Page 1534 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 85 T-Cell Lymphomas 1361

the CTCLs and an annual incidence of approximately four cases per Nonrandom deletions of chromosomes 1p, 6, 8, 9p10q, and 17p have
million people. MF and SS are the most common primary lympho- been reported, with gains in chromosome 17q and 4p occurring in
mas involving the skin. Data collected from the SEER program more than 25% of cases. Regions of the genome that include genes
showed a rapidly increasing incidence from 0.2 cases per 100,000 encoding the TCR do not appear to be involved, suggesting that the
people in 1973 to 0.4 cases per 100,000 people in 1984. This increas- genetic basis for malignant transformation in MF/SS appears to be
ing trend has stabilized in the last decade, with an incidence of 10.2 different from that involved in other T-cell malignant disorders.
new annual cases per million during the period 2005–2009 (PMID: Modest data exist on the aberrant expression of oncogenes and
24005876). suppressor genes in MF/SS. Loss of heterozygosity is identified in
Whether this represented a true increase in incidence or was 30%–60% of patients, commonly at 9p, 10q, 1p, and 17p. Loss of
attributable to a better awareness and therefore more frequent recog- heterozygosity in early stages of disease is associated with a threefold
nition of this disease has not been resolved. Since that time the increase in mortality. Various mutations involving the Fas pathway
incidence rate of CTCL has stabilized at 0.36 cases per 100,000 are commonly seen from the early stages of lymphomagenesis, reflect-
persons, and the mortality rate has declined. The incidence of MF/ ing an initial accumulation of abnormal lymphocytes secondary to
SS increases with advancing age, as does the incidence of NHLs in abnormal proapoptotic pathways. Mutant forms of the p53 tumor
general. The average age at presentation is approximately 50 years. suppressor gene are rarely observed, usually in tumor stage and large-
Although cases in very young patients have been reported, most cell transformation of MF. LYT-10, a member of the NFκB family
patients are at least 30 years of age. MF/SS is seen in all racial groups. of transcription factors associated with translocations in lymphoid
There is a 1.6 : 1 ratio of African-Americans to whites and a 2.2 : 1 malignancies, is rearranged in a small proportion of cases. However,
ratio of men to women with this disorder. MF is less common in the BCL2, a gene whose rearrangement is characteristic of follicular B-cell
Asian population. Identification of clusters of CTCL in certain lymphomas and which slows programmed cell death, is overexpressed
geographic regions has been reported using two distinct cancer reg- in MF. Constitutive phosphorylation of STAT3 (a member of the
istries (PMID: 25728286; PMID: 25046454). transcription factor family that contributes to the diversity of cytokine
Clusters of cases of MF/SS within families have been reported. responses) has been reported and suggests that these malignant T cells
An association with histocompatibility antigens AW31, AW32, B8, are activated. Altered expression or release of select cytokines or their
BW35, and DR5 has been described. However, a solid genetic pre- receptors, including IL-1, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12,
disposition or inherited genetic defect has not been demonstrated. and TGF-β receptor II, has been noted. IL-7 and IL-15 have been
identified as growth factors for MF/SS and shown to regulate expres-
sion of the BCL2 and MYB oncogenes and stimulate DNA binding
Pathobiology of STAT proteins. NFκB has also been demonstrated to be constitu-
tively activated in CTCL and leads to transcription of antiapoptotic
The T lymphocyte is central to the body’s ability to mount an genes (e.g., Bcl-2, cIAP1, and cIAP2), proinflammatory genes, and
immune response and is the precursor of neoplastic cells in MF/SS. antiinflammatory genes, resulting in increased survival and the
Sézary cells respond to phytohemagglutinin and perform T-cell immunosuppressive nature of CTCLs. Constitutive activation of
immunoregulatory functions similar to normal lymphocytes. The c-Jun N-terminal kinases (JNKs) and JAK may lead to elevated levels
clonal nature of CTCL has been demonstrated by Southern blotting of VEGF, resulting in increased angiogenesis. Massive parallel targeted
or polymerase chain reaction methods for analysis of the TCR. sequencing of a set of 524 genes from CTCL samples revealed fre-
The development of monoclonal antibodies directed against dif- quent mutations of the NFκB, JAK/STAT, and PLC pathways. Three
ferent T-cell antigens has allowed for more precise identification of samples harbored mutations of PLCG1, the gene that encodes for
surface markers on the malignant T cells. Most cases of MF and SS phospholipase C, gamma 1. Further analysis of another cohort of
are comprised of the helper memory or effector T cells with a samples from 42 CTCL patients revealed the presence of PLCG1
+
+
CD4 CD45RO phenotype. In most instances, the cells express the S345F mutation in 19% of the cases and was associated with increased
pan–T-cell antigens CD2 (the sheep erythrocyte receptor), CD3, and signaling of calcineurin/nuclear factor of activated T cells (NFAT).
