Bone Marrow Necrosis
JOHN F. KIRALY, III, M.D.’ MUNSEY S. WHEBY, M.D. Charlottesville, Virginia
From the Department of Medicine, University of Virginia School of Medicine, Chat lottesville, Virginia 22901. Requests for reprints shoukl be addressed to Dr. Munsey S. Wheby, Department of Medicine. University of Virginia School of Medicine, Charlottesville, Virginia 22901. fvlanuscript accepted September 4, 1975. Present address: 2311 West Elm Street, Lodie, California 95240 l
The clinical findings of bone marrow necrosis in 13 patients undergoing bone marrow examlnation to tnvesttgate a peripheral blood cytopenla or leukoerythroblaetlc blood smear were reviewed and compared to those tn the ftterature. Exctudtng stckle cell disease, all cases of bone marrow necrosts dlagnoeed durtng ltfe were associated with a neoplastic process InvoMng the marrow. A myeloproltferative disorder was found In five patients, metastatic carcinoma in five patients, a lymphoma tn two patients, and both a myeloprotiferative disorder and metastatic carcinoma in one patient. Marrow necrosis was found to involve the marrow at muttipfe sites in a piecemeal fashton with areas of necrotic marrow and structurally intact marrow adjacent to each other. Severe bone pain without roentgenographtc abnormattty was the major symptom In 85 per cent of the patients. Marrow and fat emboli, hypercalcemla and peripheral Mood cytopenlas were identified as direct complications of marrow necrosis. The prognosis of patients wtth marrow necrosis secondary to neoplastic disease was found to be extremely poor with a median survival of less than one month. However, one pattent responded to antineoplastfc chemotherapy and showed healing of the bone marrow. Bone marrow necrosis has rarely been reported in bone marrow samples obtained during life although it is often found at autopsy. On postmortem examination bone necrosis has been found to be associated with a number of different conditions [l-21] (Table I). It has also-been described in association with avascular necrosis of the femoral head, a disorder of diverse etiology. Only 21 cases of bone marrow necrosis diagnosed antemortem by aspiration or needle biopsy are reported in the literature [ 1,21-271 (Table II). In the majority of these 21 cases the underlying disease was either acute lymphocytic leukemia or sickle ceil disease. The significance of bone marrow necrosis is unclear, except as a poor prognostic sign in acute lymphoblastic leukemia [21,22] and as a potential cause of fat and marrow emboli in patients with sickle cell crisis [912,231. The purpose of the present study was to determine the causes, diagnostic features and clinical significance of bone marrow necrosis in a series of 13 adult patients who were found to have this lesion on bone marrow aspiration or biopsy. MATERIALS AND METHODS The University of Virginia Hospital records of 13 adult patients found to have bone marrow necrosis on bone marrow aspiration and/or needle biopsy from January 1, 1962 to December 31, 1974 were reviewed. Each March 1976
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BONE MARROW NECROSIS-KIRALY,
TABLE I
WHEBY
Conditions Associated with Bone Marrow in Autopsy Series
Leukemias [l-61 Myelofibrosis [l
Antitumor
I
chemotherapy
[lJ
Caissons disease [201
Bacterial infection [I, 191 Irradiation [l, 181 Sickle diseases [l, 7-121 Intravenous sulfathiazole [ll Lymphoma [l, 161 Carcinoma [I, 13-151 Aplastic anemia (1, 171
Megaloblastic anemia [ 191 Myeloma [I 1 Histiocytosis [ 1 I Hypovolemic shock [I I Embolism [l I Sideroblastic
anemia
[l I
record was reviewed to determine the patient’s age, sex, race and presenting clinical and laboratory findings at the time bone marrow necrosis was noted. In addition we reviewed the indications for bone marrow examination, underlying illnesses, relationship of necrosis to prior treatment, role of infection, clinical course before and after bone marrow necrosis, and results of autopsies. All bone marrow aspirates and biopsy specimens were reexamined to verify the diagnosis of bone marrow necrosis. Smears of bone marrow aspirates and touch preparations of bone marrow biopsy specimens were stained with Wright’s stain. Needle biopsy specimens were obtained with the Vim-Silverman or Jamshidi biopsy needle and handled as surgical specimens, being stained with hematoxylin and eosin. On Wright’s stain, bone marrow necrosis has a characteristic appearance (Figure 1). The recognizable features of individual cells are obscured. The cells have indistinct margins, intensely basophilic nuclei and are usually surrounded by amorphous acidophilic material [ 1,281. In fixed sections stained with hematoxylin and eosin (Figure 2) destruction of normal marrow architecture is evident. Again, the cellular margins are indistinct and the cells are scattered in a background of amorphous eosinophilic material. TABLE
II
Major Associated Diseases Previously Reported in Cases of Bone Marrow Necrosis in Which Diagnosis was Made During Life Based on Needle Aspiration or Biopsy*
Associated Disease Acute lymphocytic leukemia Kundel et al. 1964 Nies et al. 1965 Brown 1972 Sickle disease Wade, Stevenson 1941 Charache, Page 1967 Nachamie, Dorfman 1974 Brown 1972 Carcinoma Bousser, Bristol 1961 Brown 1972 Chronic granulocytic leukemia Brown 1972 Unknown (DIG ?) Rose 1973 *Excludes
362
Source
No. Cases
10
t211 [221 [II
6 3 1
I231 [241 [251 [II
1 4 1 1
[261 [ll
1 1
[II
1
[271
1
7
2
1 1
patients with aseptic necrosis of femoral
March 1976
Total No. Cases
head.
The American Journal of Medicine
RESULTS
Incidence.
The incidence
of bone marrow
necrosis
was one of every 664 (0.15 per cent) marrow examinations performed between January 1, 1962 and December 31, 1974. Nine of the 13 cases (69 per cent)
were found in the last five years, giving a current incidence of 1.8 cases per year. Age, Sex and Race. The mean age of the patients was 59 years and the median age was 62 years with a range of 39 to 80 years. Eight patients were female and five were male. All patients were white. Major Underlying Diseases (Table III). The major underlying disease in all patients was neoplastic; two patients had two concurrent neoplastic diseases. In every case the neoplastic disease involved the bone marrow. Six patients had carcinoma-three adenocarcinoma of the stomach, two mutinous cystadenocarcinoma of the ovary, and one anaplastic bronchogenie carcinoma. A myeloproliferative disorder was present in six patients-acute granulocytic leukemia in four: erythroleukemia in one; and myelofibrosis with myeloid metaplasia in one. The latter patient also had a bronchogenic carcinoma. One patient with acute granulocytic leukemia also had chronic lymphocytic leukemia for two years before the onset of the acute leukemia. Two patients had a lymphomaone a well differentiated lymphocytic lymphoma and one a diffuse undifferentiated lymphoma. In seven patients the underlying neoplastic disease and bone marrow necrosis were diagnosed simultaneously. In four patients the underlying disease was diagnosed within a month of the development of bone marrow necrosis. Two patients had been under treatment of neoplastic disease for 16 and 31 months. Symptoms and Signs. The only symptom specifically related to bone marrow necrosis was bone pain which was a major symptom in 11 (85 per cent) patients. The pain was described as severe: it was located in the lower back alone or was generalized involving the back and extremities. Duration of bone pain prior to the diagnosis of bone marrow necrosis varied from five days to one month. Although no other symptom could be directly related to bone marrow necrosis, most of the patients had one or more of the following: fever, weight loss, night sweats, weakness and malaise. The only physical finding that could be directly related to bone marrow necrosis was pain on percussion over the vertebral column, pelvis or long bones which was elicited in all four patients in whom this sign was sought. Fever (temperature greater than 38OC) was present in 38.5 per cent of the patients. No patient had evidence of major infection at the time of bone marrow necrosis: two female patients had asymptomatic bacteriuria. Pallor was noted in
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Figure 1. Photomicrograph showing bone marrow necrosis on a smear of aspirated bone marrow. WrightGiemsa stain, magnification X 920, reduced by 50 per cent. eight patients (62 per cent) and a systolic flow murmur was recorded in six patients (46 per cent). Petechiae and/or ecchymoses were present in two patients (15 per cent). Other physical findings were hepatomegaly in nine patients (69 per cent), splenomegaly in five patients (38 per cent), jaundice in 31 (23 per cent), abdominal mass in 3 (23 per cent) and lymphadenopathy in three (23 per cent). Peripheral Blood. As shown in Table IV, the major peripheral blood abnormalities were anemia, thrombocytopenia and a leukoerythroblastic picture (nucleated red cells and immature granulocytes). Hematocrit values ranged from 16 to 49 per cent with a mean and median of 29 per cent. The leukocyte count was abnormal in eight patients at the time of bone marrow necrosis. Five patients had a leukocytosis (white blood cell count more than 1 0,000/mm3) and three patients were leukopenic (white blood cell count less than 4,000/mm3). Two of the patients with leukopenia had acute granulocytic leukemia and were pancytopenic. One patient TABLE III
The Major Underlying Diseases in 13 Cases of Bone Marrow Necrosis in which Diagnosis was Made During Life
MyeloproliferativeDisorder
Figure 2. Section of bone marrow biopsy specimen from a patient with carcinoma of the stomach and marrow metastasis. The dense spicule of bone separates normal marrow (below) from the necrotic marrow containing metastatic malignant cells (above). Hematoxylin and eosin stain; magnification X 170, reduced by 50 per cent.
