Blood and BM Path Chapter 30 - Abnormalities of Ig Producing Cells

Question 1

Myeloma pathogenesis spectrum

Answer 1

Question 2

The bone marrow stromal niche and myeloma

Answer 2

Myeloma cells respond to binding the bone marrow stroma by paracrine secretion of IL-6, IGF-1, and VEGF.

These growth factors help mediate survival in the setting of chemotherapy.

Question 3

Myeloma cell adhesion molecules along disease progression

Answer 3

The plasma cell adhesion molecules inlude CD138 (syndecan), CD56 (NCAM), and VLA-5.

Similar to EMT and MET, myeloma cells undergo loss of these adhesion molecules in order to become leukemic, then regain them in order to metastasize at distant sites.

Question 4

Key myeloma signaling pathways

Answer 4

IL-6 is of particular importance to myeloma growth within the BM niche. It can be induced locally via TNFa.

Here “p13 kinase” should say “PI3 kinase”

Question 5

Chromosomal translocations most commonly seen in myelomas

Answer 5

All involve chromosome 14’s IGH locus:

• t(4;14) IGH-FGFR3
• t(11;14) IGH-Cyclin D1 (just like MCL!)
• t(6;14) IGH-Cyclin D3
• t(14;16) IGH-c-MAF
• t(14;20) IGH-mafB

Question 6

Chromosomal hyperploidys that can trigger myeloma

Answer 6

• Often hyperdiploidy of odd numbered chromosomes except 1, 9, 13, and 23. Hyperdiploid cases make up ~50% of myelomas.
• Hyperploidy:
  
  • 3
  • 5
  • 7
  • 11
  • 15
  • 19
  • 21

Question 7

Chromsome 13 anomalies in myeloma

Answer 7

Monosomy 13

OR

del(13q): Causes Rb1 loss. Often associated with t(4;14) in myeloma.

One of these two is present in ~50% of myeloma cases.

Question 8

Non-13 chromosomal anomalies in myeloma

Answer 8

del(17p): Causes p53 loss.

del(1p): Causes loss of FAF1 and p18INK4C

amp(1q): Often linked with del(1p). Associated with high risk of pericentromeric chromatin breaks and successive 1q duplications, termed “jumping 1q syndrome.” The exact mechanism of increased proliferation is unknown. Present in ~30% of myelomas.

del(16q): Loss of WWOX (oxidoreductase enzyme) and CYLD (lysine deubiquitinase).

Question 9

Progression of genome changes in myeloma

Answer 9

Question 10

c-MAF

Answer 10

Cellular variant of the viral Musculoaponeurotic Avian Fibrosarcoma oncogene.

Leucine-zipper containing transcription factor that has activatory or inhibitory transcription depending on binding partner.

Question 11

Maf-B

Answer 11

Homolog of c-MAF

Question 12

Myeloma with t(4;14)

Answer 12

10-15% of myelomas

FGFR3 under the IGH promoter

Clinically have a short duration of response to chemotherapy, resistance to alkylating agents, and overall poor prognosis.

Most of these patients also have a deletion (partial or total/monosomy) of chromosome 13.

Question 13

Myeloma with t(11;14)

Answer 13

15% of myelomas

Cyclin D1 under the IGH promoter (classically MCL translocation)

Associated with small plasma cell / lymphoplasmacytic morphology, CD20 expression, and lambda light chain. CD56 is usually low.

The rare IgM myelomas often carry t(11;14).

If t(11;14) is an isolated genetic anomaly, it is a good prognosis (unlike in lymphomas, where it is a poor prognosis).

Question 14

Myeloma with del(17p)

Answer 14

Characterized by aggressive disease course with predisposition to extramedullary disease.

Effect thought to be due to loss of p53

Question 15

Pathogenesis of bone disease in myeloma

Answer 15

Myelomas produce or induce cytokines which then induce RANKL, resulting in osteoclast differentiation.

These osteoclasts, in the process of resorption, then release matrix growth factors that encourage myeloma proliferation.

Question 16

Prevalence of different M proteins

Answer 16

Question 17

Hyperviscosity syndrome

Answer 17

Associated with elevated serum IgM or IgA – so typically IgA if the patient has myeloma or IgM for plasmacytoid lymphomas.

Clinical features include: Tendency to bleed from mucosal sites, CNS disturbances (headache, drowsiness, weakness, confusion, epileptiform activity, paralysis, coma), visual abnormalities, and constitutional symptoms (fatigue).

Question 18

Answer 18

Flame cell

Seen in IgA myelomas. The “flame” is made up of IgA with secretory component, and is thus hyperglycosylated.

Question 19

Major DDx for multiple myeloma

Answer 19

• Waldenstrom’s
• Non-Hodgkin’s lymphoma
• MGUS/Smoldering myeloma
• AL amyloidosis
• Idiopathic cold agglutinin disease
• Essential or secondary cryoglobulinemia
• Heavy-chain disease

Question 20

Staging of multiple myeloma by serum β2 microglobulin and albumin

Answer 20

Stage 1: β2m 3.5 g/dl, albumin >3.5 g/dl – Median survival 62 mo

Stage 2: Neither I or III – Median survival 44 mo

Stage 3: β2m >3.5 mg/l, albumin <3.5 g/dl – Median survival 29 mo

Question 21

Plasmablastic morphology in multiple myeloma

Answer 21

Associated with a significantly worse prognosis – median survival 16 months as opposed to 35 months with other subtypes

Compared to the classic plasma cell, plasmablasts have more dispersed chromatin (rather than clockface), higher N:C ratio, and more prominent nucleoli.

