Non-Hodgkin lymphoma pathophysiology: Difference between revisions

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*It supports rapid B-cell proliferation for [[immunoglobulin]] affinity maturation and production of antibody diversity through two processes know as [[somatic hypermutation]] (SHM) and [[Class switching|immunoglobulin class switching]].
*It supports rapid B-cell proliferation for [[immunoglobulin]] affinity maturation and production of antibody diversity through two processes know as [[somatic hypermutation]] (SHM) and [[Class switching|immunoglobulin class switching]].
*Both of these processes require  rapid cell turnover and multiple double stranded [[DNA]] breaks, which is error-prone.
*Both of these processes require  rapid cell turnover and multiple double stranded [[DNA]] breaks, which is error-prone.
*Somatically acquired genetic alterations ( mainly [[Chromosomal translocation|translocations]]) of these processes is probably the underlying cause of lymphomagenesis.<ref name="pmid25712152">{{cite journal |vauthors=Basso K, Dalla-Favera R |title=Germinal centres and B cell lymphomagenesis |journal=Nat. Rev. Immunol. |volume=15 |issue=3 |pages=172–84 |date=March 2015 |pmid=25712152 |doi=10.1038/nri3814 |url=}}</ref><ref name="pmid10648419">{{cite journal |vauthors=Nardini E, Aiello A, Giardini R, Colnaghi MI, Ménard S, Balsari A |title=Detection of aberrant isotype switch recombination in low-grade and high-grade gastric MALT lymphomas |journal=Blood |volume=95 |issue=3 |pages=1032–8 |date=February 2000 |pmid=10648419 |doi= |url=}}</ref><ref name="pmid18097447">{{cite journal |vauthors=Klein U, Dalla-Favera R |title=Germinal centres: role in B-cell physiology and malignancy |journal=Nat. Rev. Immunol. |volume=8 |issue=1 |pages=22–33 |date=January 2008 |pmid=18097447 |doi=10.1038/nri2217 |url=}}</ref>
*Somatically acquired genetic alterations ( mainly [[Chromosomal translocation|translocations]]) of these processes is probably the underlying cause of lymphomagenesis.


* The major subtypes of non-hodgkin lymphoma include the following:<ref name="pmid21261684">{{cite journal| author=Coupland SE| title=The challenge of the microenvironment in B-cell lymphomas. | journal=Histopathology | year= 2011 | volume= 58 | issue= 1 | pages= 69-80 | pmid=21261684 | doi=10.1111/j.1365-2559.2010.03706.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21261684  }}</ref><ref>{{cite journal|doi=10.1182/blood-2016- 01-643569}}</ref>
* The major subtypes of non-hodgkin lymphoma include the following:
** Mature B-cell neoplasms:
** Mature B-cell neoplasms:
*** [[Burkitt's lymphoma|Burkitt lymphoma]]  
*** [[Burkitt's lymphoma|Burkitt lymphoma]]  
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==Genetics==
==Genetics==


