-cell lymphoma Unknown Inherited mutations of PAX5, ETV6, and TP53	+	–	–	–	Painless mass at extranodal sites mainly of the skin, bone and lymph node.	Bleeding Dyspnea Joint pain	CD20+ CD10+	Consists of small to medium-sized lymphoid cells with blastic nuclear chromatin and a high mitotic rate.	Down syndrome
Follicular lymphoma		Mature B-cell lymphoma Reciprocal translocation t(14;18) Overexpression of BCL2	20% of patients present with: Fever Weight loss Night sweats	+	+	±	Painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions Asymptomatic large abdominal mass	Seizures Chest pain Bone pain Cough Dyspnea	CD21 CD23	Nodular growth pattern	Most common clinically indolent NHL Peripheral nerve compression
Burkitt's lymphoma		Mature B-cell lymphoma Translocation of chromosome 8 myc locus such as: t(8;14) t(2;8) t(8;22)	Fever Night sweats Unexplained weight loss	–	+	–	Swollen lymph nodes in the neck, axilla, or groin Jaw mass Abdominal masses	Ascites Proptosis	CD19 CD20 CD22 CD10 BCL6 BCL2 and TdT	Round and small nucleoli basophilic cytoplasm "Starry-sky pattern"	EBV infection HIV infection Immunosuppression Abdominal distention
B cell chronic lymphocytic leukemia/small lymphocytic lymphoma		Mature B-cell Lymphoma Ch 13 abnormalties	33% of patients present with: Fever Weight loss Night sweats	–	–	–	Painless lymphadenopathy	May be asymptomatic Fatigue Recurrent infections Hepatosplenomegaly	CD5 CD38	Monoclonal small well differentiated B cells. Significant number of smudge cells or basket cells.	Autoimmune hemolytic anemia Red cell aplasia Autoimmune thrombocytopenia
Marginal zone lymphoma	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type	Mature B-cell lymphoma Recurrent translocation of such as: t(1;14)(p22;q32) t(11;18)(q21;q21) t(14;18)(q32;q21) t(3;14)(p14.1;q32)	B symptoms may or may not be present	±	+	+	Painless or painfull lymphadenopathy which can be gastric or non-gastric. Lump in the superior lateral quadrant of the orbit, breast, neck, or salivary gland	Symptoms depend on the location of the tumor: Fatigue Heartburn Fever Cough with blood in sputum, Shortness of breath	B-cell associated antigens that co-express BCL-2 CD19 CD20 CD22 CD79a Negative for: CD5 CD10 CD43 cyclin D1.	Presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in lamina propria Prominent lymphoepithelial lesions and consisting of small atypical cells with monocytoid features.	H. pylori infection Hashimoto's thyroiditis Sjogren’s syndrome Celiac disease.
	Splenic marginal zone lymphoma	Mature B-cell lymphoma Clonal rearrangements of the immunoglobulin genes (heavy and light chains) Deletion 7q21-32 Translocations of the CDK6 gene located on 7q21	Fever Weight loss Night sweats	+	+	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen	Chest pain Bone pain	CD20 CD79a	Small lymphocytes Transformed blasts Epithelial histocytes Plasmacytic differentiation of neoplastic cells	Hepatitis C infection
	Nodal marginal zone B-cell lymphoma	Mature B-cell Lymphoma Stimulation of antigen receptor by autoantigen and co-stimulatory molecule CD40 Mutations in KMT2D, PTTPRD, NOTCH2, KLF2	Fever Weight loss Night sweats	+	–	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen Generalized and local lymphadenopathy	Hemorrhage Dyspepsia	Follicular cells in reactive zone Centrocyte like cells in marginal zone lymphoma	Centrocytes Centroblasts Plasma cells Immunoblasts	Hepatitis C infection Chronic infectious conditions or autoimmune processes, such as: H pylori gastritis Hashimoto thyroiditis Sjögren syndrome
Lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia)		Mature B-cell Lymphoma Mutation of the MYD88 gene (L265P) Nonsense or frameshift mutations in the CXR4 gene	Weakness Anorexia Weight loss Fever	–	–	+	Generalized and local lymphadenopathy	Retinal hemorrhage with blurring of vision Vertigo Dizziness Headache Nystagmus Tinnitus Ataxia Bleeding	Express pan B-cell antigens CD19 CD20 CD22 CD79A CD5 Variable expression of CD11c CD43, CD25 Majority express: IgM surface immunoglobulin Fewer express IgG or IgA Lack IgD	Russell bodies (intracytoplasmic inclusions) and Dutcher bodies (intranuclear inclusions) Prominent epithelioid histiocytes	Diffuse large B-cell lymphoma Myelodysplastic syndrome/Acute myeloid leukemia Brain tumor Renal MALT lymphoma
