Broadly, disorders of white cells are proliferative or cause deficiency of leukocytes (leukopenia). Proliferative disorders can be further classified as reactive—such as in the setting of inflammation—or neoplasitc. The latter, while uncommon, are of greater clinical significance.
Leukopenias are most often caused by reductions in the number of neutrophils i.e. neutropenia also called granulocytopenia. As a corollary, lymphopenais are less common and are often seen in congenital immunodeficiency or in advanced HIV infections; glycocorticoid or cytotoxic drug therapy; autoimmune disorders; malnutrition; or acute viral infections. While the latter most etiology might seem paradoxical, acute infection tiggers secretion of type I interferons, which then stimulate T cell migration (and sequestration) to lymph nodes and adherence to endothelial cells.
Agranulocytosis is termed for clinically significant neutropenia, leading to dangerous susceptibility to bacterial and fungal infections.
As with other hematologic deficiencies, neutropenia can be caused by ineffective granulopoiesis as well as increased destruction or sequestration of neutrophils in the periphery.
Disorders of granulopoiesis.
Disorders of disruction or sequestration.
Neoplasms are classified in to the following broad categories:
While neoplastic disorders of white cells are highly varied in their etiology and presentation, there are several thematic etiologies
There are several specific translocations and chromosomal aberrations that can cause white cell neoplasms.
Inherited disorders that confer genetic instability: Bloom syndrome, Fanconi anemia, and ataxia telangiectasia are associated with acute leukemia. Trisomy 21 and type 1 nerofibromatosis are associated with childhood leukemia.
3 viruses are named for their causative roll in development of white cell neoplastic disorders: human T-cell leukemia virus-1 (HTLV-1), Epstein-Barr virus (EBV), and Karposi sarcoma/human herpesvirus-8 (HHV-8).
Traditionally leukemia and lymphoma refer to white cell neoplasms involving the bone marrow and discrete tissue masses, respectively. However, as the etiology of white cells neoplastic disorders is becoming better defined, the terms merely reflect the involved tissue at presentation as leukemias can evolve into lymphomas or have nontraditional tissue involvement. The distinctive pathological findings some lymphomas such as: Hodgkin lymphoma and plasma cell neoplasms—have earned them their own classifications. The clinical presentations of most non-Hodgkin lymphomas and essentially all Hodgkin lymphomas included enlarged, non-tender, fixed lymph nodes; others involved extranodal sites (skin, stomach, or brain). The most common plasma cell neoplasm, multipule myeloma, causes bony lesions and pathologic fractures. Currently the WHO suggests a classification scheme that uses morphologic, immunophenotype, genotype, and clinical features to develop 5 classifications: the 4 permutations of peripheral/precursor and B-cell/T-cell (NK-cell) as well as Hodgkin lymphoma. Identification of each class neoplasm can be guided by the following principles:
Acute lymphoblastic leukemias/lymphomas are neoplastic disorders of immature B and T cells. Hence, their named lymphoblasts. Most ALLs are disorders of B cells, which tend to affect children as leukemias and uncommonly present as masses in the skin and bone. In contrast, disorders T cells tend to present in adolescents as thymic lymphomas. The can be significant overlap, however, as T cell thymomas can evolve in presentation to one typical of leukemias. B-ALL is most common at age 3 when the pre-B cells is highest in early life and T-ALL is most common in adolescence when thymus is largest. All forms of ALL are more common in hispanics followed by whites then blacks.
Pathogeneis. There are number of characteristic oncogenic mutations that give rise to ALL, all of which promote maturation arrest and increase stem-cell phenotype. 90% of ALLs have numerical or structural chromosomal changes; the most common of which is hyperploidy. Some changes are important for diagnosis and prognosis. As examples hyperdiploidy and hypodiploidy are seen only in B-ALLs. Moreover, mutually exclusive sets of translocations are associated with B- and T-ALL. This suggests distinct etiologies.
T-ALL: 70% of T-ALLs have a gain-of-function in NOTCH1, a gene essential T cell maturation
While pathogenic variants that are associated with ALL typically are of transcription factors, t(9;22) creates the constitutively active tyrosine kinase BCR-ABL protein. It differs in the t(9;22) chromosomal abnormality pathognomic for CML as it is 190kDa rather than 210kDa. As with most cancers one would not expect a single mutation to cause pathology but would expect mutations in the tyrosine kinase RAS signaling pathway as well.
