BMB results — Science, fantasy…or luck?
Not sure of your diagnosis? The only way to be certain, is to have a bone marrow biopsy done to check for myeloid expansion, clusters of funny looking megakaryocytes and reticulin fiber deposition…or is all that just another urban myth?
The European Bone Marrow Working group Thomas Buhr, et al., reported in Haematologica (March 1, 2012) on a study of 102 bone marrow trephines, reviewed by six hematopathologists from five countries . Bottom line: More than half of the trephines could not be reproducibly classified. As a result the number of unclassified MPNs rose from 2% to 23% and,when incorporating the WHO criteria for primary myelofibrosis, the frequency of PMF among the 102 dropped from 23% to 7%.
Dr. Jurgen Thiele — along with Orazi, Tefferi, Passamonti, Barbui and others –objected to the findings primarily based on the absence of clinical input, also suggesting the hematopathologists were likely unfamiliar with the WHO criteria
In a stinging rebuttal Buhr pointed out all members of the panel were experienced hematopathologists who have used the WHO criteria in their daily practice for many years and cited the many distinguished hematologists who have cast doubt on thye value of a pre-fibrotic myelofibrosis diagnosis, citing Richard Silver, Jerry Spivak , F.J. Cervantes, and Claire Harrison among others.
Part of the difficulty may be in defining elements of the biopsy, but part may be definitions of MPN sub-types. Buhr footnoted a quote from Willam Dameshek on the difficulty of sub-typing MPNs:
“Transitions and overlaps among these various conditions are common, so that were one begins and the other ends is often uncertain….Sometimes as with the various members of the Myeloproliferative syndromes, a supposedly accurate diagnosis can be mosre inaccurate than the use of the rather vague term of a chronic…myeloprolifrative disorder.”
In any event, the search for diagnostic certainty clearly does not end at the pathologists’s lab.
Bridget Wilkins, histopathologist Guy’s & St Thomas’ NHS, et al. published a study on bone marrow pathology and interobserver reliability in Blood testing the usefulness and reliability of identifying MPN disease subtypes. The conclusion was unequivocal:
BMBs from 370 patients with ET were studied by three experienced hematopathologists basing their diagnoses on WHO criteria. “Our results show substantial interobserver variability, particularly for overall diagnosis…” a polite way of saying there was little consensus.
And as to the usefulness of the pre-PMF diagnosis: “No differences could be discerned between patients labeled as having prefibrotic myelofibrosis” or “true ET” in clinical and laboratory features at presentation , JAK2 status, survival, thrombosis, major hemorrhage or myelofibrotic transformation….”
Dr. Wilkins did offer up some practical advice for a cooperative, team effort between pathologist and hematologist that might help turn things around. She wrote, In the Journal of Clnical Pathology,
“There has been a long controversy, reflected in ongoing differences in local practice, as to whether haematologists or histopathologists are best placed to report BM[B]. Clearly, local expertise varies but, with the strengthening position of haematopathology as a subspecialisation in histopathology and a continuing decline in the direct involvement of haematologists in laboratory work, the case for BM[B] to be reported primarily by haematopathologists becomes increasingly persuasive. However, the fundamental caveat in this regard is that haematopathologists cannot work in isolation from their haematology colleagues in this task; clinical information, blood and marrow aspirate findings, genetic and imaging data are all crucial elements in the dialogue required for BM[B] interpretation.”
Taken on its own, bone marrow biopsy cannot always provide conclusive diagnostic conclusions. For an example of the difficulty of depending solely on blood marrow findings , here’s Dr. Richard Silver’s comments on his slide from Morphology of the Blood and Marrow in Clinical Practice (1970) “A more unusual example of hyperplasia in early “myelofibrosis” Biopsy. Note the predominance of megakaryocytes. This picture is indistinguishable from that seen in some patients with idiopathic thrombocythemia, polycythemia vera or chronic granulocytic leukemia. The fact that the disease was myelofibrosis and not one of the others in the myeloproliferative group was shown by other clinical and hematologic characteristics and by the subsequent course of the patient.”
(*Note: In Dr. Wilkins remarks you’ll see BM[B]. This is to indicate our replacement of her term, BMT, referring to bone marrow trephine since it is confused with the American acronym for bone marrow (stem cell) transplant. Thank you to those who pointed out the confusion.)
Take me back to the Contents
© Zhenya Senyak and MPNforum.com, 2012. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content.
