Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
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Hematopathology Topics
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  • CBC (complete blood count test) topics.
  • Heme molecular & cytogenic RESOURCE web site.
  • Thymic/thoracic
  • Bone marrow exam adequacy (an almost-Q-probes CAP paper...early 1990s)
  • Bone marrow findings:
    1. resolved referral problem5 [WRA]: if marrow was scheduled & performed for a specific problem and no problem is discerned during the pathology study, a reasonable way to diagnose the case is as a "resolved" problem. Example: patient referred for marrow for anemia and not anemic and all looks hematologically normal, the diagnosis is, "unremarkable peripheral blood & marrow, anemia resolved".
    2. studied for a heme problem but no etiology found5 [WRA]: marrow was scheduledd for pancytopenia in a 77 y/o; but, the macrocytic anemia has not had an etiology defined after MDS molecular workup, flow for blasts, and karyotypic workup. A good way to portray the case situation, for example, is, "Macrocytic anemia, etiology as yet undetermined; no evidence of leukemia or MDS ".
    3. restaging marrows5 [WRA]: H&E sections and Wright's smears are the classical benchmark upon which to "rest" the new marrow status. Upon that benchmark, one evaluates the significance of ancillary flow cytometry studies and FISH panel results. Could any of the ancillaries be negative due to an insufficient marrow sample? If restaging specimen is "negative", a good way to portray the thought in the diagnosis of a myeloma case, for example, is, "Previously diagnosed myeloma under treatment, marrow sample currently with less than 2% plasma cells".
    4. megakaryocytes[JBC]: until a marrow can be performed or reported, the CBC parameter of elevated MPV acts as a surrogate for the presence of active marrow megakaryocytes. And, this may be especially helpful in avoiding a marrow exam in cases of neonatal thrombocytopenia.
  • Coagulation
  • Plasma cell lesions:
    1. FLOW CHART of lines of evidence: HERE, chart containing link to IMWG respons status info.
    2. serum & urinary evidence: serum immunofixation electrophoresis (IFE) must logically follow a "negative" serum protein electrophoresis (SPE) because it is more sensitive. Potentially even more sensitive is a search for light chains in a 24 hour urine sample as routinely performed with 100x concentration of the urine sample prior to IFE.
    3. histological evidence: Here is a primary colonic malignant plasmacytoma [L11-6912] and a bilateral pelvic adnexal myeloma with myelomatous breast mas some years later (B11-246).
    4. flow cytometry evidence: this may be the easiest way to show monoclonality.
    5. molecular genetics probe evidence: in well differentiated populations of increased plasma cells, presence of FISH probe abnormalities favors plasma cell dyscrasia [S11-7528].
  • spleen findings:
    1. siderosis: implies hemolytic anemia or hemochromatosis [L07-6908].
    2. increased foamy macropahges: implies platelett consumption by spleen as in ITP.
    3. increased red pulp polys: implies sepsis..."septic splenitis" (or prolonged operative manipulation).
    4. enlarged & inflammed spleen (acute, subacute, or chronic splenitis [likely related to some systemic infection...FA08-32]; acute or chronic splenic tumor or pseudotumor; septic spleen): is enlargement primarily congestion?...if so, would not use the tumor or pseudotumor term.
    5. increased red pulp fibrosis: implies increased portal forward or back pressure.
    6. splenomegally HERE.
  • benign pathological lymph nodes:
    1. infectious:
      • suppurating stellate granulomatous adenitis:
        1. cat scratch (Bartonella): whole node often destroyed [L07-2437].
        2. LGV (Chlamydia).
        3. tularemia: likely quite ill.
        4. always check for mycobacterial.
      • casseating granulomatous lymphadenitis: AFB or fungal infections.
      • hyperplasia with prominent & serpigenous germinal centers: think viral.
    2. noninfectious (at least no organism demonstrated):
      • stellate granulomatous, nonsuppurative: think of rheumatoid problems; when optimally processed and no serological, culture, or PCR evidence of causative organism, default DX is "idiopathic necrotizing granulomatous lymphadenitis" [L08-4147].
      • mesenteric: at autopsy, one fairly frequently notes some small bowel mesentery nodularity...especially in thick, fatty mesenteries...which has a tan-yellowish cut surface involving fatty nodes with some orange perinodal fatty discoloration..."nodular mesenteric adenopathy".