with acute granulocytic leukemia had a normal white blood cell count and the fourth had a leukocyte count The median white cell count for all of 30,500/mm3.
13 patients was 9,1 80/mm3 with a range of 1,800 to 30,500/mm3. Nine (69 per cent) patients were thrombocytopenic (platelets less than 150,000/mm3). One patient with myelofibrosis and myeloid metaplasia had a thrombocytosis (platelets more than 400,000/mm3). The median platelet count was 74,000/mm3 range of 6,000 to 5 19,000/mm3.
TABLE IV
Peripheral Blood Findings in 13 Patients with Bone Marrow Necrosis
*One patient with acute granulocytic leukemia had chronic phocytic leukemia for two years prior to acute leukemia. +Same patient.
Finding
4 1 1
Anemia Leukocyte
3 2 1
Normal Decreased Increased Platelet count
1 1 lym-
March
with a
The peripheral blood smear was abnormal in all patients. Nucleated red blood cells were present in every smear. Eleven (85 per cent) of the patients also had immature granulocytes. Schistocytes were found in blood smears from three patients in association with either an increased reticulocyte count, a low serum haptoglobin level or urine hemosiderin. Coagulation studies were not performed routinely in all patients. The plasma prothrombin time was nor-
No.
Acute granulocytic leukemia* Erythroleukemia Myelofibrosis+ Carcinoma Adenocarcinoma-stomach Mutinous cystadenocarcinoma-ovary+ Anaplastic carcinoma-lung Lymphoma Lymphocytic Undifferentiated
WHEBY
%
12
92
5 3 5
38 23 38
3 9 1 13 11 3
23 69 8 100 85 23
count
Normal Decreased Increased Nucleated red cells Leukoerythroblastic Schistocytes
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TABLE V
WHEBY
Serum Chemistries in 13 Patients with Bone Marrow
Test Lactic acid dehydrogenase Alkaline phosphatase Total bilirubin Serum glutamic-oxaloacetic transaminase Uric acid Calcium Phosphorus
Necrosis
Increased
No. Performed
No.
%
12 12 12 11
12 11 5 5
100 92 42 46
9 13 13
8 1 0
89 8 0
mal in all 10 patients in whom it was determined. The partial thromboplastin time was increased in one of five patients and the fibrinogen level was decreased in one of four patients. None of the patients with abnormal coagulation tests had further studies to define the disorder of coagulation. Serum Chemistries. As shown in Table V, the major serum chemistry abnormalities were elevations of the serum alkaline phosphatase, lactic acid dehydrogenase and uric acid levels. The serum alkaline phosphatase level was elevated in 11 of 12 (92 per cent) patients. An average value of the alkaline phosphatase could not be determined because of varying methods of determination. Total serum bilirubin was increased in five of 12 patients; three patients were clinically jaundiced. The range of hyperbilirubinemia was from 2.1 to 5.0 mg/lOO ml. In only one patient was the bilirubin fractionated, and in this case it was predominantly indirect acting. One patient with an elevated bilirubin level had liver metastases from adenocarcinoma of the stomach. The four remaining patients with hyperbilirubinemia had no evidence of liver disease. The presence of urine hemosiderin in one and a low serum haptoglobin level in another suggest hemolytic disease as a cause of the indirect hyperbilirubinemia in these two patients. Serum uric acid was increased in eight of nine patients (89 per cent), being greater than 8.3 mg/lOO ml in females and 7.8 mg/lOO ml in males. The serum lactic dehydrogenase (LDH) level was elevated in all 12 patients having this test, and the serum TABLE VI
Initial Bone Marrow Findings in 13 .Patients with Bone Marrow Necrosis No. Examined
Finding Necrosis on aspirate Necrosis on biopsy Neoplastic cells on aspirate and/or biopsy Necrosis at multiple sites
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No. with % Findings Abnormal
13 12 13
13 9 12
100 75 92
7
6
85
glutamic oxaloacetic transaminase @GOT) level was elevated in five of 11 (46 per cent) patients. Hypercalcemia was found in one of 13 patients, a patient with acute granulocytic leukemia who died with massive bone marrow necrosis. Postmortem examination in this patient revealed normal parathyroid glands. Bone Marrow Examlnation. The indication for bone marrow examination in all patients was an abnormality in the peripheral blood, either a leukoerythroblastic blood smear or an abnormal white blood cell or platelet count. Necrotic bone marrow (Table VI) was found by aspiration in all 13 patients and by needle biopsy in nine of 12 patients (75 per cent) who underwent biopsy. The underlying neoplastic disease was demonstrated in the marrow of 12 (92 per cent) patients either before or at the time bone marrow necrosis was detected. The remaining patient with carcinoma of the stomach had extensive tumor in the marrow at autopsy 19 days after the finding of bone marrow necrosis. Seven patients presented with bone marrow necrosis and the underlying neoplastic disease on initial bone marrow examination; four of these patients had carcinoma and three had acute leukemia. In the six remaining patients the underlying disease was known from 31 months to 8 days before the episode of bone marrow necrosis occurred. In seven patients multiple aspiration and biopsy specimens were obtained from various sites; in six of seven patients (85 per cent) necrotic marrow was found in both the sternum and iliac crest. Roentgenographic Examination. In three patients osteolytic or osteoblastic lesions were demonstrated on metastatic bone survey at the time of bone marrow necrosis; all three patients had carcinoma involving the spine and pelvis. Four patients had negative metastatic bone surveys, and the remaining six patients had no bone involvement on chest and abdominal roentgenograms. Prior Therapy. At the time of bone marrow necrosis only four patients had received previous treatment for neoplastic disease. Two patients, one with ovarian carcinoma and the other with lymphocytic lymphoma, received pelvic irradiation for abdominal masses from two to 57 days before the onset of bone marrow necrosis. One patient with acute leukemia received 6-mercaptopurine for six days before the onset of bone marrow necrosis. The patient with coincident acute granulocytic leukemia and chronic lymphocytic leukemia had been treated with chlorambucil and prednisone intermittently for two years, but had received no treatment in the six months before presentation with acute leukemia and bone marrow necrosis. Clinical Course. At the time of study all patients had died from neoplastic disease. Median survival from
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BONE MARROW
the diagnosis of bone marrow necrosis was 22 days with a range of five days to 11 months. Only four patients survived longer than one month from the diagnosis of bone marrow necrosis. The median survival from diagnosis of the underlying neoplastic disease was 24 days with a range of five days to 31 months. In two of four patients who survived longer than one month, there was sufficient follow up data to assess the natural history of bone marrow necrosis. One patient with ovarian carcinoma, who survived 11 months from the time bone marrow necrosis was detected, recovered from anemia and thrombocytopenia while receiving chemotherapy. Repeat bone marrow examinations three and seven months after the detection of necrosis showed neither tumor nor necrosis. The other patient who had coincident acute granulocytic leukemia and chronic lymphocytic leukemia, survived two months from the detection of bone marrow necrosis. Repeat bone marrow examination one month after the detection of necrosis continued to show extensive acute bone marrow necrosis. Postmortem examination was not performed in either patient with long survival. Postmortem Examfnation. Seven patients had postmortem examination. Six of the seven patients (85 per cent) still had bone marrow necrosis at the time of death. In all patients showing marrow necrosis at postmortem examination, the lesion showed little evidence of healing. The one patient in whom marrow necrosis was not found at autopsy died five days after a marrow specimen from the iliac crest showed necrosis. At autopsy only a single rib and vertebrae were examined in this patient. The patients examined at autopsy died soon after diagnosis with a median survival from the diagnosis of necrosis of eight days with a range of five days to 30 days. A small amount of marrow fibrosis was demonstrated in one patient who died 19 days after presentation with marrow necrosis from metastatic carcinoma of the stomach. In all seven autopsy cases, the neoplastic disease involved the bone marrow. Marrow necrosis was extensive in the six patients who showed this lesion at autopsy. Necrotic marrow was found in all bones examined, generally the sternum, pelvis and vertebrae; however, the necrosis was multifocal in each bone examined, leaving occasional areas of marrow intact. One patient with acute leukemia had extensive marrow necrosis with fat emboli in the pulmonary arteries, the immediate cause of death in this patient. The patient with erythroleukemia died eight days after the finding of necrosis, and at autopsy had widespread gram-negative bacterial abscesses. One patient with carcinoma of the stomach had fibrin thrombi in the kidney which were attributed to disseminated intravascular coagulation.
