• 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

• 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

B-ALL and T-ALL are associated with completely different sets of translocations

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

the nucleus is larger due to the fact the maturing lymphocytes need space for all the machinery for the proliferation

compared with myeloblasts, lymphoblasts have more condensed chromatin, less conspicuous nucleoli, smaller amounts of cytoplasm without granules.

also expressed in non-neoplastic immature lymphoblasts of the thymus tissue and in thymoma

• 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)

• the more immature tumors are usually negative for CD3, CD4 and CD8
• late pre-T cell tumors are positive for these markers

accumulation of neoplastic blasts in the bone marrow suppresses normal hematopoiesis

• 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)

• 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

tumors with unmutated Ig segments pursue a more aggressive course

• focal lesions are more indolent, whereas diffuse pattern is more aggressive
• in almost all cases, the spleen and liver are involved

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

• easy fatigability
• weight loss
• anorexia
• generalized lymphadenopathy
• hepato-splenomegaly

• median survival is 4 to 6 years
• more than 10 years in individuals with indolent tumors

• presence of deletion of ch 11 or 17
• lack of somatic hypermutation
• expression of ZAP-70
• presence of NOTCH1 mutations

rapidly enlarging mass within a lymph node or the spleen

nodular or nodular-and-diffuse growth pattern is observed in involved lymph nodes

in most follicular lymphomas, centrocytes are the majority

splenic white pulp and hepatic portal triads are also frequently involved

grade 3a: >15 centroblasts and presence of centrocytes
grade 3b: >15 centroblasts and few/lack of centrocytes

BCL2 is expressed in more than 90% of cases, in distinction to normal follicular center B cells, which are BCL2-negative

Ki67 proliferation index distinguishes a reactive follicle (germinal center with high proliferation, 80%) from a neoplastic follicle of a FL (low proliferation, 20%)

involvement of extranodal sites, such as GIT, CNS or testis, are relatively uncommon

transformation events are frequently associated with aberrations that increase the expression of MYC

median survival is less than 1 year after transformation

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

some tumors with BCL2 rearrangements may arise from unrecognized FL

5% of DLBCLs are associated with translocations involving MYC (similar to Burkitt lymphoma)

• 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
  

• 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

more anaplastic tumors may contain multinucleated cells with large inclusion-like nucleoli that resemble Reed-Sternberg cells

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

• 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

• 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

CAR T cells directed against the B cell antigen CD19 are now available for the treatment of patients with relapsed refractory DLBCL

1. African (endemic) BL
2. sporadic (nonendemic) BL
3. subset of aggressive lymphomas occurring in individuals infected with HIV

TCF3 drives the expression of a set of genes, including cyclin D1, that collaborate with MYC to enable a very rapid growth

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

in the lymph node, there are macrophages

extranodal sites
are involved

surface IgM, CD19, CD20, CD10 and BCL6, consistent with a germinal center B cell origin

IMPORTANT FOR THE DD WITH DLBCL

• mass involving the mandible
• unusual predilection for involvement of abdominal viscera (kidneys, ovaries, adrenal glands)

• mass involving ileocecum and peritoneum
• bone marrow and peripheral blood involvement is uncommon

• BL is very aggressive, but responds well to intensive CT
• most children and young adults can be cured

• uncommon lymphoid neoplasm
• fifth to sixth decades of life
• male predominance
• tumor cells closely resemble the normal mantle zone B cells

• 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

typically, the proliferation consists of a homogeneous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours

nuclear chromatin is condensed, nucleoli are inconspicuous, and the cytoplasm is scant (dark blue appearance)

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)

blastoid variant has a proliferative expression profiling signature, TP53 mutations and shorter survival

tumor cells show evidence of somatic hypermutation and are considered of memory B cell origin

1. arousal within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology
   e.g. Sjogren syndrome, Hashimoto thyroiditis, Helicobacter gastritis
2. remaining localized for prolonged periods, spreading systemically only late in their course
3. probable regression if the inciting agent (H. pylori) is eradicated

the disease begins as a polyclonal immune reaction to chronic inflammation

withdrawal of the responsible antigen causes tumor involution

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

• proliferation of very small lymphocytes
• partial or total effacement of architecture
• monocytoid infiltrate
• centrocyte-like B cells are 2-3x larger than small lymphocytes

similar morphology to MALT lymphoma or splenic marginal zone B cell lymphoma

positive for pan-B markers as CD19, CD20, CD79a

• peripheral blood cytopenia
• splenomegaly
• small number of circulating neoplastic cells with hair-like cytoplasmic projections

