AJCP / Original Article
Bone Marrow Necrosis Ten-Year Retrospective Review of Bone Marrow Biopsy Specimens Geoffrey D. Wool, MD, PhD,1,2 and Anne Deucher, MD, PhD2 From the 1Department of Pathology, University of Chicago, Chicago, IL; and 2Department of Laboratory Medicine, University of California, San Francisco.
CME/SAM
Key Words: Bone marrow; Necrosis; Metastatic; Neuroblastoma Am J Clin Pathol February 2015;143:201-213 DOI: 10.1309/AJCP0TN1MCMOLMPK
ABSTRACT Objectives: Bone marrow can undergo necrosis for many different causes; malignant causes are reported to be more frequent. Methods: We undertook a 10-year retrospective review of all bone marrow biopsy specimens with bone marrow necrosis at our institution. Results: Identified cases represented approximately 0.3% of our bone marrow cases. Most identified bone marrow cases with necrosis were involved by metastatic tumor or hematolymphoid malignancy (90% of total) in relatively equal proportions. In those cases of bone marrow necrosis with hematolymphoid malignancy, lymphoid disease predominated and the necrosis was often seen in the setting of chemotherapy. In metastatic tumor cases, necrosis seemed to enrich in prostate adenocarcinoma and Ewing sarcoma/ primitive neuroectodermal tumor; neuroblastoma showed much less necrosis. Ten percent of patients with bone marrow necrosis had no underlying malignancy, and the associated causes varied. Conclusions: The causes of bone marrow necrosis are diverse but should always prompt careful assessment for malignancy and infectious etiology.
© American Society for Clinical Pathology
Upon completion of this activity you will be able to: • identify the morphologic difference between bone marrow serous fat atrophy and coagulative necrosis. • list the potential causes of bone marrow necrosis and the most common etiologies. • describe a reasonable work-up by special stains and/or immunohistochemistry of a bone marrow case with necrosis of unclear etiology. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 306. Exam is located at www.ascp.org/ajcpcme.
Hematopathologists encounter bone marrow biopsy specimens with marrow necrosis relatively infrequently, and the potential etiologies are diverse. Numerous causes of bone marrow necrosis have been identified, including malignancy, radiation/chemotherapy, anorexia, human immunodeficiency virus (HIV)/AIDS, medication, infection, autoimmune disease, disseminated intravascular coagulation, antiphospholipid syndrome and other thrombotic disorders, granulocyte–colony-stimulating factor (G-CSF) exposure, and hemoglobinopathies.1-4 One prior retrospective review showed the prevalence of bone marrow necrosis to be approximately 2%.3 While bone marrow necrosis is not uncommon in site-directed biopsy specimens or autopsy material, substantial necrosis is much less common in nondirected bone marrow biopsy specimens.3
Am J Clin Pathol 2015;143:201-213 201
DOI: 10.1309/AJCP0TN1MCMOLMPK
Wool and Deucher / Bone Marrow Necrosis
❚Table 1❚ Bone Marrow Necrosis Casesa Circulating Disease in Present Case
% Marrow Necrosis (of Cellularity)
Refractory Ph+ B-ALL following induction 4 mo later Down syndrome and relapsed B-ALL, day 28 of reinduction
Yes No Yes
Recurrent B-ALL with near tetraploidy following reinduction B-ALL with normal karyotype following induction 10 d later B-ALL with normal karyotype, day 14 of induction chemotherapy CML, lymphoid blast phase, following chemotherapy 2 mo later 3 mo later 4 mo later Burkitt lymphoma Burkitt lymphoma, following chemotherapy Relapsed Burkitt lymphoma High-grade B-cell lymphoma following chemotherapy Gastric high-grade B-cell lymphoma Prior DLBCL following distant chemotherapy, long history of ankylosing spondylitis DLBCL following chemotherapy DLBCL 1 mo later, after chemotherapy PTLD with plasmablastic features AITL 3 months following allogeneic stem cell transplant Monocytic AML with 11q23 rearrangement following induction Monocytic AML with normal karyotype following induction