Different subtypes of non Hodgkin lymphoma and their genetic involvements::<ref>Burkitt's Lymphoma. Wikibooks. https://en.wikibooks.org/wiki/Radiation_Oncology/NHL/Burkitt_lymphoma#Pathology Accessed on October,5 2015</ref><ref>{{cite web|title=NIH study shows Burkitt lymphoma is molecularly distinct from other lymphomas|url=http://cancer.gov/newscenter/newsfromnci/2012/BurkittReleaseStaudt|publisher=National Cancer Institute}}</ref><ref>Staudt L, et al. Burkitt Lymphoma Pathogenesis and Therapeutic Targets from Structural and Functional Genomics. Nature. August 12, 2012 {{DOI|10.1038/nature11378}}</ref><ref name="pmid21804550">{{cite journal |vauthors=Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, Wells VA, Grunn A, Messina M, Elliot O, Chan J, Bhagat G, Chadburn A, Gaidano G, Mullighan CG, Rabadan R, Dalla-Favera R |title=Analysis of the coding genome of diffuse large B-cell lymphoma |journal=Nat. Genet. |volume=43 |issue=9 |pages=830–7 |date=July 2011 |pmid=21804550 |pmc=3297422 |doi=10.1038/ng.892 |url=}}</ref><ref name="pmid26573234">{{cite journal |vauthors=Ye Q, Xu-Monette ZY, Tzankov A, Deng L, Wang X, Manyam GC, Visco C, Montes-Moreno S, Zhang L, Dybkær K, Chiu A, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Choi WW, van Krieken JH, Huh J, Ponzoni M, Ferreri AJ, Parsons BM, Møller MB, Piris MA, Winter JN, Medeiros LJ, Hu S, Young KH |title=Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma |journal=Oncotarget |volume=7 |issue=3 |pages=2401–16 |date=January 2016 |pmid=26573234 |pmc=4823044 |doi=10.18632/oncotarget.6262 |url=}}</ref><ref name="pmid28379189">{{cite journal |vauthors=Nguyen L, Papenhausen P, Shao H |title=The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects |journal=Genes (Basel) |volume=8 |issue=4 |pages= |date=April 2017 |pmid=28379189 |pmc=5406863 |doi=10.3390/genes8040116 |url=}}</ref><ref name="OffitCoco1994">{{cite journal|last1=Offit|first1=Kenneth|last2=Coco|first2=Francesco Lo|last3=Louie|first3=Diane C.|last4=Parsa|first4=Nasser Z.|last5=Leung|first5=Denis|last6=Portlock|first6=Carol|last7=Ye|first7=Bihui H.|last8=Lista|first8=Florigio|last9=Filippa|first9=Daniel A.|last10=Rosenbaum|first10=Ayala|last11=Ladanyi|first11=Marc|last12=Jhanwar|first12=Suresh|last13=Dalla-Favera|first13=Riccardo|last14=Chaganti|first14=R.S.K.|title=Rearrangement of the bcl-6 Gene as a Prognostic Marker in Diffuse Large-Cell Lymphoma|journal=New England Journal of Medicine|volume=331|issue=2|year=1994|pages=74–80|issn=0028-4793|doi=10.1056/NEJM199407143310202}}</ref><ref name="pmid9787151">{{cite journal |vauthors=Kramer MH, Hermans J, Wijburg E, Philippo K, Geelen E, van Krieken JH, de Jong D, Maartense E, Schuuring E, Kluin PM |title=Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma |journal=Blood |volume=92 |issue=9 |pages=3152–62 |date=November 1998 |pmid=9787151 |doi= |url=}}</ref><ref>{{Cite journal
Different subtypes of non Hodgkin lymphoma and their genetic involvements::
| author = [[Itziar Salaverria]], [[Cristina Royo]], [[Alejandra Carvajal-Cuenca]], [[Guillem Clot]], [[Alba Navarro]], [[Alejandra Valera]], [[Joo Y. Song]], [[Renata Woroniecka]], [[Grzegorz Rymkiewicz]], [[Wolfram Klapper]], [[Elena M. Hartmann]], [[Pierre Sujobert]], [[Iwona Wlodarska]], [[Judith A. Ferry]], [[Philippe Gaulard]], [[German Ott]], [[Andreas Rosenwald]], [[Armando Lopez-Guillermo]], [[Leticia Quintanilla-Martinez]], [[Nancy L. Harris]], [[Elaine S. Jaffe]], [[Reiner Siebert]], [[Elias Campo]] & [[Silvia Bea]]
| title = CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma
| journal = [[Blood]]
| volume = 121
| issue = 8
| pages = 1394–1402
| year = 2013
| month = February
| doi = 10.1182/blood-2012-08-452284
| pmid = 23255553
}}</ref>


{| class="wikitable"
{| class="wikitable"
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|}
|}


