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1698 Part XI: Malignant Lymphoid Diseases Chapter 104: Mature T-Cell and Natural Killer Cell Lymphomas 1699

waxing and waning of symptoms over several years before a diagnosis ALK-positive ALCL accounts for 16 percent, 6 percent, and 3 percent
is made. Patients with AITL can develop diffuse large B-cell lymphoma, of PTCL in North America, Europe, and Asia, respectively. The median
3
which evolves from EBV-positive B cells, which usually are present in age of ALK-positive ALCL is 30 to 40 years old. Ninety percent of chil-
the lymphoid infiltrate. Emergence of diffuse large B-cell lymphoma dren with ALCL are ALK-positive. 83,87 In the United States and Asia,
can occur concomitantly with AITL at the time of diagnosis or may be the ALK-positive phenotype is more common (ratio being 2:1 and 3:2,
the primary histology at relapse; therefore, repeat biopsies are strongly respectively), whereas in Europe the ALK-negative phenotype is more
3
encouraged whenever relapse is suspected in order to guide therapy. 69,70 common (3:2). Both diseases exhibit a slight male predominance.
ALK-negative ALCL accounts for 8 percent, 9 percent, and 3 percent of
3
LABORATORY FINDINGS PTCL in North America, Europe, and Asia, respectively. The median
3,14,67
age of presentation is 55 to 60 for ALK-negative ALCL.
Histopathology
AITL is characterized histologically by effacement of the normal lym- CLINICAL FEATURES
phoid architecture with a pleomorphic cellular infiltrate and prolifera-
tion of small arborizing blood vessels. Small lymphocytes, plasma cells, ALCL has an aggressive clinical course, frequently presenting with
immunoblasts, histiocytes, and eosinophils infiltrate involved lymph systemic symptoms, advanced disease, and extranodal localization.
nodes. As a result, the normal lymphoid architecture may be obliterated, Patients with ALK-positive ALCL tend to be younger and have better
with loss of germinal centers and extensive intranodal neovasculariza- performance statuses and lower serum LDH levels. Approximately
tion and expansion of the follicular dendritic cell meshwork (CD21). 8 to 12 percent of patients with ALK-positive ALCL have morphologic
2–4
Scattered EBV+ B cells are almost always present and reflect the accom- evidence of marrow involvement. The rate of detection of marrow
panying immunodeficient state. The malignant cells are CD4+ αβ T cells involvement doubles when immunohistochemical staining techniques
with TCR-β and -γ rearrangements 70–72 and express CD10, a marker typ- with anti-CD30 and anti-ALK antibodies are used. 88
ical for AITL, approximately 90 percent of the time. Abnormal karyo- Patients with ALK-negative ALCL tend to be older, with higher
73
types involving the X chromosome and chromosomes 1, 3, and 5 are LDH values, and worse performance status than ALK-positive cases.
frequently found in AITL. A complex karyotype is a negative prognostic Extranodal presentations are more common in the ALK-negative pop-
14
factor for AITL. The normal counterpart of AITL is suspected to be the ulation, and include sites such as the marrow, liver, lung, and skin, but
77
follicular T-helper cell based on genomic profiling, which reveals over- rarely the central nervous system. Marrow involvement occurs in 12 to
expression of specific markers, including CXCL13 and PD1. 74,75 A subset 22 percent of cases of ALK-negative ALCL. 2–4
of PTCL-NOS exhibits a similar gene-expression profile, suggesting it A new clinical variant of ALK-negative ALCL associated with tex-
may behave similarly. 76 tured saline and silicone breast implants has been reported. Although
the natural history and treatment course of this variant needs further
TREATMENT AND PROGNOSIS elucidation, the clinical course seems to be less aggressive and patients
with localized disease may be adequately treated merely by surgical
Most patients with AITL are treated with CHOP-based regimens as dis- removal of the implant and capsule. 85,89–91 In the largest series to date
cussed in the section Approach to Initial Therapy. The CR rate is similar (60 patients), most presented with disease limited to the breast (83 per-
to the rate observed with PTCL-NOS (approximately 50 to 60 percent). cent), whereas 10 percent and 7 percent, respectively, presented with
Nonrandomized data support upfront ASCT in patients who achieve a stage II and stage IV disease. Patients most commonly presented with an
22
CR to first-line therapy. Rare patients may be managed with glucocor- effusion within the breast and less frequently with a distinct breast mass. 85
ticoid monotherapy, which can induce remissions, although responses
are rarely sustained. Responses to low-dose methotrexate and cyclo- LABORATORY FEATURES
78
sporine have also been reported. 79–81 Finally, response rates as high as
50 percent have been reported in CD30-positive relapsed/refractory ALCL cells tend to grow cohesively and are found preferentially invad-
92
AITL treated with brentuximab vedotin. 32 ing lymph node sinuses. There are three morphologic variants based
93
Both the IPI and the PIT have been used to risk stratify patients but on the size of the neoplastic and admixed reactive cells : the “common
have not been used to direct therapy (see Table 104–3). 13,12,82 One group type,” representing most cases, is characterized by large pleomorphic
has reported that immunoglobulin A levels, age older than 60 years, tumor cells; the “small cell variant,” representing 5 to 10 percent of
more than one extranodal site of involvement, anemia, and thrombocy- cases, has a dominant population of small- to medium-size tumor cells
topenia may also be of prognostic value in this disease. 82 mixed with large anaplastic cells that stain for CD30 and ALK; and the
“lymphohistiocytic variant,” representing 5 to 10 percent of cases, that
is closely related to the small cell variant and contains small neoplastic
ANAPLASTIC LARGE CELL LYMPHOMA cells mixed with large anaplastic cells and a large number of histiocytes
(Chap. 96). 94
DEFINITION ALK-positive ALCL is characterized by a nonrandom t(2;5)
95
ALCL is defined as a CD30+ peripheral T-cell neoplasm. The disease (p23;q35) translocation resulting in fusion of the NPM and ALK genes.
has been provisionally subdivided into those that are ALK-positive The resultant NPM-ALK fusion gene encodes an 80-kDa chimeric pro-
(60 to 70 percent) or negative (30 to 40 percent). 1,83,84 In addition to the tein NPM-ALK (p80) that functions as an oncogene in ALK-positive
systemic form, there are primary cutaneous forms (Chap. 103), which ALCL. Of note, other translocations resulting in ALK expression in
generally behave in an indolent fashion, as well as a recently identified ALK-positive ALCL have also been identified but are rarer. 50,96–102 Thus,
entity called breast implant–associated ALCL. 85,86 ALK immunoreactivity is a highly specific marker for this disease. 83,84,96
Either T or null immunophenotypes may be observed in ALCL. The
T-cell variant expresses pan-T antigens CD2, CD2, CD4, CD5, and
EPIDEMIOLOGY CD7, whereas the null variant lacks both T-cell and B-cell antigens, but
2–4
ALCL accounts for 6 to 24 percent of all T-cell lymphomas. However, usually expresses cytotoxic molecules such as granzyme B and perforin,
the prevalence of ALCL varies by geographic region (see Table 104–2). and has rearranged TCR genes, suggesting a T-cell origin. 102,103

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