Hairy cell leukemia		Production of cytokines, such as TNF alpha and IL-2R, provide important stimuli for malignant B cells proliferation in hairy cell leukemia. The p38-MAPK-JNK cascade The MEK-ERK cascade The Phosphatidylinositol 3 kinase (PI3K)-AKT cascade	Fever Night sweats Fatigue Easy bruising or bleeding Generalized weakness Weight loss Recurrent infections Early satiety	–	+	–	Pallor Petechiae Splenomegaly	N/A	Annexin A1 CD20 CD25 CD103 CD19 CD11c FMC7	Small cells with "fried egg"-like appearance Well-demarcated thread-like cytoplasmic extensions Clear cytoplasm Central round nucleus Peri-nuclear clearing ("water-clear rim" appearance)	Abdominal distention
Disease		Etiology	Constitutional symptoms	Rash	Abdominal pain	Diarrhea	Mass/Lesion	Other	Immunochemistry	Histopathology	Associated findings
Non-Hodgkin's Lymphoma (T Cell Lymphoma)
Precursor T-cell lymphoblastic leukemia/lymphoma		Precursor T-cell lymphomas	Fever Fatigue Weight loss Night sweats	+	-	-	In most patients the mediastinal mass is anterior; associated with pleural effusions Can produce such complications as superior vena cava syndrome Skin and bone abnormalities Enlarged liver and/or spleen Tracheal obstruction Pericardial effusions	Skin rash Chest pain	CD3 CD7 TDT	Blast-like cells with scant cytoplasm, convoluted nuclei, fine chromatin, indistinct nucleoli. Some lymphoblasts have cytoplasmic pseudopods	Males in their teens to early twenties Lymphadenopathy in cervical, supraclavicular, axillary ,and mediastinum
T-cell granular lymphocytic		Clonal proliferation of CD8 T cells Constant immune stimulation Absence of homeostatic apoptosis	Fatigue Fever Night sweats	-	-	-	Lymphadenopathy Hepatosplenomegaly	Frequent infections	CD8 CD57 TCRαβ CD3 CD16 Granzyme b TIA1	Medium / large lymphocytes with abundant cytoplasm having azurophilic granules	May be associated with the following conditions: Monoclonal gammopathy of unknown significance (MGUS) B-chronic lymphocytic leukemia (B-CLL) Hairy cell leukemia Myeloid hypoplasia
T-cell prolymphocytic leukemia		Abnormal proliferation of mature T cells (post thymic)	Fever Fatigue Weight loss Night sweats	+	-	-	Lymphadenopathy Splenomegaly Hepatomegaly	Skin rash	CD2 CD3 CD4 CD5 CD7 CD56 TCL1	Lymphocytes with abundant basophilic, nongranular cytoplasm, atypical nucleus Cytoplasmic protrusions (blebs)	Pleural effusion
Adult T cell leukemia/lymphoma		Mature T-cell lymphoma Human T-lymphotrophic virus 1 infection	Hepatosplenomagaly T-cell deficiency leading immunodeficiency causing opportunistic infection	+	-	-	Hepatosplenomegaly	Hypercalcemia Skin lesions Lytic bone lesions Elevated LDH	Adult T-cell leukemia cells are typically positive for: CD2 CD4 CD5 CD8	Charecterstic leukemia cells with sharp nuclear indentations and a prominent nucleoli "Cloverleaf" or "flower" cells	Hypercalcemia
Anaplastic large cell lymphoma		Mature T-cell lymphoma	Fever Weight loss Night sweats	+	+	-	Painless swelling in : Neck Axilla Groin Thorax Abdomen	Skin rash Chest pain Abdominal pain Bone pain	Strongly immunoreactive for : CD30 Anaplastic lymphoma kinase (ALK) EMA vimentin	Nucleoli tend to be more prominent The cytoplasm may be either basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin	May be caused by textured breast implants