== Differential diagnosis of Lymphocytosis ==
{| class="wikitable"
|+
!
!Pathophyisiology
!Symptoms
!History
!Physical Examination
!Laboratory Findings
|-
|AML
|
* Mutation of myeloblast freezes the cell in its immature state and prevent [[cellular differentiation|differentiation]].
|
* Persistent or frequent [[infections]].
* [[Anemia]] leads to fatigue, paleness, and shortness of breath.
* Thrombocytopenia leads to  bruising or bleeding with minor trauma.
|
* History of pre-existing hematological disorder (e.g [[aplastic anemia]], [[PNH]], [[myelofibrosis]])
* History of exposure to anti-cancer [[chemotherapy]] agents especially alkylating agents
* History of exposure to [[ionizing radiation]]
* History of occupational exposure to [[benzene]] and other [[aromatic hydrocarbons]]
* History of any [[congenital]] disorders (e.g [[Down syndrome]], [[Bloom syndrome]])
|
* Bone tenderness
* Skin manifestations
|
* Immature Myeloblasts on blood smear
* Flow cytometry
* +Aur Rods
|-
|ALL
|
* Arrest of  [[lymphoblasts]].
* [[Chromosomal translocations]] involved
** 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1''
** 12 and 21, t(12;21)(p13;q22) ''TEL-AML1''
** 5 and 14, t(5;14)(q31;q32)''IL3-IGH''
** 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''  
|
* Generalised weakness and [[Fatigue (physical)|fatigue]]
* Frequent or unexplained [[fever]] and [[Infection|infections]]
* [[Weight loss]] and/or loss of appetite
* Excessive [[bruising]], [[Hemorrhage|bleeding]] from wounds, [[Nosebleed|nosebleeds]], [[petechiae]], [[bone pain]], [[Joint pain|joint pains]] and [[dyspnea]].
|
* History of cancer
* History of drug exposure
|
* [[Lymphadenopathy]]
* [[Hepatomegaly|Hepato-splenomegaly]]
* [[Stridor]]
* [[Pallor]]
* P[[Petechiae|etechiae]]
* B[[Bruising|ruising]]
* [[Papilledema]]
* Nuchar rigidity
* [[Cranial nerve palsy]]
* Testicular enlargement
|
* [[Eosinophilia]]
* [[Lymphocytosis]]
* Decreased erythrocytes production 
* [[Thrombocytopenia]].
* Chemistry panels with altered levels of [[uric acid]], [[creatinine]], [[blood urea nitrogen]], [[potassium]], [[phosphate]], [[calcium]], [[bilirubin]], [[hepatic transaminases]] and [[ferritin]].
* A [[Lumbar puncture|spinal tap]] will tell if the spinal column and [[Central nervous system|brain]] has been invaded.
|-
|CML
|
* Myeloproliferative expansion of pluripotent stem cells.
* Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2)
** Resulting in a derivative 9q+ and a small 22q-. results in a ''BCR-ABL'' fusion gene
** Ativates numerous downstream targets including
*** ''c-myc''
*** ''Akt''
*** ''Jun'',
|
* Insidious in onset
* Nonspecific symptoms of fatigue and weight loss.
* Early satiety and decreased food intake due to splenic compression of stomach
* Low-grade fever and excessive sweating
|
|
* Splenomegaly
** Correlates with granulocyte counts
* Findings of leukostasis and hyperviscosity.
* Funduscopy may show papilledema, venous obstruction, and hemorrhages.
|
* WBC counts, exceeding 300,000-600,000 cells/μL
* Elevated alkaline phosphatase (ALP)
* Philadelphia (Ph1) chromosome\
*
|-
|CLL
|
* Clonal B cells arrested in the B-cell differentiation pathway,
* [[Genetic mutation|Genetic mutations]] that promote both [[malignant]] leukemic proliferation and [[apoptotic]] resistance of mature B cells.
* Structural [[Genetic mutation|genetic mutations]] involved in the pathogenesis of chronic lymphocytic leukemia include [[chromosome]] 13q deletion, chromosome 17p deletion, and chromosome 11q deletion.
** ''SF3B1'' gene located on [[chromosome 2]]
** ''FBXW7'' gene located on [[chromosome 4]]
** ''MYD88'' gene located on [[chromosome 3]]
** ''TP53'' gene located on [[chromosome 7]]
** ''NOTCH1'' gene located on [[chromosome 9]]
** ''ATM'' gene located on [[chromosome 11]]
** ''CHD2'' gene located on [[chromosome 15]]
|
* [[Fever]]
* Recurrent [[bleeding]]
* [[Weight loss]]
* [[Muscle wasting]]
* Generalized [[weakness]]
* Anorexia
* [[Night sweats]]
* [[Abdominal pain]]
* Recurrent [[Infection|infections]]
|
* Review family history for members with positive history of the disease
* Review occupational history related to farming
* Review any exposure to herbicides or insecticides
|
* Skin [[pallor]]