Immunophenotype. 95% of all ALLs are terminal deoxynucleotidyl transferase postitive (TdT+). B-ALL can be distinguished by:
While T-ALL can be distinguished by:
Clinical Features. The clinical presentation of ALL and AML are very similar and hence a diagnosis cannot be made without immnohistochemistry and cytogenetic studies. Symptom and signs often have “stormy onset” and include:
Prognosis. Most pediatric cases of ALL will go in to remission or be cured while most cases of adult ALL are not. Indicators of a worse prognosis are:
Favorable markers of prognosis include:
Aside from the obvious differences implied by their names, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) differ only in the degree of peripheral blood lymphocytosis; a diagnostic criteria for CLL: absolute lymphocyte count > 5000 cells/mm3. CLL is the most common leukemia of adults. The median age of diagnosis is 60 and occurs about twice as often in men. SLL only accounts for 4% of NHLs.
Pathogenesis. The most common genetic aberrations that are associate with CLL/SLL are:
The originating neoplastic cell may be post germinal center memory B cell or a naive B cell as sequencing of Ig genes of neoplastic cells in CLL/SLL has found some to have undergone somatic hypermutation. NOTCH1 pathogenic variants are expected to in occur in 10-18% of cases of CLL/SLL. Growth of neoplastic cells takes place in proliferative centers, which is pathognomonic. Experimental evidence suggests that tumor cells rely on B cell receptor signaling pathways that include burton tyrosine kinase (BTK)—the protein that is defective in congenital X-linked agammaglobulinemia—making it a target for development of new treatments.
Immunophenotype. CLL/SLL tumor cells are CD19+ and CD20+; a subset of tumor cells are CD23+ and CD5+. Surface Ig (typically IgM or both IgM and IgD) usually have suppressed expression.
Clincial features. Most cases of CLL/SLL are found incidentally as individuals are often asymptomatic. When symptomatic, individuals are present with nonspecific signs of cancer. A majority of patients will have generalized lymphadenopathy and hepatosplenomegaly. Leukopenia can be seen in individuals with SLL and bone marrow involvement. Hypogammaglobinemia is common due to uncertain mechanisms and—as expected—have increased susceptibility to bacterial (and other) infections. Hemolytic anemia or thrombocytopenia is seen in 10-15% of individuals due to autoantibodies made by non-neoplastic B cells.
Treatment for CLL/SLL is only indicated with patients are symptomatic and is never aggressive as it does not enter remission or is ever cured. Non-aggressive chemotherapy is used as well as monoclonal antibodies directed at CD20.
Prognosis. Median survival time ranges from 4 to 6 years; 10 years is common to individuals with minimal tumor burden. Genetic traits that are associated with worse prognosis are:
5-10% of individuals will develop diffuse large B-cell lymphoma, called Richter syndrome. Survival is less than 1 year.
Follicular is the most common indolent NHL typically presents in middle age and affects men and women at the same rate.
Pathogenesis. The disorder arises for the germinal centers and is strongly associated with BCL2, an antagonist to apoptosis. MLL2—a gene of unknown significance—is also present in as many as 90% of cases. Its most characteristic maker is t(14;18), which juxtaposes IGH from chromosome 14 and BCL2 from 18.
Immunophenotype. Neoplastic cells are CD10+, CD19+, CD20+, and CD5-. Surface Ig is expressed along with BCL6. Expression of BCL2 is distinctive as normal follicular B cells are BCL6-.
Clinical features. Presentation typically includes painless, generalized lymphadenopathy. Extranodal sites include gastrointestinal tract, CNS, or testis is relatively uncommon.
Treatment is palliative low-dose chemotherapy or immunotherapy (anti-CD20) if individuals are symptomatic.
Rarely follicular lymphoma can transform into diffuse large B-cell lymphoma or Burkitt lymphoma, the latter is less common and typically involves translocation of MYC.
Diffuse large B-cell lymphoma (DLBCL) is the most common NHL. Males are slightly more likely to develop the disorder around the age of 60 though it occurs in young adults and children.
Pathogenesis. The most frequent etiological event is dysregulation of BCL6, and transcription factor required for formation of germinal centers (repression of factors that promote: B-cell differentiation, growth arrest, and apoptosis). Various translocation have a common breakpoint in BCL6 at 3q37. Acquired pathogenic variations in the promoter region of BCL6 that abrogate negative-autoregulation are common. It is hypothesized that the major driving factor is “mistargeted” somatic hypermutation as pathogenic variants of MYC and other onogenes are typically found DLBCL making it sometimes challenging to differentiate from Burkitt lymphoma. t(14;18) affecting BCL2 (see follicular lymphoma) is seen in 10-20% of cases of DLBCL. Tumors with pathogenic variants of BCL2 often lack those of BCL6. Variants in p300 and CREBP are also seen.
