Although bone marrow metastases are frequently encountered in patients with disseminated solid tumors, it is not a common event as a presenting sign. It stems from two possible reasons: i) in general, bone marrow is seldom the sole site of systemic involvement by malignant disease and ii) bone marrow examination in evaluating patients with suspected malignancy has a limited value unless supported by some other clinical finding, such as a leukoerythroblastic reaction [1, 3, 4]. Although there are a number of correlates that may be useful, there is no single specific finding that is an indicator of marrow infiltration. Furthermore, in most patients with neoplastic infiltration of the marrow, the peripheral blood findings do not differ significantly from those without marrow involvement. Our series showed that MAHA, LEB and unexplained cytopenias are strong indicators of the necessity of bone marrow examination. When we reviewed routine hematologic and biochemical parameters we found that only four were present in all patients: anemia, thrombocytopenia, elevated RDW and hypoproteinemia. However, our results should be interpreted with caution, as the current study was not designed to determine the predictive parameters of marrow metastases.
LEB is the term used to describe the combination of nucleated red cells (erythroblasts) and immature myeloid precursors (e.g. myelocytes and myeloblasts) in the peripheral blood film. The mechanism of leukoerythroblastic reactions is not defined. The invasion of metastatic cancer cells may cause the early release of some cytokines, leading to the development of a myelophthisic blood picture even before the marrow is completely replaced. This is a possible explanation for some instances of leukoerythroblastic changes in the blood of the patients with tumors in whom marrow metastases are not documented by histologic examination. Although metastatic foci can be found in a high percentage of some carcinomas, the development of frank LEB occurs much less frequently, so its absence should not exclude marrow involvement. If there is LEB in a case of suspected malignancy, bone marrow examination should be considered. Our series confirmed this judgment, because fifteen of the patients were presented with LEB. On the other hand despite clear bone marrow involvement in 4 patients there were no erythroid and myeloid precursors in their peripheral blood films (patients # 10, 11, 14, 15). LEB was reported at different rates in different series consisting of cancer patients with bone marrow metastases: 10/27 [5]; 19/25 [6]; 5/63 [7]; 26/73 [2]. Our relatively high LEB ratio (15/19) is not comparable with other series because they consisted of cancer patients who were diagnosed before bone marrow examination. Our high LEB ratio, when considered along with the bad outcomes, may reflect the late and advanced cases. In recent years there is a scarcity of publications on the association of myelophthisis with cancer. As mentioned by the authors in a recent report [8], early diagnosis and more effective therapies are possible explanations for this decrease.
MAHA or thrombotic microangiopathy (TM) describes the association of hemolytic anemia with red cell fragmentation caused by microangiopathy mechanically. Cancer related thrombotic microangiopathy (CR-TM) is a rare and severe complication; it usually occurs in the late or terminal stage of cancer with a short-term life-threatening prognosis [9, 10]. CR-TM shares certain clinical similarities with thrombotic thrombocytopenic purpura such as neurological and renal impairment; also both are characterized by circulating platelet aggregates containing ultra large multimers of Von Willebrand factor (VWF). A recent report showed no VWF cleaving protease deficiency in a patient with metastatic adenocarcinoma of the colon and microangiopathic hemolysis, who is refractory to plasma exchange [11]. We do not have any data about protease activity but, because of an almost identical clinical picture with TTP as presentation, we started plasma exchange immediately in patient # 1 and # 2 but therapy failed as expected. Hemolysis, in our CR-TM patients, was so severe that several units of transfusion per day were required to maintain a safe hemoglobin level. Reticulocytosis is expected but this finding could not be a reliable indicator of hemolysis, as seen in our patients, because of marrow infiltration or chronic disease. In our series, seven out of eight MAHA patients showed LEB and six showed abnormality in some coagulation tests suggesting disseminated intravascular coagulation. When we reviewed our eight MAHA cases there were two TUO and one prostate carcinoma. All definitive stomach carcinomas and a probable gastrointestinal carcinoma were in the MAHA group. The survivals of our MAHA patients were between 11 and 51 days except for one (patient # 18; prostate carcinoma). This suggests that once microangiopathic hemolysis is seen in a patient with disseminated carcinoma, the overall prognosis is poor, especially in stomach adenocarcinoma presented with MAHA.
"Dry tap" is a term used to describe failure to obtain bone marrow on attempted marrow aspirations. Extensive marrow fibrosis and hypercellularity have been proposed as mechanisms to account for the inability to withdraw marrow by aspiration [12, 13]. Because it can be attributed to faulty technique it should only be used retrospectively after review of the biopsy. We have two dry taps (patients # : 4, 6). If the definition of dry tap includes cases in which material is obtained but no, or inadequate marrow cells found in films we have four additional cases (patients # 1, 2, 3, 13). We concluded that bone marrow biopsy is certainly indicated whenever aspiration results in an insufficient material especially in the presence of LEB, MAHA, cytopenias and an elevated serum LDH.
Classically, marrow biopsy is unequivocally the best method of detecting lymphomatous involvement because in approximately one-third of cases, the aspirate is unremarkable and the biopsy shows tumor. In solid tumors other than those of lymphomatous origin the data in the literature comparing the relative value of bone marrow aspiration and biopsy in detecting marrow involvement are not so conclusive. [2, 14]. Naturally trephine biopsies have a definitive advantage over aspirates in cases of dry tap. Additionally histologic sections may allow classification of the type of tumor cells, and this is of particular value in the investigation of a patient with a malignancy of unknown primary site. Aspirations were diagnostic in 12 patients in our series. The other attempts yielded no, or inadequate material. Cytological diagnoses could not be confirmed in one patient because of the patient's objection to biopsy procedure. Only in one instance was cytology superior to biopsy in first examination (a retrospective examination of biopsy confirmed the cytological finding in this patient). Although biopsies have some advantages, tumor cells occasionally can be seen in aspirate preparations when biopsy sections are normal as mentioned in literature, these two procedures should therefore be regarded as complementary.
The management of a patient, whose solid malignancy is disclosed from bone marrow, depends on his/her primary tumor. The pathologist can assist the clinician by thoroughly examining the histologic specimen. In some cases an immunoperoxidase staining for organ-specific antigen examination might be sufficient to bring out of the primary focus. As an example, an immunoperoxidase stain for prostatic acid phosphatase or prostate-specific antigen may be helpful in establishing a diagnosis of metastatic prostate cancer. On the opposite side of the spectrum in some cases the pathologist could not comment on the primary site because of a poorly differentiated tumor. Maximum effort should be made to minimize the target. In these tumors as a first step leukocyte common antigen may be used to differentiate lymphohematopoietic neoplasm from other cancers. Patient # 7 and 10, who were reported recently elsewhere separately [15, 16], are good examples for bringing out the primary focus by extra stainings. The examination of patients with bone marrow metastases of unknown origin should focus on detecting treatable primary tumors [17]. This work up may result in certain improvements in survivals of patients with prostate carcinoma. Bone marrow metastases commonly arise from lung, breast and prostate cancers; therefore, in case of no clinical sign a reasonable work up should include a chest roentgenogram, a prostate examination with serum prostate specific acid phosphotase (PAP) in men; a breast examination and mammography in women; computed tomography scans also should be performed in suspected cases. Serum tumor markers are not so useful in many cases except PAP; considering their less specificity it is no surprising. Because the expected survival of many patients is quite short, laboratory and imaging studies should be considered in view of their rationality.