myelomas – path

what are most plasma cell disorders a result of?
monoclonal plasma cells synthesizing excess L, H chains, or complete Igs – immunosecretory disease that leads to osteolytic lesions in the ribs, sternum, and vertebrae.
who do plasma cell disorders usually affect?
mostly males in their 70s
what are the cells involved in plasma cells characterized by?
neoplastic cells constitue >30% of marrow cellularity (associated wiht BM changes and or fibrosis) and the plasma cells can range from very immature to mature
how do plasma cells appear?
eccentric nucleus, perinuclear huff, clock face pattern from chromatin.
how does bone marrow appear histologically in plasma cell disorders?
fibrotic: dark, squiggly lines
what is the morphology of bones affected by plasma cell disorders?
the red/soft/gelationous bone lesion begins in the medullary cavity, cancelous bone is eroded and the outer complex can be destroyed. this is why pathologic fractures can occur. radiologically, this appears as “holes of lucency”. diffuse demineralization can also occur occasionally
where are multiple myelomas mose visible?
how do neoplastic plasma cells appear?
they have perinuclear clearing (huff) due to a prominent golgi apparatus and an eccentrically placed nucleus. bizzare multinucleated cells may be visible. b/c Ig synthesis is disregulated, secretion of Ig can lead to accumulation of intact or partially degraded Ig (can lead to renal problems)
what is a flame cell?
fiery red cytoplasm
what are mott cells?
these have multiple blue grapelike cytoplasmic droplets of abnormal Ig accumulation. they may also have fibrils, crystalline rods, and globules may also be seen
what are russel bodies?
cytoplasmic inclusions (russell has “s” which sounds like cytoplasm)
what are dutcher bodies?
nuclear inclusions (dutcher has “u” and “c” like “nuclear”)
what happens as MM progresses?
as the disease progresses, neoplastic cells infiltrate solid organs, lungs, kidneys, lymph nodes, etc
what is rouleaux formation?
high levels of M protein are produced by neoplastic plasma cells leading to sticky RBCs
can neoplastic plasma cells be seen in peripheral blood smears?
yes – mimics leukemia
what is one of the main targets of injury in MM?
kidney due to: bence jones proteinuria/cast nephropathy, amyloidosis, light chain deposition disease, and osteolytic lesions
what is bence jones proteinuria and cast nephropathy?
some light chains are dirctly toxic to epithelial cells in the kidney. also, bence jones protiens can combine with urinary glycoproteins (esp under acidic conditions) and produce contentrated laminated casts – obstruct lumen of renal tubes = inflammatory rxn (noticable with abnormal BUN/creatinine)
what is amyloidosis?
light chains can accumulate and produce amyloid fibrosis -> pinkish glassy material forming beta pleated sheets can build up in the kidney
what is light chain deposition disease?
light chains can be deposited in in glomerular basement membrane – leading to nephritis
how do osteoclytic lesions harm the kidneys?
higher levels of bone breakdown = hypercalcemia/hyperuricemia which can be injurious to the kidney
what are clinical features of MM? what is the prognosis?
bone resporption (osteoclastic activity can lead to hypercalcemia), abnormal plasma cells/abnormal Ig = prone to infection, humoral immunity is affected (CMI is unaffected), and anemia (normocytic/normochromic – RBC forced out of BM). generally: poor prognosis
what is the difference between plasma cell myeloma and a plasma cytoma?
plasma cell myeloma: multiple myeloma, plasma cell myeloma: solitary lesion
what is the M component?
a monoclonal Ig in the blood, this HMW component that should not be in the urine unless the glomerulus is injured, (should be restricted to plasma and extrcellular fluid). <- potential dx modality
what are bence jones protiens?
light chains produced by neoplastic plasma cells that can be excreted in urine due to their small size. they can be detected in the blood in cases of renal failure or if synthesized in high enough levels. they can also combine with urinary glycoproteins (esp under acidic conditions) and produce contentrated laminated casts – obstructing the lumen of renal tubes = inflammatory rxn
what is the most common symptomatic monoclonal gammopathy?
multiple myeloma, which consists of multiple nodules composed of abnormal plasma cells – though it may be a solitary myeloma as well
what area of the body besides bone can be involved with multiple myelomas?
lymph nodes and skin (may mimic sezary/MF) as well as the multiple lytic skeletal lesions.
what cytokines are involved with multiple myelomas? why is this associated with a poorer prognosis?