V600E mutation is also found at high frequencies in many other neoplasms (melanoma, Langerhans cell histiocytosis)

more commonly: bone marrow, peripheral blood and spleen

• pan-B-cell markers (CD19 and CD20)
• some surface Ig (usually IgG)
• relatively distinctive markers (CD11c, CD25, CD103)

hepatomegaly and lymphadenopathy are rarer

this causes pancytopenia in 50% of cases,
then causing secondary infections

• 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

• 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
  

this may result from widespread epigenetic changes of uncertain etiology

types 1, 2, 3 and 4 are classified as "classic forms", while type 5 is classified as "nodular lymphocyte predominance"

• 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)

RSCs undergo a form of death, in which the cell shrinks and becomes pyknotic ("mummification")

RS cells are found in a polymorphous background of T cells, eosinophils, plasma cells and macrophages

also, DLBCL is PAX5+, but with a very strong staining

other tissues, e.g. mediastinum, may be involved only in advanced stages

a core biopsy is performed and typically the sample is made up of only fibrosis

more commonly associated with EBV iinfections

• 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 +++

• 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

• 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

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

• average age at diagnosis of HL is 32y
• one of the most common tumors of young and adolescents
• it is curable in most cases

patients with the nodular sclerosis or lymphocyte predominance types tend to have stage I or II disease and are usually free of systemic manifestations

due to the production of
cytokines and chemokines

a majority of patients where this transformation occurs are males, usually <35 years of age, with cervical or axillary lymphadenopathy

1. nodal disease
2. splenic disease
3. hepatic disease
4. 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

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

• 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

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

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

NK markers are CD11b, CD11c, CD16, CD56, CD57 and polyclonal CD3

it suggests a role in the effector phase of the innate immune system

expression of CD2, CD3, CD5 and either alpha-beta or gamma-delta T cell receptors;
some also express CD4 or CD8

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

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

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

in those patients not responding to conventional CT, ALK inhibitors have shown to be very effective

both ALK+ and ALK− tumors
usually express CD30

this morphological classification
does not affect the clinical course

most patients present with rapidly progressive disease that is fatal within months to 1 year

it starts in the skin, as a cutaneous lesion and spreads to lymph nodes or to the bone marrow

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)

they respond well to radiation therapy, but are resistant to chemotherapy

CD4+, CD10+, CXCL13+, PD1+, CD21+, EBV+ B cells

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

extranodal sites such as the lungs, skin or bone marrow are frequently involved

large, often polymorphic lymphoid cells, CD56-

there could be variants not associated with celiac disease

it may also occur in the duodenum, stomach, colon or outside the GI tract

• recurrnces most frequently in the small intestine
• death for abdominal complications
• uncontrolled malabsorption

• 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

restricted to the plasma and EC fluid

Bence Jones proteins are small free light chains being excreted in the urine

usually presents as tumor masses scattered throughout the skeletal system

uncommon variant of myeloma, defined by a lack of symptoms and a high plasma M component
(>3 g/dL)

synthesis and secretion of free heavy chain fragments

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

possibly transforming to multiple myeloma or other symptomatic plasma cell neoplasms

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

globular inclusions are referred to as Russell bodies (if cytoplasmic) or Dutcher bodies (if nuclear)

in advanced disease, plasma cell infiltrates may be present in the spleen, liver, kidneys, lungs, lymph nodes and other soft tissues

very characteristic as plasma cells are positive for CD138 and often express CD56

identification of clonal plasma cells in the bone marrow

hypercalcemia, renal dysfunction, anemia and bone lesions

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

microscopically it is a proliferation of monoclonal plasma cells

extraosseous lesions are often located in the lungs, oronasopharynx or nasal sinuses

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

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

at diagnosis, the tumor has usually disseminated to the lymph nodes, spleen and liver

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

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

• 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)

• plasmapheresis
• low doses of CT and immunotherapy (Rituximab)
• BTK inhibitors (good response)