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HEMATOPATHOLOGY 3 (WHO classification) - Coggle Diagram
HEMATOPATHOLOGY 3
(WHO classification)
precursor B (and T) cell neoplasms
ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (ALL)
neoplasms composed of immature B (pre-B) or T (pre-T) cells
referred to as "lymphoblasts"
typically, childhood acute leukemias
B-ALL uncommonly presents as a mass in the skin or a bone and T-ALL presents with or evolve to a leukemic picture
epidemiology
ALL is the most common cancer in children
3x more common in Caucasians than in African-Americans
M>F
B-ALL peaks in incidence at about 3y
T-ALL peaks in adolescence (thymus at its max size)
B-ALL and T-ALL also occur less frequently in adults of all ages
pathogenesis
many chromosomal aberrations dysregulate the expression and function of transcription factors required for normal B and T cell development
T-ALLs
mutations of NOTCH1
B-ALLs
PAX5, TCF3, ETV6, RUNX1
90% of ALLs have numerical or structural chromosomal changes
the most common is hyperploidy, but hypoploidy and a variety of balanced chromosomal translocations are also seen
B-ALL
hyperdiploidy and hypodiploidy
(better and worse prognosis respectively)
B-ALL and T-ALL are associated with completely different sets of translocations
morphology
the bone marrow is hypercellular and packed with lymphoblasts, which replace normal marrow elements
mediastinal thymic masses occur in 50-70% of T-ALLs, which are also more likely than B-ALLs to be associated with lymphadenopathy and splenomegaly
tumor cells have scant basophilic cytoplasm and large nuclei
the nucleus is larger due to the fact the maturing lymphocytes need space for all the machinery for the proliferation
nuclear chromatin is delicate and finely stippled, nucleoli are usually small and often demarcated by a rim of condensed chromatin
compared with myeloblasts, lymphoblasts have more condensed chromatin, less conspicuous nucleoli, smaller amounts of cytoplasm without granules.
immunophenotype
TdT immunostaining +++ in 95% of cases
specialized DNApol expressed only
in pre-B and pre-T lymphocytes
also expressed in non-neoplastic immature lymphoblasts of the thymus tissue and in thymoma
B-ALLs are arrested at various stages of pre-B cell development
lymphoblasts: pre-B cell marker CD19 and transcription factor PAX5 and CD10
in very immature B-ALLs, CD10 is negative
late pre-B-ALLs: CD10, CD19, CD20 and cytoplasmic IgM heavy chains (mi chain)
T-ALLs are positive for CD1a, CD2, CD5, CD7
the more immature tumors are usually negative for CD3, CD4 and CD8
late pre-T cell tumors are positive for these markers
clinical features
accumulation of neoplastic blasts in the bone marrow suppresses normal hematopoiesis
more common ones
abrupt stormy onset within days to a few weeks of the first symptoms
symptoms related to depression of marrow function, including fatigue due to anemia, fever (neutropenia-related), bleeding (thrombocytopenia-related)
mass effect caused by neoplastic infiltration, including bone pain resulting from marrow expansion and infiltration of the subperiosteum
CNS manifestations, such as headache, vomiting and nerve palsies (meningeal spread)
treatment
with aggressive CT about 95% of children obtain complete remission
75-85% are cured
ALL remains a leading cause of cancer deaths in children
35-40% of adults are cured
factors associated with worse prognosis
age <2y
presentation in adolescence or adulthood
peripheral blood blast counts >100,000
factors associated with favorable prognosis
age between 2 and 10y
low WBCs count
hyperdiploidy
trisomy of chromosomes 4, 7 and 10
t(12;21)
peripheral B cell neoplasms
(mature B cell neoplasms)
CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) / SMALL LYMPHOCYTIC LYMPHOMA (B-SLL)
indolent lymphoma
CLL and SLL differ only in the degree of peripheral blood lymphocytosis
equal from a morphological and an immunophenotypical POV
CLL is the most common leukemia of adults in the Western world
median age at diagnosis is 60 y
M>F
CLL
peripheral lymphocytosis
SLL
nodal lymphocytosis
pathogenesis
chromosomal translocations are rare
most common genetic anomalies are deletions of chromosomes 13q14.3, 11q and 17p and trisomy 12q
the loss of miR-15a/16-1 is believed to result in overexpression of the anti-apoptotic protein BCL2
Ig genes of some CLL/SLL are somatically hypermutated
the cell of origin may be either a post–germinal center after somatic hypermutation memory B cell or a naive B cell
tumors with unmutated Ig segments pursue a more aggressive course
morphology