NECROSIS-KIRALY,
WHEBY
COMMENTS The major underlying disease associated with bone marrow necrosis varies greatly with the setting in which the bone marrow is examined. Reports based on postmortem studies (Table I) have demonstrated a wide variety of associated disorders, with bacterial infection being found in about two-thirds of the cases [ 11. When marrow necrosis is found in a needle aspirate or in a biopsy specimen of the bone marrow during life, the number of underlying disorders narrows dramatically to include mainly sickle cell diseases and neoplastic disorders [ 1,22-271 (Table II). The obvious reason for this disparity between clinical and autopsy reports is that bone marrow examination in living patients is not routine, as it is in autopsies, but is dependent on clinical indications. Historically, the first diseases to be associated with bone marrow necrosis were sickle cell diseases, with most reports based on autopsy cases [ 7- 121. Aspiration of necrotic marrow during life in patients with sickle diseases has been associated with SS, SC, SD, sickle trait and S thalassemia [23-251. The incidence of bone marrow necrosis in patients with sickle disease presenting with tender bones has been reported to be as high as one in six patients [ 241. Marrow necrosis has also been previously recognized during life in patients with leukemia. In a series of 40 patients with acute lymphocytic leukemia Kundel et al. [21] found six cases of bone marrow necrosis. Marrow necrosis has been reported during life in one patient with chronic granulocytic leukemia [ 11. In patients who die with acute granulocytic leukemia, marrow necrosis has been found at autopsy [2,22], but it was not found during life in a series of 20 patients with acute granulocytic leukemia studied retrospectively [ 2 11. There are few reports of marrow necrosis during life in patients with lymphoma. Brittin and Brecher [28] reported finding marrow necrosis in cases of lymphosarcoma involving the bone marrow, but specific clinical details were not included in their report. There are two reports of marrow necrosis found during life in patients with metastatic carcinoma of the bone marrow. One concerned a patient with carcinoma of the stomach who died two days after bone marrow examination to investigate leukopenia and a leukoerythroblastic blood smear [ 261. At autopsy, extensive marrow necrosis and metastases were found. The second patient had a squamous cell carcinoma of the esophagus and one day prior to death had tumor cells and necrosis in bone marrow examined after the development of leukopenia and thrombocytopenia [ 11. There is a reported case of marrow necrosis occurring during life in a postpartum patient with an intrauterine bacterial infection: however, there is insuf-
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WHEBY
ficient data to ascertain the pathogenesis of marrow necrosis in this case. Thus, excluding sickle cell diseases, the finding of marrow necrosis during life has been associated to date only with neopbstic disease involving the bone marrow (Table II). As a consequence, the finding of marrow necrosis should prompt a search for neoplastic disease involving the bone marrow if it is not found on the initial marrow examination. The clinical manifestations specifically attributable to marrow necrosis are few. The outstanding symptom is severe bone pain often involving the spine, pelvis and extremities. Severe pain was reported in 85 per cent of the patients in the current series and has been previously noted as the major symptom of marrow necrosis in acute lymphocytic leukemia and chronic granulocytic leukemia [ 1,21,22]. Fever may be a consequence of marrow necrosis, possibly by release of pyrogens from necrotic marrow constituents. Five patients (38 per cent) in this series had fever which could not be attributed to infection. Fever has been recorded at the time of marrow necrosis in patients with sickle disease, chronic granulocytic leukemia and carcinoma of the stomach [ 1,23,24,26]. Although marrow necrosis may cause fever, occult infection is difficult to exclude. Other than bone tenderness, no physical finding can be specifically related to marrow necrosis. Many patients have findings of widespread neoplastic disease such as hepatomegaly, spfenomegaly and lymphadenopathy. The hematologic findings in this series were indicative of a bone marrow abnormality, with every patient having nucleated red blood cells in the peripheral blood and 85 per cent having leukoerythroblastic blood smears. Although these findings can be attributed to leukemia or metastatic disease in the bone marrow alone [ 291, the extensive disruption of marrow architecture by necrosis may be a significant factor. Laboratory abnormalities such as elevations of the lactic acid dehydrogenase, alkaline phosphatase, uric acid, bilirubin and serum glutamic oxaloacetic transaminase levels could result from the destruction of cells in the bone marrow. However, tumor metastases to marrow or liver can produce many of these laboratory abnormalities with associated marrow necrosis; thus, these findings are not specific for marrow necrosis [ 291. Marrow necrosis generally produces no roentgenographic findings, a point stressed in reports on acute lymphocytic leukemia (ALL) [21,22]. In only three patients in our series were destructive or osteobfastic lesions of bone marrow seen roentgenographically: all of these patients had metastatic solii tumors.
