WHO5-w:updates.docx

Chapter 2: Myeloid Proliferations and Neoplasms =============================================== Myeloid precursor lesions Clonal hematopoiesis **Condition** **Description** --------------------------------------------------------- ------------------...

Chapter 2: Myeloid Proliferations and Neoplasms =============================================== Myeloid precursor lesions Clonal hematopoiesis **Condition** **Description** --------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- **Clonal haematopoiesis** Clonal outgrowth of haematopoietic cells from affected stem or progenitor cells, regardless of cause or disease state **Age-related clonal haematopoiesis (ARCH)** CH detectable in PB or BM a/w ageing w/o a diagnosed heme disorder or cytopenia; does not refer to specific gene alterations or quantitative criteria reflecting clonal abundance **CHIP** CH with somatic mutations of myeloid malignancy--associated genes detected at a VAF ≥ 2% , w/o a diagnosed haematological disorder or unexplained cytopenia **CCUS** CH w/ 1+ persistent cytopenia that are otherwise unexplained by other conditions and do not meet diagnostic criteria for defined myeloid neoplasms **Idiopathic cytopenia of unknown significance (ICUS)** Sustained and unexplained cytopenia without detectable blood cancer--associated driver mutations Clonal hematopoiesis - Clonal hematopoiesis of indeterminate potential (CHIP) - VEXAS syndrome - X-linked gene UBA1, and they usually have a progressive systemic autoinflammatory syndrome involving the skin, lungs, blood vessels, joints, and cartilage, and/or various hematological conditions, including cytopenias - VAF ≥ 2% (≥ 4% for X-linked gene mutations in male patients) Clonal cytopenia of undetermined significance Myeloproliferative neoplasms Myeloproliferative neoplasms Chronic myeloid leukemia - Splenomegaly - Leukocytosis, **myelocyte bulge, \20% myeloid blasts or \>5% lymphoid blasts Chronic neutrophilic leukemia - M:E ratio may exceed 20:1 w/ no fibrosis or dysplasia - **CSF3R^T6181^** - Also common mutations in ASXL1, TET2 +/or DNMT3A - \~ 2 years survival, with death occurring from infxn, bleeding, or disease-related organ failure - Better prog if STAT5B p.N642H as the sole abnormality or in combination with SF3B1 vs STAT5B p.N642H combined with other additional somatic mutations (median survival time: 14 months) - **Toxic granulation and Dohle bodies** +-----------------------------------------------------------------------+ | WBC count **≥ 25 × 10^9^/L; segs + bands ≥ 80% of the WBCs**; neut | | precursors (promyelocytes, myelocytes, and metamyelocytes) constitute | | \ 1.5 × 109/L on at least two occasions over an interval of at least 4 weeks - Flow cytometric analysis to demonstrate abnormal T-cell populations (often sCD3−/CD4+) may identify lymphocytic variant HES, in which cytokine release from a clonal circulating T-cell population with a T helper 2 (Th2) profile results in secondary non-clonal eosinophiliaA diagram of a medical flowchart Description automatically generated Polycythemia vera - MPN characterized by erythrocytosis, frequently accompanied by leukocytosis and/or thrombocytosis, and typically associated with activating JAK2 mutations. **PV dx criteria- either all 3 major or 1^st^ 2 major + minor** ----------------------------------------------------------------- **Major criteria:** **Minor criterion:** **Diagnostic criteria for post--polycythaemia vera MF** **Required criteria:** **Additional criteria (two are required):** +-----------------------------------------------------------------------+ | **PV Risk factors** | +=======================================================================+ | **Risk-stratified survival data from a large study at Mayo Clinic ** | | conventional risk model included age (≥ 67 years, 5 points; | | 57--66 years, 2 points), venous thrombosis (1 point), and | | leucocytosis (≥ 15 × 10^9^/L; 1 point) | +-----------------------------------------------------------------------+ |  Median survival time: HR (≥ 3 points), 9.6 years; intermediate risk | | (1--2 points), 18 years; low risk (0 points), 28 years | +-----------------------------------------------------------------------+ | **Three-tiered model: MIPSS-PV**  | +-----------------------------------------------------------------------+ |  Hazard ratio--based risk factors: | +-----------------------------------------------------------------------+ | **Selected risk factors (selected literature):** | +-----------------------------------------------------------------------+ |  **Substantiated** | +-----------------------------------------------------------------------+ |  Age: \> 65 years, ≥ 65 years, ≥ 50 years  | +-----------------------------------------------------------------------+ |  History of thrombotic events | +-----------------------------------------------------------------------+ |  Erythrocytosis: Haematocrit ≥ 45--50% significantly increased the | | risk of major thrombosis (CYTO-PV study | +-----------------------------------------------------------------------+ |  **Described but not universally utilized** | +-----------------------------------------------------------------------+ |  Leukocytosis | +-----------------------------------------------------------------------+ |  *JAK2* p.V617F allele burden | +-----------------------------------------------------------------------+ |  Arterial hypertension | +-----------------------------------------------------------------------+ |  Hyperlipidaemia | +-----------------------------------------------------------------------+ |  Red blood cell distribution width (RDW) | | | | - Thrombotic-free survival was shorter when RDW was \ 15.6% | +-----------------------------------------------------------------------+ |  Inflammation ↑ CRP was a/w ↑ major thrombotic events | +-----------------------------------------------------------------------+ |  Major haemorrhage- Risk factor for thrombosis | +-----------------------------------------------------------------------+ Essential thrombocythemia - ET progresses to the AP and BP, diagnosed when BM / PB blasts are 10--19% and ≥ 20%, respectively - If erythrocytosis is present -- must r/o PV - **Normocellular** BM - No dysplasia or increased blasts - Dx criteria: need all 3 major or 1^st^ 3 major + a minor criterion - Major criterion - 1\. **Platelet count ≥ 450 × 10^9^/L** - 2\. BM bx showing prolif mainly of megs, with [↑ ]{.math.inline}\# of **enlarged, mature megakaryocytes with hyperlobulated nuclei**; no sig [↑ ]{.math.inline}or left shift in neutrophil granulopoiesis or erythropoiesis very rarely a **minor (grade 1) increase in retic fibres** - 3\. WHO criteria for *BCR*::*ABL1*-positive CML, PV, PMF, and other myeloid neoplasms are not met - 4\. Presence of JAK2, CALR, or MPL mutation - Minor criterion - Presence of clonal marker - Exclusion of reactive Primary myelofibrosis - Complex karyotype, inv(3), monosomy 5 or del(5q), monosomy 7 or del(7q), del(12p), 11q23 rearrangement, and i(17q) are considered unfavorable **Prefibrotic primary myelofibrosis: 3 major criteria and ≥1 minor on 2 consecutive biopsies** ------------------------------------------------------------------------------------------------------------------------------ **Major criteria:** **Minor criteria:** MF fibrotic stage Major criteria includes: Megakaryocytic prolif and atypia, accompanied by reticulin and/or collagen fibrosis grade 2 or 3^a^ Minor add: leukoerythroblastosis **Grade** **Grade definition** **Collagen pattern** **Osteosclerosis** ----------- ------------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------ **MF-0** Scattered linear reticulin with no intersections corresponding to normal bone marrow Perivascular collagen only (normal) Regular bone trabeculae (distinct paratrabecular borders) **MF-1** Loose network of retic with many intersections, esp in perivascular areas Focal paratrabecular or central collagen deposition w/ no connecting meshwork Focal budding, hooks, spikes, or paratrabecular apposition of new bone **MF-2** Diffuse and dense ↑ in retic w/ extensive intersections, occas w/ focal bundles of thick fibres mostly c/w collagen and/or focal osteosclerosis Paratrabecular or central deposition of collagen w/ focally connecting meshwork or generalized paratrabecular apposition of collagen Diffuse paratrabecular formation of new bone w/ thickening of trabeculae, occasionally w/ focal interconnections **MF-3** Diffuse and dense ↑ in reticulin w/ extensive intersections & **coarse** bundles of thick fibres -collagen usually aw **osteosclerosis** Diffuse (complete) connecting meshwork of collagen in \> 30% of marrow spaces Extensive interconnecting meshwork of new bone w/ effacement of marrow spaces Juvenile myelomonocytic leukemia - Splenomegaly present at dx in \~90% - Often thrombocytopenia - Aberrant blast pop expressing CD7 and ↓ levels of CD13 and CD33 - Poor prognostic factors include older age (\> 2 years), ↓ platelet counts (\< 33 × 109/L), ↑ hemoglobin F levels and/or overexpression of LIN28B (a regulator of hemoglobin F expression) - \~25% develop in pts w/ germline mutations - **JMML w/ PTPN11 or KRAS mutations have aggressive clinical course** - NF1 - xanthomas and café-au-lait spots (≥ 6 lesions of \> 5 mm in size) - Neurofibromin-1 is a GTP-ase activating protein which are negative modulators of GTPases - Noonan syndrome - facial dysmorphia, congenital heart defects, and lymphatic effusions, among other developmental defects, short stature, webbed neck, café au lait - PTPN11 in \~50% - vaf of 1.0 - \~10% dev JMML - CBL - autoimmunity, particularly vasculitis (Noonan syndrome--like disorder with or without JMML +-----------------------------------------------------------------------+ | **Clinical, haematological, and laboratory criteria (all criteria are | | required):** | +=======================================================================+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | **Genetic criteria (one criterion is required):** | +-----------------------------------------------------------------------+ | - Mutation in a component or a regulator of the canonical RAS | | pathway: | | | | - Clonal somatic mutation in *PTPN11*, *KRAS*, | | or *NRAS*, **or** | | | | - Clonal somatic or germline *NF1* & LOH or compound | | heterozygosity of *NF1*, **or** | | | | - Clonal somatic or germline *CBL *mutation and loss of | | heterozygosity of *CBL* | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | **Other criteria:** | +-----------------------------------------------------------------------+ | Cases that do not meet any of the genetic criteria listed above (or | | for which genetic testing is not available) must meet ≥2 of the | | following criteria in addition to above clinical, haematological, and | | laboratory criteria: | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ Myeloproliferative neoplasm NOS (unclassifiable) +-----------------------------------------------------------------------+ | **Requires all three of the following:** | +=======================================================================+ | Presence of features of any one of the following features: | | | | - Clinical and heme features of an MPN (e.g. splenomegaly, | | leucocytosis, thrombocytosis) in the absence of significant | | monocytosis and significant eosinophilia | | | | - BM hypercellularity with megakaryocytic hyperplasia and varying | | degrees of granulocytic and erythroid hyperplasia, w/o dysplastic | | features | | | | - Clinical and morphological features can be discrepant | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | **Requires the absence of both of the following:** | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ Mastocytosis Cutaneous mastocytosis - Adults: KIT p.D816V mutation in exon 17 - Kids: D816V in \~30-40%, KIT mutations in exons 8--11 (40%) or WT - Tends to resolve @ puberty - ↑ tryptase is not reliable---usually only in skin in kids - Brentoximab -- monoclonal anti-CD30 antibody for tx of relapsed HL and ALCL - Subtypes - Maculopapular cutaneous mastocytosis (MPCM) - Trunk and proximal extremities - Palms/soles/central face spared - Perivascular/adnexal or form small, or band-like, infiltrates in the upper dermis - Polymorphic MPCM - Usually seen in children - Brown, yellow, or pale red papules, plaques, and/or nodules - Heterogeneity in \#, shape, size, margination, and degree of confluence - Monomorphic MPCM - MC subtype in adults - Small, round, pigmented macules and papules - Diffuse cutaneous mastocytosis (DCM) - V rare - Generalized erythroderma, thickened skin, exaggerated folds, and episodic blistering often accompanied by severe systemic symptoms - Absence of individual skin lesions - Mastocytoma - MC on trunk and scalp - MC type in infants - Usually solitary but as many as 3 lesions is OK - Yellow/brown papules/nodules/plaques - Rubbing may cause wheals, blisters and occasionally flushing/hypotension (Darier sign) - **Essential and desirable diagnostic criteria  ** - *Essential:* cutaneous lesions with clin fx typical of mastocytosis; absence of clinical signs of systemic mastocytosis; BM evaluation (when indicated) not meeting the criteria for systemic mastocytosis; skin biopsy showing increased numbers of mast cells; mast cells immunoreactive for KIT (CD117) and/or tryptase. - *Desirable:* aberrant dermal mast cell immunophenotype (CD2+, CD25+, and/or CD30+); detection of *KIT* mutation in lesional skin Systemic mastocytosis - Metachromatic granules in Pappenheim/Wright--Giemsa or toluidine blue stains - Naphthol AS-D CAE but neg MPO - **Aberrant CD25** (more sensitive), CD2, and CD30 - Well diff SM -more common in F - CD25−/low, CD2−/low, CD30+ - KIT mutations are rare +-----------------------------------------------------------------------+ | **Systemic mastocytosis: require all 4 and ≥1 minor or if ≥3 minor** | +=======================================================================+ | **Major criterion:** | +-----------------------------------------------------------------------+ | Multifocal dense infiltrates of mast cells (≥ 15 cells) in BM &/or | | other extracutaneous organ(s) | +-----------------------------------------------------------------------+ | **Minor criteria:** | +-----------------------------------------------------------------------+ | Atypical mast cell morph- spindle shape or immature morphology, in | | \> 25% of all mast cells | | | | Aberrant exp of 1 + of the following antigens: **CD2, CD25, CD30** | | | | *KIT* p.D816V mutation or other activating *KIT* mutation  | | | | Baseline serum tryptase concentration of \> 20 ng/mL in the absence | | of an associated myeloid neoplasm | | | | In the case of a known HαT, the tryptase level could be adjusted | +-----------------------------------------------------------------------+ **B findings:** ----------------- **C findings:** +-----------------+-----------------+-----------------+-----------------+ | **Subtype** | **Diagnostic | **Morphological | **Other | | | criteria- all | features** | features** | | | have SM | | | | | criteria | | | | | (above)** | | | +=================+=================+=================+=================+ | BMM | No skin | Low MC burden | Look for other | | | involvement | in BM | regions---KIT | | | | | may not be | | | No B findings | Compact bone | found if WD | | | | marrow MC | | | | Basal serum | infiltrates | | | | tryptase \ 30% of | present, | | | | section area) | usually with | | | | | multilineage | | | | Diffuse-compact | involvement | | | | MC infiltration | | | | | pattern | High tryptase | | | | | levels, | | | | \- | organomegaly, | | | | spindle-shaped | and skin | | | | MCs embedded in | lesions in most | | | | a dense | cases | | | | fibrotic stroma | | | | | with pronounced | | | | | osteosclerosis | | | | | | | | | | Haematopoiesis | | | | | often with mild | | | | | dysplastic | | | | | changes (not | | | | | fulfilling WHO | | | | | criteria for | | | | | AHN) | | +-----------------+-----------------+-----------------+-----------------+ | **ASM** | \>=1C | ↑ to ↑↑MC | *KIT* p.D816V | | | | burden in the | almost always | | | | BM | present, | | | | | usually with | | | | Diffuse-compact | multilineage | | | | MC infiltration | involvement | | | | pattern | | | | | | High tryptase | | | | Usually | levels | | | | spindle-shaped | | | | | MCs embedded in | Skin lesions | | | | a dense | frequently | | | | fibrotic | absent | | | | stroma, | | | | | occasionally w/ | | | | | pronounced | | | | | osteosclerosis | | | | | | | | | | Pure ASM is | | | | | less frequent | | | | | than ASM-AHN | | | | | | | | | | In BM smears, | | | | | MCs \> 5% and | | | | | \=1 lineages, w/o thrombocytosis - Erythroid lineage dysplasia - Blasts \< 5% of BM and \< 2% of PB - Detection of SF3B1 mutation (high VAF, avg 35-43%) (if SF3B1 mutation analysis is not available, demonstration of ring sideroblasts constituting ≥ 15% of the erythroid precursors) - **VAF \=1 lineages - Dysplasia involving one or more lineages - Blasts constitute \< 20% PB/BM - Detection of one or more TP53 mutations - In the presence of one TP53 mutation - direct or indirect evidence of TP53 copy loss or copy-neutral LOH. - Often complex karyotype (\>=3 abnormalities) - VAF of \> 49% can be presumptive (not definitive) of copy loss on the trans allele or copy-neutral LOH when a constitutional TP53 variant can be ruled out - Two or more TP53 mutations are detected, can be considered multi-hit events Myelodysplastic neoplasms defined morphologically Myelodysplastic neoplasm with low blasts - Cytopenia definitions include: - hemoglobin \< 13 g/dL in male patients and \< 12 g/dL in female patients for anemia, - ANC \< 1.8 × 109/L for leukopenia - Platelets \< 150 × 109/L for thrombocytopenia - BM usually hypercellular - \ 50 × | | 109/L, thrombocytopenia, and hemoglobin level \< 10 g/dL have | | been reported to be adverse prognostic factors | +-----------------------------------------------------------------------+ Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis +-----------------------------------------------------------------------+ | Peripheral blood: | +=======================================================================+ | Bone marrow cytology: | +-----------------------------------------------------------------------+ | Molecular analyses of blood or bone marrow: | +-----------------------------------------------------------------------+ | *If molecular analyses are unavailable:* | +-----------------------------------------------------------------------+ | ** **Peripheral blood: | +-----------------------------------------------------------------------+ | ** **Bone marrow cytology: | +-----------------------------------------------------------------------+ | To be excluded: | +-----------------------------------------------------------------------+ | Specific situation: | +-----------------------------------------------------------------------+ Myelodysplastic/myeloproliferative neoplasm NOS (unclassifiable) +-----------------------------------------------------------------------+ | Peripheral blood: | +=======================================================================+ | Bone marrow cytology: | +-----------------------------------------------------------------------+ | Molecular analyses of blood or bone marrow: | +-----------------------------------------------------------------------+ | To be excluded: | | | | - Cases w/ del(5q) and JAK2 p.V617F mut be classified as MDS with | | isolated del(5q) rather than MDS/MPN-NOS | +-----------------------------------------------------------------------+ Acute myeloid leukemia Acute myeloid leukemia with defining genetic abnormalities Acute promyelocytic leukemia with PML::RARA fusion - t(15;17) = PML-RARA fusion - Increased PB and/or BM atypical promyelocytes showing characteristic abnormal hypergranular promyelocytes or microgranular blasts (may be \< 20%) - Detection of PML::RARA - No history of exposure to cytotoxic therapy - WBC count of ≥ 10 × 109/L places patients into a high-risk subset - FLT3 mutations include FLT3 ITD and FLT3p.D835; they are generally associated with an elevated WBC count - Median age 40 - Variants - t(11;17) -- PLZF (resistant to ATRA) - ZBTB16 and STAT5B respond poorly to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapies - ZBTB16 at 11q23 - ZBTB16::RARA shows a predominance of cells with regular nuclei, many granules, usually an absence of Auer rods, neutrophils with pseudo--Pelger--Huët changes, and strong myeloperoxidase reactivity - STAT5B at 17q21 - t(5;17) -- NPM1 - t(11;17) -- NuMA - CD13+, CD33+ (bright), CD117+ - CD34-, HLA-DR- - CD2+, CD34+ in microgran Acute myeloid leukemia with RUNX1::RUNX1T1 fusion - Blast may be \< 20% - **Detection of RUNX1::RUNX1T1 t(8;21)(q22;q22)** - Not fulfilling dx MN post cytotoxic therapy - del(9q), loss of X in F and loss of Y in M - Blasts are **large**, with abundant **basophilic** cytoplasm, often containing numerous azurophilic ("salmon pink") granules and **perinuclear clearing (hof)** and occasional long thin auer rods - **Bright CD34 and aberrant expression of the lymphoid markers CD19 and cCD79a** - **Usually MPO +, PAX5 +** - **CD33 usually neg** - KIT p.D816 in adults correlates with a lower relapse-free survival rate, whereas hyperdiploidy and/or the presence of del(9q) is associated with a longer overall survival Acute myeloid leukemia with CBFB::MYH11 fusion - Blasts may be **\< 20**% - **CBFB::MYH11, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)** - **Trisomy 22** - Not fulfilling diagnostic criteria for myeloid neoplasm post cytotoxic therapy - **Favorable prognosis** - **Monocytic diff w/ variable \# of eos having large purple-violet granules** - **MPO and Toludine blue negative** - Marrow eosinophilia w/ abnormal eosinophils is common - naphthol AS-D CAE reaction, which is normally negative in eosinophils, faintly positive - 2 aberrant blast populations are usually identified may be CD2+ - 1\. CD45-dim immature blasts, + CD34 and myeloid markers such as CD13, KIT (CD117), and MPO - 2\. more mature mono CD45-bright, monocytic Ag such as CD14, CD64, and lysozyme, in addition to myeloid markers, but lacks CD34 expression Acute myeloid leukemia with DEK::NUP214 fusion - Blasts may be \< 20% - **DEK::NUP214 fusion, t(6;9)(p22.3;q34.1) -- poor prog** - fusion disrupt the localization of proteins essential for nucleocytoplasmic transport - **FLT3 ITD** co mutation is common, no TKD -- does not affect prognosis - **Present w/ anemia and thrombocytopenia** - Multilineage dysplasia and erythroid hyperplasia is common - **Hypercellular BM w/ basophilia** - exclude myeloid neoplasm post cytotoxic therapy - CD13, CD33, CD34, CD38, KIT (CD117), CD123, HLA-DR, and MPO - CD7, CD9, CD15, CD64, and TdT are variably expressed, and CD34 may be negative - **High WBC count is predictive of shorter OS** Acute myeloid leukemia with RBM15::MRTFA (MKL1) FUSION t(1;22)(p13.3;q13.1) - AML characterized by **megakaryocytic differentiation** - Infants/young children \ 20% blasts** expressing a myeloid immunophenotype in the BM and/or peripheral blood - Detection of BCR::ABL1 at initial diagnosis - Lack of features of CML before or at diagnosis or after therapy - Cryptic del w/in IG and TR genes and freq w/ losses of IKZF1 and/or CDKN2A/B genes detected by array comparative genomic hybridization - RUNX1 mutations are common - CD34, HLA-DR, and myeloid Ag (CD13, CD33, and KIT \[CD117\]). Exp of CD7, CD19, and TdT is not uncommon Acute myeloid leukemia with KMT2A rearrangement - Myeloid neoplasm with ↑ PB/BM blasts (may be \< 20%), or the presence of a myeloid sarcoma - **MC genetic abnormality in peds** - **Often w/ ↑↑ WBC** - Monocytic phenotype - Gingival hypertrophy common - **CD33**, CD65, **CD4**, CD15, HLA-DR, and lysozyme - **CSPG4 (NG2)** - r/o myeloid neoplasm post cytotoxic therapy - KMT2A::MLLT3 and KMT2A::MLLT10 - can present as AMkL - KMT2A on chromosome 11q23.3 is fused many partners - **t(11;16)(q23;p13) - KMT2A::CREBBP is presumptive evidence malignancy and cytotoxic therapy** - Commonly seen after use with topo II inhibitors - dx as myeloid neoplasm post cytotoxic therapy - ABI1, AFDN, AFF1, MLLT1, and MLLT10 have been associated with a high risk of relapse Acute myeloid leukemia with MECOM rearrangement - Blasts may be \< 20% - MECOM rearrangement; no hx of MPN or dx criteria of MN post cytotox - **inv(3)(q21.3q26.2), t(3;3)(q21;q26), t(3;21)(q26.2;q22), or t(3;12)(q26.2;p13)** - High CD34 expression is MC with inv(3) than with t(3;3) - CD34, CD33, CD13, KIT (CD117), and HLA-DR; most are CD38-positive, with aberrant CD7 expression frequently observed - PB: **giant platelets, thrombocytosis, anemia and occasional Pelger Huet like neutrophils** - BM aspirate shows multilineage dysplasia w/ dysmegakaryopoiesis (micromegs) being MC Acute myeloid leukemia with NUP98 rearrangement - Characterized by chromosomal translocations involving NUP98 on chromosome 11p15.4 and various partner genes - Detection of NUP98 rearrangement and/or specific fusion products such as NUP98::NSD1 - Loss of RB1 (at 13q14) is particularly associated with NUP98::KDM5A Acute myeloid leukemia with NPM1 mutation - Blasts may be \< 20% - Detection of NPM1 mutation - No history of exposure to cytotoxic therapy - Some patients may present initially with myeloid sarcoma involving the skin, gingiva, lymph nodes, or other extramedullary sites - Often anemia, thrombocytopenia and ↑ WBC counts than other - F\>M - Common FLT3 ITD mutation - BM is hypercellular w/ multilineage dysplasia - Commonly have CD34 negative blasts - CD33, KIT (CD117), and CD123 expression is common, whereas CD13 is usually low - MC normal karyotype Acute myeloid leukemia with CEBPA mutation - **≥ 20% blasts** with a myeloid immunophenotype in the bone marrow or blood - Presence of biallelic mutations in CEBPA, or a single mutation located in the bZIP region - Absence of criteria allowing for classification into other AMLs with defining genetic abnormalities - Not fulfilling diagnostic criteria for myeloid neoplasm post cytotoxic therapy - Detection of biCEBPA should raise suspicion of a germline CEBPA variant and referral for genetic counselling - Blast cells displays the erythrophagocytosis characteristic for this genetic aberration Acute myeloid leukemia, myelodysplasia-related - ≥ 20% blasts in blood or marrow - Presence of at least one of the following two criteria - \(1) a history of MDS or MDS/MPN - \(2) one or more cytogenetic or molecular abnormalities listed - Absence of the following - a history of exposure to cytotoxic therapy, a history of myeloproliferative neoplasm, criteria for AML with defining genetic abnormalities, and criteria for myeloid neoplasms associated with germline predisposition - Defining cytogenetic abnormalities - Complex karyotype (at least three abnormalities) - 5q deletion or loss of 5q due to unbalanced translocation - Monosomy 7, 7q deletion, or loss of 7q due to unbalanced translocation - 11q deletion - 12p deletion or loss of 12p due to unbalanced translocation - Monosomy 13 or 13q deletion - 17p deletion or loss of 17p due to unbalanced translocation - Isochromosome 17q - idic(X)(q13) - Defining somatic mutations: - ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 Acute myeloid leukemia with other defined genetic alterations CBFA2T3::GLIS2 -- inv(16)(p13q24) - Megakaryoblastic - **strong CD56 expression**, variable or moderate CD34, variable KIT (CD117), and negative expression of CD7, CD11b, CD13, CD36, CD45, CD38, and HLA-DR - IHC staining with von Willebrand factor is positive in biopsy sections KAT6A::CREBBP -- t(8;16)(p11.2;p13.3) - Myelomonocytic/monocytic - Erythrophagocytosis - HLA-DR, CD15, MPO, CD13, CD33, sometimes **CD56, CD14** - Negative CD24 and 117 - Recurrent mut in: *ASXL1*, *FLT3*, *TP53*, *RUNX1*, *TET2*, complex FUS::ERG- t(16;21) (p11.2;q22) - Any, except erythroid differentiation w/Auer rods - +8, +10, complex k type - Poor prog MNX1::ETV6\-- t(7;12) (q36;p13) - Min diff or w/o maturation - Positive: CD34, HLA-DR, often KIT (CD117), T-cell markers CD7 and CD4 - +19, sometimes +8 - Poor prog NPM1::MLF1 \-- t(3;5) (q25;q35) - +8, complex - Poor prog Acute myeloid leukemia defined by differentiation Acute myeloid *leukemia* with minimal differentiation - ≥ 20% blasts in BM and/or blood, lacking morp and cytochemical evidence of myeloid differentiation - positive for at least 2 myeloid-associated immunophenotypic markers (e.g. CD13, CD33, CD117) - Not fulfilling diagnostic criteria for AML types with defined genetic alterations - Not fulfilling dx criteria for MPAL; not fulfilling dx criteria for myeloid neoplasm post cytotoxic therapy - Rearrangements of BCL11B on chromosome 14q32 Acute myeloid leukemia without maturation - **+ for MPO and/or Sudan Black B (≥ 3%).