Hodgkin's lymphoma pathophysiology
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Hodgkin lymphoma (HL) is a neoplasm characterized by involving lymph nodes and the lymphatic system, and is classified according to WHO classification into two major subgroups: nodular lymphocyte predominant and classic Hodgkin's lymphoma. Classic Hodgkin's lymphoma is further divided into four subtypes: nodular sclerosis , mixed cellularity , lymphocyte rich, and lymphocyte . Hodgkin lymphoma is characterized by the presence of multinucleated giant cells Reed-Sternberg cells, derived from germinal center or postgerminal center B cells. In all four subtypes of classic Hodgkin lymphoma the Reed-Sternberg cells have a similar immunophenotype. Whereas in the NLPHL the Reed-Sternberg cells have a distinctive B-cell immunophenotype. On gross pathology, white-grey, uniform, and enlarged lymph nodes are characteristic findings of Hodgkin's lymphoma. On microscopic histopathological analysis, Reed-Sternberg cells, reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin's lymphoma.
Hodgkin's lymphoma is a potentially curable cancer, in which malignancy originates from lymphocytes. Hodgkin lymphoma is characterized by the presence of multinucleated giant cells Reed-Sternberg cells, derived from germinal center or postgerminal center B cells. In all four subtypes of classic Hodgkin lymphoma the Reed-Sternberg cells have a similar immunophenotype. Whereas in the NLPHL the Reed-Sternberg cells have a distinctive B-cell immunophenotype.
- Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers. Molecular analysis of single isolated Reed-Sternberg cells and variants has been determined the origin of the neoplastic Reed-Sternberg cells.
- Despite having the genetic signature of a B cell, the Reed-Sternberg cells of classical HL fail to express most B-cell–specific genes, including the Ig genes and no longer able to produce antibodies. The Ig genes of Reed-Sternberg cells have undergone both V(D)J rearrangements and somatic hypermutation.
- Growth and survival of classic RS cells are dependent to the activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. This activation can occur by several mechanisms:
- NF-κB may be activated either by EBV infection or by some other mechanism and turns on genes that promote lymphocyte survival and proliferation. The constitutive nuclear activity of NF-kB can both prevent apoptosis and promote cell proliferation.
- EBV+ tumor cells express viral latent membrane protein-1 (LMP-1), a protein encoded by the EBV genome that transmits signals leads to NF-kB activation.
- NF-kB is degraded normally by the "I kappa B (IkB)" family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation.
- In Hodgkin's lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A.
- Unstopped activation of (NF-kB):
- Active (NF-kB) will lead to constituent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells.
- Activation of (NF-kB) occurs due to the following causes:
- Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB
- Alteration in the NF-kB itself protecting it from inhibition by IkB
- Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB
- NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:
- Besides NF-kB signaling pathway, Hodgkin's lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.
Reports from countries like Honduras, China, Mexico, Peru, and Malaysia suggest an association between EBV infection and Hodgkin's lymphoma, an association that is more evident in the pediatric population and in the subtype of mixed cellularity.
On gross pathology, affected lymph nodes (most often, latero cervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform. In some histological subtypes (e.g. nodular sclerosis), the cut surface may have a nodular aspect.
Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed-Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45-, CD30+, and CD15+/- immuno phenotype. In approximately 50% of cases, the Reed-Sternberg cells are infected by the Epstein-Barr virus.
|Type of cell||Characteristics|
|Reed-Sternberg cells (RSC)||Include large size (20–50 micro metres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed close to the nuclear membrane).|
|Hodgkin cells (Atypical mononuclear Reed-Sternberg cell)||Have the same characteristics as Reed-Sternberg cells (RSC), but is mono nucleated.|
|Lacunar Reed-Sternberg cells||Have a single hyper lobulated nucleus, multiple, small nucleoli and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space ("lacunae").|
|Pleomorphic Reed-Sternberg cells||Have multiple irregular nuclei.|
|"Popcorn" Reed-Sternberg cells (Lympho-histiocytic variant)||Have a very lobulated nucleus and small nucleoli.|
|"Mummy" Reed-Sternberg cells||Have a compact nucleus with no nucleolus and basophilic cytoplasm.|
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