Comments on: "Bone marrow biopsy — Not as sure as you think" (5)
Dear Mr. Senyak, Dear Zhen,
I enjoyed reading the MPN Forum articles and I believe you are doing an excellent service to the MPN patient community. Similar to other specialized fields of pathology, bone marrow hematopathology requires considerable experience. The biopsy is not a stand-alone test but rather an important component within a complex diagnostic algorithm. The two main studies which took issues with the WHO 2008 classification system have both stressed the poor reproducibility of the histologic findings. This has not been confirmed by the majority of the studies based on the WHO Classification which have been published since 2008. In addition, it is not our experience here in the US, where at least in academic medical centers, we have board certified hematopathologists who are responsible for comprehensive evaluation of bone marrow aspirate, biopsy, flow cytometry and peripheral blood smear. Such comprehensive evaluation is regularly performed in the light of clinical information. Please bear in mind that the way the diagnostic process is done differs dramatically from one country to another and it would be unwarranted for US patients to extrapolate too much from some of the European papers. At least in Dr. Silver’s and mine opinion, there is no substitute for expert pathology review particularly for patients under consideration for transplant or enrollment in experimental clinical trials.
The enclosed article which deals with lymphoma, a group of neoplasms which shares with MPN a similarly complicated diagnostic process, makes similar recommendation. See: Jaffe ES. Centralized review offers promise for the clinician, the pathologist, and the patient with newly diagnosed lymphoma. J Clin Oncol. 2011 Apr 10;29(11):1398-9. The article is authored by the head of NCI/NHI Hematopathology Service Dr. Elaine Jaffe.
[…] Bone marrow biopsy — Not as sure as you think […]
Comment from Dr. Richard T. Silver (Due to travel schedules, posted by his request)
Your commentary in the MPNforum has created quite a stir! Apparently some of our distinguished hematopathologists are concerned about the negative impact on performing bone marrow biopsies that your recent on-line editorial might induce. They have emailed me their concerns.
By the way, it was very kind of you to quote my book, which was printed 40 years ago! We have made some improvements in diagnosis and bone marrow interpretation since. Incidentally, I hope you notice that William Damaschek wrote the introduction.
No one ever implied that bone marrow biopsy is “diagnostic” in all cases. For example, some patients with CML with granulocytic hyperplasia may be difficult to distinguish from a morphologic standpoint from patients with a severe leukemoid reaction. This distinction is resolved by using cytogenetics or molecular genetics (BCR-ABL). In our experience, we believe that we can distinguish 90% of cases or more of patients with PM from those with ET. The bone marrow in polycythemia is not always distinguishable from ET but most often is, and we reported this in an abstract in Blood just this past year. (Prospective Evaluation of the World Health Organization Criteria for the Diagnosis of Polycythemia Vera, Authors include Richard T. Silver, William Chow, Stephen P Arles, Katherine Vandris, Ivy Tam, Anita Narayan, Maria T De Sancho, Attilio Orazi and Stanley J Goldsmith, ASH Annual Meeting & Exposition, San Diego, CA, December 10 – 13, 2011).
Further, we demand a red blood cell mass for the diagnosis of PV and ET since we believe that the bone marrow is not always diagnostic in early cases. Further, the use of erythropoietin (EPO) levels is not satisfactory because in about 15% of cases of PV it is normal. (Data very similar among Silver, Spivak and Prchal).
Notwithstanding the aforementioned, as clinicians we at Cornell believe every patient with an MPD should have a bone marrow biopsy at diagnosis. This allows for more adequate evaluation for fibrosis cellularity, etc. and establishes a baseline to evaluate subsequent response, evolution, etc.
Most importantly it is necessary for the experienced clinician (hematologist) to review all his cases personally with an experienced hematopathologist. We are extremely fortunate to have here at Cornell, Professor Attilio Orazi, a world famous hematopathologist who along with Thiele is a leader in the field.
As always, I send my best regards.
Richard T. Silver, M.D.
* As you know, the first histopathologic criteria seemed “Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes.” Blood. 2008;111(1):60-70). Subsequently, an overall “blinded” consensus ranged from 88% from 2 European centers (295 cases) (Thiele, J et al. “Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification.” Blood. 2011;117(21):5710–8) to 93% from 7 international centers (1104 cases) (Barbui, T et al. “Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study” J Clin Oncol. 2011;29(23):3179-84).
The importance of distinguishing ET from cellular PM relates to the fact that patients with WHO-defined ET show a slower risk of developing overt myelofibrosis, AML evolution and a better survival and our paper showed reversal of change in early PM. (Silver RT, Vandris K, and Goldman J: “Recombinant interferon alpha may retard progression of early primary myelofibrosis: a preliminary report.” Blood, 2011;117(24):6669-72).
There are 4 slashes in the web address for your article instead of 2..took me a while to notice that so I could read the article since I kept getting ‘incorrect address’ when I tried to read it. Nice article!
Thanks, Nancy…on both accounts. I’m a little confused though. How did you get to the article? The link is embedded on the Contents page and in the drop down June, 2012 menu in the header and in the Catalog page, so you shouldn’t have to deal with URLs at all. I’d like to get rid of those extra slashes, so if you get a chance please do let me know where you ran across them. (Hmmm, sounds like The Quest for the Slasher.)