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Bone marrow aspirate in our series showed necrotic marrow in all patients as did 75 per cent of the needle biopsy specimens. This differs from the reported experience in AU in which biopsy was usually necessary to obtain marrow showing necrosis [ 21,221. Biopsy specimens may show both necrosis and structurally Intact marrow infiltrated by the underlying neoplastic disease (Figure 2). In an occasional patient multiple aspirations or biopsies at various sites are required to demonstrate the neoplastic disease since marrow necrosis often is very diffuse. Nevertheless, the involvement in each bone is multifocal, with areas of structurally intact marrow interspersed with areas of necrosis. Thus, a single random biopsy specimen or aspirate may yield only necrotic marrow or only structurally intact marrow. The tendency of marrow necrosis to be widespread has been observed previously in ALL, and its piecemeal involvement of a single bone has been noted in sickle diseases [21,22,24]. If marrow necrosis is found on marrow examination and the underlying disease is not evident, marrow biopsies should be repeated until structurally intact marrow is found; neoplastic disease is usually revealed in the intact areas. The natural history of the necrotic lesion is quite variable in patients who survive long enough to have serial marrow examinations over an extended pericd. Two patients in our series illustrate the varying courses which range from persistent acute necrosis to resolution of a single episode following antiiumor therapy. Patients with ALL have shown similar courses ranging from self-limited single episodes to persistent necrosis up to nine months [ 211. Afthough many patients die shortly after presentation with necrosis, some recover and respond to antlneoplastic therapy. When marrow necrosis heals, it may allow repopulation of the marrow cavity with normal hematopoeitic elements leaving small fibrotic scars surrounding bone spicules without osteocytes [ 2 1,241. The prognosis of patients who present with marrow necrosis and neoplastic disease is extremely poor with only 30 per cent surviving over one month and none surviving a year after the occurrence of marrow necrosis. This is not too surprising since all patients had extensive neoplastic diseases. lt has been previously noted that patients with acute lym phocytic leukemia and bone marrow necrosis respond poorly to chemotherapy [ 221. Among the four patients with acute granulocytic leukemia In our series, only two patients survived long enough to receive chemotherapy. One survived two months, obtaining a partial remission during chemotherapy; the other died on the sixth day of treatment. The effect of marrow necrosis on the response to chemotherapy of the granulocytic leukemias could not be assessed from our data. 60
BONE MARROW
An unexpected finding in the current series was that marrow necrosis may be an important presenting sign of occult malignancy. Why patients with occult malignancy have marrow necrosis more commonfy than patients with previously diagnosed cancer is unclear. It seems unlikely that necrosis would be missed in our hospital as marrow examination is performed in most cancer patients with unexplained peripheral blood abnormalities. A major complication of marrow necrosis is fat and bone marrow emboli to the pulmonary arteries and fat emboli to the brain and kidneys. The clinical syndrome of fat and marrow embolization is characterized by sudden coma, hypoxemia, respiratory distress and renal insufficiency [ 111. Fat may be demonstrated in sputum or urine with Sudan stain [ 111. This syndrome is known to be a fatal consequence of marrow necrosis in sickle diseases, particularly SC disease [ 1,9,10,11,12,23,24]. One of our patients with acute granulocytic leukemia died following bone marrow and fat embolization to the pulmonary arteries. The factors associated with the initiation of bone marrow necrosis are not entirely clear. Previous chemotherapy has been associated with marrow necrosis in autopsy series and has been implicated as the precipitating event in acute leukemia [ 1,4]. In our series, marrow necrosis closely followed chemotherapy in only one patient with acute granulocytic leukemia, but occurred prior to initiation of chemotherapy in the other three patients with leukemia. Therapeutic irradiation has been considered a contributing factor in the production of marrow necrosis in some autopsy series [ 1,5]. Typically, therapeutic irradiation over normal bone marrow does not produce the morphologic picture of necrosis, but rather pyknosis and karyorrhexis of individual marrow cells followed by a disappearance of cells from the marrow [30,31]. Typical bone marrow necrosis has been described at autopsy in an atomic bomb casualty [ 161, but not after therapeutic irradiation. In the present series two patients received irradiation over areas subsequently found to contain necrotic bone marrow. Therapeutic irradiation may have been a contributing factor in these two patients. Infection has been associated at autopsy with marrow necrosis [ 1,191, but no patients in our series had major systemic infection documented at the time of necrosis. Endotoxin can produce hemorrhagic marrow necrosis in mice [32] but so far no such mechanism has been demonstrated in man. The pathophysiologic mechanism underlying bone marrow necrosis is uncertain, but most hypotheses have incorporated vascular obstruction as the critical element. If this is so, then consideration of marrow circulation is important. The arterial circulation of the
NECROSIS-KIRALY,
WHEBY
bone marrow consists of a longitudinal central artery which runs and branches centripetally to supply a network of capillaries adjacent to the endostium [33]. Some of the capillaries penetrate the endostium, supply bone and return; others turn directly into the medullary sinusoids, which separated by hematopoietic cords, drain into the central vein [33]. Because of the rich anastomoses in the endostial and capillary systems, marrow infarction on the basis of obstruction of a single marrow vessel should be difficult to produce. Brown [l] reported cases of infarction of the marrow as a resuft of systemic embolization from meumaticalfy affected heart valves and from medullary venous thrombosis of unknown cause; however, pathologic details on the nature and extent of these obstructions were not reported. A role for thrombosis has been postulated as a cause of marrow necrosis through the mechanism of disseminated intravascular coagulation [ 271. Except for one patient who showed fibrin thrombi in the kidney at autopsy, none of the patients in our series showed evidence of disseminated intravascular coagulation. Experimental models have not served adequately to demonstrate the role of vascuhr obstruction in marrow infarction, as some investigators have produced experimental infarction in animals with nutrient artery occlusion whereas others have been unsuccessful [34,35]. Vascular occlusion and marrow necrosis have been produced by emboli of foreign materials injected into the nutrient artery, but some of these experiments produced necrosis of bone as well as marrow [34,36]. Widespread microvascular obstruction with resufting infarction seems plausible as a mechanism of marrow infarction in sickle cell disease, in which masses of sickle cells are seen occluding the marrow capillaries and sinusoids. In the neoplastic diseases such diffuse obstruction of the microvascular supply of the marrow has not been shown. It is possible that masses of tumor cells or of poorly deformable blast forms growing within noncompliant bone could impede blood flow either by extrasinusoidal compression or intravascuhr obstruction. However, marrow infarction does not occur as regularly in neopbstic diseases as in sickle diseases and factors other than simple vascular obstruction must be operative. As a general statement, marrow infarction would occur when the regional oxygen tension falls below the critical level required to maintain cellular viability. Factors that result in increasing oxygen consumption, such as proliferating neoptastic cells, erythroid hyperplasia in sickle diseases, or fever could serve to lower oxygen tension. Systemic hypoxemia, anemia,
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WHEBY
hypotension or the impediment to flow as mentioned could lower regional oxygen supply further to create the conditions required for necrosis. Although the most likely common mediator of marrow necrosis is hypoxia, it may be that chemical factors could play a role. For example, enzymes released by cells from tumor populations with a high death rate could directly injure adjoining cells in re-
gions of the marrow. Interestingly, many of the solid tumors associated with marrow necrosis consist of mucin producing cells; possibly mucin or some other cellular element could initiate bone marrow necrosis. ACKNOWLEDGMENT We would like to thank Dr. Grace E. Suttle and Dr. William G. Porter for their assistance in this study.
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36.
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WJ. Howard EB, Hackett PL, eds), Oak Ridge, U.S. Atomic Energy Commission, Division of Technical Information, 1970. Kahlstrom SC, Burton CC, Phemister DB: Aseptic necrosis of bone. I. Infarction of bones in caisson disease resufting in encapsulated and calcified areas in diaphyses and in arthritis deformans. Surg Gynecol Obstet 68: 129, 1939. Kundel DW, Brecher G, Bodey G, Brittin GM: Reticulin fibrosis and bone infarction in acute leukemia. Implications for prognosis. Blood 23: 526, 1964. Nies BA, Kundel DW, Thomas LB, Freireich EJ: Leukopenia, bone pain, and bone necrosis in patients with acute leukemia. Ann Intern Med 62: 698, 1965. Wade LJ, Stevenson LD: Necrosis of the bone marrow with fat embolism in sickle cell anemia. Am J Pathol 17: 47, 1941. Charache S, Page DL: Infarction of bone marrow in the sickle cell disorders. Ann Intern Med 67: 1195, 1967. Nachamie BA, Dorfman HD: lschemic necrosis of bone in sickle cell trait. Mt Sinai J Med NY 41: 527, 1974. Bousser J, Christol D: Necrose aique quasi generallsee de la moelle osseuse, d’origine metastatlque. Nouv Rev Fr Hematol 1: 363, 1961. Rose MS: Apparent necrosis of bone marrow in a patient with disseminated intravascular coagulation, post parturn. Lancet 2: 730, 1973. Brittin GM, Brecher G: Appearance of bone marrow smears with necrotic tumor cells. Blood 38: 229, 1971. Pittman G, Tung KSK, Hoffman GC: Metastatic cells in the bone marrow. Cleve Clin Q 38: 55, 1971. Ellinaer F: Medical Radiation Bioloov. Sorinafiild. Ill.. Charles C Thomas, 1957, p 336. -I ’ Bond VP, Fliedner TM, Archambeau JO: Mammalian Radlltion Lethality, New York, Academic Press, 1965 p 159. Yoshiia M, Hirata M, lnada I: Hemorrhage and necrosis in mouse bone marrow induced by endotoxin. Jap J Exp Med 43: 393, 1973. Root WS: The flow of blood through bones and joints, chap 47. Handbook of Physiology, Circulation sect 2, vol II (Hamilton WF. DOW P, eds), Baltimore, Williams 8. Wllkins, 1963. Kistler GH: Formation of bone by periosteum after experimental infarction by embolism of femur in rabbfs. Proc Sot Exp Biol Med 31: 1218, 1934. Huggins C, Wiege E: The effect on the bone marrow of disruption of the nutrient artery and vein. Ann Surg 110: 940, 1939. Kistler GH: Sequences of experimental bacterial infarction of the femur in rabbits. Surg Gynecol Obstet 60: 913, 1935.