in lymphocytes, there are small lymphocytes with round to slightly irregular nuclei, condensed chromatin and scant cytoplasm
proliferation centers are pathognomonic for CLL/SLL
focal lesions are more indolent, whereas diffuse pattern is more aggressive
in almost all cases, the spleen and liver are involved
immunophenotype
CLL tumor cells express the pan B-cell markers CD19 and CD20 (CD19 is a bit more immature than CD20);
CLL tumor cells express as well CD23 and CD5
there are also other less specific markers
low-level expression of surface Ig
high-level expression of BCL2
clinical features
pts are often asymptomatic (monoclonal lymphocytosis of uncertain significance)
if present, symptoms are not specific
easy fatigability
weight loss
anorexia
generalized lymphadenopathy
hepato-splenomegaly
prognosis
median survival is 4 to 6 years
more than 10 years in individuals with indolent tumors
worse outcome
presence of deletion of ch 11 or 17
lack of somatic hypermutation
expression of ZAP-70
presence of NOTCH1 mutations
evolution of the tumor can be indolent, progressive or there may be transformation to a more aggressive tumor
in 5-10% of cases there is transformation into DLBCL
(Richter syndrome)
rapidly enlarging mass within a lymph node or the spleen
treatment
“gentle” chemotherapy
immunotherapy, e.g. Rituximab
FOLLICULAR LYMPHOMA
the most common form of indolent NHL
not aggressive at presentation
usually presenting in middle age
F = M
less common in Europe and rare in Asia
pathogenesis
chromosomal translocations involving BCL2
hallmark is a t(14;18) translocation: it juxtaposes the IGH locus on ch14 and the BCL2 locus on ch18
t(14;18) is seen in up to 90% of FLs and leads to overexpression of BCL2
promoting FL cells survival
antagonising apoptosis
morphology
nodular or nodular-and-diffuse growth pattern is observed in involved lymph nodes
two principal cell types exist
centrocytes
small cells with irregular or cleaved nuclear contours and scant cytoplasm
in most follicular lymphomas, centrocytes are the majority
centroblasts
larger cells with clear nuclear chromatin, several nucleoli abd modest amounts of cytoplasm
grading system
grade 1: follicular or diffuse pattern; cells are CD10+ and BLC2+ at IHC, translocations are seen with FISH
grade 2: similar in pattern, butthere must be 6-15 centroblasts per HPF
grade 3: more aggressive, prominent diffuse follicular pattern
grade 3a: >15 centroblasts and presence of centrocytes
grade 3b: >15 centroblasts and few/lack of centrocytes
bone marrow involvemeent occurs in 85% of cases and characteristically takes the form of paratrabecular lymphoid aggregates
splenic white pulp and hepatic portal triads are also frequently involved
immunophenotype
neoplastic cells closely resemble normal germinal center B cells, expressing CD19 and CD20 (B cell markers), CD10 (follicle marker)
normal and the neoplastic cells are expressing the same immunoprofile, the difference lies in the morphology
Ki67 proliferation index distinguishes a reactive follicle (germinal center with high proliferation, 80%) from a neoplastic follicle of a FL (low proliferation, 20%)
hyperexpression of BCL6 and BCL2 is more common in lymphoma
BCL2 is expressed in more than 90% of cases, in distinction to normal follicular center B cells, which are BCL2-negative
clinical features
painless and generalized lymphadenopathy
involvement of extranodal sites, such as GIT, CNS or testis, are relatively uncommon
prognosis
incurable, indolent waxing and waning course
median survival: 7-9 years
no survival improval by aggressive therapy
palliative therapy with low-dose CT and immunotherapy (e.g. Rituximab) when tumors become symptomatic
histologic transformation occurs in 30-50% of follicular lymphomas, most commonly to DLBCL
transformation events are frequently associated with aberrations that increase the expression of MYC
median survival is less than 1 year after transformation
DIFFUSE LARGE B CELL LYMPHOMA
the most common form of NHL
aggressive lymphoma
slight male predominance
median age: 60y
it can also occur in children and young adults
pathogenesis
DLBCL is molecularly heterogeneous
dysregulation of BCL6 seems to play an important role; it is a DNA-binding zinc-finger transcriptional repressor required for the transformation of normal germinal centres
30% of DLBCLs contain various translocations that have in common a breakpoint in BCL6 at ch 3q27
BCL6 represses the expression of factors that promote germinal center B-cell differentiation, growth arrest and apoptosis
--> the loss of these mechanisms causes hyper proliferation of cells
10% to 20% of tumors are associated with the t(14;18)
this leads to the overexpression of the BCL2