Yes No No No Yes Yes Yes Yes Yes No No Yes Yes No No No No No No No No
80 >90 >90 (on clot material) 50 >95 80 10 >95 >95 >95 50 90 60b 90b 50 60 50 50 30 70 >90 66 60 40
Monoblastic AML with trisomy 8 following induction AML with normal karyotype and FLT3 ITD and NPM1 mutation following induction AML with myelodysplasia-related changes, recently achieved remission; had neutropenic fever; budding yeast and necrosis on clot section Breast invasive ductal carcinoma diagnosed 10 y earlier, had pancytopenia Breast invasive ductal carcinoma diagnosed 1 mo earlier, imaging consistent with metastases, pancytopenia
No No No
>95 30 50% of biopsy necrotic), 37% were grade II (20%-50% of biopsy necrotic), and 17% were grade I (50
51
M
NA
30
79 62
M M
NA NA
10 10
77
M
Bilateral lung explants with large cell undifferentiated carcinoma; 1 mo later had fever, pancytopenia Esophageal mixed adenocarcinoma/large cell neuroendocrine carcinoma with metastases found after investigation of severe bone pain and pathologic fracture Prostate adenocarcinoma, with bony metastases, treated with chemotherapy; now with mild splenomegaly and myelophthisic blood smear Prostate adenocarcinoma, now pancytopenic Prostate adenocarcinoma with metastases diagnosed 6 y previous, now with leukoerythroblastosis Prostate adenocarcinoma, now with cytopenias
NA
5
66 62
M M
NA NA
10 20
19
M
Prostate adenocarcinoma, with bony metastases Invasive high-grade urothelial carcinoma, with metastatic disease and cytopenias Ewing sarcoma/PNET of left chest wall, with bony metastases
NA
14 25 21 13 2
M F F F F
NA NA NA NA NA
4 20
M M
Ewing sarcoma/PNET of pelvis with bony metastases Ewing sarcoma/PNET of pelvis Ewing sarcoma/PNET of left medial distal femoral metaphysis Abdominal neuroblastoma diagnosed 6 y earlier Abdominal neuroblastoma with metastases following stem cell transplant 5 mo earlier; receiving chemoradiation Adrenal neuroblastoma with bony metastases Alveolar rhabdomyosarcoma of pelvic mass, widely metastatic, diagnosed 2 y earlier 1 mo later Alveolar rhabdomyosarcoma of maxilla, with metastases, with cytopenias Alveolar rhabdomyosarcoma of left calf Large complex sacrococcygeal tumor with metastatic germ cell tumor Pancytopenia and antiphospholipid syndrome Fevers, anemia, Hb SC, HIV Pancytopenia Cytopenias Cytopenias, lymphadenopathy, splenomegaly, sclerotic bony lesions, weight loss, parotid gland enlargement; HIV negative, no evidence of malignancy; nonnecrotizing granulomas present on biopsy
Not quantified, counted as “moderate”c 95 >50c >50c 30
46 12 3 27 49 28 64 39
M M F F M M M M
AITL, angioimmunoblastic T-cell lymphoma; AML, acute myeloid leukemia; B-ALL, B-lymphoblastic leukemia/lymphoma; CML, chronic myelogenous leukemia; d/c, discharged; DLBCL, diffuse large B-cell lymphoma; f/u, follow-up; G-CSF, granulocyte–colony-stimulating factor; Hb, hemoglobin; HIV, human immunodeficiency virus; NA, not applicable; Nl, normal; Ph, Philadelphia chromosome; Plt, platelet; PNET, primitive neuroectodermal tumor; PTLD, posttransplant lymphoproliferative disorder; ↓, decrease; ↑, increase. a Italics signifies repeat marrow biopsy on the same patient. WBC, Hb, and Plt are reported based on UCSF hematology laboratory age-adjusted normal ranges. b For cases with bilateral bone marrow core biopsy specimens, the value of “percent necrosis” represents the percentage of marrow cellularity with necrosis from the biopsy side with disease/higher disease burden. c Cases sent to our institution for consultation where not all diagnostic slide(s) were available for retrospective review.