Question 22

Russel bodies

Answer 22

Inclusion bodies within atypical plasma cells. May be relatively small and multiple or quite large. White on cytologic preparations, eosinophilic on H&E preparations. Large russel bodies may also be autofluorescent.

Characteristic of a distended endoplasmic reticulum.

Question 23

Multiple myeloma in bone marrow biopsies

Answer 23

In healthy marrow, plasma cells tend to cluster around blood vessels.

In MM, this pattern is lost and plasma cells are often found as single cells or small clusters between adipocytes. Plasma cells typically make up >10% of the marrow in MM. Infiltration of the BM may be patchy or diffuse replacement.

Question 24

Myeloma with del(13q)

Answer 24

45-50% of myelomas

Loss of Rb1

Can be associated with t(4;14), which heralds a poor prognosis. Otherwise prognosis is neutral.

Question 25

Multiple myeloma with plasmablastic features

Answer 25

About 8% of myelomas have this histologic type Plasmablasts have a **fine reticular chromatin pattern, large nucleoli and less abundant cytoplasm (less than half of the nuclear area).** This morphologic subset is associated with a **high PCLI (plasma cell labeling index)**, more advanced and aggressive disease, and a worse prognosis

Question 26

Overarching prognostic indicators for multiple myeloma

Answer 26

1. PCLI (plasma cell labeling index -- basically bromodeoxyuridine uptake) 2. Serum beta-2 microglobulin 3. Serum free light chain 4. Flow immunophenotype: 1. Good prognosis: CD28-CD117+ 2. Intermediate prognosis: Double negative *or* double positive 3. Poor prognosis: CD28+CD117-

Question 27

Diagnostic criteria for MGUS

Answer 27

Question 28

Diagnostic criteria for smouldering myeloma

Answer 28

Question 29

Diagnostic criteria for multiple myeloma

Answer 29

Question 30

Diagnostic criteria for plasma cell leukemia

Answer 30

**Old criteria:** \>20% circulating plasma cells and absolute PC count of \>2 x 10⁹ PCs/L in peripheral blood, with or without a history of MM. **Proposed new criteria (based on worse prognosis than MM):** Meeting diagnostic criteria for multiple myeloma with \>5% circulating plasma cells

Question 31

Primary vs Secondary Plasma Cell Leukemia

Answer 31

Primary: No preceding diagnosis of a plasma cell dyscrasia. ~60% of cases. Secondary: Preceding diagnosis of a plasma cell dyscrasia. ~40% of cases.

Question 32

Mutations highly associated with plasma cell leukemia (and preceding high-risk MM that often becomes secondary PCL)

Answer 32

1) Frequent translocations involving 11q (cyclin D1) 2) Amplification of c-myc (often due to complex cytogenetic anomalies) 3) Mutations in Ras 4) Mutations in p53 5) Mutations involving proteins that regulate adhesion

Question 33

Solitary plasmacytoma

Answer 33

When you have a *single* lesion of myeloma Pretty rare, but it does happen. Typically on the axial skeleton with overlying pain. Full-body imaging is necessary to differentiate this from multiple myeloma, CRAB Sx must be absent, and random BM biopsy must demonstrate normal non-clonal plasma cells. Isolated extramedullary plasmacytomas also occur occasionally.

Question 34

Disorders that may be associated with an IgM paraprotein

Answer 34

1. **Lymphoplasmacytic lymphoma (LPL)**, most common by far 2. Rarer causes: * MGUS with IgM paraprotein * IgM multiple myeloma * CLL/SLL * Splenic lymphoma with villous lymphocytes (SLVL) * Splenic MZL

Question 35

Russell bodies vs Dutcher bodies

Answer 35

Dutcher bodies (A) are intranuclear inclusions Russell bodies (B) are cytoplasmic inclusions Both are found in plasma cells or other Ig producing cells and are the result of abnormal Ig accumulation Both stain PAS+

Question 36

LPL typically involves. . .

Answer 36

. . .**the bone marrow** In fact, it involves the marrow even moreso than lymph nodes in most cases. Bone marrow involvement is characterized by a nodular, dffuse, and/or interstitial infiltrate composed of predominantly small lymphocytes admixed with variable numbers of plasma cells/plamacytoid lymphocytes. Increased mast cells are often also present.

Question 37

MYD88 mutation is found not only in LPL, but also in. . .

Answer 37

. . . 50% of IgM MGUS cases, as well as many cases of SMZL and B cell chronic ymphoproliferative disorder. MYD88 p.L265P, to be specific

Question 38

TEMPI syndrome

Answer 38

Paraneoplastic syndrome sometimes associated with plasma cell neoplasms Stands for **telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting** Its manifestations appear to result from the monoclonal plasma cell proliferation and associated M protein, similar to POEMS syndrome.

Question 39

POEMS syndrome

Answer 39

Paraneoplastic syndrome sometimes associated with plasma cell neoplasms Name stands for **polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.** Pathologically characterized by fibrosis and osteosclerotic changes in bone trabeculae, and often with lymph node changes resembling the plasma cell variant of Castleman disease