some tumors with BCL2 rearrangements may arise from unrecognized FL
5% of DLBCLs are associated with translocations involving MYC (similar to Burkitt lymphoma)
special subtypes
IIMMUNODEFICIENCY-ASSOCIATED
it occurs in the setting of T cell immunodeficiency (AIDS, transplant)
neoplastic B cells are usually infected with EBV
restoration of T cell immunity may lead to regression of these proliferations
PRIMARY EFFUSION LYMPHOMA
a DLBCL in the pleural/peritoneal cavity
presentation: malignant pleural or ascitis effusion
pts with advanced HIV infection or in order adults
tumor cells are often anaplastic in appearance and typically fail to express surface B- or T-cell markers, but have clonal IGH gene rearrangements
morphology
ALL CENTROBLASTS
relatively large cells size
diffuse pattern of growth
round or oval nucleus
nucleus appears vesicular due to margination of chromatin to the nuclear membrane
large multilobated / irregular nuclei are prominent in some cases
cells are clear (unstained) with dispersed chromatin
nucleoli are 2/3 and located adjacent to the nuclear membrane or single and centrally placed
cytoplasm is usually moderately abundant and may be pale or basophilic
more anaplastic tumors may contain multinucleated cells with large inclusion-like nucleoli that resemble Reed-Sternberg cells
mature B-cell tumors again express CD19 and CD20
also, there may be variable expression of germinal center B-cell markers such as CD10 and BCL6
high-level expression of both MYC and BCL2 proteins is seen in some cases and may predict a more aggressive behavior
clinical features
rapidly enlarging mass
nodal or extranodal site
virtually anywhere in the body
Waldeyer ring is commonly involved
primary / secondary involvement of the liver and spleen may take the form of large destructive masses
extranodal sites include GIT, skin, bone, brain and other tissues
rarely, a leukemic picture emerges
treatment and prognosis
DLBCLs are aggressive tumors that are rapidly fatal without treatment
intensive combination CT --> 60% to 80% of patients achieve a complete remission
40% to 50% are cured
MYC translocations bring a worse prognosis
adjuvant therapy with anti-CD20 antibodies improves both the initial response and the overall outcome
(Burkitt lymphoma's options are best in the presence of MYC translocations)
CAR T cells directed against the B cell antigen CD19 are now available for the treatment of patients with relapsed refractory DLBCL
BURKITT LYMPHOMA
types
African (endemic) BL
sporadic (nonendemic) BL
subset of aggressive lymphomas occurring in individuals infected with HIV
pathogenesis
always associated with translocations of the MYC gene on ch8
among the fastest-growing human tumors (very aggressive)
MYC translocation partner is usually the IGH locus [t(8;14)], sometimes also Ig κ [t(2;8)] or λ [t(8;22)] light chain loci
all endemic Burkitt lymphomas are latently infected with EBV
MYC gives the oncogenic transformation and the IGH locus the proliferating potential !!!
most tumors have mutations that increase the activity of the transcription factor TCF3
TCF3 drives the expression of a set of genes, including cyclin D1, that collaborate with MYC to enable a very rapid growth
morphology
cells look as centroblasts in shape
diffuse infiltrate of intermediate-sized lymphoid cells 10-25μm in diameter with round or oval nuclei, coarse chromatin, several nucleoli and a moderate amount of cytoplasm
tumor exhibits a high mitotic index (80-90%) and contains numerous apoptotic cells
phagocytes have abundant clear cytoplasm, creating a characteristic “starry sky” pattern
diffuse blu growth with clear cells which are normal macrophages that phagocyte the apoptotic cells
similar to macrophages in reactive germinal centers,
but morphology is different
active GC
in the lymph node, there are macrophages
in BL
extranodal sites
are involved
immunophenotype
surface IgM, CD19, CD20, CD10 and BCL6, consistent with a germinal center B cell origin
unlike most other tumors of germinal center origin, BL almost always fails to express the antiapoptotic protein BCL2
rather, it expresses MYC
IMPORTANT FOR THE DD WITH DLBCL
clinical features
mainly in children or young adults
most tumors manifest at extranodal sites
endemic BL
mass involving the mandible
unusual predilection for involvement of abdominal viscera (kidneys, ovaries, adrenal glands)
sporadic BL
mass involving ileocecum and peritoneum
bone marrow and peripheral blood involvement is uncommon
treatment and prognosis
BL is very aggressive, but responds well to intensive CT
most children and young adults can be cured
MANTLE CELL LYMPHOMA