      • extramedullary hematopoiesis(EMH): though EMH tends to imply either restricted marrow so that hematopoiesis MUST become EMH or some other primary hematological disease, megakaryocytes have been reported in axillary nodes in breast cancer cases12 [L11-1165].
      • foreign material:
        1. silicone adenopathy [L07-8846].
        2. joint prosthetic "wear & tear debris" detritic lymphadenopathy8 which tends to enlarge by sinus histiocytosis, silicone & polyethylene debris refractile on polarized light exam & metallic debris causing black nodes.
        3. oleogranulomatous lymphadenopathy: in abdominal nodes & due to oral ingestion of waxy lipids as part of the cooking process [L08-12403 cystic duct node].
      • suppurating stellate granulomatous splenitis:
        1. infectious, as above, but incompletely worked up
        2. idiopathic necrotizing granulomatous lymphadenitis (intense study is negative for organisms known to cause this reaction)[L08-4147].
    3. other:
      • primarily lymphoid enlargement:
      • primarily nonlymphoid enlargement:
        1. medullary stromal elements increased:
          1. fibrovascular, cause unknown [L09-5338].
          2. detritic sinus/medullary histiocytosis related to orthopedic prostheses.
        2. plasma cell rich: autoimmune types of adenopathy.
  • Pseudolymphoma (vs. not-as-yet-diagnosable lymphoma):
    1. skin: Spiegler-Fendt "sarcoid" is a lymphoid skin lesion that tends to be circumscribed & "top-heavy", has polymorphic (not monomorphic) follicular cellularity often with germinal centers, eosinophiles, and faint granulomatous component and which, after IHC-stain analysis, is called "cutaneous B-cell pseudolymphoma"13. [MMM, S-05-6780; HAB, S-06-16018...use of CD3, CD20, & CD23 (also maybe CD5, CD4 & CD8) to show a benign, non-monotypic immunoarchitectural pattern]. Lymphoma would have a more monotypic study by H&E and IHC markers. [S09-7686 recurring skin of head & neck lesions of pseudolymphomatous perifolliculitis; S11-1017 S-F sarcoid].
    2. nodes:
      • in a case of "common variable immunodeficiency (compensatory increase in T-cell component) [LMC-05-6145].
      • atypical hyperplasia: can't diagnose lymphoma but note atypical features by H&E and/or IHC "immuno-architecture", such as bcl-2 positive cells "invading" germinal centers [L10-10535].
    3. lung:
      • in a case of "common variable immunodeficiency (compensatory increase in T-cell component) [LMC-05-6145].
    4. other: Castleman's disease [L09-5594] B-cell tumor. Initial attempts to diagnose a mass may be VERY problematic [L11-2190] & show lymphoid tissue which cannot be diagnosed as lymphoma but flow cytometry finds something like a monoclonal B-cell population (until a proven DX later, best to label a process at this stage as "monoclonal B-cell population of uncertain significance"9).
  • Malignant lymphoma:
    1. Hodgkin's disease:
      • lymphocyte predominant can be very subtle, even failing to show atypical histiocytes or R-S cells [___].
      • syncytial variant can be confused with ALCL [L10-6325].
    2. non-Hodgkin's lymphoma.
    3. a case of T-cell rich Diffuse Large B-cell lymphoma [S10-12478].
  • Leukemia: (blast count is a morphological decision!)
    1. acute: hypercellular marrow & peripheral blasts may be absent (aleukemic), or at low levels (subleukemic [L09-3953])
      • lymphoid
      • monocytoid: spectrum of with or without "differentiation" [S-04-5214].
      • granulocytic (AML...blast count >30%)
      • mixed: AMML
      • other (mast cells, plasma cells, megakaryocytes, lymphoma cells)
    2. hypoplastic acute: hypocellular marrow with increased blasts; peripheral blood may or may not be blastic. If thought benign & given GCSF and Procrit, will dump increased blasts into PB because these agents cannot make leukemic blasts mature5.
    3. smoldering: hypercellular marrow
      • lymphoid
      • monocytoid
      • granulocytic [S-03-4109 ].
      • other (mast cells, plasma cells, megakaryocytes, lymphoma cells).
