CLINICAL WORKSHOP- MYELOMA Histopathology

Question 1

What is the appearance of the skull in the skull X ray (see slide 2 of pp)?

Answer 1

can see multiple lytic lesions

appearance is called - pepperpot appearance

Question 2

What is pepperpot appearance?

Answer 2

when multiple tumour deposits have replaced parts of the skull

Question 3

What is the cause of the pepperpot appearance?

Answer 3

either because the tumour has stimulated osteoclast activity (which break down bone)
OR
the tumour is putting pressure on the bone causing its atrophy

Question 4

What is the differential diagnosis for multiple lesions on bone?

Answer 4

metastatic carcinoma of breast, lung, prostate, thyroid

Question 5

What do you take from the bone to diagnose myeloma?

Answer 5

bone marrow aspirates (ie a small bone marrow sample) and bone marrow trephines (a small cylinder of bone marrow) are taken from a patient for diagnosis

Question 6

Which one out of bone marrow aspirates and bone marrow trephines give the final diagnosis of myeloma?

Answer 6

bone marrow aspirates may not be taken from areas of plasma cell malignancies, and thus trephines are used to make a final diagnosis

Question 7

Under light microscopes, what do normal plasma cells look like?

Answer 7

Under light microscopy, normal plasma cells have an eccentric nucleus (nucleus not in the centre of the cell), with chromatin condensation, and a pallor showing rough endoplasmic reticulum

Question 8

What is an active plasma cell?

Answer 8

making antibody

Question 9

What is a neoplastic plasma cell?

Answer 9

cancerous cell

Question 10

Why do we need to stain the kappa and lambda chains?

Answer 10

because it is hard to tell the difference between active plasma cells and neoplastic plasma cells

Question 11

What happens if there is an excess of one chain (kappa/lambda)?

Answer 11

myeloma indicative= daughter cells produce same light chains as parent so in cancer keep replicating one chain

If the plasma cells were making antibodies for inflammation, there would have been a large number of diverse immunoglobulins secreted by a large number of plasma cells, and they would include both kappa and lambda chains

a neoplasm such as myeloma is clonal, ie is derived from a single mutated parent cell

Question 12

Where are osteoclasts derived from?

Answer 12

bone marrow monocytes

which proliferate and fuse to form multinucleate osteoclasts

Question 13

What inactivates an osteoclast?

Answer 13

calcitonin

Question 14

What does active osteoclast look like?

Answer 14

ruffled border
round
bigger in size

Question 15

What happens in paget’s disease?

Answer 15

osteoclasts get overactivated and grow in size

Question 16

What do myeloma cells do to bone?

Answer 16

secrete hormones and cytokines to stimulate osteoclast activity

Question 17

Other than in myeloma, which other disease also has high osteoclast?

Answer 17

osteoporosis

Question 18

What do osteoclasts do?

Answer 18

osteoclast:
resorb bone
when active- release calcium into bone

Question 19

Where are osteoclasts derived from?

Answer 19

derived from bone marrow monocytes- proliferate and fuse to form multinucleate osteoclasts

Question 20

What do osteoclasts activate?

Answer 20

activates TGF= which stimulates bone deposition by osteoblasts

Question 21

What do osteoblasts do?

Answer 21

produce bone

Question 22

Where are osteoblasts derived from?

Answer 22

periosteum

bone marrow stromal cells

Question 23

What suppresses osteoclasts?

Answer 23

calcitonin

medically: bisphosphonates

Question 24

Where is calcitonin from?

Answer 24

C cells in the thyroid

Question 25

How does the RANK ligand work?

Answer 25

there is a receptor called RANK which is present on osteoclasts and bone marrow stromal cells −when the RANK ligand binds to the RANK receptor, it causes progenitor cells to fuse and become osteoclasts

Question 26

How do osteoblasts regulate osteoclasts?

Answer 26

osteoblasts can upregulate osteoclasts activity osteoblasts begin to secrete monocyte CSF and RANK ligand in response to parathyroid hormone osteoblasts can also downregulate osteoclast activity osteoblasts can secrete osteoprotogerin in response to calcitonin which blocks the RANK receptor-OPG (osteoprotogerin) is a secreted glycoprotein and is thought to be a member of the TNF super family

Question 27

How do myeloma cells act on osteoclasts?