uncommon lymphoid neoplasm
fifth to sixth decades of life
male predominance
tumor cells closely resemble the normal mantle zone B cells
pathogenesis
all mantle cell lymphomas have an t(11;14) translocation involving the IGH locus on ch14 and the cyclin D1 locus on ch11
overexpression of cyclin D1 is an hallmark of diagnosis
up-regulation of cyclin D1 promotes G1-to S-phase progression during the cell cycle
morphology
generalized lymphadenopathy
peripheral blood involvement
extranodal involvement includes the bone marrow, spleen, liver and gut
lymphomatoid polyposis occurs sometimes
in nodal sites tumor cells may surround reactive GCs to produce a nodular appearance at low power or diffusely efface the node
typically, the proliferation consists of a homogeneous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours
large cells resembling centroblasts and proliferation centers are absent
important for DD with FL and CLL/SLL
nuclear chromatin is condensed, nucleoli are inconspicuous, and the cytoplasm is scant (dark blue appearance)
immunophenotype
high levels of cyclin D1
CD19, CD20
moderately high levels of surface Ig
this tumor is usually CD5+ and CD23-, which helps to distinguish it from CLL/SLL
IGH genes lack somatic hypermutation, supporting an origin from a naive B cell (pre-GC)
clinical features
painless lymphadenopathy
generally, indolent lymphoma
some blastoid variants are more aggressive
symptoms related to spleen and gut involvement are common
MCL is moderately aggressive and incurable
median survival is 8-10 y
blastoid variant has a proliferative expression profiling signature, TP53 mutations and shorter survival
MARGINAL ZONE LYMPHOMA
heterogeneous group of B-cell tumors that arise within lymph nodes, spleen or extranodal tissues
extranodal tumors were initially recognized at mucosal sites and are often referred to as MALTomas
e.g. oropharynx, lung, gut
MZLs at extranodal sites share three specific features
arousal within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology
e.g. Sjogren syndrome, Hashimoto thyroiditis, Helicobacter gastritis
remaining localized for prolonged periods, spreading systemically only late in their course
probable regression if the inciting agent (H. pylori) is eradicated
tumor cells show evidence of somatic hypermutation and are considered of memory B cell origin
pathogenesis
the disease begins as a polyclonal immune reaction to chronic inflammation
with the acquisition of unknown initiating mutations, a B cell clone emerges and it still depends on antigen-stimulated T-helper cells for signals that drive growth and survival
withdrawal of the responsible antigen causes tumor involution
tumors may acquire additional mutations that render their growth and survival antigen-independent, such as (11;18), (14;18) or (1;14) chromosomal translocations
these translocations up-regulate the expression and function of BCL10 or MALT1
with further clonal evolution, spread to distant sites and transformation to DLBCL may occur
morphology
proliferation of very small lymphocytes
partial or total effacement of architecture
monocytoid infiltrate
centrocyte-like B cells are 2-3x larger than small lymphocytes
tumor cells surround and infiltrate glandular structures, have moderately abundant pale cytoplasm, round or irregular nuclei with clumped chromatin
similar morphology to MALT lymphoma or splenic marginal zone B cell lymphoma
immunophenotype
EXCLUSION
PHENOTYPE
negative for: CD5, CD10, CD23, cyclin D1
positive for pan-B markers as CD19, CD20, CD79a
HAIRY CELL LEUKEMIA
rare indolent lymphoproliferative neoplasm of mature B cells
distinct clinical presentation, that includes
peripheral blood cytopenia
splenomegaly
small number of circulating neoplastic cells with hair-like cytoplasmic projections
pathogenesis
associated in more than 90% of cases with activating point mutations in the serine/threonine kinase BRAF
V600E mutation is also found at high frequencies in many other neoplasms (melanoma, Langerhans cell histiocytosis)
involved sites
more commonly: bone marrow, peripheral blood and spleen
uncommonly: liver, lymph nodes and skin
diagnosis is based on
peripheral blood morphology
bone marrow morphology
flow cytometry immunophenotyping
immunohistochemistry
molecular studies
morphology
leukemic cells have fine hair-like projections
on routine peripheral blood smears, hairy cells have round, oblong or reniform nuclei and moderate amounts of pale blue cytoplasm with thread-like or bleb-like extensions
highly variable number of circulating cells
these cells are enmeshed in an extracellular matrix composed of reticulin fibrils
inaspirable!