** They are usually negative for naphthol AS-D CAE - blasts are medium/ large, with ↑ N:C ratios, pale grey-blue cytoplasm, round, or slightly indented nuclei, and one to two distinct nucleoli. Acute myeloid *leukemia* with maturation - ≥ 20% blasts BM/PB, with cytochemical evidence of myeloid diff and morph features of gran maturation in ≥ 10% of bone marrow cells - \+ \>=2 myeloid-associated markers (e.g. MPO, CD13, CD33, CD117); monos \< 20% of bone marrow cells - Not fulfilling criteria for AML types with defined genetic alterations - Not fulfilling diagnostic criteria for myeloid neoplasm post cytotoxic therapy - Intermediate to strong expression of MPO and 2+ myeloid-associated antigens, such as CD13, CD33, and CD117 - \+ for CD34 and HLA-DR. and markers associated with gran maturation: CD11b, CD15, and CD65 - onocytic markers (e.g. CD11c, CD14, CD36, and CD64) is rare. CD7 and CD56 are occasionally expressed - Expression of CD2, CD5, CD19, c/sCD22, and cCD79a is uncommon Acute basophilic *leukemia* - ≥ 20% blasts, with ↑ immature and mature basophils - Blasts/basophils metachromatic on toluidine blue staining and negative for MPO, Sudan Black B, and NSE - Blasts positive for at least two myeloid-associated markers (e.g. myeloperoxidase, CD13, CD33, CD117) - Not fulfilling criteria for AML types with defined genetic alterations; not fulfilling diagnostic criteria for myeloid neoplasm post cytotoxic therapy - Typically + CD9 and/or CD203c, and negative for HLA-DR - A rare subtype occurs in infant boys, characterized by t(X;6)(p11;q23) generating a MYB::GATA1 fusion gene - basophilic differentiation by inducing the expression of IL-33 and nerve growth factor (NGF), the ligands of IL1RL1 and NTRK1, respectively - \+ for CD11b, CD13, CD33, CD34, CD38, CD123, and CD203c. Blasts may also express CD9 and weak CD117 but are usually negative for HLA-DR - Blasts and immature forms show characteristic metachromatic staining with toluidine blue - A lack of CAE reactivity can distinguish basophilic blasts from mast cells Acute myelomonocytic *leukemia* - ≥ 20% blasts and blast equivalents (promonocytes) in bone marrow and/or blood; positive for myeloid-associated markers (e.g. myeloperoxidase, CD13, CD33, CD117) - Maturing granulocytes constitute ≥ 20% of bone marrow cells - Monocyte-lineage cells constitute ≥ 20% of bone marrow cells - Not fulfilling criteria for AML types with defined genetic alterations - Not fulfilling diagnostic criteria for myeloid neoplasm post cytotoxic therapy - Blasts are positive (≥ 3%) for myeloperoxidase - Monoblasts, promonocytes, and monocytes are typically positive NSE +/- MPO-+ granules Acute monocytic *leukemia* - ≥ 20% blasts and blast equivalents (promonocytes) in bone marrow and/or blood - ≥ 80% of the leukemic cells are monos and their precursors, including monoblasts and promonocytes - \ 70% | Variable | | genetic | often | translocati | aberrant | | | alterations | complex | ons | karyotype | | | ** | k-types | | | | | | | *KMT2A* fus | Typically | | | | Loss of 5q, | ions | unbalanced | | | | 7q, 17p | | chromosome | | | | | t(15;17)(q2 | aberrations | | | | Loss of 3p, | 4;q21) | | | | | 11q, 12p, | | \- 5q, 7q, | | | | 13q, 18q, | inv(16)(p13 | 17p | | | | 21q | q22) | | | | | | | \- 12p, | | | | Trisomy 8 | t(8;21)(q22 | 13q, 18q, | | | | and 11 | ;q22) | 20q | | | | | | | | | | Frequently  | t(3;21)(q26 | \+ 1q, 21q | | | | *TP53* dele | ;q22) | | | | | tions | | Freq del | | | | + *TP53* mu | | *TP53*  | | | | tations | | + *TP53* mu | | | | | | t | | +-------------+-------------+-------------+-------------+-------------+ | **Outcome** | Unfavourabl | Favourable; | Poor prog: | Variable | | | e | like | low- to | | | | | de novo AML | intermediat | | | | | (if | e-risk | | | | | appropriate | IPSS-R^b^ s | | | | | treatment | ubgroups | | | | | can be | show | | | | | given)  | inferior | | | | | | outcomes | | | | | | compared | | | | | | with | | | | | | de novo MDS | | +-------------+-------------+-------------+-------------+-------------+ **Alkylating agents** ------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin C, thiotepa, lomustine **Ionizing radiation therapy** Large fields containing active bone marrow **Topoisomerase II inhibitors** Etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, dactinomycin **Others** Antimetabolites: thiopurines, mycophenolate mofetil, fludarabine Antitubulin agents (usually in combination with other agents): vincristine, vinblastine, vindesine, paclitaxel, docetaxel PARP1 inhibitors Myeloid neoplasms associated with germline predisposition +-----------------------------------+-----------------------------------+ | **Disorder** | **Recurrent somatic alterations** | +===================================+===================================+ | **MN with germline predisposition | | | without a pre-existing platelet | | | disorder or organ dysfunction** | | +-----------------------------------+-----------------------------------+ |  ***CEBPA*-associated familial | Alteration in the | | AML** | second *CEBPA* allele | +-----------------------------------+-----------------------------------+ |  ***DDX41*** | Mutation in the | | | second *DDX41* allele | | | (*DDX41* p.R525H) | +-----------------------------------+-----------------------------------+ |  ***TP53*** | Complex karyotype, alteration in | | | the second *TP53* allele | +-----------------------------------+-----------------------------------+ | **Myeloid neoplasms with germline | | | predisposition and pre-existing | | | platelet disorders** | | +-----------------------------------+-----------------------------------+ |  **Familial platelet disorder w/ | w/in the myeloid malignancy, | | associated myeloid** | alteration in the 2^nd^ | | |  *RUNX1* allele is common, | | | *GATA2*, *CBL*, *DNMT3A*, *KRAS*, | | | and *FLT3*, and monosomy 7 | +-----------------------------------+-----------------------------------+ | **Myeloid neoplasms with germline | | | predisposition and potential | | | organ dysfunction** | | +-----------------------------------+-----------------------------------+ |  ***GATA2* haploinsufficiency | *RUNX1*, *SETBP1*, *IKZF1*, *CRLF | | syndromes** | 2*, | | | monosomy 7, trisomy 8 | +-----------------------------------+-----------------------------------+ |  **Severe congenital | Monosomy 7, *RUNX1*, *CSF3R* | | neutropenia** | | +-----------------------------------+-----------------------------------+ |  **Schwachman--Diamond syndrome** | *TP53*, monosomy 7 / del(7q) | | | (*TP53* mutations in | | | Schwachman--Diamond syndrome are | | | not diagnostic of MDS, nor do | | | they portend impending malignant | | | transformation, and they can | | | persist at a low VAF for many | | | years without progression; common | | | cytogenetic abnormalities that | | | are not associated with a high | | | risk of progression to MDS/AML | | | include 20q deletion and | | | isochromosome 7q) | +-----------------------------------+-----------------------------------+ |  **Fanconi anaemia** | Gain of 3q, deletion of 7q, | | | monosomy 7, complex, *RUNX1* | +-----------------------------------+-----------------------------------+ |  ***CBL* syndrome** | Acquired uniparental disomy of | | | the mutated allele (except in | | | occasional cases with splice-site | | | mutations) | +-----------------------------------+-----------------------------------+ |  **Neurofibromatosis type 1** | LOF alteration of the 2^nd^ | | | allele | +-----------------------------------+-----------------------------------+ |  ***SAMD9*-related syndromes** | Monosomy 7, loss of (partial) | | | chromosome 7 carrying | | ***SAMD9L*-related syndromes** | the *SAMD9L* variant | +-----------------------------------+-----------------------------------+ Myeloid proliferations associated with Down syndrome - AML risk 150-fold higher in young children w/ DS than normal - Myeloid leukemia associated with Down syndrome - Confirmation of DS - MN with persistent increased peripheral blood and/or bone marrow blasts (may be \< 20%) - Detection of exon 2/3 GATA1 mutation - Clin - Med age onset 1.6 y/o - May have fibrosis - Transient abnormal myelopoiesis (TAM) - Confirmation of DS - PB leukocytosis with increased blasts - Detection of exon 2/3 GATA1 mutation (GATA1 exon 2/3 sequencing should be performed in all cases with \> 10% peripheral blood blasts - Clin - Usually w/in 7 days of birth Myeloid/lymphoid neoplasms Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions Myeloid/lymphoid neoplasm with PDGFRA rearrangement - Myeloid or (less frequently) lymphoid neoplasm, usually w/ prominent peripheral and/or tissue eos - PDGFRA fusion gene, usually with FIP1L1 - Most are cytogenetically cryptic