Lymphoplasmacytic lymphoma
This is a tumor of mature B-cells, in which these tumor cells differentiate largely into immunoglobulin M producing plasma cells. It usually affects people between 60 & 70 years of age.
Histologically, these neoplastic plasma cells contain Russell bodies (Cytoplasmic Ig) & Dutcher bodies (nuclear Ig) on periodic acid-Schiff stain. The cause is deletion on chromosome 6q. Diagnostic markers include: surface IgM, CD20 on immunophenotyping.
Clinical manifestations: fatigue; weight loss; lymphadenopathy & hepatosplenomegaly (from infiltration); anemia (marrow infiltration); hemolytic anemia by cold agglutinins (IgM ppt. at body T-<37*C); hyperviscosity syndrome (Waldenstrom macroglobulinemia).
Hyperviscosity syndrome includes: visual impairment; confusion; headache; dizziness; deafness; bleeding; Raynaud phenomenon & cold urticaria due to cryoglobulinemia (IgM ppt. at cold temp.)
This tumor is incurable & has a poor prognosis with a life expectancy of 4 yrs. In addition to chemotherapy and immunotherapy, plasmapheresis can de done to alleviate symptoms.
Mantle cell lymphoma
This is a tumor of the mantle zone mature naive B-cell in the lymph node. Cytologically, they are small cells with irregular cleaved nuclear margin (centrocytes). It usually affects male than female between age 50 & 60.
The cause include: chromosomal translocation t(11q;14q) produces IgH/cyclin D. This causes cyclin D1 overexpression that promotes G1-S phase faster. Using immunotyping, diagnostic marker is cyclin D1 protein.
Clinical manifestations: generalized lymphadenopathy; metastasis to spleen; liver; bone marrow; G.I tract.
It is incurable with a poor prognosis. Life expectancy is about 4 years.
Marginal zone lymphoma
A tumor of mature B-cell, especially of memory B-cell origin that develops in marginal zones of lymph nodes & spleen. It also develops in extranodal sites during autoimmunity & infection.
These extranodal sites include: thyroid (Hashimoto thyroiditis), salivary gland (Sjogren syndrome), & stomach affected by autoimmunity & infection (H. pylori).
In these extranodal sites, hyperplastic reactive inflammation results in mucosa-associated lymphoid tumors (Maltomas). Overall, it has a good prognosis with removal of inciting agent.
Hairy cell leukemia
A tumor of mature B-cell, especially of post germinal center memory B-cell origin that develops in the bone marrow. Cytologically, they have round/reniform/oblong nuclei, moderate cytoplasm with threadlike extensions. It affects white male between 40 and 70 years.
Clinical manifestations: splenomegaly (very common); hepatomegaly; pancytopenia; infiltration of the bone marrow, liver, spleen. Overall, prognosis is excellent with chemotherapy. On immunophenotyping, diagnostic markers include: CD19; CD20; IgG.
Multiple myeloma
This is the neoplastic proliferation of plasma cells within bone marrow of the axial skeleton. They originate from post germinal center memory B-cells in lymph nodes that reside in the bone marrow. It affects people between 65 & 70 years.
The cause includes: chromosomal translocation t(4p;14q) which creates a fusion gene transcript IgH/FGFR3. This fusion transcript overexpresses tyrosine kinase rceptor that drives cell’s uncontrollable proliferation.
It usually affects vertebral column, ribs, skull & very occasionally other bones. Radiographically, bone lesions appear as punched-out lesions (1-4cm diameter). Morphologically, they are thick, soft tumor masses.
In the bone marrows these tumor cells develop ability to proliferate uncontrollably due to chromosomal abnormalities.
Clinical manifestations: inefficient antibody proteins; pathologic fractures and chronic pain; hypercalcemia; confusion; weakness; constipation; polyuria; bacterial infection; renal insufficiency.
The main cause of renal insufficiency is Bence jones proteinuria. Bence jones proteins are free light chains κ, λ proteins that damage the renal epithelial tubules.
To diagnose, blood serum test and urine electrophoresis are necessary. In multiple myeloma, >3gm/dl IgG, IgA (M proteins) in serum is abnormal, while >6gm Bence jones protein in urine is also abnormal. Prognosis is poor.
Peripheral T-cell lymphoma, Unspecified
This is a group of mature malignant T-cells with no distinct morphological feature, but are pleomorphic with irregular nuclear margins. They proliferate in lymph nodes extensively.