splenic red pulp is usually heavily infiltrated
(sometimes, hepatic portal triads are involved)
immunophenotype
pan-B-cell markers (CD19 and CD20)
some surface Ig (usually IgG)
relatively distinctive markers (CD11c, CD25, CD103)
clinical features
infiltration of the bone marrow, liver and spleen
SPLENOMEGALY is the most common finding
this causes pancytopenia in 50% of cases,
then causing secondary infections
hepatomegaly and lymphadenopathy are rarer
prognosis and treatment
indolent course
exceptionally sensitive to "gentle" CT
--> long-lasting remission
tumors often relapse after 5 or more years
BRAF inhibitors appear to produce excellent responses in tumors that have failed conventional CT
overall prognosis is excellent
HODGKIN LYMPHOMA
general information
HL arises in a single node (typically the latero-cervical one) or in a chain of nodes
it spreads to anatomically contiguous lymphoid tissues
at the beginning it is a pure nodal disease
pathognomonic finding
(important for DD with NHL)
REED-STENBERG CELLS
they release factors inducing the accumulation of reactive lymphocytes, macrophages and granulocytes inside the nodes
reactive cells are higher in number compared to RSCs
these cells are similar to EBV-infected B cells
factors typically released
cytokines: IL-5, IL-10, M-CSF
chemokines: eotaxin
origin
from a GC or post-GC B cell
despite their B cell origin, RSCs fail to express most B cell-specific genes
this may result from widespread epigenetic changes of uncertain etiology
WHO classification
nodular sclerosis
mixed cellularity
lymphocyte-rich
lymphocyte depletion
nodular lymphocyte predominance
types 1, 2, 3 and 4 are classified as "classic forms", while type 5 is classified as "nodular lymphocyte predominance"
NODULAR SCLEROSIS
nodular formations can be observed and they are surroounded by fibrosis/sclerosis
inside these nodules, there is the cellular microenvironment for HL
RS cells are found in a polymorphous background of T cells, eosinophils, plasma cells and macrophages
fibrosis may be scant or aboundant
more commonly associated with EBV iinfections
the most common
form of HL
(65-70%)
characterized by the presence of lacunar variant RSCs and deposition of collagen in bands that divide involved LNs into circumscribed nodules
diagnostic RSCs are scarce
markers
PAX5+
it is a B cell transcription factor, which in RSCs appears more faint if compared to the staining of B cells
also, DLBCL is PAX5+, but with a very strong staining
CD15+ and CD30+
membranous markers
CD20- and CD79-
other B cell markers
T cell markers -
CD45-
leukocyte common antigen
involvement of the spleen, liver, bone marrow and other organs and tissues may appear during the course of the disease
other tissues, e.g. mediastinum, may be involved only in advanced stages
diagnosis
great amount of fibrosis in nodular sclerosis, with a relatively small amount of neoplastic cells poses a challenge during the diagnostic process, as the mass is not removable surgically
a core biopsy is performed and typically the sample is made up of only fibrosis
MIXED CELLULARITY TYPE
heterogeneous cellular infiltrate in LNs (T cells and many eosinophils, white-pink)
it is very rare to find eosinophils in LNs
also, plasma cells and plasma cells and benign macrophages are found with RSCs and mononuclear variants
RSCs are infected with EBV in 60-70% of cases
immunophenotype: CD15, CD30 and faint PAX5 +++
20-25% of cases
LYMPHOCYTE-RICH TYPE
uncommon form of classic HL
reactive lymphocytes mainly compose the cellular infitrate
follicular architecture of LN cannot be recognized
immunophenotyping reveals that these are T lymphocytes
DD with PYMPHOCYTE PREDOMINANCE FORM through the presnce of frequent mononuclear variants and diagnostic RSCs
there is no mixed cellularity in this subtype, but a lymphocyte population with RS cells
association with EBV in 40% of cases
very good-to-excellent prognosis
LYMPHOCYTE DEPLETION TYPE
aka "reticular variant"
depletion of lymphocytes from the microevironment and what is left of fibrosis
least common form of HL
characterized by a paucity of lymphocytes and a relative aboundance of RSCs
immunophenotyping is identical to the one seen in other classic types of HL
<5%
NODULAR LYMPHOCYTE
PREDOMINANCE TYPE
uncommon, "nonclassic" variant
involved LNs are effaced by nodules of small lymphocytes, mixed with variable numbers of macrophages
classic RBCs are difficult to find
it contains L&H RBC variants with multilobed nuclei, resembling popcorn kernels
eosinophils and plasma cells are usually scant or absent
L&H variants express B cell markers, typical of germinal center B cells: CD20+ and BCL6+; they are negative for CD15 and CD30
in 3-5% of cases, it transforms into a tumor, resembling DLBCL
a majority of patients where this transformation occurs are males, usually <35 years of age, with cervical or axillary lymphadenopathy
5%
nodular pattern of growth is due to the presence of expanded B-cell follicles, populated by L&H variants, numerous reactive B cells and follicular dendritic cells
morphology
Reed-Stenberg cells:
large (45 microns)
with multiple nuclei or a single nucleus with multiple nuclear lobes
each nucleulus has a large inclusion-like nucleolus about the size of a lymphocyte
multilobulated nuclei (pink-stained) could appear as multiple nuclei
cytoplasm is aboundant