deletion of 4q12, = formation of the FIP1L1::PDGFRA fusion - Serum tryptase is often elevated (≥ 12 ng/mL) - Can cause irreversible cardiac damage, pulmonary fibrosis and venous/arterial thrombotic events - Marked increased B12 - Strong male predominance - Charcot crystals may be seen - Eosinophils may show expression of activation markers such as CD23, CD25, and CD69 - Mast cells typically show aberrant CD25, but are CD2 neg Myeloid/lymphoid neoplasm with PDGFRB rearrangement - Myeloid or lymphoid neoplasm, often w/ prominent eosinophilia w/ varying degrees of neutrophilia or monocytosis - PDGFRB fusion gene - **Exclusion of BCR::ABL1-like B-ALL without evidence of an associated myeloid neoplasm** - Male predominance - MC **is t(5;12)(**q32;p13.2), resulting in **ETV6::PDGFRB** Myeloid/lymphoid neoplasm with FGFR1 rearrangement - MPN or MPN/MDS w/ prominent eosinophilia, w/w/o neutrophilia or monocytosis or w/ increased blasts of myeloid or T- or B-cell lineage, or of mixed phenotype - Presence of an FGFR1 fusion gene by t(8;13)(p11.2;q12.1) or an alternative translocation partner - MC present with HSP and LAD - ZMYM2::FGFR1 is associated with a high incidence of T-lymphoblastic leukemia - BCR::FGFR1 and TPR::FGFR1 have been associated with myeloproliferative neoplasms with basophilia, morphologically resembling chronic myeloid leukemia (CML) - CEP43::FGFR1 and CNTRL::FGFR1 frequently impart a chronic myelomonocytic leukemia--like phenotype Myeloid/lymphoid neoplasm with JAK2 rearrangement - Myeloid or lymphoid neoplasm, often w/ prominent eosinophilia - Presence of a JAK2 fusion gene - most common fusion partner for this entity is PCM1 8p22 - **unique and include a typical triad of bone marrow hypercellularity with eosinophilia, large aggregates of immature erythroid precursors, and myelofibrosis** - Exclusion of BCR::ABL1-like B-ALL without evidence of an associated myeloid neoplasm - HSP and LAD are common - Striking male predom - ETV6::JAK2 may present with B-cell lymphoid blast-phase disease - BCR::JAK2 may present with MN that resemble MDS/MPN with neutrophilia or B-ALL with BCR::ABL1-like features - Resistant to first- and second-generation tyrosine kinase inhibitors Myeloid/lymphoid neoplasm with FLT3 rearrangement - Myeloid or lymphoid neoplasm, with or without associated eosinophilia, with chromosomal rearrangements leading to the formation of a FLT3 (13q12 )fusion gene - MC partner gene is ETV6/12p131 Myeloid/lymphoid neoplasm with ETV6::ABL1 fusion - a hematopoietic (myeloid or lymphoid) neoplasm, usually in the chronic phase; presence of ETV6::ABL, t(9;12)(q34;p13) - Eosinophilia is nearly universal in cases manifesting as myeloid neoplasms and less common in cases presenting as lymphoblastic leukemia Myeloid/lymphoid neoplasms with other tyrosine kinase gene fusions Acute leukemias of mixed or ambiguous lineage +-----------------------------------+-----------------------------------+ | **Lineage** | **Criterion** | +===================================+===================================+ | **B lineage** | | +-----------------------------------+-----------------------------------+ |  CD19 strong | One or more of the following also | | | strongly expressed: CD10, CD22, | | | CD79a | +-----------------------------------+-----------------------------------+ | **OR** | | +-----------------------------------+-----------------------------------+ |  CD19 weak | Two or more of the following also | | | strongly expressed: CD10, CD22, | | | CD79a | +-----------------------------------+-----------------------------------+ | **T lineage** | | +-----------------------------------+-----------------------------------+ |  CD3 (cytoplasmic or surface) | Intensity in part exceeds 50% of | | | that of mature T cells by flow | | | cytometry | | | | | | **OR** | | | | | | Immunocytochemistry positive with | | | non--ζ-chain reagent | +-----------------------------------+-----------------------------------+ | **Myeloid lineage** | | +-----------------------------------+-----------------------------------+ |  Myeloperoxidase | Intensity in part exceeds 50% of | | | mature neutrophil level | +-----------------------------------+-----------------------------------+ | ** OR** | | +-----------------------------------+-----------------------------------+ |  Monocytic differentiation | 2+ : NSE, CD11c, CD14, CD64, | | | lysozyme | +-----------------------------------+-----------------------------------+ Acute leukemia of ambiguous lineage with defining genetic abnormalities Mixed-phenotype acute *leukemia* with BCR::ABL1 fusion - ≥ 20% blasts in BM and/or PB w/ an immunophenotype that meets the diagnostic criteria for MPAL - BCR::ABL1 and/or t(9;22)(q34;q11.2) detected at initial diagnosis - No prior or subsequent evidence of CML; no history of exposure to cytotoxic therapy Mixed-phenotype acute *leukemia* with KMT2A rearrangement - Usually has a B/myeloid immunophenotype - Blasts may be \1 y/o - If lung---d/t smoking - Multisystem LCH (MS-LCH) - Younger - Occurs in two or more organ systems - Bone, skin, liver, and spleen involvement, with additional extraosseous involvement, including LN involvement, visceral mass lesions, and cystic pulmonary nodules - MS-LCH with bone marrow, spleen, or liver involvement is considered high-risk - Neurodegenerative effects: - b/l and symmetrical MRI signal intensity ∆, often cerebellum, brainstem, and basal ganglia - MAPK pathway gene mutations are present in the majority (\> 85%) of cases, with near-universal expression of phosphorylated ERK - BRAF pV600E are MC - MAP2K1 Langerhans cell sarcoma - Pleomorphic histiocytes with high-grade cytology; increased mitoses; immunoreactivity for CD1a, S100, and CD207, any of which can be focal - Also + for vimentin, CD68, cyclin D1, and HLA-DR - Mutations in MAPK pathway genes, including KRAS - Clinical findings of rapid tumor progression - Subtypes: - Primary Langerhans cell sarcoma - 2^o^ Langerhans cell sarcoma (following or associated with another hematological neoplasm) - Has been a/w FL and CLL Other dendritic cell neoplasms Indeterminate dendritic cell tumour - Tissue infiltration by cells morphologically reminiscent of Langerhans cells - Lesional cells positive for S100 and CD1a, and negative for CD207 (langerin) - Absence of the typical picture of multisystem Langerhans cell histiocytosis (lytic bone lesion, pituitary dysfunction - Generalized skin eruption is MC presentation - Only rare BRAF Interdigitating dendritic cell sarcoma - Prolif of spindle to epithelioid cells with abundant cytoplasm and indistinct cell borders - Vesicular nuclei with or without nuclear grooving - \+ for S100 (w/ dendritic cell processes highlighted) and 1+hema/lymph marker (e.g. CD45, CD4, CD43) - Negative for Langerhans cell & FDC markers; lack of expression of melanocytic markers - Solitary lymph node involvement is most common - Usually + for fascin, CD68, lysozyme, CD4, CD45, p75-NGFR, and β-catenin Histiocyte/macrophage neoplasms Histiocytic neoplasms Juvenile xanthogranuloma - Circumscribed lesion w/ histiocytes (commonly foamy) lacking significant nuclear pleomorphism - Dermal macrophage immunophenotype (CD68, CD163, and factor XIIIa) - positive for CD68, CD163, CD4, CD14, factor XIIIa, and fascin - Negativity for CD1a, CD207 (langerin), and ALK - Touton giant cells - Clinical exclusion of Erdheim--Chester disease - If CD163-positive macrophages stain for mutation-specific BRAF VE1, adult patients should be clinically evaluated for Erdheim--Chester disease - Generally confined to the skin, with a predilection for the head and neck, upper trunk, and proximal extremities - V rare in adults Erdheim-Chester disease - Neoplasm characterized by an accumulation of mature histiocytes in many different organs and associated with inflammation and fibrosis - ECD can be associated with Langerhans cell histiocytosis in \> 10% of cases (known as mixed histiocytosis) - Symmetrical osteosclerosis of the leg bones is highly suggestive - Detection of mass-like infiltration of the right atrium on MRI (in 33% of cases) or sclerosis of sinuses of the face on CT are also suggestive of ECD - BRAF p.V600E - CD163, CD68, CD14, and CD4, and negative for CD1a and CD207. They may also be positive for factor XIIIa, fascin, and (less commonly) S100 Rosai-Dorfman disease - Large histiocytes with round nuclei, prominent nucleoli, and abundant pale cytoplasm, often with emperipolesis - Abundant plasma cells in background; positive immunostaining for S100, which also highlights the emperipolesis - In diagnostically challenging cases, expression of OCT2 and cyclin D1 in the absence of CD1a, CD207 (langerin), and ALK - Germline mutations - nucleoside transporter gene SLC29A3 (H syndrome / Faisalabad histiocytosis) - FAS deficiency with heterozygous germline mutations in FAS (TNFRSF6) (autoimmune lymphoproliferative syndrome) +-----------------------------------+-----------------------------------+ | **Subtype** | **Characteristic features** | +===================================+===================================+ | **Classic (nodal) RDD** | MC involves cervical LN (87%), | | | inguinal (26%), axillary (24%), & | | | mediastinal (15%) LN | +-----------------------------------+-----------------------------------+ | **Extranodal RDD** | Extranodal sites involved in 43% | | | of patients: MC the nasal cavity, | | | paranasal sinuses, salivary | | | gland, skin, soft