JOHN F. KIRALY, III, M.D.’ MUNSEY S. WHEBY, M.D. Charlottesville, Virginia
From the Department of Medicine, University of Virginia School of Medicine, Chat lottesville, Virginia 22901. Requests for reprints shoukl be addressed to Dr. Munsey S. Wheby, Department of Medicine. University of Virginia School of Medicine, Charlottesville, Virginia 22901. fvlanuscript accepted September 4, 1975. Present address: 2311 West Elm Street, Lodie, California 95240 l
The clinical findings of bone marrow necrosis in 13 patients undergoing bone marrow examlnation to tnvesttgate a peripheral blood cytopenla or leukoerythroblaetlc blood smear were reviewed and compared to those tn the ftterature. Exctudtng stckle cell disease, all cases of bone marrow necrosts dlagnoeed durtng ltfe were associated with a neoplastic process InvoMng the marrow. A myeloproltferative disorder was found In five patients, metastatic carcinoma in five patients, a lymphoma tn two patients, and both a myeloprotiferative disorder and metastatic carcinoma in one patient. Marrow necrosis was found to involve the marrow at muttipfe sites in a piecemeal fashton with areas of necrotic marrow and structurally intact marrow adjacent to each other. Severe bone pain without roentgenographtc abnormattty was the major symptom In 85 per cent of the patients. Marrow and fat emboli, hypercalcemla and peripheral Mood cytopenlas were identified as direct complications of marrow necrosis. The prognosis of patients wtth marrow necrosis secondary to neoplastic disease was found to be extremely poor with a median survival of less than one month. However, one pattent responded to antineoplastfc chemotherapy and showed healing of the bone marrow. Bone marrow necrosis has rarely been reported in bone marrow samples obtained during life although it is often found at autopsy. On postmortem examination bone necrosis has been found to be associated with a number of different conditions [l-21] (Table I). It has also-been described in association with avascular necrosis of the femoral head, a disorder of diverse etiology. Only 21 cases of bone marrow necrosis diagnosed antemortem by aspiration or needle biopsy are reported in the literature [ 1,21-271 (Table II). In the majority of these 21 cases the underlying disease was either acute lymphocytic leukemia or sickle ceil disease. The significance of bone marrow necrosis is unclear, except as a poor prognostic sign in acute lymphoblastic leukemia [21,22] and as a potential cause of fat and marrow emboli in patients with sickle cell crisis [912,231. The purpose of the present study was to determine the causes, diagnostic features and clinical significance of bone marrow necrosis in a series of 13 adult patients who were found to have this lesion on bone marrow aspiration or biopsy. MATERIALS AND METHODS The University of Virginia Hospital records of 13 adult patients found to have bone marrow necrosis on bone marrow aspiration and/or needle biopsy from January 1, 1962 to December 31, 1974 were reviewed. Each March 1976
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BONE MARROW NECROSIS-KIRALY,
TABLE I
WHEBY
Conditions Associated with Bone Marrow in Autopsy Series
Leukemias [l-61 Myelofibrosis [l
Antitumor
I
chemotherapy
[lJ
Caissons disease [201
Bacterial infection [I, 191 Irradiation [l, 181 Sickle diseases [l, 7-121 Intravenous sulfathiazole [ll Lymphoma [l, 161 Carcinoma [I, 13-151 Aplastic anemia (1, 171
Megaloblastic anemia [ 191 Myeloma [I 1 Histiocytosis [ 1 I Hypovolemic shock [I I Embolism [l I Sideroblastic
anemia
[l I
record was reviewed to determine the patient’s age, sex, race and presenting clinical and laboratory findings at the time bone marrow necrosis was noted. In addition we reviewed the indications for bone marrow examination, underlying illnesses, relationship of necrosis to prior treatment, role of infection, clinical course before and after bone marrow necrosis, and results of autopsies. All bone marrow aspirates and biopsy specimens were reexamined to verify the diagnosis of bone marrow necrosis. Smears of bone marrow aspirates and touch preparations of bone marrow biopsy specimens were stained with Wright’s stain. Needle biopsy specimens were obtained with the Vim-Silverman or Jamshidi biopsy needle and handled as surgical specimens, being stained with hematoxylin and eosin. On Wright’s stain, bone marrow necrosis has a characteristic appearance (Figure 1). The recognizable features of individual cells are obscured. The cells have indistinct margins, intensely basophilic nuclei and are usually surrounded by amorphous acidophilic material [ 1,281. In fixed sections stained with hematoxylin and eosin (Figure 2) destruction of normal marrow architecture is evident. Again, the cellular margins are indistinct and the cells are scattered in a background of amorphous eosinophilic material. TABLE
II
Major Associated Diseases Previously Reported in Cases of Bone Marrow Necrosis in Which Diagnosis was Made During Life Based on Needle Aspiration or Biopsy*
Associated Disease Acute lymphocytic leukemia Kundel et al. 1964 Nies et al. 1965 Brown 1972 Sickle disease Wade, Stevenson 1941 Charache, Page 1967 Nachamie, Dorfman 1974 Brown 1972 Carcinoma Bousser, Bristol 1961 Brown 1972 Chronic granulocytic leukemia Brown 1972 Unknown (DIG ?) Rose 1973 *Excludes
362
Source
No. Cases
10
t211 [221 [II
6 3 1
I231 [241 [251 [II
1 4 1 1
[261 [ll
1 1
[II
1
[271
1
7
2
1 1
patients with aseptic necrosis of femoral
March 1976
Total No. Cases
head.
The American Journal of Medicine
RESULTS
Incidence.