RSCs variants
mononuclear variants
a single nucleus
large inclusion-like nucleolus
lacunar cells
seen in the nodular sclerosis subtype
delicate, folded or multilobulated nuclei
abundant pale cytoplasm, often disrupted during the cutting in sections (leaving the nucleus sitting in an empty space)
classic forms of HL
RSCs undergo a form of death, in which the cell shrinks and becomes pyknotic ("mummification")
lymphohistiocytic variants
(L&H cells)
polypoid nuclei
incospicuous nucleoli
moderately aboundant cytoplasm
LYMPHOCYTE
PREDOMINANCE
binucleated cells
the more typical appearance of RSCs
two nuclei and two very large pink nucleoli
aka "diagnostic RSCs"
clinical features
average age at diagnosis of HL is 32y
one of the most common tumors of young and adolescents
it is curable in most cases
it most commonly presents as painless lymphadenopathy
patients with the nodular sclerosis or lymphocyte predominance types tend to have stage I or II disease and are usually free of systemic manifestations
patients with disseminated disease (stages III and IV) or the mixed-cellularity or lymphocyte depletion subtypes are more likely to have constitutional symptoms
due to the production of
cytokines and chemokines
fever, night sweats, weight loss
staging system
the spread of Hodgkin lymphoma is remarkably stereotypic
nodal disease
splenic disease
hepatic disease
bone marrow (and
other organs) disease
physical examination, radiologic imaging of the abdomen, pelvis, chest and biopsy of bone marrow
for current treatment protocols, tumor stage is more important than histologic type for prognostic evaluation
stages
I:
involvement of a single LN region or a single extralymphatic organ/site
II:
involvement of two or more LN regions on the same sid of the diaphragm alone or localized involvement of an extralymphatic organ or site
III:
involvement of LN regions on both sides of the diaphragm without or with localized involvement of an extralymphatic organ/site
IV:
diffuse involvement of one or more extralymphatic organs or sites with or without lymphatic involvement
peripheral T and NK cell neoplasms
heterogeneous group of neoplasms, having phenotypes resembling mature T and NK cells
T and NK cells are considered together because they are closely related and share immunophenotypic, functional and sometimes clinical properties
most T cell lymphomas are nodal
most NK cell lymphomas are extranodal
(more commonly skin and GIT, while more rarely lungs and CNS)
the majority of patients present with an advanced stage disease, associated with a secondary involvement of the liver, bone marrow, spleen and other extranodal sites
T and NK cell neoplasms can also involve the peripheral blood
clinical presentation plays a major role in the subclassification of T and NK cell malignancies
hypercalcemia ia associated with adult T cell leukemia
hemophagocytic syndrome occurs more frequently in cytotoxic T or NK cell malignancies
persistent severe neutropenia is a common feature of T cell granular lymphocyte leukemia
systemic symptoms (edema, pleural effusion, ascites, arthritis, anemia and polyclonal hypergammaglobulinemia) are relatively specific for angioimmunoblastic T cell lymphoma
mature T and NK cell neoplasms are grouped into 9 families based on diverse concepts
cell of origin/differentiation state
clinical scenario
disease localization
cytomorphology
immunophenotype
cells are negative for B cell markers (CD19, CD20, etc.), but positive for T cell markers (CD2, CD3, CD5, CD7, CD43 and CD45)
aberrant T cell phenotypes exist, but CD2 seems to be the most stable marker
rarely they co-express B cell markers, such as CD20 and CD79a
granzyme M is sometimes expressed
it suggests a role in the effector phase of the innate immune system
NK markers are CD11b, CD11c, CD16, CD56, CD57 and polyclonal CD3
types of cell neoplasms
Peripheral T-Cell Lymphoma, Unspecified
no morphologic feature is pathognomonic
when a nodal site is involved, these tumors efface LNs diffusely and are composed of a mixture of malignant T cells
there is often a prominent infiltrate of reactive cells (eosinophils and macrophages)
brisk neoangiogenesis (NOT FOUND IN B CELL NEOPLASMS)
by definition, all peripheral T-cell lymphomas are derived from mature T cells
expression of CD2, CD3, CD5 and either alpha-beta or gamma-delta T cell receptors;
some also express CD4 or CD8
many tumors have phenotypes that do not resemble any known normal T cell
in difficult cases, where DD lies between lymphoma and a florid reactive process, DNA analysis is used to confirm the presence of clonal T cell receptor gene rearrangements
signs and symptoms
lymphadenopathy, sometimes accompanied by eosinophilia, pruritus, fever and weight loss
although cures of peripheral T-cell lymphoma have been reported, these tumors have a significantly worse prognosis than comparably aggressive mature B-cell neoplasms
Anaplastic Large Cell Lymphoma
(ALK+)
rearrangements in the ALK gene on ch23, which break the ALK locus and lead to the formation of chimeric genes, encoding ALK fusion proteins
RAS and JAK/STAT signaling pathways are triggered
proliferation of the neoplastic cells is caused
these tumors are common in children or young adults and they are very aggressive, frequently involving also soft tissues
they carry a good prognosis:
cure rate with chemotherapy is 75% to 80%
in those patients not responding to conventional CT, ALK inhibitors have shown to be very effective
this tumor is typically composed of large anaplastic cells, some containing horseshoe-shaped nuclei and a voluminous cytoplasm (HALLMARK CELLS)
tumor cells often cluster around venules and infiltrate lymphoid sinuses, mimicking the appearance of metastatic carcinoma
there are ALK- anaplastic large cell lymphomas, which are more common in older adults and have a substantially worse prognosis
both ALK+ and ALK− tumors
usually express CD30
Adult T Cell Leukemia/Lymphoma
neoplasm of CD4+ T cells
only observed in adults infected by HTLV1
mainly occurring in regions where HTLV1 is endemic (south Japan, west Africa, Caribbean basin)
common findings: skin lesions, lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia
paracortical T cell zones involvement
typically characterized by diffuse architectural effacement
subdivided according to
cell type and pattern into
pleomorphic small cell
pleomorphic medium and large cell
anaplastic large cell-like
angioimmunoblastic T cell lymphoma-like
Hodgkin lymphoma-like
this morphological classification
does not affect the clinical course
most patients present with rapidly progressive disease that is fatal within months to 1 year
Mycosis Fungoides /
Sezary Syndrome
different manifestations of a tumor of CD4+ helper T cells that is home to the skin,
called "mycosis" for its peculiar appearance
cutaneous lesions of mycosis fungoides progress through three somewhat distinct stages
inflammatory premycotic phase
plaque phase
tumor phase
late disease progression is characterized by extracutaneous spread, most commonly to LNs and bone marrow
it starts in the skin, as a cutaneous lesion and spreads to lymph nodes or to the bone marrow
Sezary syndrome is a variant in which skin involvement is manifested as a generalized exfoliative erythroderma
in contrast to mycosis fungoides, the skin lesions rarely proceed to tumefaction
(there are not all the three phases)
and there is an associated leukemia of
Sezary cells (cerebriform nuclei)
Extranodal NK/T Cell Lymphoma
rare in the US and in Europe
most frequently presents as a destructive nasopharyngeal mass (less commonly, seen at the level of testis and skin)
tumor cell infoltrate typically surrounds and invades small vessels --> ischemic necrosis)
extranodal NK/T cell lymphoma is highly associated with EBV (unclear pathogenesis)
most extranodal NK/T-cell lymphomas are highly aggressive neoplasms
they respond well to radiation therapy, but are resistant to chemotherapy
markers
CD3 -
T cell receptor rearrangements -
NK cell markers +
Angioimmunoblastic T Cell Lymphoma
peripheral T cell lymphoma
(borderline B and T cell lymphoma)
very rare
systemic disease
median age of patients: 65y
no gender predisposition
polymorphous infiltrate involving LNs and a prominent proliferation of endothelial venules and follicular dendritic cells
partially-to-completely effaced nodular architecture due to vascular proliferations
extranodal sites such as the lungs, skin or bone marrow are frequently involved
immunophenotype
CD4+, CD10+, CXCL13+, PD1+, CD21+, EBV+ B cells
signs and symptoms
angioimmunoblastic lymphadenopathy with dysproteinemia, immunoblastic lymphadenopathy, lymphogranulomatous and immune dysplastic disease
AITL is included in the differential diagnosis of reactive mixed cellularity, which constitutes a sort of granulation tissue
Enteropathy-associated T Cell lymphoma
lymphoma associated with refractive celiac disease
tumor of intestinal intraepithelial T cells
sites typically affected are jejunum and ileum
it may also occur in the duodenum, stomach, colon or outside the GI tract
large, often polymorphic lymphoid cells, CD56-
there could be variants not associated with celiac disease
epidemiology
childhood onset is possible
in adults, celiac disease is diagnosed simultanoeusky with lymphoma
treatment and prognosis
are poor in both cases
recurrnces most frequently in the small intestine
death for abdominal complications
uncontrolled malabsorption
microscopic findings
relatively monotonous
medium to large cells with round/angulated vesicular nuclei
prominent nucleoli
moderate/abundant pale cytoplasm
infiltration by inflammatory cells with numerous histiocytes and eosinophils
plasma cell neoplasms
they are B-cell proliferations containing neoplastic plasma cells that virtually always secrete monoclonal Ig or Ig fragments
monoclonal Ig identified in the blood is referred to as an M component
restricted to the plasma and EC fluid
excluded from the urine in the absence of glomerular damage
clinicopathological entities
MULTIPLE MYELOMA
usually presents as tumor masses scattered throughout the skeletal system
there is also a solitary form of myeloma, called PLASMACYTOMA
it is an infrequent variant that presents as a single mass in bone or soft tissue
microscopically it is a proliferation of monoclonal plasma cells
extraosseous lesions are often located in the lungs, oronasopharynx or nasal sinuses
DD: lung mass of solid tumor
SMOLDERING MYELOMA
uncommon variant of myeloma, defined by a lack of symptoms and a high plasma M component
(>3 g/dL)
morphology
destructive plasma cell tumors involving the axial skeleton
bones most commonly affected: vertebral column, ribs, skull, pelvis, femur, clavicle and scapula
