Page 1107 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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patients with a broader morphological spectrum and better by GEP. Tumor necrosis factor receptor–associated factor 1
survival 24,25 as a consequence of decreased immune surveillance. expression and c-REL amplification also are seen in both types
These should be distinguished from EBV-associated atypical of neoplasms and could also be detected with appropriate
hyperplasia and lesions associated with iatrogenic or age-related immunohistochemical studies.
immunosuppression, as well as those typified by an isolated and Gray-zone lymphomas are more common in males than
circumscribed cutaneous or mucosal presentation, with an indolent females, present with bulky mediastinal masses, and appear to
behavior and a self-limiting clinical course as EBV-positive have a more aggressive clinical course compared with either
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mucocutaneous ulcer. Lymphomatoid granulomatosis is an EBV- PMBCL or CHL. Previously, methylation profiling showed a
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positive B-cell lymphoproliferative disorder (LPD) associated with signature distinct from both CHL and PMBCL. However, as
an inflammatory background rich in T cells. The lung is nearly shown by FISH studies, gray-zone lymphomas, PBMCL, and
always involved; additionally, skin, kidneys, the liver, and the brain CHL all share a number of common cytogenetic aberrations,
are frequently affected as well. DLBCL associated with chronic including gains at 2p16.1 (REL/BCL11A locus), 9p24.1 (JAK2/
inflammation are EBV-driven large B-cell proliferations encountered PDL2), and rearrangements of 16p13.13 (CIITA). DA-EPOCH
in diverse clinical settings, usually associated with a confined R has been effective in both PMBL and DLBCL; however, it is
anatomical space and a background of chronic inflammation. not clear how these patients should be managed clinically, but
These cases appear to have a good prognosis if successfully resected. they appear to benefit from combined modality therapy. 31,32
Human herpes virus 6/Kaposi sarcoma herpes virus (HHV-8/
KSHV)–associated LPDs are also documented. These include CLINICaL PEarLS
primary effusion lymphoma (PEL), multicentric Castleman disease
(MCD), and lymphomas arising in the context of MCD. The Highly Aggressive Lymphomas
cells of PEL are usually coinfected with EBV, and the disease is • More common in children
most often diagnosed in the setting of HIV infection and • Natural history similar to acute leukemia
immunosuppression. Although pleural or peritoneal effusions • Successful treatment includes high-dose chemotherapy (induction,
are most common, extracavitary PEL can present as a tumor consolidation, and maintenance phases) with central nervous system
mass, usually in extranodal sites. PEL has a phenotype resembling prophylaxis
terminally differentiated B cells (i.e., plasmablastic).
Two other lymphomas with a plasmablastic phenotype include
plasmablastic lymphoma (PBL) and ALK-positive large B-cell Burkitt Lymphoma
lymphoma. PBL is usually positive for EBV, most often extranodal, Burkitt lymphoma (BL) occurs most commonly in children and
and is associated with immunosuppression from either human accounts for up to one-third of all pediatric lymphomas in the
immunodeficiency virus (HIV) infection or advanced age. Recent United States. Three clinical variants of BL are recognized—
studies have identified a high incidence of MYC translocation endemic, sporadic, and immunodeficiency-associated. The
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in PBL. ALK-positive large B-cell lymphomas show overexpres- endemic cases are seen in equatorial Africa and mostly involve
sion of ALK, usually as a consequence of translocation. They the jaw and other facial bones. African BL occurs in malaria-
mainly affect older individuals but can occur at any age. endemic regions. In non–malaria-endemic regions, such as the
United States, extranodal sites are frequent, including the ileocecal
Primary Mediastinal Large B-Cell Lymphoma region, ovaries, kidneys, or breasts. Bone marrow involvement
PMBCL has a distinct constellation of clinical and morphological is a sign of poor prognosis.
features. PMBCL shows marked female gender predominance EBV has been shown to be a cofactor for the development
in adolescents and young adults. The clinical presentation is that of BL and shows varying degrees of positivity in the variant
of a rapidly growing anterior mediastinal mass with frequent subtypes. BL is one of the more common tumors associated
superior vena cava syndrome and/or airway obstruction. Nodal with HIV. It can present at any time during the clinical course
involvement is uncommon at presentation and also at relapse. and also can be the initial acquired immunodeficiency syndrome
Frequent extranodal sites of involvement, particularly at relapse, (AIDS)–defining illness. Recent GEP data have supported a
include the liver, kidneys, adrenal glands, ovaries, the GI tract, common pathogenetic mechanism in cases of HIV infection
and the CNS. The treatment approach includes aggressive systemic and endemic malaria–related immunosuppression.
chemotherapy plus rituximab, along with radiation therapy used Cytologically, BL shows monomorphic medium-sized cells
in some centers. A relatively abundant pale cytoplasm with distinct with round nuclei, multiple (2–5) basophilic nucleoli, and
cytoplasmic membrane and fine compartmentalizing sclerosis moderately abundant deeply basophilic cytoplasm. Cytoplasmic
are characteristic. The tumor appears to be derived from medul- lipid vacuoles reflecting a high proliferation rate and apoptosis
lary B cells within the thymus gland. These cells express CD20 are frequent. It is the most rapidly growing of all lymphomas,
and CD79a, but not surface Ig. CD23 is frequently positive, and with 100% of the cells in cell cycle at any time. The characteristic
MUM-1/IRF4 coexpression is also common. A unique signature “starry sky” pattern of BL is a manifestation of the numerous
was identified by GEP in PMBCL that shared similarities with benign macrophages that have ingested karyorrhectic or apoptotic
HL cell lines, including constitutive activation of the nuclear tumor cells. BL has a mature B-cell phenotype, expressing CD19,
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factor-κB and recurrent gains and amplification of c-Rel. The CD20, CD22, CD79a, and monoclonal surface Ig, nearly always
expression of the MAL gene has been detected in PMBCL but IgM. CD10 is positive in almost all cases, whereas CD5, CD23,
not in other DLBCLs. and BCL2 are consistently absent.
The 2008 WHO classification included borderline categories, The pathogenesis of BL is related to the MYC oncogene
one of which manifests features intermediate between DLBCL, translocations seen in virtually 100% of cases. The MYC transloca-
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especially PMBCL and classic HL (CHL) “gray-zone lymphomas.” tion is considered a primary event and often is the sole karyotypic
A close relationship between PMBCL and CHL has been supported abnormality detected. This is in contrast to other aggressive