The incidence
of bone marrow
necrosis
was one of every 664 (0.15 per cent) marrow examinations performed between January 1, 1962 and December 31, 1974. Nine of the 13 cases (69 per cent)
were found in the last five years, giving a current incidence of 1.8 cases per year. Age, Sex and Race. The mean age of the patients was 59 years and the median age was 62 years with a range of 39 to 80 years. Eight patients were female and five were male. All patients were white. Major Underlying Diseases (Table III). The major underlying disease in all patients was neoplastic; two patients had two concurrent neoplastic diseases. In every case the neoplastic disease involved the bone marrow. Six patients had carcinoma-three adenocarcinoma of the stomach, two mutinous cystadenocarcinoma of the ovary, and one anaplastic bronchogenie carcinoma. A myeloproliferative disorder was present in six patients-acute granulocytic leukemia in four: erythroleukemia in one; and myelofibrosis with myeloid metaplasia in one. The latter patient also had a bronchogenic carcinoma. One patient with acute granulocytic leukemia also had chronic lymphocytic leukemia for two years before the onset of the acute leukemia. Two patients had a lymphomaone a well differentiated lymphocytic lymphoma and one a diffuse undifferentiated lymphoma. In seven patients the underlying neoplastic disease and bone marrow necrosis were diagnosed simultaneously. In four patients the underlying disease was diagnosed within a month of the development of bone marrow necrosis. Two patients had been under treatment of neoplastic disease for 16 and 31 months. Symptoms and Signs. The only symptom specifically related to bone marrow necrosis was bone pain which was a major symptom in 11 (85 per cent) patients. The pain was described as severe: it was located in the lower back alone or was generalized involving the back and extremities. Duration of bone pain prior to the diagnosis of bone marrow necrosis varied from five days to one month. Although no other symptom could be directly related to bone marrow necrosis, most of the patients had one or more of the following: fever, weight loss, night sweats, weakness and malaise. The only physical finding that could be directly related to bone marrow necrosis was pain on percussion over the vertebral column, pelvis or long bones which was elicited in all four patients in whom this sign was sought. Fever (temperature greater than 38OC) was present in 38.5 per cent of the patients. No patient had evidence of major infection at the time of bone marrow necrosis: two female patients had asymptomatic bacteriuria. Pallor was noted in
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BONE MARROW NECROSIS-KIRALY,
Figure 1. Photomicrograph showing bone marrow necrosis on a smear of aspirated bone marrow. WrightGiemsa stain, magnification X 920, reduced by 50 per cent. eight patients (62 per cent) and a systolic flow murmur was recorded in six patients (46 per cent). Petechiae and/or ecchymoses were present in two patients (15 per cent). Other physical findings were hepatomegaly in nine patients (69 per cent), splenomegaly in five patients (38 per cent), jaundice in 31 (23 per cent), abdominal mass in 3 (23 per cent) and lymphadenopathy in three (23 per cent). Peripheral Blood. As shown in Table IV, the major peripheral blood abnormalities were anemia, thrombocytopenia and a leukoerythroblastic picture (nucleated red cells and immature granulocytes). Hematocrit values ranged from 16 to 49 per cent with a mean and median of 29 per cent. The leukocyte count was abnormal in eight patients at the time of bone marrow necrosis. Five patients had a leukocytosis (white blood cell count more than 1 0,000/mm3) and three patients were leukopenic (white blood cell count less than 4,000/mm3). Two of the patients with leukopenia had acute granulocytic leukemia and were pancytopenic. One patient TABLE III
The Major Underlying Diseases in 13 Cases of Bone Marrow Necrosis in which Diagnosis was Made During Life
MyeloproliferativeDisorder
Figure 2. Section of bone marrow biopsy specimen from a patient with carcinoma of the stomach and marrow metastasis. The dense spicule of bone separates normal marrow (below) from the necrotic marrow containing metastatic malignant cells (above). Hematoxylin and eosin stain; magnification X 170, reduced by 50 per cent.
with acute granulocytic leukemia had a normal white blood cell count and the fourth had a leukocyte count The median white cell count for all of 30,500/mm3.
13 patients was 9,1 80/mm3 with a range of 1,800 to 30,500/mm3. Nine (69 per cent) patients were thrombocytopenic (platelets less than 150,000/mm3). One patient with myelofibrosis and myeloid metaplasia had a thrombocytosis (platelets more than 400,000/mm3). The median platelet count was 74,000/mm3 range of 6,000 to 5 19,000/mm3.
TABLE IV
Peripheral Blood Findings in 13 Patients with Bone Marrow Necrosis
*One patient with acute granulocytic leukemia had chronic phocytic leukemia for two years prior to acute leukemia. +Same patient.
Finding
4 1 1
Anemia Leukocyte
3 2 1
Normal Decreased Increased Platelet count
1 1 lym-
March
with a
The peripheral blood smear was abnormal in all patients. Nucleated red blood cells were present in every smear. Eleven (85 per cent) of the patients also had immature granulocytes. Schistocytes were found in blood smears from three patients in association with either an increased reticulocyte count, a low serum haptoglobin level or urine hemosiderin. Coagulation studies were not performed routinely in all patients. The plasma prothrombin time was nor-
No.
Acute granulocytic leukemia* Erythroleukemia Myelofibrosis+ Carcinoma Adenocarcinoma-stomach Mutinous cystadenocarcinoma-ovary+ Anaplastic carcinoma-lung Lymphoma Lymphocytic Undifferentiated
WHEBY
%
12
92
5 3 5
38 23 38
3 9 1 13 11 3
23 69 8 100 85 23
count
Normal Decreased Increased Nucleated red cells Leukoerythroblastic Schistocytes
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TABLE V
WHEBY
Serum Chemistries in 13 Patients with Bone Marrow
Test Lactic acid dehydrogenase Alkaline phosphatase Total bilirubin Serum glutamic-oxaloacetic transaminase Uric acid Calcium Phosphorus
Necrosis
Increased
No. Performed
No.
%
12 12 12 11
12 11 5 5
100 92 42 46
9 13 13
8 1 0
89 8 0
mal in all 10 patients in whom it was determined. The partial thromboplastin time was increased in one of five patients and the fibrinogen level was decreased in one of four patients. None of the patients with abnormal coagulation tests had further studies to define the disorder of coagulation. Serum Chemistries. As shown in Table V, the major serum chemistry abnormalities were elevations of the serum alkaline phosphatase, lactic acid dehydrogenase and uric acid levels. The serum alkaline phosphatase level was elevated in 11 of 12 (92 per cent) patients. An average value of the alkaline phosphatase could not be determined because of varying methods of determination. Total serum bilirubin was increased in five of 12 patients; three patients were clinically jaundiced. The range of hyperbilirubinemia was from 2.1 to 5.0 mg/lOO ml. In only one patient was the bilirubin fractionated, and in this case it was predominantly indirect acting. One patient with an elevated bilirubin level had liver metastases from adenocarcinoma of the stomach. The four remaining patients with hyperbilirubinemia had no evidence of liver disease. The presence of urine hemosiderin in one and a low serum haptoglobin level in another suggest hemolytic disease as a cause of the indirect hyperbilirubinemia in these two patients. Serum uric acid was increased in eight of nine patients (89 per cent), being greater than 8.3 mg/lOO ml in females and 7.8 mg/lOO ml in males. The serum lactic dehydrogenase (LDH) level was elevated in all 12 patients having this test, and the serum TABLE VI
Initial Bone Marrow Findings in 13 .Patients with Bone Marrow Necrosis No. Examined
Finding Necrosis on aspirate Necrosis on biopsy Neoplastic cells on aspirate and/or biopsy Necrosis at multiple sites
364
March 1976
The
No. with % Findings Abnormal
13 12 13
13 9 12
100 75 92
7
6
85
glutamic oxaloacetic transaminase @GOT) level was elevated in five of 11 (46 per cent) patients. Hypercalcemia was found in one of 13 patients, a patient with acute granulocytic leukemia who died with massive bone marrow necrosis. Postmortem examination in this patient revealed normal parathyroid glands. Bone Marrow Examlnation. The indication for bone marrow examination in all patients was an abnormality in the peripheral blood, either a leukoerythroblastic blood smear or an abnormal white blood cell or platelet count. Necrotic bone marrow (Table VI) was found by aspiration in all 13 patients and by needle biopsy in nine of 12 patients (75 per cent) who underwent biopsy. The underlying neoplastic disease was demonstrated in the marrow of 12 (92 per cent) patients either before or at the time bone marrow necrosis was detected. The remaining patient with carcinoma of the stomach had extensive tumor in the marrow at autopsy 19 days after the finding of bone marrow necrosis. Seven patients presented with bone marrow necrosis and the underlying neoplastic disease on initial bone marrow examination; four of these patients had carcinoma and three had acute leukemia. In the six remaining patients the underlying disease was known from 31 months to 8 days before the episode of bone marrow necrosis occurred. In seven patients multiple aspiration and biopsy specimens were obtained from various sites; in six of seven patients (85 per cent) necrotic marrow was found in both the sternum and iliac crest. Roentgenographic Examination. In three patients osteolytic or osteoblastic lesions were demonstrated on metastatic bone survey at the time of bone marrow necrosis; all three patients had carcinoma involving the spine and pelvis. Four patients had negative metastatic bone surveys, and the remaining six patients had no bone involvement on chest and abdominal roentgenograms. Prior Therapy. At the time of bone marrow necrosis only four patients had received previous treatment for neoplastic disease. Two patients, one with ovarian carcinoma and the other with lymphocytic lymphoma, received pelvic irradiation for abdominal masses from two to 57 days before the onset of bone marrow necrosis. One patient with acute leukemia received 6-mercaptopurine for six days before the onset of bone marrow necrosis. The patient with coincident acute granulocytic leukemia and chronic lymphocytic leukemia had been treated with chlorambucil and prednisone intermittently for two years, but had received no treatment in the six months before presentation with acute leukemia and bone marrow necrosis. Clinical Course. At the time of study all patients had died from neoplastic disease. Median survival from