* Palpable [[cervical]] [[Lymph node|lymph nodes]]
* [[Hepatomegaly]].
|
* Monoclonality of kappa and lambda producing [[B cell|B cells]]
* Presence of smudge cells
* CBC
** Absolute [[lymphocytosis]] (>5000 cells/μl)
** Decreased [[hemoglobin]] concentration
** Decreased [[Platelet|platelets]] count
* Express [[CD19]], [[CD20]], [[CD23]], and [[CD5]] on the [[cell]] surface
|}
{| class="wikitable"
|+
!
! rowspan="2" |Pathophysiology
! rowspan="2" |Symptoms
! rowspan="2" |History
! rowspan="2" |Physical Examination
! colspan="3" |Laboratory Findings
|
|-
!
!CBC
!Blood smear
!Immunophenotype
!
|-
|'''Monoclonal B lymphocytosis'''
|
* Monoclonal population of B lymphocytes <5000 cells/microL
|
* Without other features of
** Lymphadenopathy
** Organomegaly
** Extra-medullary involvement
|
* Active or prior infections
* History of hematologic malignancy
* Medications
* Family history of chronic lymphocytic leukemia (CLL)
|
* Fever
* Lymphadenopathy
* Hepatosplenomegaly
* Joint redness
* Abdominal pain
* Lung findings.
|
* Lymphocytosis  ≥4000 lymphocytes/microL
*
|
* Lymphocytes in MBL have no distinguishing appearance
* Appear as small, mature mononuclear cells.
|
* CD19, CD20, and CD23
|
* Does not require bone marrow examination or imaging for diagnosis
|-
|'''Congenital B cell lymphocytosis'''
|
|
|
|
|
|
|
*
|
|-
|'''Large granular lymphocyte leukemia'''
|
* T-cell (T-LGL)
* Natural killer cell (NK-LGL)
|
* Recurrent infections
* Fever
* Night sweats
* Unintended weight loss
* Lymphadenopathy
|
|
|
* Pancytopenia
* Splenomegaly
|
|
* CD3, CD57, CD56
* CD3-, CD56+
|
|-
|'''Chronic lymphocytic leukemia'''
|
|
|
|
|
|
|
|
|-
|'''Sezary syndrome'''
|
|
|
|
|
|
|
|
|-
|'''Mantle cell lymphoma'''
|
|
|
|
|
|
|
|
|-
|'''Follicular lymphoma'''
|
|
|
|
|
|
|
|
|-
|'''Splenic marginal zone lymphoma'''
|
|
|
|
|
|
|
|
|-
|'''Acute lymphoblastic leukemia'''
|
|
|
|
|
|
|
|
|-
|'''Acute Promyelocytic Leukemia'''
|
|
|
|
|
|
|
|
|-
|'''Diffuse Large Cell Lymphoma'''
|
|
* Enlarged painful lymph node
*
|
* Neurological or gastrointestinal manifestations
* History of environmental and/or infectious disease exposure
|
* Lymphadenopathy
* Splenomegaly
* Low-grade fever
* Pedal edema:
|
|
|
|
|}
== Differential for Eosinophilia ==
{| class="wikitable"
|+
!
!Pathophysiology
!Symptoms
!History
!Physical Examination
!Laboratory Findings
|-
|Parasitic Infections
|
* Egg deposition
* Liberation of [[antigens]] of adult worms and eggs
* Strong [[inflammatory response]] characterized by high levels of pro-inflammatory [[cytokines]]
** I[[IL-1|nterleukins 1]], [[Interleukin 6|6]], [[TNF-α|tumor necrosis factor-α]], and circulating [[immune complexes]] participates in the pathogenesis of the acute phase of the [[disease]]
|Vary depending on the organism
* GI
* STD
* Neurological
* Swollen lymph nodes and muscle aches or pains
|
* History of travel
|
* Rash
* Fever
* Lymphadenopathy
* Ulcers
|
* +Stool examination
* + Serologic testing
* Urinalysis
|-
|Allergy/ Atopic Diseases
|
* Allergic hypersensitivity
** IgE stimulation
|'''Systemic anaphylaxis'''
* Reaction occurs within minutes
* Leading to symptomatology such as
** Acute asthma
** Laryngeal edema
** Diarrhea
** Urticaria
** Shock.
* Classic examples are penicillin allergy and bee sting allergy.
'''Local anaphylaxis (atopy)'''
* About 10% of people have "atopy" and are easily sensitized to allergens that cause a localized reaction when inhaled or ingested.
** Hay fever
** Hives, asthma.
* Classic examples are food allergies and hay fever to ragweed pollen
*
|
* History consistent with allergy and specific allergens
|
* [[Eczema]] ([[atopic dermatitis]])
* [[Allergic conjunctivitis]]
* [[Allergic rhinitis]]
* [[Asthma]]
*
|
* Increase in eosinophils
* Serum tryptase positive reaction
* Testing for specific IgE antigen.
|-
|Hypereosinophilic syndromes (HES)
|
* Activation of tyrosine kinases
** Clonal eosinophilic proliferation
** Overproduction of eosinophilopoietic cytokines.
|
* [[Shortness of breath]]
* [[Skin rash]]
* [[Cough]]
* [[Diarrhea]]
* [[Myalgias]]
* [[Fatigue]]
* [[Weight-loss]]
|
|
* [[Skin rash]]
:* Thickening of the skin ([[lichenification]])
:* Eczema (flexural areas)
:* [[Dermographism]]
* [[Low-grade fever]]
* [[Raynaud phenomenon]]