Clinical manifestation: generalized lymphadenopathy; eosinophilia; pruritus; fever; weight loss. On immunophenotyping markers include: CD2, CD3, αβ T-cell receptors. The prognosis is very poor.
Anaplastic large-cell lymphoma
This is a tumor of mature T-cell that is largely anaplastic with horseshoe-shaped nuclei and large cytoplasm. It affects children and young adults.
The cause includes: chromosomal translocation affecting ALK gene on chromosome 2p23. This results in overexpression of anaplastic lymphoma kinase (ALK) that drives uncontrolled proliferation and growth.
Clinical manifestation: They cause enlargement of lymph nodes, spleen and other soft tissues. On immunophenotyping, diagnostic marker is the ALK protein.
Prognosis is very good with chemotherapy.
Adult T-cell leukemia/lymphoma
This is a tumor of mature T-cells, especially CD4+ T-cells, after infection with human T-cell leukemia retrovirus-type 1 (HTLV-1). The cells present as multilobulated nuclei (“flower cells”). They are endemic in southern Japan, Caribbean basin, West Africa.
The cause include: HTLV-1 infection produces Tax protein that activates the transcription factor (NF-κB) that drives uncontrolled proliferation and survival.
Clinical manifestations: generalized lymphadenopathy; splenomegaly; skin lesions; lymphocytosis; hypercalcemia. Prognosis is very poor with life expectancy of a month to 1 yr.
Mycosis fungoides/Sezary syndrome
These are separate manifestations of the tumor of CD4+ helper T cells in the skin, affecting epidermis and upper dermis. Cytologically, CD4+ helper T-cells present as cells with folded (cerebriform) nuclei.
Mycosis fungoides presents as red, scaly, itchy rashes; scaly plaques; nodular skin lesions; lymph node & bone marrow metastasis.
Sezary syndrome presents as an exfoliative erythroderma, and blood infiltration of neoplastic CD4+T cells.
Adhesion molecules such as cutaneous-lymphocyte associated antigen (CLA) & β chemokine receptors CCR4, CCR10 are seen on immunophenotyping. These molecules attract the T-cell to the skin.
Prognosis is poor with life expectancy of about 9 yrs.
Large granular lymphocytic leukemia
These are lymphoproliferative tumor variants affecting T lymphocytes and NK cells in the bone marrow. Cytologically, they present as large granular lymphocytes with blue cytoplasm and sparsely few azurophilic granules. The T-cell variant is usually common.
Clinical manifestations: lymphocytosis; splenomegaly; neutropenia; anemia; liver and spleen metastasis; Felty syndrome (rheumatoid arthritis, splenomegaly, neutropenia).
On immunophenotyping, CD3 is indicative of T-cell variant, while CD56 is indicative of NK variant. NK variants are more aggressive than T-cell variants.
HODGKIN LYMPHOMA (HL)
This consists of a diverse group of neoplasms that are commonly localized in lymph nodes and spread to other tissues in an orderly pattern. It features the presence of neoplastic giant Reed-Sternberg cells surrounded by reactive T-cells, eosinophils, macrophages, & plasma cells within lymph nodes. These features together cause lymph node enlargement.
Diagnostic Reed-Stenberg cells are ≥45μm in diameter with multiple nuclei/multilobed nucleus each containing inclusion-like nucleolus. These neoplastic cells originate from germinal center or post germinal center B -cells.
The median age at diagnosis is 32 yrs., and usually affects adolescents and young adults. It commonly affects cervical, paraaortic, & mediastinal lymph nodes.
The classical types are: nodular sclerosis, mixed cellularity; lymphocyte rich; lymphocyte depletion. Non-classical type includes the lymphocyte predominance.
Nodular sclerosis Hodgkin lymphoma (HL)
This presents in about 7 in 10 cases of HLs. It presents as lacuna variant Reed-Sternberg cells with collagen deposition around distinct lymph nodes. It affects lower cervical, supraclavicular & mediastinal lymph nodes.
Lacuna variant Reed-Sternberg cells have folded or multilobed nuclei with a pale disrupted cytoplasm. Diagnostic markers are: Pax5 (B-cell transcription factor). This tumor has an excellent prognosis.
Mixed cellularity HL
It appears in about 3 in 10 cases of HLs. It presents as combination of plentiful diagnostic Reed-Sternberg cells and mononuclear variant Reed-Sternberg cells.