tissue, upper | | | respiratory tract, bone, | | | retro-orbital tissue, and CNS, | | | and less commonly single organs | | | | | | Splenic involvement is rare | | | | | | Cases of disseminated RDD have | | | been rarely reported | +-----------------------------------+-----------------------------------+ | **Familial RDD** | Described in a/w germline | | | mutations | | | in *SLC29A3* (H syndrome / | | | Faisalabad histiocytosis; 20%) | | | or *FAS* (*TNFRSF6*) (ALPS; 41%) | +-----------------------------------+-----------------------------------+ | **Neoplasia-related RDD** | Described in a/w lymphoma, | | | leukaemia, and other | | | histiocytoses including | | | Langerhans cell histiocytosis and | | | Erdheim--Chester disease | +-----------------------------------+-----------------------------------+ | **Immune-related RDD** | Described in a/w SLE, idiopathic | | | juvenile arthritis, autoimmune | | | haemolytic anaemia, and HIV | | | | | | May be associated with ↑ IgG4+ | | | plasma cells, although other | | | features of IgG4-related disease | | | are absent | +-----------------------------------+-----------------------------------+ ALK-positive histiocytosis - Tissue infiltration by aggregates and sheets of histiocytes lacking high-grade atypia - Positive immunostaining for two or more histiocytic markers (CD163, CD68, CD14, CD4, lysozyme) - histiocytes (including foamy histiocytes) are ALK-positive (by definition), in a cytoplasmic pattern or (rarely) in a membranous or Golgi dot pattern, but practically never in a nuclear pattern - variable positivity for histiocytic markers, such as CD68, CD163, CD14, CD4, and lysozyme. Some cases show staining for S100, cyclin D1, or OCT2 - Fascin and factor XIIIa are commonly positive, whereas CD30, CD1a, and CD207 (langerin) are negative. The Ki-67 proliferation fraction is low. - Neuro involvement is common - multisystem systemic form occurs in infancy - multisystem (others) and single-system forms can occur in any age group, including children and adults - characterized by ALK gene translocation, most commonly with exon 24 of KIF5B fused to exon 20 of ALK Histiocytic sarcoma - Tumor composed of non-cohesive large cells with abundant eosinophilic cytoplasm - Variably pleomorphic neoplastic cells with reniform, grooved, or irregularly folded nuclei and distinct nucleoli - Positive immunostaining for two or more histiocytic markers; negative for CD1a, CD207 (langerin), CD21, CD35 - Tumorous proliferations of acute monocytic leukemia are excluded - Expression of PU.1, CD31, CD45, CD45RO, and CD4 is common, whereas S100 immunoreactivity is variable and usually patchy if positive Chapter 4: B-cell lymphoid proliferations and lymphomas ======================================================= Tumor-like lesions with B-cell predominance ------------------------------------------- ### Reactive B-cell-rich lymphoid proliferations that can mimic lymphoma ### PTGC - Single LN, asyx, young - Micro - Exploded GC-disrupted follicles - Follicular hyperplasia - Epithelioid histiocytes around transformed follicle - Association -  NLP Hodgkin's (CD20 popcorn with rosetting CD57 T-cell) ### Infectious Mono - Clinical - Self-limited, cervical LN, teens - Micro - Paracortical immunoblasts - Sinuses with monocytoid B-cells, immunoblasts - Heterogenous population paracortex - Focal necrosis/apoptosis - Hodgkin like cells-immunoblasts - Smaller, no halo, Hof - CD30+, CD15-, CD45+, EBV+ - Atypical cells - PB - CD8+ cells = atypical lymphs - IHC - LMP+ - EBER+ - CD30+   ### HIV LAD (not in WHO) Micro (3 stages) - Follicular hyperplasia   - Giant irregular **GC-geographic** - RBC in GC - Disappearing mantle zone - Warthin-Finkeldey GC - Follicular involution - Involuted follicles - Follicular lysis-small lymphs disrupt GC - CD8\>CD4 (inversion) - Lymphocyte depletion - Small, fibrotic, vascular - No follicles - Lots of histiocytes-RBCs, dendritic cells ### Toxo - Posterior cervical LN​ - Toxoplasma gondii​ - Serology to DX​   - Micro​ - **Follicular hyperplasia**​ - **Epithelioid histiocytes near/in GC**​ - **Monocytoid B-cell hyperplasia**​ ### Kimura - Young Asian men​ - Enlarging nodular mass, head/neck, postauricular​ - PB = eosinophilia, IgE​ - Tx = removal, steroids, radiation​ - Micro​ - **GC hyperplasia**​ - **Massive perinodal eosinophilic infiltrate**​   - Eosinophilia with microabscesses​ - Cortical and paracortical hypervascularity​ - Can have **Warthin-Finkeldey GC**​ ### Dermatopathic LAD - Chronic dermatoses​ - Axillary, inguinal​ - Micro​ - Paracortex with pale histiocytes, melanin​ - Langerhan's cells, interdigitating retciular cells​ - Both stain s100, cd1a​ - **Paracortical hyperplasia w/ ↑\# interdigitating dendritic cells, lengerhans cells andhistiocytes containing melanin** - Association​ - Mycosis fungoides (atypical T cells) ### Cat scratch lymphadenitis - Contact with cat​ - Bartonella henselae​ - Serology diagnosis​ - Looks just like lymphogranuloma vernerum in inguinal lymph nodes​ - **Stellate abscesses, granulomas**​ - **PMNs, monocytoid B-cell hyperplasia**​ - Granulomas outside LN​ - Warthin-Starry​ - Severe form is bacillary angiomatosis (pictured) - Typically immunocomp. - Micro​ - Vascular nodular proliferation​ - Amphophilic and eosinophilic material​ - Vascular spaces​ - IHC​ - Warthin-Starry ### Yersinia - Kids, food borne​ - Enterocolitis, pseudoappendicitis, mesenteric LAD​ - Necrotizing granulomas​ - Granulomas in GC ### IgG4-related disease - Immune-mediated dz characterized by mass-forming lesions with a LPL infiltrate rich in IgG4+ plasma cells and storiform fibrosis, usually with an elevated serum IgG4 titer - IgG4+ plasma cell--rich lymphoplasmacytic and eosinophilic infiltrate, and storiform fibrosis - IgG4+:IgG+ ratio (\> 40%) - Nodal presentation - Essential: presence of extranodal IgG4-RD (prior, synchronous, or subsequent development); polytypic IgG4+ plasma cells \> 400/mm^2^, and an IgG4+:IgG+ plasma cell ratio of \> 40%; exclusion of well-defined entities that mimic IgG4-RD (as listed above), hyper--IL-6 syndrome, and syphilis. - Desirable: + plasma cells and eosinophils in the fibrotic and/or interfollicular zones of lymph nodes ### LUpus lymphadenitis ### Unicentric Castleman disease - Concentric rings of CD21+, CD23+, CD35+, and (usually) CD106 (VCAM1)+ FDCs - Clinical -- 1LN (\>10 mm in short axis) or multiple enlarged LN in 1 station - Hyaline vascular - Most common, mediastinal in YA - Not a/w HHV8 infxn - **TdT + T cell lymphoblasts can be seen as rare cells or forming focal clusters** - Numerous small regressively transformed GC (grade 2-3 required) - Surrounded by expanded mantle zones - Twinning - Hypervascular interfollicular regions - Plasma cell - B sx, older -- grade 2-3 plasma cytosis - Follicular hyperplasia, Regressed/atrophic GC - Multiple GC in single follicle, twinning - Broad mantle zone, onion skinning - Penetrating vessels, lollipop - Interfollicular vascularity - PC/MC Type - Paracortical expansion plasma cells, polytypic ### Idiopathic multicentric Castleman disease - Lymphoproliferative disorder involving two or more lymph node sites, associated with systemic inflammatory symptoms and organ dysfunction related to hypercytokinaemia - ≥ 10 mm in short-axis diameter in at least **two lymph node stations** +-----------------------------------+-----------------------------------+ | **iMCD-NOS** | | +===================================+===================================+ | **Major criteria (all three | | | required)** | | +-----------------------------------+-----------------------------------+ | Enlarged lymph nodes | Enlarged lymph nodes in at least | | | two lymph node stations | +-----------------------------------+-----------------------------------+ | Morph features c/w Castleman | Including: | | disease spectrum | | | | Grade 2--3 regressed | | | follicles **OR** grade 2--3 | | | plasmacytosis | +-----------------------------------+-----------------------------------+ | KSHV/HHV8 LANA IHC | Negative | +-----------------------------------+-----------------------------------+ | **Minor criteria** | Need at least two of the criteria | | | below, with at least one | | | laboratory criterion | +-----------------------------------+-----------------------------------+ | Laboratory criteria | Anaemia (\ 2 mg/dL and ≥3 | | | lab/clinical criteria that are | | | not related to other HIV | | | infection complications | +-----------------------------------+-----------------------------------+ | Laboratory criteria | Hyponatraemia, albuminemia anemia | | | and thrombocytopenia (including | | | autoimmune haemolytic anaemia) | | | | | | For flares: ↑KSHV/HHV8 viral load | +-----------------------------------+-----------------------------------+ | Clinical criteria | Splenomegaly, Fatigue, Weight | | | loss, Respiratory symptoms, | | | Gastrointestinal symptoms, | | | Neuropathy, Headache, | | | edema/effusions, Rash, Myalgia | +-----------------------------------+-----------------------------------+ Precursor B-cell neoplasms -------------------------- ### B-Prolymphocytic Leukemia/Lymphoma**- ICC ONLY** ### B-lymphoblastic Leukemias/lymphomas - Essentially always express the B lineage--associated antigens CD19, cytoplasmic CD79a, c & sCD22 - Need either strong sCD19 and 1 additional B cell marker (CD10, CD22 or CD79a) or if sCD19 is weak need 2 additional markers - Tx can be