* [[Wheezing]]
|
* Persistently [[Eosinophilia|elevated eosinophil count]] (≥ 1500 eosinophils/mm³) in the blood
:* At least six months without any recognizable cause
:* Involvement of either the [[heart]], [[nervous system]], or [[bone marrow]].
|-
|Acute myelogenous leukemias
|
* Mutation of myeloblast freezes the cell in its immature state and prevent [[cellular differentiation|differentiation]].
|
* Persistent or frequent [[infections]].
* [[Anemia]] leads to fatigue, paleness, and shortness of breath.
* Thrombocytopenia leads to  bruising or bleeding with minor trauma.
|
* History of pre-existing hematological disorder (e.g [[aplastic anemia]], [[PNH]], [[myelofibrosis]])
* History of exposure to anti-cancer [[chemotherapy]] agents especially alkylating agents
* History of exposure to [[ionizing radiation]]
* History of occupational exposure to [[benzene]] and other [[aromatic hydrocarbons]]
* History of any [[congenital]] disorders (e.g [[Down syndrome]], [[Bloom syndrome]])
|
* Bone tenderness
* Skin manifestations
|
* Immature Myeloblasts on blood smear
* Flow cytometry
* +Aur Rods
|-
|Hodgkin's, T- and B-cell lymphomas)
|
* Reed-Sternberg cell
** B-cell origin
** CD30 (Ki-1) and CD15 (Leu-M1) antigens
|
* Painless localized peripheral lymphadenopathy
* B symptoms
|
* Presence or absence, duration, and severity of other associated systemic symptoms.
* History of previous malignancy (including other lymphomas)
* Prior treatment with chemotherapy or radiotherapy
* Previous immunosuppressive illness
* Family history of HL or other lymphoproliferative, myeloproliferative, or tissue malignancies.
|
* Palpable, painless lymphadenopathy
* Superior vena cava
* Central nervous system (CNS) symptoms
* Paraneoplastic syndromes including
** Cerebellar degeneration
** Neuropathy
** Guillain-Barre syndrome
** Multifocal leukoencephalopathy
|
* Fine-needle aspiration
** Mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells
* Lactate dehydrogenase (LDH) may be increased.
* ESR elevated
* Serum creatinine elevated in nephrotic syndrome.
* Alkaline phosphatase (ALP) increased
* Hypercalcemia, hypernatremia, and hypoglycemia.
|-
|Churg-Strauss
(Eosinophilic granulomatosis with polyangiitis)
|
* Complex interaction involving [[Genetics|genetic]] and environmental factors that lead to an [[Inflammation|inflammatory response]] involving [[Eosinophil granulocyte|eosinophils]], [[B cell|lymphocytes]] and [[Macrophage|giant cells]]
|
* '''Prodromal phase:'''  [[Rhinitis|Allergic rhinitis]] and [[asthma]].
* '''Eosinophilic phase:''' [[Eosinophilia|Peripheral eosinophilia]] and infiltration of [[Eosinophil granulocyte|eosinophils]] to [[lung]] and [[Gastrointestinal tract|GI tract]].
* '''Vasculitic phase:'''
** Small and medium-sized [[vasculitis]] and inflammatory granuloma formation.
** [[Granuloma|Granulomas]] can be either vascular or extravascular.
|
* History of allergy
*
|
* Skin involvement (60%)
* Nasal polyposis
* Peripheral neuropathy
|
* P-ANCA positive in most cases
* Elevated levels of [[Immunoglobulin E|IgE]]
* Elevated levels of [[rheumatoid factor]] at low titer
* [[Hypergammaglobulinemia]]
* Biopsy is diagnostic
** Eosinophilic infiltration
** Vasculitis of small and medium-sized vessels
** [[Granuloma]] formation.
|-
|Systemic mastocytosis
|
* Infiltration of bone marrow by mast cell affecting the peripheral blood and coagulation system. 
* The neoplastic clone of mast cells express abnormal cell surface markers CD25 and/or CD2.
|
* GI
* Cutaneous
* Urticaria pigmentosa
* Musculoskeletal
* Idiopathic and/or recurrent anaphylactoid reactions
|History of/ Associated with
* Hypereosinophilic syndrome
* Castleman disease
* Monoclonal gammopathy
* Hairy cell leukemia
* Non-Hodgkin lymphoma
* Polycythemia vera
* Primary thrombocythemia
|
* Signs of anemia,
* Hepatoslenomegaly
* Lymphadenopathy
* Urticaria
** Flushing
* Osteolysis
|
* CBC
** Eosinophilia
** Basophilia
** Thrombocytosis
** Monocytosis
* Total–to–beta-tryptase ratio greater than 20:1 is suggestive.
* CD117 positive and CD25 and/or CD2 positive.
* Abnormal mast cells.
** Larger than normal mast cells
** Irregularly shaped nuclear outlines
** Less densely packed mast cell granules
|}
<references />
<references />