IL-6 leads to proliferation and increased survival of plasma cells. *high levels of IL-6 are associated with a poor prognosis b/c this allows the plasma cells to continue to proliferate
what are the mechanisms by which bone destruction takes place in MM?
neoplastic plasma cells induce MIP-1, a macrophage inflammatory protein and the receptors activator of the NF kappa B ligand. both of these are considered osteoclast activating factors (OAFs)
what are karyotypic abnormalities associated with MMs?
deletions of portions of chr 13, translocations of IgH heavy chain on locus 14, abnormalities of fibroblast growth factor receptor 3 (FGFR3 on chr 4) which encodes a tyrosine kinase receptor (cell proliferation)
what problematic cyclins are associated with MMs?
cyclin D1 on chr 11 and cycline D3 on chr 6 (keep these cells permanently in the cell cycle)
what other genes are associated with MMs? what is the benefit of investigating these genetic associations?
cMAF: transcription factor on chr 16, and MUM1/IRF4: gene for IFN reg factor. all of these can be targeted by more specific therapy.
**what is the criteria for major MM?
marrow plasmacytosis 30%+, plasmacytoma on bx, and M component (IgG >3.5, IgA >2, and urine >1g/24 hr of BJ protein)
**what is the criteria for minor MM?
marrow plasmacytosis of 10-30%, M component present but less than major, lytic bone lesions and reduced normal serum Ig (<50%)
what criteria is needed for an MM dx?
1 major or 3 minor criteria
what is waldenstrom’s macroglobulinemia? heavy chain disease?
both waldenstrom’s macroglobulinemia and heavy chain disease are NOT associated with lytic lesions, in these cases, neoplastic cells infiltrate the spleen, liver, and other various body tissues.
what is a localized plasmocytoma?
a single lesion, (can be skeletal or a mass in the upper respiratory tract) that rarely disseminates
what is an osteosclerotic myeloma? what is it associated with?
POEMS (stands for associated pathologies) is a plama cell disorder associated with osteosclerotic bone lesions (different than osteolytic bone lesions). it is associated with *demyelinating polyneuropathy, organomegaly, endocrinopathy, and skin changes. megakaryocytes may be large with hyperlobated nuclei and thrombocytosis may occur.
what is a plasmacytoma? do M proteins increase?
a single myeloma in the bone/soft tissue (nasopharynx/sinuses). there is a modest increase in M proteins in blood/urine and the *osseous variety commonly progesses to MM
how would an extraosseous plasmacytoma appear histologically?
almost all plasma cells, pleimorphic (various size/shape), some are bi-nucleated and have a high nucleus to cytoplasm ratio
what is monoclonal gammopathy of undetermined significance (MGUS)? why does this need to be monitored?
a serum monoclonal gammopathy, w/minimal or no BJ protein. there are no bone lesions, renal impairments or hypercalcemia. a bone bx may be normal or show a slight increase in plasma cells. this can become a MM or undergo other types of lymphoproliferative changes, so periodic assessment of BJ and M protein needs to be monitored.
what is lymphoplasmacytic lymphoma?
aka waldenstrom’s macroglobulinemia, this is a B cell lymphoma of older adults. it has a superficial resemblance to CLL/SLL. tumor cells undergo terminal differentiation to plasma cells (hybrids, look like lymphocytes and plasma cells) and hepatosplenomegaly/lymphadenopathy. *NOT associated with lytic lesions.
what are clinical features of lymphoplasmacytic lymphoma?
visual abnormalities, neurologica abnormalities, HA, dizziness, stupor, anemia and hyperviscosity. bleeding can occur due to complexes b/w macroglobulins and platelets (inactivation). NO boney erosions, but the BM, LN, liver and spleen are affected.
what are russel/dutcher bodies associated with?
both are indicative of problems with plasma cells, russel: cytoplasm/dutcher: nucleus
what are some histoligical manifestations of lymphoplasmacytic lymphoma? what is the prognosis?
hemolysis by cold Igs (IgM binds to RBC below 37 C), which can lead to raynaud’s syndrome (decreased blood flow, purple color and numbness). the bone marrow is sparse at time with plasma cells, lymphocytes, and plasmacytoid lymphocytes. there may be a hyperplasia of mast cells, dutcher and russel bodies may be apparent. prognosis is poor: median survival is only several years
what is heavy chain disease? what are the two kinds?
this is a rare disease where only heavy chains are produced and can mimic various types of leukemias/lymphomas. the 2 kinds are IgG HCD (associated with diffuse lymphadenopathy and hepatosplenomegaly) and IgA HCD (predelection for the small intestine and respiratory tract)
what is immunocyte-associated amyloidosis? where is this seen?
a lot of these disorders have monocytes that are secreting free L chains that can be pressed together to form amyloid. this is seen in the kidney and other organs
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