American Journalcl Medicine Volume 60
BONE MARROW
the diagnosis of bone marrow necrosis was 22 days with a range of five days to 11 months. Only four patients survived longer than one month from the diagnosis of bone marrow necrosis. The median survival from diagnosis of the underlying neoplastic disease was 24 days with a range of five days to 31 months. In two of four patients who survived longer than one month, there was sufficient follow up data to assess the natural history of bone marrow necrosis. One patient with ovarian carcinoma, who survived 11 months from the time bone marrow necrosis was detected, recovered from anemia and thrombocytopenia while receiving chemotherapy. Repeat bone marrow examinations three and seven months after the detection of necrosis showed neither tumor nor necrosis. The other patient who had coincident acute granulocytic leukemia and chronic lymphocytic leukemia, survived two months from the detection of bone marrow necrosis. Repeat bone marrow examination one month after the detection of necrosis continued to show extensive acute bone marrow necrosis. Postmortem examination was not performed in either patient with long survival. Postmortem Examfnation. Seven patients had postmortem examination. Six of the seven patients (85 per cent) still had bone marrow necrosis at the time of death. In all patients showing marrow necrosis at postmortem examination, the lesion showed little evidence of healing. The one patient in whom marrow necrosis was not found at autopsy died five days after a marrow specimen from the iliac crest showed necrosis. At autopsy only a single rib and vertebrae were examined in this patient. The patients examined at autopsy died soon after diagnosis with a median survival from the diagnosis of necrosis of eight days with a range of five days to 30 days. A small amount of marrow fibrosis was demonstrated in one patient who died 19 days after presentation with marrow necrosis from metastatic carcinoma of the stomach. In all seven autopsy cases, the neoplastic disease involved the bone marrow. Marrow necrosis was extensive in the six patients who showed this lesion at autopsy. Necrotic marrow was found in all bones examined, generally the sternum, pelvis and vertebrae; however, the necrosis was multifocal in each bone examined, leaving occasional areas of marrow intact. One patient with acute leukemia had extensive marrow necrosis with fat emboli in the pulmonary arteries, the immediate cause of death in this patient. The patient with erythroleukemia died eight days after the finding of necrosis, and at autopsy had widespread gram-negative bacterial abscesses. One patient with carcinoma of the stomach had fibrin thrombi in the kidney which were attributed to disseminated intravascular coagulation.
NECROSIS-KIRALY,
WHEBY
COMMENTS The major underlying disease associated with bone marrow necrosis varies greatly with the setting in which the bone marrow is examined. Reports based on postmortem studies (Table I) have demonstrated a wide variety of associated disorders, with bacterial infection being found in about two-thirds of the cases [ 11. When marrow necrosis is found in a needle aspirate or in a biopsy specimen of the bone marrow during life, the number of underlying disorders narrows dramatically to include mainly sickle cell diseases and neoplastic disorders [ 1,22-271 (Table II). The obvious reason for this disparity between clinical and autopsy reports is that bone marrow examination in living patients is not routine, as it is in autopsies, but is dependent on clinical indications. Historically, the first diseases to be associated with bone marrow necrosis were sickle cell diseases, with most reports based on autopsy cases [ 7- 121. Aspiration of necrotic marrow during life in patients with sickle diseases has been associated with SS, SC, SD, sickle trait and S thalassemia [23-251. The incidence of bone marrow necrosis in patients with sickle disease presenting with tender bones has been reported to be as high as one in six patients [ 241. Marrow necrosis has also been previously recognized during life in patients with leukemia. In a series of 40 patients with acute lymphocytic leukemia Kundel et al. [21] found six cases of bone marrow necrosis. Marrow necrosis has been reported during life in one patient with chronic granulocytic leukemia [ 11. In patients who die with acute granulocytic leukemia, marrow necrosis has been found at autopsy [2,22], but it was not found during life in a series of 20 patients with acute granulocytic leukemia studied retrospectively [ 2 11. There are few reports of marrow necrosis during life in patients with lymphoma. Brittin and Brecher [28] reported finding marrow necrosis in cases of lymphosarcoma involving the bone marrow, but specific clinical details were not included in their report. There are two reports of marrow necrosis found during life in patients with metastatic carcinoma of the bone marrow. One concerned a patient with carcinoma of the stomach who died two days after bone marrow examination to investigate leukopenia and a leukoerythroblastic blood smear [ 261. At autopsy, extensive marrow necrosis and metastases were found. The second patient had a squamous cell carcinoma of the esophagus and one day prior to death had tumor cells and necrosis in bone marrow examined after the development of leukopenia and thrombocytopenia [ 11. There is a reported case of marrow necrosis occurring during life in a postpartum patient with an intrauterine bacterial infection: however, there is insuf-
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NECROSIS-KRALY,
WHEBY
ficient data to ascertain the pathogenesis of marrow necrosis in this case. Thus, excluding sickle cell diseases, the finding of marrow necrosis during life has been associated to date only with neopbstic disease involving the bone marrow (Table II). As a consequence, the finding of marrow necrosis should prompt a search for neoplastic disease involving the bone marrow if it is not found on the initial marrow examination. The clinical manifestations specifically attributable to marrow necrosis are few. The outstanding symptom is severe bone pain often involving the spine, pelvis and extremities. Severe pain was reported in 85 per cent of the patients in the current series and has been previously noted as the major symptom of marrow necrosis in acute lymphocytic leukemia and chronic granulocytic leukemia [ 1,21,22]. Fever may be a consequence of marrow necrosis, possibly by release of pyrogens from necrotic marrow constituents. Five patients (38 per cent) in this series had fever which could not be attributed to infection. Fever has been recorded at the time of marrow necrosis in patients with sickle disease, chronic granulocytic leukemia and carcinoma of the stomach [ 1,23,24,26]. Although marrow necrosis may cause fever, occult infection is difficult to exclude. Other than bone tenderness, no physical finding can be specifically related to marrow necrosis. Many patients have findings of widespread neoplastic disease such as hepatomegaly, spfenomegaly and lymphadenopathy. The hematologic findings in this series were indicative of a bone marrow abnormality, with every patient having nucleated red blood cells in the peripheral blood and 85 per cent having leukoerythroblastic blood smears. Although these findings can be attributed to leukemia or metastatic disease in the bone marrow alone [ 291, the extensive disruption of marrow architecture by necrosis may be a significant factor. Laboratory abnormalities such as elevations of the lactic acid dehydrogenase, alkaline phosphatase, uric acid, bilirubin and serum glutamic oxaloacetic transaminase levels could result from the destruction of cells in the bone marrow. However, tumor metastases to marrow or liver can produce many of these laboratory abnormalities with associated marrow necrosis; thus, these findings are not specific for marrow necrosis [ 291. Marrow necrosis generally produces no roentgenographic findings, a point stressed in reports on acute lymphocytic leukemia (ALL) [21,22]. In only three patients in our series were destructive or osteobfastic lesions of bone marrow seen roentgenographically: all of these patients had metastatic solii tumors.