CD5. CD7 is a T-cell marker expressed in early differentiation, but In vitro inhibition of PLC and calcineurin led to decreased cell
usually absent in T-cell homing to the skin. Although benign condi- proliferation and increased apoptosis in mutant cells. There is also
tions may show some downregulation of CD7, marked deletion of evidence of the role of the mTOR-containing complex 1 (mTORC1)
CD7 is commonly used by the pathologist as an ancillary confirma- pathway in CTCL pathogenesis, along with evidence to support the
tory test for CTCL. Flow cytometry provides a sensitive method for beneficial role of its inhibition simultaneously with inhibition of
detecting early peripheral blood involvement in patients by detection MNK kinase. Various cancer-testis antigens, normally observed only
+
−
of CD4 CD26 T-cell populations. A small subset of MF is character- in testicular germ cells, appear to be ectopically expressed in CTCL,
ized by the expression of CD8, a marker that is essentially never as does B-lymphoid tyrosine kinase (Blk), a member of the Src kinase
expressed in SS. Low expression of the α-chain component of the family, which is normally only expressed in B cells and thymocytes.
IL-2 receptor (CD25) is detected with heterogeneous expression by Supporting the tumorigenic role of Blk, there was antitumor activity
+
the malignant cells in less than half of the patients. The implication of dasatinib, a Src kinase inhibitor, within a Blk CTCL cell line and
of this finding is of uncertain significance, because both activated T a xenograft mouse model. There is recent evidence suggesting that SS
cells and immunoregulatory T cells can express CD25. Key signaling and MF may follow different molecular pathways with dysregulation
pathway alterations that affect MF and SS include Notch overexpres- of genes encoding c-Myc and c-Myc regulatory proteins commonly
sion, Fas underexpression, and the association of PKC inhibition with associated with SS but not with MF.
apoptosis. Also of particular relevance is the observation of increased The cause of MF/SS remains unknown. It is considered to be a
expression of programmed death-1 (PD-1) on SS cells, compared sporadic disease without compelling evidence of transmissibility.
+
with CD4 cells from healthy volunteers and from MF patients, likely Several viruses have been implicated in the pathogenesis of MF/SS,
contributing to the impaired immunity (antitumor and antiinfec- including HTLV-1 and HTLV-2, herpes simplex virus, human her-
tious) noted in SS patients. Overexpression of KIR3DL2 (CD158k) pesvirus 6, and EBV. However, a viral cause of MF/SS has not been
has also been observed in SS and advanced MF, and may assist in proven, and no epidemiologic evidence supports these hypotheses
distinguishing CTCL cells from normal ones, but more important, (PMID: 23806159).
it may have targeted therapeutic implications. Increased mRNA Investigators have suggested that prolonged antigenic stimulation
expression of PLS3, DNM3, and TWIST1 have also been reported via exposure to contact allergens or superantigen stimulation associ-
in most cases (PMID: 18033314). ated with infections may lead to enhanced immune responses, with
Cytogenetic analyses have demonstrated numeric and structural subsequent mutations in apoptotic pathway leading directly or
chromosomal abnormalities in MF/SS, although usually in advanced- indirectly to the development of MF/SS. Sézary cells respond in vitro
stage disease. Hyperdiploidy and complex karyotypes are common. to superantigenic exotoxins, and colonization by Staphylococcus aureus