thrombocytopenia. The specific hematolymphoid malignancies were the following (listed in decreasing order): diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (five patients, 24% of patients with hematolymphoid malignancy-associated necrosis), acute myeloid leukemia (AML) (five patients, 24%), B-lymphoblastic leukemia/lymphoma (B-ALL) (five patients, 24%), Burkitt lymphoma (BL) (three patients, 14%), and other (chronic myelogenous leukemia in lymphoid blast phase, EpsteinBarr virus–positive posttransplant lymphoproliferative disorder with plasmablastic features, and angioimmunoblastic T-cell lymphoma) (one patient each). Fifteen (56%) of the cases with hematolymphoid malignancy-associated marrow necrosis had persistent disease by morphology,
204 Am J Clin Pathol 2015;143:201-213 DOI: 10.1309/AJCP0TN1MCMOLMPK
immunohistochemistry, or cytogenetics. While the necrotic cells are favored to represent malignant cells by morphology and distribution, this was proven only with immunohistochemical stains in four cases: CD10 staining in necrotic cells in one case of B-ALL, CD20 staining in necrotic cells in two cases of DLBCL, and lysozyme staining in one case of monocytic AML (not shown). Interestingly, the AML cases with necrosis were predominantly of monocytic differentiation (three of five AML cases). All of these AML cases were apparently de novo, without a reported preceding history of myeloproliferative or myelodysplastic neoplasm. Twenty-one (78%) of the cases with hematolymphoid malignancy-associated marrow necrosis had recent preceding chemotherapy exposure. Six (22%) of the cases with
© American Society for Clinical Pathology
AJCP / Original Article
Osteonecrosis
Viable Malignant Cells Present in Marrow
Trilineage Hematopoiesis Present WBC
Hb
Plt
G-CSF
Follow-up
No
Yes
Yes
↓
↓
↓
No mention
Died, 5-mo f/u
Not overtc
Yes
Yes
Nl
↓
Nl
No mention
Alive, 1-mo f/u
Yes
Yes
No
Nl
↓
Nl
No mention
Died, 4-mo f/u
Yes Yes
Yes Yes
Yes No
NA Nl
NA ↓
NA ↓
No mention No mention
No f/u Died,
Bone Marrow Necrosis Ten-Year Retrospective Review of Bone Marrow Biopsy Specimens Geoffrey D. Wool, MD, PhD,1,2 and Anne Deucher, MD, PhD2 From the 1Department of Pathology, University of Chicago, Chicago, IL; and 2Department of Laboratory Medicine, University of California, San Francisco.
CME/SAM
Key Words: Bone marrow; Necrosis; Metastatic; Neuroblastoma Am J Clin Pathol February 2015;143:201-213 DOI: 10.1309/AJCP0TN1MCMOLMPK
ABSTRACT Objectives: Bone marrow can undergo necrosis for many different causes; malignant causes are reported to be more frequent. Methods: We undertook a 10-year retrospective review of all bone marrow biopsy specimens with bone marrow necrosis at our institution. Results: Identified cases represented approximately 0.3% of our bone marrow cases. Most identified bone marrow cases with necrosis were involved by metastatic tumor or hematolymphoid malignancy (90% of total) in relatively equal proportions. In those cases of bone marrow necrosis with hematolymphoid malignancy, lymphoid disease predominated and the necrosis was often seen in the setting of chemotherapy. In metastatic tumor cases, necrosis seemed to enrich in prostate adenocarcinoma and Ewing sarcoma/ primitive neuroectodermal tumor; neuroblastoma showed much less necrosis. Ten percent of patients with bone marrow necrosis had no underlying malignancy, and the associated causes varied. Conclusions: The causes of bone marrow necrosis are diverse but should always prompt careful assessment for malignancy and infectious etiology.
© American Society for Clinical Pathology
Upon completion of this activity you will be able to: • identify the morphologic difference between bone marrow serous fat atrophy and coagulative necrosis. • list the potential causes of bone marrow necrosis and the most common etiologies. • describe a reasonable work-up by special stains and/or immunohistochemistry of a bone marrow case with necrosis of unclear etiology. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 306. Exam is located at www.ascp.org/ajcpcme.