    4. subacute: hypercellular marrow
      • lymphoid
      • monocytoid
      • granulocytic
      • other (mast cells, plasma cells, megakaryocytes, lymphoma cells)
    5. chronic: hypercellular marrow
      • lymphoid: adult T-cell lymphoma/leukemia [S07-2516]
      • monocytoid
      • granulocytic (CGL, CML): 95% have the Philadelphia chromosome gene rearrangement by reciprocal translocation between 9 & 22 and located on 22. Surveilence during therapy or post transplant is by FISH probes to BCR/abl (sensitive to about 1 in a 100 cells) or by RNA PCR amplification for the BCR/abl genetic abnormality (sensitive at between 1 in 1000 to 1 in 1,000,000 cells)...in early 2009, "FISH negative" indicates "remission" (or continued remission [L07-5759]) despite any positivity of PCR (tho such positivity stands as a clue to increased risk that remission may come to an end).
      • other (mast cells, plasma cells, megakaryocytes, lymphoma cells)
  • Myeloproliferative syndromes (MPS or CMPD): though always trying to be clinically helpful, avoid rendering a diagnosis in terms more specific than than the evidence allows, as in a leukocytosis (especially granulocytosis) work up (if basophiles not increased, keep reactive causes highly in mind...may see "extreme left-shifted granulocytic leukocytosis of uncertain significance"); MPS/CMPD is a hypercellular marrow with some effectiveness in raising counts of one or more peripheral blood elements; the JAK2 gene related to tyrosine kinase is altered as a point mutation into an oncogene & is strongly specific for MPS [S08-3992] (JAK2V617F mutations are present in almost all patients with polycythemia vera, and in approximately half of those with essential thrombocytosis and myelofibrosis). The old LAP score is an obsolete test, though still useful as an on-site proxy test for the Ph1 chromosome or the BCR/ABL gene mutation (on chromosome 9, the "abl" gene can translocate onto chromosome #22 at the "BCR" gene & make a "BCR/abl gene" mutation which then causes the cells to release tyrosine kinase which drives the stem cells to produce too many WBCs [95% of CMLs have this 9/22 translocation]).
    1. polycythemia vera (Osler–Vaquez disease).
    2. thrombocytosis: reactive vs. essential thrombocythemia (ET) vs. pre-polycythemic phase of PV...the role of JAK2 & marrow morphology in the DDX
    3. chronic idiopathic myelofibrosis/myelosclerosis (agnogenic myeloid metaplasia)
    4. chronic myelogenous (myeloid) leukemia
    5. atypical chronic myelogenous (myeloid) leukemia
    6. chronic neutrophilic leukemia
    7. chronic myelomonocytic leukemia, myeloproliferative variant
    8. juvenile chronic myeloid leukemia
    9. chronic eosinophilic leukemia (and the hypereosinophilic syndrome)
    10. MPS/CMPD, unclassifiable
  • Myelodysplastic syndromes (MDS): hypercellular marrow with some ineffectiveness in one or more peripheral blood elements so that there are usually -cytopenias at presentation.
    1. WARNING! Primary MDS (the blast % is based on morphology) N/C asynchrony shows up as an elevated blast % by such as CD34 flow cytometry (FCM) markers sooner than morphological blastic nuclear change2 [S-03-12958]...phenomenon of failed or faulty development of epitopes or "lagging epitope" expression [coined by WRA] or phenomenon9,11:
      • refractory anemia (RA) [S-04-3702].
      • refractory anemia with ringed sideroblasts (RARS)
      • refractory anemia with excess of blasts (RAEB-1 if no Auer rods seen & RAEB-2 if Auer rods seen [L12-3220])...blasts <20%
      • refractory anemia with excess of blasts in transformation (RAEB-T)...blasts 20-30%; new WHO advocates dropping this acronym and calling this "AML >20%".
      • chronic myelomonocytic leukemia (CMML)
      • chronic myelomonocytic leukemia in transformation (CMML-T)
      • myelodysplastic syndrome, unclassified (MDS-U)
        1. megakaryocytic type [S-03-15566] (meg-only dysplasia)
      • "5Q- syndrome": predominantly in elderly women and consists of macrocytic anemia, thrombocytosis (50% of patients), erythroblastopenia and megakaryocyte dyspoietic hyperplasia with nuclear hypolobation & chromosome 5q deletion.
    2. secondary (therapy/toxic related): same warning as above about blast count.
    3. bicytopenia workup for MDS often turns out to be (a) leukopenia or thrombocytopenia of some non-MDS etiology PLUS (b) anemia of chronic disease (iron uptake blockade of RES iron and scant sideroblasts)9.