Revision as of 21:33, 19 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Non Hodgkin's Lymphoma represents a heterogeneous group of diseases with varied clinical presentation and histological appearance.It arises from cell of the lymphoid system, tumors are mainly derived from B lymphocytes, but are also from T lymphocytes, or natural killer cells. Lymphomas rise from different stages of B and T cell differentiation. Aberrations in the tightly controlled steps of B cell development can lead to oncogenesis. These aberrations are mainly seen in form of chromosomal translocation.


Pathophysiology

Pathogenesis

  • The major subtypes of non-hodgkin lymphoma include the following:
    • Mature B-cell neoplasms:
    • Mature T and NK neoplasms:
      • Adult T-cell lymphoma
      • Mycosis fungoides
      • Sezary syndrome
      • Peripheral T cell lymphoma

Genetics

Different subtypes of non Hodgkin lymphoma and their genetic involvements::

Pathophysiology Symptoms History Physical Examination Laboratory Findings
Immunochemistry Blood work Biospy
B cell lymphoma Mantle cell lymphoma
  • Stage IV disease
  • B symptoms,
  • Generalized lymphadenopathy
  • Abdominal distention
  • Fatigue
  • Extranodal involvement of gastrointtestinal (GI) tract, lungs, and central nervous system (CNS)
  • History of Night sweats
  • Weight Loss
  • Generalized lymphadenopathy
  • Hepato-splenomegaly
  • Mental Retardation
  • Less commonly
    • Palpable masses in skin, breast, and salivary glands
  • CD5+
  • B-cell antigen positive
    • CD19
    • CD20
    • CD22
  • Cyclin D1 is overexpressed.
CBC
  • Anemia and cytopenias are secondary to bone marrow infiltration
  • Lymphocytosis > 4000/µL
  • Elevated LDH
  • Germinal centers filled by small-to-medium atypical lymphocytes.
  • Nodular appearance may be evident from expansion of the mantle zone in 30-50% of patients early in the disease.
Nodal marginal zone B-cell lymphoma
  • Arise from memory B cells. Include
    • Splenic marginal zone lymphoma
    • Nodal marginal zone lymphoma
    • Extranodal marginal zone lymphoma.
  • Stimulation of antigen receptor by autoantigen and co-stimulatory molecule CD40.
  • Depends largely on its location
  • Gastric marginal zone lymphoma
    • Dyspepsia
    • Abdominal pain
    • Hemorrhage
  • Chronic infectious conditions or autoimmune processes, such as
    • H pylori gastritis
    • Hashimoto thyroiditis
    • Sjögren syndrome.
  • AE1/AE3
  • B-cell markers CD20, CD79a, CD10, CD23, and bcl-2 are expressed
  • Follicular cells in reactive zone
  • Centrocyte like cells in marginal zone lymphoma
Splenic marginal zone lymphoma
  • Clonal rearrangements of the immunoglobulin genes (heavy and light chains) .
    • Deletion 7q21-32
    • Translocations of the CDK6 gene located at 7q21.
  • B-cells replace the normal white pulp of the spleen.
  • The neoplastic cells compromise
  • Sinus invasion
  • Epithelial histocytes
  • Plasmacytic differentiation of neoplastic cells.
  • Splenic Hilar Lymph Nodes
  • Bone Marrow Biopsy
    • Splenic marginal zone lymphoma in bone marrow displays a nodular pattern with morphology similar to what is observed in the splenic hilar lymph nodes.
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
  • Review occupational history related to sawdust exposure
  • Review any exposure to radiations
  • Review any exposure to herbicides or diesel
  • Tartrate-resistant acid phosphatase positive
  • CBC
  • 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)
Plasma cell myeloma
Diffuse large B-cell lymphoma
  • Germinal centre B-cell-like (GCB)
  • Activated B-cell-like (ABC).
    • B cell receptor (BCR) signalling
    • B cell migration/adhesion
    • Cell-cell interactions in immune niches
    • Production and class-switching of immunoglobulins
  • Neutropenia
  • Anemia
  • Hypergammaglobulinemia