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Bone marrow aspirate in our series showed necrotic marrow in all patients as did 75 per cent of the needle biopsy specimens. This differs from the reported experience in AU in which biopsy was usually necessary to obtain marrow showing necrosis [ 21,221. Biopsy specimens may show both necrosis and structurally Intact marrow infiltrated by the underlying neoplastic disease (Figure 2). In an occasional patient multiple aspirations or biopsies at various sites are required to demonstrate the neoplastic disease since marrow necrosis often is very diffuse. Nevertheless, the involvement in each bone is multifocal, with areas of structurally intact marrow interspersed with areas of necrosis. Thus, a single random biopsy specimen or aspirate may yield only necrotic marrow or only structurally intact marrow. The tendency of marrow necrosis to be widespread has been observed previously in ALL, and its piecemeal involvement of a single bone has been noted in sickle diseases [21,22,24]. If marrow necrosis is found on marrow examination and the underlying disease is not evident, marrow biopsies should be repeated until structurally intact marrow is found; neoplastic disease is usually revealed in the intact areas. The natural history of the necrotic lesion is quite variable in patients who survive long enough to have serial marrow examinations over an extended pericd. Two patients in our series illustrate the varying courses which range from persistent acute necrosis to resolution of a single episode following antiiumor therapy. Patients with ALL have shown similar courses ranging from self-limited single episodes to persistent necrosis up to nine months [ 211. Afthough many patients die shortly after presentation with necrosis, some recover and respond to antlneoplastic therapy. When marrow necrosis heals, it may allow repopulation of the marrow cavity with normal hematopoeitic elements leaving small fibrotic scars surrounding bone spicules without osteocytes [ 2 1,241. The prognosis of patients who present with marrow necrosis and neoplastic disease is extremely poor with only 30 per cent surviving over one month and none surviving a year after the occurrence of marrow necrosis. This is not too surprising since all patients had extensive neoplastic diseases. lt has been previously noted that patients with acute lym phocytic leukemia and bone marrow necrosis respond poorly to chemotherapy [ 221. Among the four patients with acute granulocytic leukemia In our series, only two patients survived long enough to receive chemotherapy. One survived two months, obtaining a partial remission during chemotherapy; the other died on the sixth day of treatment. The effect of marrow necrosis on the response to chemotherapy of the granulocytic leukemias could not be assessed from our data. 60
BONE MARROW
An unexpected finding in the current series was that marrow necrosis may be an important presenting sign of occult malignancy. Why patients with occult malignancy have marrow necrosis more commonfy than patients with previously diagnosed cancer is unclear. It seems unlikely that necrosis would be missed in our hospital as marrow examination is performed in most cancer patients with unexplained peripheral blood abnormalities. A major complication of marrow necrosis is fat and bone marrow emboli to the pulmonary arteries and fat emboli to the brain and kidneys. The clinical syndrome of fat and marrow embolization is characterized by sudden coma, hypoxemia, respiratory distress and renal insufficiency [ 111. Fat may be demonstrated in sputum or urine with Sudan stain [ 111. This syndrome is known to be a fatal consequence of marrow necrosis in sickle diseases, particularly SC disease [ 1,9,10,11,12,23,24]. One of our patients with acute granulocytic leukemia died following bone marrow and fat embolization to the pulmonary arteries. The factors associated with the initiation of bone marrow necrosis are not entirely clear. Previous chemotherapy has been associated with marrow necrosis in autopsy series and has been implicated as the precipitating event in acute leukemia [ 1,4]. In our series, marrow necrosis closely followed chemotherapy in only one patient with acute granulocytic leukemia, but occurred prior to initiation of chemotherapy in the other three patients with leukemia. Therapeutic irradiation has been considered a contributing factor in the production of marrow necrosis in some autopsy series [ 1,5]. Typically, therapeutic irradiation over normal bone marrow does not produce the morphologic picture of necrosis, but rather pyknosis and karyorrhexis of individual marrow cells followed by a disappearance of cells from the marrow [30,31]. Typical bone marrow necrosis has been described at autopsy in an atomic bomb casualty [ 161, but not after therapeutic irradiation. In the present series two patients received irradiation over areas subsequently found to contain necrotic bone marrow. Therapeutic irradiation may have been a contributing factor in these two patients. Infection has been associated at autopsy with marrow necrosis [ 1,191, but no patients in our series had major systemic infection documented at the time of necrosis. Endotoxin can produce hemorrhagic marrow necrosis in mice [32] but so far no such mechanism has been demonstrated in man. The pathophysiologic mechanism underlying bone marrow necrosis is uncertain, but most hypotheses have incorporated vascular obstruction as the critical element. If this is so, then consideration of marrow circulation is important. The arterial circulation of the
NECROSIS-KIRALY,
WHEBY
bone marrow consists of a longitudinal central artery which runs and branches centripetally to supply a network of capillaries adjacent to the endostium [33]. Some of the capillaries penetrate the endostium, supply bone and return; others turn directly into the medullary sinusoids, which separated by hematopoietic cords, drain into the central vein [33]. Because of the rich anastomoses in the endostial and capillary systems, marrow infarction on the basis of obstruction of a single marrow vessel should be difficult to produce. Brown [l] reported cases of infarction of the marrow as a resuft of systemic embolization from meumaticalfy affected heart valves and from medullary venous thrombosis of unknown cause; however, pathologic details on the nature and extent of these obstructions were not reported. A role for thrombosis has been postulated as a cause of marrow necrosis through the mechanism of disseminated intravascular coagulation [ 271. Except for one patient who showed fibrin thrombi in the kidney at autopsy, none of the patients in our series showed evidence of disseminated intravascular coagulation. Experimental models have not served adequately to demonstrate the role of vascuhr obstruction in marrow infarction, as some investigators have produced experimental infarction in animals with nutrient artery occlusion whereas others have been unsuccessful [34,35]. Vascular occlusion and marrow necrosis have been produced by emboli of foreign materials injected into the nutrient artery, but some of these experiments produced necrosis of bone as well as marrow [34,36]. Widespread microvascular obstruction with resufting infarction seems plausible as a mechanism of marrow infarction in sickle cell disease, in which masses of sickle cells are seen occluding the marrow capillaries and sinusoids. In the neoplastic diseases such diffuse obstruction of the microvascular supply of the marrow has not been shown. It is possible that masses of tumor cells or of poorly deformable blast forms growing within noncompliant bone could impede blood flow either by extrasinusoidal compression or intravascuhr obstruction. However, marrow infarction does not occur as regularly in neopbstic diseases as in sickle diseases and factors other than simple vascular obstruction must be operative. As a general statement, marrow infarction would occur when the regional oxygen tension falls below the critical level required to maintain cellular viability. Factors that result in increasing oxygen consumption, such as proliferating neoptastic cells, erythroid hyperplasia in sickle diseases, or fever could serve to lower oxygen tension. Systemic hypoxemia, anemia,
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ol Madkin
Vohme
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BONE MARROW NECROSIS-KIRALY,
WHEBY
hypotension or the impediment to flow as mentioned could lower regional oxygen supply further to create the conditions required for necrosis. Although the most likely common mediator of marrow necrosis is hypoxia, it may be that chemical factors could play a role. For example, enzymes released by cells from tumor populations with a high death rate could directly injure adjoining cells in re-
gions of the marrow. Interestingly, many of the solid tumors associated with marrow necrosis consist of mucin producing cells; possibly mucin or some other cellular element could initiate bone marrow necrosis. ACKNOWLEDGMENT We would like to thank Dr. Grace E. Suttle and Dr. William G. Porter for their assistance in this study.
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