lesions begin in the medullary cavity, erode cancellous bone and progressively destroy the bony cortex
pathological fractures are usually the first sign
bone lesions appear radiographically as punched-out defects; they consist soft, gelatinous and red tumor masses
less commonly, widespread myelomatous bone disease produces diffuse demineralization (osteopenia)
microscopically
the marrow contains an increased number of plasma cells; plasma cells may infiltrate the interstitium in a subtle fashion or completely replace the normal elements
like their benign counterparts, malignant plasma cells have a perinuclear clearing due to a prominent Golgi apparatus and an eccentrically placed nucleus
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other cytologic variants
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immunophenotype
very characteristic as plasma cells are positive for CD138 and often express CD56
clinical features
the effects of plasma cell growth in tissues, particularly the bones
the production of excessive Igs, which often have abnormal psychochemical properties
the suppression of normal humoral immunity
bone resorption often leads to pathologic fractures and chronic pain
hypercalcemia, due to the bone destruction, can give rise to neurologic manifestations, such as confusion, weakness, lethargy, constipation and polyuria, and contributes to renal dysfunction
pathogenesis of renal failure
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diagnosis
identification of clonal plasma cells in the bone marrow
presence of the CRAB criteria
hypercalcemia, renal dysfunction, anemia and bone lesions
prognosis
median survival is 4 to 7 years and cures have yet to be achieved
translocations involving cyclin D1 are associated with a good outcome, whereas deletions of 13q, deletions of 17p, and the t(4;14) are all associated with a more aggressive course
WALDENSTROM
MACROGLOBULINEMIA
syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood
it occurs in older adults
association with lymphoplasmacytic lymphoma
HEAVY-CHAIN DISEASE
rare monoclonal gammopathy, seen in association with a diverse griup of disoders, including lymphoplasmacytic lymphoma and the Mediterranean lymphoma
common feature
synthesis and secretion of free heavy chain fragments
PRIMARY or IMMUNOCYTE-
ASSOCIATED AMYLOIDOSIS
it results from a monoclonal proliferation of plasma cells secreting light chains (lambda isotype) that are deposited in the EC of tissues, as amyloid
some patients have overt multiple myeloma, others have only a minor clonal population of plasma cells in the marrow, BUT THEY ALL HAVE AMYLOID DEPOSITION
MGUS
applied to patients without signs or symptoms, who have small to moderately large M components in their blood
common in older adults
possibly transforming to multiple myeloma or other symptomatic plasma cell neoplasms
most common plasma cell disorder
pts are asymptomatic and serum M protein level is <3 g/dL
clonal plasma cells in MGUS contain many of the same chromosomal translocations and deletions that are found in full-blown multiple myeloma, indicating that MGUS is an early stage of myeloma development
in most patients with plasma cell tumors, the level of free light chains is elevated and markedly skewed towards one light chain (e.g., κ) at the expense of the second one (e.g., λ)
Bence Jones proteins are small free light chains being excreted in the urine
lymphoplasmacytic lymphoma
B-cell neoplasm of older adults
sixth or seventh decade of life
superficially resembling CLL/SLL
a substantial fraction of the tumor cells undergo terminal differentiation to plasma cells
plasma cell component secretes monoclonal IgM, often in amounts sufficient to cause a hyperviscosity syndrome (Waldenström macroglobulinemia)
complications are rare and bone destruction does not occur
hyperviscosity syndrome
visual impairment (venous congestion)
neurologic problems (headache, dizziness, deafness, stupor)
bleeding (due to the formation of complexes between macroglobulins and clotting factors)
cryoglobulinemia (due to the precipitation of macroglobulins at low temperatures, producing symptoms such as Raynaud's phenomenon and cold urticaria)
pathogenesis
acquired mutations in MYD88
at diagnosis, the tumor has usually disseminated to the lymph nodes, spleen and liver
morphology
the marrow contains an infiltrate of lymphocytes, plasma cells and plasmacytoid lymphocytes,
often accompanied by mast cell hyperplasia
some tumors also contain a population of larger lymphoid cells with more vesicular nuclear chromatin and prominent nucleoli
periodic acid–Schiff–positive inclusions containing Ig are frequently seen in the cytoplasm (Russell bodies) or in the nucleus (Dutcher bodies) of some of the plasma cells
immunophenotyping
lymphoid component expresses B-cell markers such as CD20 and surface Ig, whereas the plasma cell component secretes the same Ig that is expressed on the surface of the lymphoid cells, usually IgM
clinical features
weakness, fatigue and weight loss
half of the patients have lymphadenopathy, hepatomegaly and splenomegaly; anemia is also a common finding
10% of patients have autoimmune hemolysis, caused by cold agglutinins
treatment
plasmapheresis
low doses of CT and immunotherapy (Rituximab)
BTK inhibitors (good response)