inotuzumab ozogamicin (anti CD22) - PAX5 is the most sensitive and specific B cell marker by IHC - NF384-rearranged, DUX4-rearranged, and PAX5 p.P80R B-ALL may show monocytic differentiation #### B-lymphoblastic Leukemia/lymphoma with high hyperdiploidy - 51--65 chromosomes, characterized by recurrent, non-random gains of one or more copies of entire chromosomes (usually the X chromosome and chromosomes 4, 6, 10, 14, 17, 18 and 21) in the absence of type-defining gene fusions and rearrangements - Low PB WBC counts - Favorable prog - RAS pathway (KRAS, NRAS, FLT3, PTPN11) and CREBBP mutations #### B-lymphoblastic Leukemia/lymphoma with hypodiploidy - ≤ 43 chromosomes - Subtypes - Near-haploid B-ALL/LBL with hypodiploidy (24--31 chromosomes) - RTK/RAS pathway mutations (NF1), IKZF3 deletion - Unfavorable - Low-hypodiploid B-ALL/LBL with hypodiploidy (32--39 chromosomes) - \~50% have germline TP53 variants (Li-Fraumeni) - RB1, CDKN2A/B, IKZF2 deletions; TP53 mutations (as many as 50% of TP53 mutations are germline variants) - Unfavorable - High-hypodiploid B-ALL/LBL with hypodiploidy (40--43 chromosomes) - Favorable #### B-lymphoblastic Leukemia/lymphoma with iAMP21 - Intrachromosomal amplification of chromosome 21 - Gains and gross rearrangements inv long arm of chrom 21 - Individuals with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have a \> 2700-fold IR - **FISH definition of B-ALL/LBL with iAMP21 is ≥ 5 copies of RUNX1 per cell, with ≥ 3 copies on a single abnormal chromosome 21** - P2RY8::CRLF2 fusion occurs at a higher frequency than in other B-ALL subtypes - Unfavorable #### B-lymphoblastic Leukemia/lymphoma with BCR::ABL1 fusion - B-lineage markers, blasts frequently express the myeloid-associated antigens CD13 and CD33. CD25 (IL2RA) is also frequently expressed - \+ of a Ph chromosome, monosomy 7, +8, +X, +21, and del(9p) commonly associated 2^o^ abnormalities - \>80% of patients with B-ALL/LBL with BCR::ABL1 fusion have del or splicing abnormalities of IKZF1 - **Unfavorable prognosis** - KZF1 deletions (in 80%) co-occurring with deletions of PAX5 and CDKN2A/B - Unfavorable #### B-lymphoblastic Leukemia/lymphoma with BCR::ABL1-like features - 50% of cases have rearrangements of CRLF2 with IGH (t(X/Y;14)) or P2RY8 (intrachromosomal del in the pseudoautosomal region of the X or Y chromosome) that lead to aberrant expression of CRLF2 - CRLF2 has poor response to gleevac - DS patients have higher frequency of CRLF2 translocations - ↑ WBC at presentation - If iAMP21 is present, it should take precedence - Unfavorable - Cases of MLNE w/ PDGFRB or PCM1-JAK2 fusion presenting w features c/w B cell neoplasm are best assigned to this category #### B-lymphoblastic Leukemia/lymphoma with KMT2A rearrangement - KMT2A (also known as MLL) is a histone H3 lysine 4 (H3K4) methyltransferase - t(4;11), typically have a CD19+, CD10−, CD24− immunophenotype and are often positive for the myeloid markers CD15 and CD65s, as well as the neural/glial antigen CSPG4 (NG2) - KMT2A rearranged cases more frequently have negative TdT - Unfavorable #### B-lymphoblastic Leukemia/lymphoma with ETV6::RUNX1 fusion - Rearrangement between ETV6 on chromosome 12p13.2 and RUNX1 on chromosome 21q22.1 - Most common recurrent translocation & w favorable prognosis - **Negative or partially positive CD9, CD20, and CD66c** - Myeloid-associated antigens, especially CD13 and CD33, are frequently expressed - ddPCR for monitoring responses #### B-lymphoblastic Leukemia/lymphoma with ETV6::RUNX1-like features - ETV6 rearrangement partners in this category identified to date include BCL2L14, BORCS5, CREBBP, MSH6, NID1, and PMEL - B-ALL/LBL with ETV6::RUNX1 fusion, this type also demonstrates a **CD27-positive, CD44-low-to-negative immunophenotype** - Fusions or copy-number alterations involving ETV6, ERG, FLI1, IKZF, or TCF3 are common - Unfavorable #### B-lymphoblastic Leukemia/lymphoma with TCF3::PBX1 fusion - Rearrangement between TCF3 on chromosome 19 and PBX1 on chromosome 1 - t(1;19)(q23;q13.3) - bright CD9 expression, dim to negative CD34 expression, and at least partial absence of CD20, in addition to CD19 and CD10 expression #### B-lymphoblastic Leukemia/lymphoma with IGH::IL3 fusion - Juxtaposition of the IGH enhancer and the IL3 promoter, with **characteristic PB & BM eosinophilia** - Balanced t(5;14)(q31.1;q32) that joins the IGH enhancer (14q32) to theIL3 gene promoter (5q31.1) - Frequent *IKZF1* deletion #### B-lymphoblastic Leukemia/lymphoma with TCF3::HLF fusion - Rearrangement between TCF3 at 19p13.3 and HLF at 17q22 - Often present with hypercalcaemia and coagulopathy - Dismal prognosis #### B-lymphoblastic Leukemia/lymphoma with other defined genetic alterations - Susceptibility to B-ALL/LBL has been described in patients with germline variants in the hematopoietic transcription factor gene PAX5 - Subtypes: - DUX4 rearrangement - **CD371 is seen in almost all cases and CD2 in a major subset** - **Monocytic differentiation** with expression of CD14, gain of CD45 and CD33, and loss of B-cell antigens is often seen early after induction therapy or dx - IGH are common, resulting in DUX4 overexpression and ERG deletions - Best outcome - MEF2D rearrangement - BCL9 is the most common translocation partner - Dim/absent CD10, positivity for CD38 and PKCμ; aberrant CD5 expression variable - ZNF384 rearrangement - Monocytic differentiation may be seen at diagnosis or early after induction therapy - CD10− , CD13+, CD33+, CD65−, CD15−, CD25 (25%), myeloperoxidase− (+ in MPAL) - Favorable for EP300::ZNF384 - Unfavorable for TCF3::ZNF384 - PAX5alt - Intermediate prognosis for children, unfavorable for adults - PAX5 p.P80R - PAX5 p.P80R may be unfavorable in children - Inactivating mut w/ a distinct expression profile and is commonly a/w deletion of alternate allele or copy-neutral LOH - CD2+, CD33+, CD65−, CD15− - NUTM1 rearrangement - Favorable - MYC rearrangement - Frequent mutations in genes involving RAS pathway, 1q gain - Unfavorable #### B-lymphoblastic Leukemia/lymphoma NOS Mature B-cell neoplasms ----------------------- ### Preneoplastic and neoplastic small lymphocytic proliferations #### Monoclonal B-cell lymphocytosis - Absolute **monoclonal** B cell count​ - Low count: ​ - CLL/SLL phenotype B cell count \ 0.5 x109/L and \5,000​ - Pseudofollicles-prolymphocytes, paraimmunoblast​ - Pale, ill-defined, no mantle zone​ - \~30% of cases, few cells in PC can stain with cyclin D1 and MYC​ - IHC​ - **CD20 (DIM), Cd79a,** ​ - **CD5, CD23, CD43**​ - **CD11c, IgM, IgD**​ - **sIg dim**​ - Molecular​ --**of all B cell neoplasms, CLL has strongest genetic influence** - Normal = 20%​ - Del(13q) = Good, most common​ - BCL2 dysregulation - Epigenetic mod thru del of miRNA-15a/16-1 on 13q14 (common in IgHV mut cases) - Trisomy 12 = poor (a/w CLL with atypical morphology, cleaved cytomorphology, lymphoplasmacytoid differentiation and proliferating large cells)​ - **Del (17p), del(11q), IgHV3-21 stereotyped BCR = poor​/worst prognosis** - TP53 mutation predicts resistance to chemo​ - Prognosis​ - CD38, Zap 70 = surrogate markers for IgH mutation status (lost)​ - Post GC = favorable, CD38, Zap70 --​ - Naïve B-cell = bad, CD38, Zap70+​ - IgH mutation status: the germline identity of the rearranged IGHV gene is \ 2.4 mitoses per PC or \> 40% Ki-67+ cells in PCs​ - Prolymphocytic progression (WHO only)​ - \>15% in PB​ - Vs prior WHO -- cases with \>55% prolymp are included in this category rather than B-prolymp leukemia​ - Richter Transformation​ - Classic Hodgkin lymphoma--type RT; often EBV + and clonally unrelated and mixed cellularity subtype is MC​ - DLBCL-type RT​ - DLBCL is defined as confluent sheets of large B cells w/ nuclear size equal to or exceeding normal macrophage nuclei or \>2x size of normal lymphocyte​ - **Richter-like transformation must be excluded reversible transformation in pts tx with ibrutinib (BTK inhibitor)​** **Stage Rai** **Definition by Rai** **Stage Binet** **Definition by Binet** --------------- -------------------------------------------------------------------------------------------------- ----------------- ---------------------------------------------------------------------------------------------------------- **Rai 0** Lymphocytosis \> 5 × 10^9^/L **Binet A** Haemoglobin ≥ 100 g/L (6.21 mmol/L), platelets ≥ 100 × 10^9^/L, fewer than three involved lymphoid sites **Rai I** Lymphocytosis and lymphadenopathy **Rai II** Lymphocytosis and hepatomegaly and/or splenomegaly with/without lymphadenopathy **Binet B** Haemoglobin ≥ 100 g/L (6.21 mmol/L), platelets ≥ 100 × 10^9^/L, at least three involved lymphoid sites **Rai III** Lymphocytosis and haemoglobin \ 7.0 g/dL - Genetics present at transformation - Complex karyotype (90%) - Del 17p - MYC rearrangement ### Marginal zone lymphoma #### Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue - Cyto and arch features reminiscent of Peyer patch lymphoid tissue, MALT. EMZL typically arises from marginal zone B cells of acquired MALT and a/w underlying chronic inflammatory disorder - Stomach - LELs common and may show eosinophilic degeneration forming incomplete glands, short cords, or signet ring--like cells mimicking carcinoma - Gastric MALT = H. pylori​ - **T(11;18) = (MLT/API2)**​ -- resistant to abx​ - Ocular - Polykaryocytes and perivascular hyalinization are common - Eye = Chlamydia psittaci​ - Salivary gland - Presence of a pale