  • MPS/MDS overlap cases: [S-03-12900]
  • Other:
    1. cytokine effect in bone marrow [LMC-03-7297]...which also may result in lagging epitope phenomenon by FCM (see above).
    2. interleukin-6 syndrome [S-03-16214].
    3. increased marrow cellularity which spares the paratrabecular areas is more likely benign & reactive10.
    4. if you spot foci of lymphoid cellularity or atypical marrow cellularity within the paratrabecular zone, be alert as to increased likelihood of neoplasia10.
    5. myeloid hyperplasia of uncertain significance (especially appropriate when hyperplasia is "central medullary" & spares paratrabecular areas [S09-4139]).
    6. marrow atrophy or hypoplasia: serous atrophy sugests an acutely atrophic state while fatty atrophy [L10-591] suggests a chronic state9.
  • Monoclonal peripheral blood cell population is present but marrow may be histologically normal: "molecular monoclonality" or "genetic monoclonality" before morphologic or clinical criteria are met for a malignant process (we'd categorize sort of like we do small monoclonal proteins as MGUS). The term monoclonal B-cell lymphocytosis (MBL) was recently introduced to identify individuals with a population of monoclonal B cells in the absence of other features that are diagnostic of a B-cell lymphoproliferative disorder. MBL is often identified through hospital investigation of a mild lymphocytosis, and approximately 1% of such individuals develop progressive disease requiring treatment per year. However, in population studies using high-sensitivity flow cytometry, MBL may be detectable in more than 10% of adults aged over 60years, and clinical progression is rare. In marrows for MGUS workups, we are trying to (1) see if we can demonstrate morphological evidence of increased plasma cells; and, (2) do we see any concerning cytological features ?; or (3) are there frankly malignant features? It often takes the IHC marker for CD138 to help one discern a not-too-great concentration of plasma cells (but CD138 makes the percentage some higher than truly is9). Failure to discern an abnormal morphological population in these tiny samples DOES NOT rule out plasma cell dyscrasia. One must also consider serum marker levels such as (1) the monoclonal protein quantity or (2) the level of beta-2 microglobulin.
References:
  1. Brunning RD & McKenna RW, Atlas of Tumor Pathology: Tumors of the Bone Marrow, AFIP 3rd series fascicle #9, 1994.
  2. Am. J. Heme, Sept. 2003.
  3. Tumors of Haematopoietic and Lymphoid Tissue, WHO, 2001.
  4. Dr. Will Armstrong's (WRA) Jan. 2005 memo (ref. AJCP [Dr. R. W. McKenna] Oct. 2004, p. 588).
  5. Our hemepath's or consultant's tips & comments.
  6. Goldman, John M., "A Unifying Mutation in Chronic Myeloproliferative Disorders", NEJM 352(17):1744-1746 April 28, 2005.
  7. Gianelli U., et. al., "The Significance of Bone Marrow Biopsy and JAK2V617F Mutation in the Differential Diagnosis Between the 'Early' Prepolycythemic Phase of Polycythemia Vera and Essential Thrombocythemia", AJCP 130(3): 336-342 September 2008.
  8. Benz EB, et. al., "Lymphadenopathy Associated with Total Joint Prostheses. A Report of Two Cases and a Review of the Literature", The Journal of Bone and Joint Surgery 78:588-93 (1996).
  9. "Pearls", W. R. Armstrong, M. D., board-certiied, our long-time hematopathologist.
  10. "Pearls", John B. Carter, M. D., our long-time practitioner of hematopathology who trained under Dr. Brunning & along with Dr. McKenna, above.
  11. Foucar K, Hematopathology Update, S. C. Society of Pathologists fall meeting, Grove Park Inn, Asheville, N. C., Sept. 2010.
  12. Bhusnurmath S, et. al., "Megakaryocytes...carcinoma", Modern Path. 20(suppl. 2): 25A, 2007 [noted in Rosen's Breast path text 3rd Ed., p1031].
  13. McKee, Calonje, & Granter, Pathology of The Skin..., 2 volumes, 3rd Ed., nearly 2000 pages , 2005.
  14. Rawston AC, "REVIEW: Occult B-cell lymphoproliferative disorders", Histopathology, 58, 81–89, 2011.
(posted 2002; additions 19 April 2003; latest addn 19 March 2013)
 
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