Mononuclear variant has a single nucleus with large inclusion-like nucleolus. This commonly affects males than any other forms within this group and presents usually with night sweats, weight loss, The prognosis is fairly good. Diagnostic marker is CD15.
Lymphocyte rich HL
This is uncommon and features a combination of diagnostic Reed-Sternberg cells and mononuclear variant Reed-Sternberg cells. Majority of the surrounding cells are reactive T-cells & plasma cells. 4 in 10 cases are in association with EBV infection of Reed-Sternberg cells. Prognosis is excellent. Diagnostic marker is CD30.
Lymphocyte depletion HL
This is also uncommon and features either of the variant forms of Reed-Sternberg cells with scarcity of surrounding T-cells & plasma cells. 9 in 10 cases are in association with EBV infection of Reed-Sternberg cells. Usually occurs in HIV+ persons, older people, and low-income countries. Diagnostic marker is CD15.
Lymphocyte predominant HL
This is uncommon and develops especially in the germinal center area of lymph nodes. It features the lymphohistocytic variant Reed-Stenberg cells, which have polypoid nuclei and a moderate cytoplasm. Surrounding them are reactive B-cells, follicular dendritic cells.
It affects mores males than females who are below 35 yrs, with presentation of cervical or axillary lymphadenopathy. Prognosis is excellent, despite possibility to recur. Diagnostic marker is BCL6 & CD20.
Cause of HL
The cause of HL may come in association with EBV infection of B-cells or other unknown mechanisms which produce molecules. These molecules may activate NF-κB which uncontrollably drives B-cell proliferation and survival.
Clinical manifestations of HL:
Painless lymphadenopathy; fever, night seats and weight loss. Metastasis is in an orderly pattern (lymph nodes-spleen-liver-bone marrow & then other tissues).
Patients with mixed cellularity and lymphocyte depletions HL. tend to have systemic symptoms than other 2 forms.
Acute myeloid leukemia
This is a tumor of myeloid origin, that comprises of immature myeloid blasts in bone marrow. It causes marrow failure with further complications. Incidence rises with increasing age, but peaks after 60 years of age.
Myeloblasts have large condensed nucleus with 2/3 nucleoli, with large cytoplasm. The cytoplasm contains specific threadlike azurophilic granules (Auer rod) that stains positive with peroxidase stain.
The most common cause is chromosomal translocation t (8q; 21q) & inv (16) (p: q) respectively. These abnormal rearrangements create abnormal fusion proteins which interrupt myeloid cell maturation.
Clinical manifestations: fever; fatigue; anemia; neutropenia; infection; thrombocytopenia; sudden mucocutaneous bleeding.
Diagnosis requires immunophenotyping which usually indicates markers CD33 & CD34.
Prognosis varies with some factors and in severe circumstances, bone marrow transplant is necessary.
Myelodysplastic syndromes
This is a neoplasm of common myeloid progenitors that retain the ability to differentiate, but do so ineffectively. This results in the replacement of bone marrow with inefficient and abnormal clonal progeny.
It may transform to AML when there is a blockage to further differentiate and mature.
This may affect any clonal progeny within the lineage of myeloid progenitors. E.g. Pseudo-Pelger Huet cells (neutrophils with just two nuclear lobes/or without nuclear segments instead of 3 to 4 lobes ).
Clinical manifestation: weakness; infection; pancytopenia. The causes may be unknown or may be due to radiotherapy or genotoxic drugs. It affects people who are 70 years and above. Overall, it has a poor prognosis.
Chronic myeloid leukemia
A tumor of maturing granulocytic precursors that causes release of mature and immature cells into the blood. There is an overwhelming infiltration of bone marrow with actively proliferating immature neutrophils, eosinophils, basophils. It affects adults between 50 and 60 yrs.
The cause mainly includes: chromosomal translocation t (9q:22q) which forms a fusion gene transcript, BCR; ABL on the Philadelphia chromosome. This abnormality creates BCR-ABL tyrosine kinase molecules that drives uncontrollable cell proliferation and survival.
Clinical manifestation: fatigue; anemia; weight loss; anorexia; splenomegaly; left upper quadrant pain (splenic pain); leukocytosis >100,000/μl.
To diagnose, doing karyotyping to identify the BCR-ABL fusion gene is necessary. Prognosis is poor.