zone (collar) of monocytoid cells around LELs is an early sign of EMZL - Cystic changes in the interspersed ducts are common - Salivary MALT = Sjogren's​ - Lung - LELs prominent; neoplastic cells often track along bronchovascular bundles at the periphery - Thymus - IgA expression is common - Thyroid - Thyroid follicles expanded by neoplastic cells forming the characteristic (although not pathognomonic) MALT balls - Hashimoto​ - highly frequent and concurrent inactivating mutations in TET2, CD274, and TNFRSF14 - Breast - Lymphoma cells in close proximity to mammary epithelium, LELs uncommon GELA grading system for post-tx evaluation of EMZL **Score** **Lymphoid infiltrate** **Lymphoepithelial lesions** **Stromal changes** ---------------------------------------------- ---------------------------------------------------------------------- ------------------------------ ------------------------------------- **Complete histological remission (CR)** Absent, or scattered plasma cells and small lymphoid cells in the LP Absent Normal, or empty LP and/or fibrosis **Probable minimal residual disease (pMRD)** Agg of lymph cells or lymph nodules in the LP, MM, or submucosa Absent Empty LP and/or fibrosis **Responding residual disease (rRD)** Dense, diffuse, or nodular, extending around glands in LP Absent/present Focal empty LP and/or fibrosis **No change (NC)** Dense, diffuse, or nodular Absent/present No changes #### Primary cutaneous marginal zone lymphoma - Multifocal (usually) red/violaceous plaques/nodules - FAS mutations affecting the death domain of the apoptosis-regulating FAS (CD95) protein in \> 60% of cases - Monocytoid B cells and plasma cells, light chain restriction, Ig (heavy or light chain) by PCR - **CD5-, CD43-** - **Cyclin D1-** - Subtypes: - Heavy chain class-switched form (IgG+, IgA+, or IgE+; \~90% of cases) - IgG, IgA or IgE; negative CXCR3 - Non-class switched (IgM+) - \+ CXCR3 #### Nodal marginal zone lymphoma - 1^o^ nodal lymphoma of small, mature B cells derived from marginal zone B cells, w/o involvement of extranodal sites or the spleen - FamHx of lymphoma, Hx of AI dz, and HCV infection are RF - Somatic IGHV mutations and biased usage towards IGHV4-34 and IGHV1-69 - NOTCH2 and KLF2 mutations are in both NMZL and SMZL but rare in others - PTPRD mutation is skewed towards NMZL - **MNDA and IRTA1** are expressed in nearly 75% of cases #### Pediatric nodal marginal zone lymphoma - H&N region of adolescent boys ### Follicular lymphoma #### In situ follicular B-cell neoplasm - partial or complete colonization of some reactive germinal centers by follicular B cells with IGH::BCL2 fusion and **strong BCL2 expression** in otherwise normal reactive lymph nodes or lymphoid tissues at extranodal sites #### Follicular lymphoma - Waxing, waning LAD​ - PB ​-- worse prog if involved - Buttock cells​ - Follicles, back-to-back, monotonous​, effaced arch, rare mites - **BM = paratrabecular**​ - IHC​ - Bcl2+ (weaker as increase grade)​ - Negative in cutaneous follicular lymphoma​ - Bcl6, CD10​ - CD19, CD20, CD79a, sIg​ - Follicular lymphoma international prognostic index - Age \>60, Hgb \4 involved nodal areas and clinical stage III/IV - Molecular​ - **t(14;18) = (IgH/BCL2)** -- overexpression BCL2​ - PCR limited due to breakpoint; FISH detects almost all​ - Genetic predictors of transformation - TP53, BTG1, MKI67, XBP1 - Genetics present at transformation - Co- MYC, BCL2, BCL6 - Mut/loss of CDKN2A/B and TP53 - +2, +3q, +5, del(1q), del(6q) - Mutations in EBF1 and MYD88 or TNFAIP3 - Mutations in TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8 - **Transformation to HG B cell lymphoma -- a/w MYC and BCL2 rearrangements** - Subtypes: - Classic FL - FL with unusual cytological features (uFL) - predominantly medium-sized cells with immature or blastoid chromatin - higher Ki-67 proliferation and IRF4 (MUM1) expression - FL with a predominantly diffuse growth pattern (dFL) - STAT6 are more frequently observed in inguinal dFL than in cFL - Follicular large B-cell lymphoma (FLBCL) - \~40% have BCL6 alterations #### Pediatric-type follicular lymphoma - GCB B cells w/a **pure follicular growth pattern**, altered LN architecture, a ↑ Ki absence of BCL2, BCL6, and IRF4 rearrangements, BCL2- - M:F \>10:1, \ - Mixed-cellularity classic Hodgkin lymphoma - Clinical - Least involvement of mediastinum  - Micro - Interfollicular growth - Interstitial fibrosis-no thick bands, capsule - IHC - Highest EBV 75% - Lymphocyte-rich classic Hodgkin lymphoma - Micro - Nodular - Regressed GC - RS in mantle zone - No eos or PMNs - Lymphocyte-depleted classic Hodgkin lymphoma - Young, men - HIV - Likes retro LN, organs, BM - Micro = - IHC = CD15, CD30, EBV+ - Neg CD45 ### Nodular lymphocyte-predominant Hodgkin lymphoma - Young, men​ - Micro​ - Nodular​ - LP cells​ - No PMNs, eos​ - Associated with PTGC​  - **CD3+/PD1+ follicular helper T cells resetting around neoplastic CD20 cells (absent in PTGC)** - **Epithelioid histiocytes** - IHC​ - **CD45, CD20 +** ​ - **CD30/15 --**​ - T-cells with CD57+ rosette​  - J-chain, EMA+​ - Both oct2 and bob.1 (only one or none in CHL)​ - Indolent, excellent prognosis, recurs easily though​ - **Most likely to progress to DLBCL**​ Plasma cell neoplasms and other diseases with paraproteins ---------------------------------------------------------- ### Monoclonal gammopathies #### Cold agglutinin disease - AI hemolytic anemia d/t monoclonal cold agglutinins (AutoAb that agglutinate at 0--4 °C) in the absence of any infection or lymphoma - Small serum monoclonal IgM often seen - IGHV4-34, mostly w/ IGKV3-20 or IGKV3-15 - Contribute to I antigen-binding - Partial +3 or gain of 12 or 18 common - KMT2D or CARD11 - BM: - small lymphoid cells mainly as nodular aggregates and as a sparse interstitial infiltrate - CD19, CD20, PAX5, CD79a, CD22, and CD79b, monotypic light chain (most often kappa), and IgM; CD5 is positive in 40% of the cases - Absence of MYD88 **Essential:** ---------------- **Desirable:** ### MGUS Risk Factors - Risk group based on the following risk factors for progression to myeloma/related: - 1\. serum M protein \ 1.5 g/dL - 2\. IgA or IgM subtype - 3**. elevated free light chain ratio \> 1.65 (single most imp RF)** #### IgM monoclonal gammopathy of undetermined significance - Essential Criteria - Serum IgM \55-60% of cells, have worse outcome - Patients with t(4;14)(p16;q32) proteasome inhibitors has improved outcomes for this group - BCL2 inhibitors has increased overall response rates in patients with t(11;14)(q13;q32) from 6% with standard therapy to 40% using BCL2 inhibitors - Small cell variant---strong CD20 and tend to harbor the t(11;14) IgH::CCND1 rearrangement +-----------------------------------+-----------------------------------+ | **Multiple myeloma** | | +===================================+===================================+ | **Essential:** | | +-----------------------------------+-----------------------------------+ | Clonal bone marrow plasma cells | | | ≥ 10% or biopsy-proven bony or | | | extramedullary plasmacytoma | | +-----------------------------------+-----------------------------------+ | **AND** | | +-----------------------------------+-----------------------------------+ | Any one or more of the following | | | myeloma-defining events: | | +-----------------------------------+-----------------------------------+ | | Evidence of end-organ damage that | | | can be attributed to the | | | underlying plasma cell | | | proliferative disorder, | | | specifically: | +-----------------------------------+-----------------------------------+ | | **OR** | +-----------------------------------+-----------------------------------+ | | Clonal bone marrow plasma cell | | | percentage ≥ 60% | +-----------------------------------+-----------------------------------+ | | **OR** | +-----------------------------------+-----------------------------------+ | | Involved: uninvolved serum free | | | light chain ratio ≥ 100 (involved | | | free light chain level must be | | | ≥ 100 mg/L) | +-----------------------------------+-----------------------------------+ | | **OR** | +-----------------------------------+-----------------------------------+ | | More than one focal lesion | | | (≥ 5 mm in size) on MRI studies | +-----------------------------------+-----------------------------------+ | | | +-----------------------------------+-----------------------------------+ **Risk stratification in plasma cell/multiple myeloma** --------------------------------------------------------- --------------------------------------------------------------------------------- ------------------------ ------------------------------------------------------------------------------------------------ **Risk model** **Low** **Standard** **High** **ISS** I: Serum B2M \2.5% of CD3+ T cells** - Detection of FAS, FASLG, CASP8, FADD or CASP10 mutation - Desirable - Increased Vit B 12, sFASL and IL10 - AI cytopenias with polyclonal hypergamma - Fam Hx - Usually in infants, \25% BM inv to define leukemia - Defined \# is not required for dz but typically \>20% - MC in male adolescents - Dysreg expression of oncogenic miRNAs - Hand mirror cells in some - Lymphoglandularbodies - **T-ALL MC present as anterior mediastinal mass with hypercalcemia** - PAS shows coarse cytoplasmic staining and NSE may show punctate or golgi staining - CD4/8+, TAL1, LMO, often CD1a and +/-CD10 - **cCD3,