Cutaneous T-cell lymphoma	Mycosis fungoides / Sézary syndrome	Mature T-cell Lymphoma The tumor cells originate from memory T cells or skin homing CD4+ T cells expressing cutaneous lymphocyte antigen (CLA) and chemokine receptors CCR4and CCR7. It is understood that cutaneous t cell lymphoma (maycosis fungoides, Sezary sydrome ) is the result of malignant T cell that derived from a mature CD41 CD45RO1 memory T cells.	Weight loss Malaise and fatigue Anemia	+	+	-	Cutaneous manifestations	Lymphadenopathy May progress to Sezary syndrome	Beta F1+ CD2-/+ CD3+ CD3- (CD4-positive variant) CD4+ (CD4-positive variant) CD4- CD5- CD7+/- CD8+ CD8- (CD4-positive variant), Granzyme B+ perforin+	Polymorphous inflammatory infiltrate in the dermis that contains small numbers of frankly atypical lymphoid cells These cells may line up individually along the epidermal basal layer The presence of spongiosis is highly suggestive of mycosis fungoides	Epidermal atrophy or poikiloderma Generalized itching(pruritus) Pain in the affected area of the skin. Insomnia Red (erythematous) patches scattered over the skin of the trunk and the extremities
Peripheral T-cell lymphoma	Subcutaneous panniculitis-like T-cell lymphoma	Mature T-cell lymphoma	Fever Chills Weight loss Night sweats	-	-	-	Painless swellings on: Extremities Trunks	Myalgias	Positive for: BetaF1 CD8 CD30 CLA T-cell intracellular antigen (T1A1) Perforin	Atypical lymphoid cells Fat necrosis Karyorrhexis	Subcutaneous panniculitis-like T-cell lymphoma can mimic the following conditions making it difficult to diagnose Begnign panniculitis Eczema Cellulitis Dermatitis
	Hepatosplenic T-cell lymphoma	Mature T-cell Lymphoma Inflammatory bowel disease Organ transplant patients (reciever) Immunosuppresent medications Thiopurines Infliximab Cyclophosphamide Vincristine Doxorubicin	Fever Fatigue Weight loss Night sweats	+	+	-	Painless swelling in : Neck Axilla Groin Thorax Abdomen	Skin rash Chest pain Abdominal pain Bone pain	CD2 CD3 CD7 CD16 CD56 or CD57 TIA1 Granzyme m Fas ligand	Intermediate sized tumor cells with clear cytoplasm, oval nuclei, slightly dispersed condensed chromatin, inconspicuous nucleoli	Patients with inflammatory bowel diseases taking immunosuppressant and anti-tumor necrosis factor-α agent are also have a higher risk for developing hepatosplenic T-cell lymphoma
	Enteropathy-type intestinal T-cell lymphoma	Mature T-cell lymphoma	Fever Weight loss Night sweats Diarrhea	+	+	+	Painless swelling in the : Neck axilla groin thorax, abdomen	Skin rash Chest pain Abdominal pain Bone pain	CD3+ CD4- CD5- CD7+ CD30+ CD56+ CD103+ CD8+/- TCR beta+/-	Lymphomatous infiltrate with neoplastic large cells May have pleomorphic, multinucleated cells Adjacent mucosa shows villous atrophy, crypt hyperplasia, increased inflammatory cells Lymphocytosis	Mostly diagnosed in the small intestine
	Extranodal T-cell lymphoma, nasal type	Mature T-cell lymphoma	Fever Weight loss Night sweats	+	-	-	Painless swelling in : Neck Axilla Groin Thorax Abdomen	Skin rash Chest pain Abdominal pain Bone pain	Cytoplasmic CD3 epsilon Granzyme B Perforin CD2 CD56	Medium sized tumor cells and polymorphic infiltrate of non-neoplastic inflammatory cells Lymphoma cells may be admixed with a polymorphic infiltrate of non-neoplastic inflammatory cells	Protrusion of eye Swelling of the face Discharge from the nose Nose bleeds Blockage of the nasal passages
	Angioimmunoblastic T-cell lymphoma	Mature T-cell lymphoma	Fever Weight loss Night sweats Edema Fatigue	+	+	-	Painless swelling in : Neck Axilla Groin Thorax Abdomen	Skin rash abdominal pain bone pain dark urine shortness of breath chronic pain and swelling of joints Chest pain	CD2 CD3 CD4 CD5 CD10 CD20 Focal positivity for CXCL13	Leukocytic infiltrate, represented mostly by elongated cells with marked artifactual changes Hyperplastic germinal centers and Reed-Sternberg cells	Monoclonal gammopathy Autoimmune hemolytic anemia
	Peripheral T-cell lymphoma, unspecified	Mature T-cell lymphoma	Fatigue Fever Frequent infections	-	+	-	Lymphadenopathy Hepatosplenomegaly	Lymphadenopathy (swollen ) Thirst Nausea Vomiting Skin and bone abnormalities Enlarged liver and/or spleen	CD2 CD3 TCR β F1 Variable CD4 CD5 CD7 Occasional CD56 Cytotoxic granule expression	Clear cytoplasm, resemble Reed-Sternberg cells, with irregular, pleomorphic, hyperchromatic or nuclei A lot of mitotic figures; very broad cytologic spectrum	Endogenous immunosupression Patients may present with p.jiroveci or varicella zoster infection Can be confused with other infectious or rheumatologic diseases