Immunophenotype. Expression of CD19 and CD20 with variable expression of germinal center markers: CD10 and BCL6.
Special subtypes.
Clinical freatures. Patients with DLBCL present with a rapidly enlarging mass(es) nodal or extranodal (GI, CNS, skin, bones, and others) anywhere in the body. Involvement of the oropharyngeal lymph tissue (tonsils, adenoids), termed Waldeyer ring, is common. Masses are often destructive.
With aggressive combination chemotherapy, adjuvant therapy of anti-CD20 antibody, 60-80% of individuals achieve remission and 40-50% are cured.
There are 3 types of Burkitt lymphoma are histologically identical but differ in clinical presentation, cytogenetic traits, and virologic traits.
Pathogenesis. All forms are highly associated with gain-of-function translocations of MYC on choromosome 8. MYC is the supreme transcriptional regulator of aerobic glycolysis leading to diversion of metabolism to pathways that favor catabolism of nucleotides, lipids, proteins, etc. that are needed for cell division. As a result Burkitt lymphomas tumors are thought to be the fastest growing human tumors.
Translocation of MYC usually in the IgH locus: t(8;14)—but are also found in the Igκ or Igλ loci: t(2;8) and t(8;22), respectively. Breakpoints in the IgH locus are usually found in the class switch region in the soproatic type while breakpoints in the 5′ V(D)J sequences are more common in the endemic type. The basis for the translocations is not known but can be introduced by AID (see Overview of white cell neoplasia etiology).
Essentially all endemic types are latently infected with EBV while infection is associated with 25% and 15-20% of HIV-types and sporadic types, respectively.
Immunophenotype. As a tumor of mature B cells, they express CD19, CD20, CD10, and BCL6. Unlike other germinal center tumors, however, they almost always do not express BCL2.
Clinical features. Endemic and sporadic types are found most often in children and young adults. Endemic type typically presents with tumors of the mandible or abdomenal visera (typically kidneys, ovaries, or adrenal glands). Sporadic type often presents with tumors in the ileocecum or preitoneum.
While aggressive the it is often cured with intensive chemotherapy in children but less so for adults.
Multiple myeloma
Multiple myeloma is a neoplastic disorder of plasma cells that is associated with boney lytic lesions, renal failure, and acquired immune disorders. It is more common among black men with peak incidence where age ∈ [65,70].
Pathogensis. It is frequently associated with translocation of the Ig heavy chain gene on 14q32 with:
Additional aberrations include:
Proliferation and survival of neoplastic plasma cells depends on IL-6 as it is an important growthfactor for all plasma cells. Elevated IL-6 is hence a indicator or poor prognosis as it indicates highly active neoplasia. Neoplastic cells secrete a number of other factors that pathogenic bone reabsorption namely: RANKL (activating osteoclasts) and modulators of the Wnt pathway ultimately inhibiting osteoblast function. The end result is bony lesions and hypercalcemia.
A common finding supportive of diagnosis is presence of M-proteins (monoclonal Ig): most often IgG followed my IgA, which can cause hyperviscosity (see lympochytic lymphoma for explanation). 1% of cases are do not have M-proteins.
Immunophenotype. Plasma cells are CD138+ (syndecan-1) and often expression of CD56.
Clinical features. Signs and symptoms are ultimately due to: plasma cell neoplasia in tissues, excessive abnormal antibody production, suppression of humoral immunity. Classical presentation includes:
Diagnosis relies on radiographic and laboratory findings. Marrow involvement typically produces nomocytic normochromic anemia with moderate leukopenia and thrombocytopenia.
Median survival is 4-7 years. Individuals with multiple untreated bony lesions typically die with a year. Favorable prognosis is associated with translocations involving Cyclin D1. Poor prognosis and aggressive treatment is indicated with presence of del(13q), del(17p), and t(4;14).
Monoclonal gammopathy of uncertain significance
By definition MGUS is an asymptomatic plasma cell dyscrasia. It occurs commonly in individuals where age > 50years. M protein levels are < 3gm/dL. ~1% of individuals with MGUS will develop sympotmatic plasma cell neoplasia, usually multiple myeloma. Hence, periodic assessment of serum M-protein and light chain proteinuria is indicated.
Lymphocytic lymphoma
It is a B cell neoplasm that typically presents in the 6th or 7th decade of life. While it resembles CLL/SLL, it differs insofar as most tumor cells undergo terminal differentiation to plasma cells. Unlike other neoplastic disorders of plasma cells, individuals do not usually present with renal failure and amyloidosis; bone destruction is never present. IgM M-protein is typically present.