Hematopathologists encounter bone marrow biopsy specimens with marrow necrosis relatively infrequently, and the potential etiologies are diverse. Numerous causes of bone marrow necrosis have been identified, including malignancy, radiation/chemotherapy, anorexia, human immunodeficiency virus (HIV)/AIDS, medication, infection, autoimmune disease, disseminated intravascular coagulation, antiphospholipid syndrome and other thrombotic disorders, granulocyte–colony-stimulating factor (G-CSF) exposure, and hemoglobinopathies.1-4 One prior retrospective review showed the prevalence of bone marrow necrosis to be approximately 2%.3 While bone marrow necrosis is not uncommon in site-directed biopsy specimens or autopsy material, substantial necrosis is much less common in nondirected bone marrow biopsy specimens.3
Am J Clin Pathol 2015;143:201-213 201
DOI: 10.1309/AJCP0TN1MCMOLMPK
Wool and Deucher / Bone Marrow Necrosis
❚Table 1❚ Bone Marrow Necrosis Casesa Circulating Disease in Present Case
% Marrow Necrosis (of Cellularity)
Refractory Ph+ B-ALL following induction 4 mo later Down syndrome and relapsed B-ALL, day 28 of reinduction
Yes No Yes
Recurrent B-ALL with near tetraploidy following reinduction B-ALL with normal karyotype following induction 10 d later B-ALL with normal karyotype, day 14 of induction chemotherapy CML, lymphoid blast phase, following chemotherapy 2 mo later 3 mo later 4 mo later Burkitt lymphoma Burkitt lymphoma, following chemotherapy Relapsed Burkitt lymphoma High-grade B-cell lymphoma following chemotherapy Gastric high-grade B-cell lymphoma Prior DLBCL following distant chemotherapy, long history of ankylosing spondylitis DLBCL following chemotherapy DLBCL 1 mo later, after chemotherapy PTLD with plasmablastic features AITL 3 months following allogeneic stem cell transplant Monocytic AML with 11q23 rearrangement following induction Monocytic AML with normal karyotype following induction
Yes No No No Yes Yes Yes Yes Yes No No Yes Yes No No No No No No No No
80 >90 >90 (on clot material) 50 >95 80 10 >95 >95 >95 50 90 60b 90b 50 60 50 50 30 70 >90 66 60 40
Monoblastic AML with trisomy 8 following induction AML with normal karyotype and FLT3 ITD and NPM1 mutation following induction AML with myelodysplasia-related changes, recently achieved remission; had neutropenic fever; budding yeast and necrosis on clot section Breast invasive ductal carcinoma diagnosed 10 y earlier, had pancytopenia Breast invasive ductal carcinoma diagnosed 1 mo earlier, imaging consistent with metastases, pancytopenia
No No No
>95 30 50% of biopsy necrotic), 37% were grade II (20%-50% of biopsy necrotic), and 17% were grade I (50
51
M
NA
30
79 62
M M
NA NA
10 10
77
M
Bilateral lung explants with large cell undifferentiated carcinoma; 1 mo later had fever, pancytopenia Esophageal mixed adenocarcinoma/large cell neuroendocrine carcinoma with metastases found after investigation of severe bone pain and pathologic fracture Prostate adenocarcinoma, with bony metastases, treated with chemotherapy; now with mild splenomegaly and myelophthisic blood smear Prostate adenocarcinoma, now pancytopenic Prostate adenocarcinoma with metastases diagnosed 6 y previous, now with leukoerythroblastosis Prostate adenocarcinoma, now with cytopenias
NA
5
66 62
M M
NA NA
10 20
19
M
Prostate adenocarcinoma, with bony metastases Invasive high-grade urothelial carcinoma, with metastatic disease and cytopenias Ewing sarcoma/PNET of left chest wall, with bony metastases
NA
14 25 21 13 2
M F F F F
NA NA NA NA NA
4 20
M M