Answer 27

myeloma cells can secrete TNF alpha, IL1, IL6= all upregulate the secretion of RANK ligand from osteoblasts = more osteoclast activity= result in osteoporosis myeloma cells are constantly expanding= put pressure on the bone =create lytic lesions when these lytic lesions are repaired, osteoclast activity outweighs osteoblast activity, leading to much more lysis of the bone

Question 28

What pharmacological agents can depress osteoclast acitivty?

Answer 28

denosumab bisphosphonates pamidronate and zoledronic acid non nitrogenous bisphosphonates

Question 29

What is denosumab?

Answer 29

monoclonal antibody binds to the RANK ligand blocks its binding to RANK on osteoclasts thus mimicking OPG (osteoprotogerin)

Question 30

What do bisphosphonates do?

Answer 30

bind calcium in bone | when osteoclasts take up calcium, they get poisoned and die prematurely

Question 31

What do pamidronate and zoledronic acid do?

Answer 31

induce OPG secretion by osteoblasts thus blocking the RANK ligand

Question 32

What do non nitrogenous bisphosphonates do?

Answer 32

induce apoptosis in the osteoclasts, whilst nitrogenous bisphosphonates interfere with actin or cytoskeletal elements important for activation of inactive osteoclasts

Question 33

What are renal complications that arise from myeloma?

Answer 33

renal calculi myeloma protein deposition amyloidosis

Question 34

What are renal calculi?

Answer 34

kindey stones occur due to hypercalcaemia calcium binds with phosphate and precipitates out (calcium phosphate stones)

Question 35

What are the consequences of renal calculi?

Answer 35

obstruct urine flow- cause stagnation- UTI

Question 36

What can infected urine lead to in the kidneys?

Answer 36

infected urine may reflex into the kidney due to back pressure causing acute or chronic pyelonephritis sepsis

Question 37

What does obstruction of urine flow by renal calculi cause?

Answer 37

back pressure causes: hydronephrosis (fluid in nephron) = this pressure may cause atrophy of the kidney (renal parenchyma which consists of the filter system of the kidney)

Question 38

What can a failing kidney cause?

Answer 38

hypertension via RAAS

Question 39

What colour does myeloma protein stain?

Answer 39

dark pink

Question 40

What can myeloid protein in the renal tubules cause?

Answer 40

rupture tubules so inflammatory cells come in cause inflammatory response (CALLED INTERSTITIAL NEPHRITIS)

Question 41

What is amyloid?

Answer 41

glycoprotein with beta pleated sheet mixture of protein and starch accumulate in interstitial space (between cells) compress cell but expand organ

Question 42

Explain the staining of amyloid:

Answer 42

starch like component of amyloid allows it to stain blue/black with Lugol’s iodine looking at this stain through polarized light will allow one to see an apple green stain on the amyloid-this is because amyloid is a glycoprotein with a beta pleated sheet structure-the anti-parallel sheets mean that the amyloid can refract light, producing an apple gree colour-

Question 43

How is amyloid formed?

Answer 43

partial degradation of light chains by macrophages-

Question 44

What is commonly seen in amyloid?

Answer 44

substance P is common in several types of amyloid, and is being used to map the extent of amyloid deposition and in treatment

Question 45

What causes localised lytic lesions?

Answer 45

the pressure of the expanding clones of myeloma cells can push on the bone causing pressure atrophy

Question 46

What is myeloma protein?

Answer 46

precipitation of free light chains

Question 47

What are the consequences of renal failure?

Answer 47

* Obstruction to urine flow causes stagnation of urine and infection can easily develop. Infected urine can reflux back up into the kidney causing acute or chronic pyelonephritis. * Back pressure from obstructed urine can lead to hydronephrosis and pressure atrophy of the renal parenchyma * Failing kidney may cause hypertension via action of RAAS * Death by chronic renal failure or by the complications of hypertension (e.g. stroke)