Pathogenesis. Lymphocytic lymphoma is associated with pathogenic variants in MYD88 which encodes protein involved in the NF-κB pathway and augments downstream signals of the B cell receptor complex.
Immunophenotype. Neoplastic lymphoid cells express B cell makers (e.g. CD20) and the same surface Ig that is secreted by neoplastic plasma cells—usually IgM.
Clincal features. Nonspecific signs of cancer along with lymphadenopathy and hepatosplenomegaly. 10% of individuals will have autoimmune hemolysis cause by cold agglutinis. High amounts of IgM M-protein can causee hyperviscosity syndrome characterized by:
It is not curable and hence treatment is palliative: low-dose chemotherapy and anti-CD20 antibodies. Median survival is 4 years.
It is a relatively uncommon NHL in the United States but more common in Europe. As its name suggests neoplastic cells resemble mantle zone B cells.
Pathogenesis. Nearly all mantle cell lymphomas have t(11;14) involving the IgH locus on chromosome 14 and cyclin D1 locus on chromosome 11. The translocation results in overexpression of cyclin D1 promoting transition from G1 to S phase. Many can be detected through karyotyping and the rest with FISH.
Immunophenotype. As a disorder of B cells CD19 and CD20 are expressed. Neoplastic cells are typically CD5+ and CD23-; helping to differentiate from CLL/SLL. Moderate-high levels of IgM and IgD with κ or λ light chain are typically expressed. IgH genes typically lack somatic hypermutation suggesting naive B cell tumor origin.
Clincal features. Painless lyphadenopathy, spleen involvement (~50%), as well as gut. All prognoses are poor—median survival is 3-4 years—the is no curative standard of care. Death usually results of organ failure caused by tumor infiltrates.
This large category encompasses many kinds of B cell neoplasms that arise from lymph nodes, spleen, or extranodal sites. If the latter most has its own name if it involved the mucosa: mucosa-associated lymphoid tumors or MALTomas. Those that show evidence of somatic hypermutation are considered to be of memory B-cell origin. The are some unique characteristics of those that involve extranodal sites:
An implication of the first item of the above is that extranodal marginal zone lymphomas are on a continuum between [reactive lymphoid hyperplasia] and lymphoma as it begins with a polyclonal immune reaction mediated by CD4+ T cells. With time B cells are more like to acquire growthfactor and survival-antigen independence e.g t(11;18), t(14;18), or t(1;14). These relatively specific translocation upregulate BCL10 and MALT1. With further evolution polyclonal marginal zone lymphomas can develop into monoclonal DLBCL
A rare but distinctive neoplastic disorder of B cells that typically affects middle-aged white males.
Pathogenesis. 90% of cases are associated with point mutations in BRAF, which codes for a serine/theonine kinase. The same mutation is also found in many melanomas and langerhan cell histiocytosis.
Immunophenotype. Hairy cell leukemias express pan-B-cell markers (CD19 and CD20), surface IgG (or others), and destictive markers: CD11c, CD25, CD103, and annexin A1.
Clinical features. Unlike other leukemias/lymphomas lymphadenopathy is rare. Splenomegaly (hepatomegaly less so) and pancytopenia are due to bone marrow, liver, and spleen infiltration. Unexplained monoctyopenia can cause atypical bacterial infections.
Hairy cell leukemia is indolent with excellent prognosis. Remission of 5 years are common with non-aggressive chemotherapy and recurrent tumors respond well to the same chemotherapeutic agents. BRAF inhibitor are very useful.
Mature T and NK cell neoplasms are relatively rare but more common in the very eastern East Hemisphere.
These refer to a “catch-all” classification of rare poorly studied T cell lymphomas. As a result there are no morphologic not pathognomonic features albeit some are characteristic. Tumors generally destroy lymph node architecture. Nodes become filled with pleomorphic malignant T cell with high variance in size. Neoangiogenesis along with reactive inflammatory infiltrates (eosinophils, macrophages, etc.) are of note.
Immunophenotype. T cell lymphomas are defined to originate from mature T cells. Hence they usually express CD2, CD3, CD5, and either αβ or γδ receptors. Tumors can also originate from CD3+ or CD4+ T cells. Many tumors bare no resemblance to a T cell at any stage of differentiation. In such cases diagnosis relies on DNA analysis for presence of clonal T cell receptor rearrangements.
Clinical feature. Patients typically present with nonspecific signs and symptoms of lymphoma. More notably eosinophilia, pruritus, and fever may be present. In contrast to analogous disorders of B cells (e.g. [DLBCL]), prognoses unspecified peripheral T cell lymphomas are much worse.