Centroblastic

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 of Hodgkin's lymphoma or Anaplastic Large cell Lymphoma.
Burkitt lymphoma
  • Translocation of chromosome 8 myc locus with 3 possible partners (accounting for 90% of translocations):
    • The Ig heavy chain region on chromosome 14: t(8;14)
    • The kappa light chain locus on chromosome 2: t(2;8)
    • The lambda light chain locus on chromosome 22: t(8;22)
  • Medium-sized (~1.5-2x the size of a RBC) with uniform size ("monotonous") -- key feature (i.e. tumor nuclei size similar to that of histiocytes or endothelial cells)
  • Round nucleus
  • Small nucleoli
  • basophilic cytoplasm
  • Brisk mitotic rate and apoptotic activity
  • Cellular outline usually appears squared off
  • "Starry-sky pattern":
    • The stars in the pattern are tingible-body macrophages (macrophages containing apoptotic tumor cells)
    • The tumour cells are the sky
T cell lymphoma T-cell granular lymphocytic leukemia
  • Disregulation of signaling pathways:
    • FAS/FAS-L
    • Phosphatidylinositol-3 kinase (PI3K),
    • Mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK)

Symptoms of T-cell large granular lymphocyte leukemia may include the following:

  • Neutropenia
  • Anemia
  • Hypergammaglobulinemia
  • Clonal rearrangements of the T-cell receptor (TCR) gene
  • Chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood
  • Large granular lymphocyte count greater than 2.0 × 109/L
  • Lymphocytosis (typically 2-20x109/L)
Mycosis fungoides / Sézary syndrome
  • Cutaneous manifestaions
Subcutaneous panniculitis-like T-cell lymphoma
Enteropathy-type intestinal T-cell lymphoma
Anaplastic large cell lymphoma
Aggressive NK-cell leukemia


Associated Conditions

Conditions associated with [disease name] include:

  • [Condition 1]
  • [Condition 2]
  • [Condition 3]

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

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Genetics

The development of Non-Hodgkin lymphoma is the result of multiple genetic mutations such as:[1][2]

  • Mutations of the B-cell receptor genes and NFKB pathway
  • RNA splicing mutations in the small lymphocytic lymphoma
  • Genetic mutations in histone formation:[3]
    • MLL2
    • MEF2B
    • EZH2
    • CREBBP
    • EP300
    • MLL2

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

  1. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A; et al. (2011). "Analysis of the coding genome of diffuse large B-cell lymphoma". Nat Genet. 43 (9): 830–7. doi:10.1038/ng.892. PMC 3297422. PMID 21804550.
  2. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C; et al. (2012). "Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing". Proc Natl Acad Sci U S A. 109 (10): 3879–84. doi:10.1073/pnas.1121343109. PMC 3309757. PMID 22343534.
  3. Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL; et al. (2013). "Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma". Blood. 121 (9): 1604–11. doi:10.1182/blood-2012-09-457283. PMC 3587323. PMID 23297126.


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