Ewing sarcoma/PNET of pelvis with bony metastases Ewing sarcoma/PNET of pelvis Ewing sarcoma/PNET of left medial distal femoral metaphysis Abdominal neuroblastoma diagnosed 6 y earlier Abdominal neuroblastoma with metastases following stem cell transplant 5 mo earlier; receiving chemoradiation Adrenal neuroblastoma with bony metastases Alveolar rhabdomyosarcoma of pelvic mass, widely metastatic, diagnosed 2 y earlier 1 mo later Alveolar rhabdomyosarcoma of maxilla, with metastases, with cytopenias Alveolar rhabdomyosarcoma of left calf Large complex sacrococcygeal tumor with metastatic germ cell tumor Pancytopenia and antiphospholipid syndrome Fevers, anemia, Hb SC, HIV Pancytopenia Cytopenias Cytopenias, lymphadenopathy, splenomegaly, sclerotic bony lesions, weight loss, parotid gland enlargement; HIV negative, no evidence of malignancy; nonnecrotizing granulomas present on biopsy
Not quantified, counted as “moderate”c 95 >50c >50c 30
46 12 3 27 49 28 64 39
M M F F M M M M
AITL, angioimmunoblastic T-cell lymphoma; AML, acute myeloid leukemia; B-ALL, B-lymphoblastic leukemia/lymphoma; CML, chronic myelogenous leukemia; d/c, discharged; DLBCL, diffuse large B-cell lymphoma; f/u, follow-up; G-CSF, granulocyte–colony-stimulating factor; Hb, hemoglobin; HIV, human immunodeficiency virus; NA, not applicable; Nl, normal; Ph, Philadelphia chromosome; Plt, platelet; PNET, primitive neuroectodermal tumor; PTLD, posttransplant lymphoproliferative disorder; ↓, decrease; ↑, increase. a Italics signifies repeat marrow biopsy on the same patient. WBC, Hb, and Plt are reported based on UCSF hematology laboratory age-adjusted normal ranges. b For cases with bilateral bone marrow core biopsy specimens, the value of “percent necrosis” represents the percentage of marrow cellularity with necrosis from the biopsy side with disease/higher disease burden. c Cases sent to our institution for consultation where not all diagnostic slide(s) were available for retrospective review.
thrombocytopenia. The specific hematolymphoid malignancies were the following (listed in decreasing order): diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (five patients, 24% of patients with hematolymphoid malignancy-associated necrosis), acute myeloid leukemia (AML) (five patients, 24%), B-lymphoblastic leukemia/lymphoma (B-ALL) (five patients, 24%), Burkitt lymphoma (BL) (three patients, 14%), and other (chronic myelogenous leukemia in lymphoid blast phase, EpsteinBarr virus–positive posttransplant lymphoproliferative disorder with plasmablastic features, and angioimmunoblastic T-cell lymphoma) (one patient each). Fifteen (56%) of the cases with hematolymphoid malignancy-associated marrow necrosis had persistent disease by morphology,
204 Am J Clin Pathol 2015;143:201-213 DOI: 10.1309/AJCP0TN1MCMOLMPK
immunohistochemistry, or cytogenetics. While the necrotic cells are favored to represent malignant cells by morphology and distribution, this was proven only with immunohistochemical stains in four cases: CD10 staining in necrotic cells in one case of B-ALL, CD20 staining in necrotic cells in two cases of DLBCL, and lysozyme staining in one case of monocytic AML (not shown). Interestingly, the AML cases with necrosis were predominantly of monocytic differentiation (three of five AML cases). All of these AML cases were apparently de novo, without a reported preceding history of myeloproliferative or myelodysplastic neoplasm. Twenty-one (78%) of the cases with hematolymphoid malignancy-associated marrow necrosis had recent preceding chemotherapy exposure. Six (22%) of the cases with
© American Society for Clinical Pathology
AJCP / Original Article
Osteonecrosis
Viable Malignant Cells Present in Marrow
Trilineage Hematopoiesis Present WBC
Hb
Plt
G-CSF
Follow-up
No
Yes
Yes
↓
↓
↓
No mention
Died, 5-mo f/u
Not overtc
Yes
Yes
Nl
↓
Nl
No mention
Alive, 1-mo f/u
Yes
Yes
No
Nl
↓
Nl
No mention
Died, 4-mo f/u
Yes Yes
Yes Yes
Yes No
NA Nl
NA ↓
NA ↓
No mention No mention
No f/u Died,
