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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 3  |  Issue : 2  |  Page : 123-129

Haematological and biochemical predictors of bone marrow metastases in non-haematological malignancies: A clinico-pathological analysis


1 Department of Pathology and Lab Medicine, AIIMS, Rishikesh, Uttarakhand, India
2 Department of Surgery, AIIMS, Rishikesh, Uttarakhand, India

Date of Submission03-Oct-2020
Date of Decision07-Jan-2021
Date of Acceptance27-Mar-2021
Date of Web Publication08-Jul-2021

Correspondence Address:
Dr. Arvind Kumar Gupta
Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JME.JME_129_20

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  Abstract 


Background: Bone marrow metastasis is an uncommon yet significant presentation of many non haematological malignancies. Aims: The present study was conducted with the aim of analysing the clinical, haematological and biochemical parameters of the patients with bone marrow metastases and determines the parameters which could possibly indicate the presence of bone marrow metastases. Patients and Methods: Bone marrow aspirate, imprint and biopsy slides of 22 cases with bone marrow metastases were reviewed and the haematological and biochemical data of all these cases were compared with that of 20 controls without any evidence of metastases. Results: The mean values of mean platelet volume (MPV), neutrophil to lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH) were found to be significantly different (P < 0.001) between the cases and controls. MPV <8.1 fL, NLR >3.5 and LDH >452 U/L showed a high likelihood ratio in predicting bone marrow metastases. Conclusion: Parameters such as MPV, NLR and LDH can be used as efficient and easily available methods to predict bone marrow metastasis for a rapid diagnosis.

Keywords: Bone marrow, lactate dehydrogenase, mean platelet volume, metastases, neutrophil to lymphocyte ratio


How to cite this article:
Agrawal S, Bhandari R, Gowda VN, Gupta A, Singh N, Chowdhury N, Rao S, Kishore S, Gupta AK, Chandra H. Haematological and biochemical predictors of bone marrow metastases in non-haematological malignancies: A clinico-pathological analysis. J Med Evid 2022;3:123-9

How to cite this URL:
Agrawal S, Bhandari R, Gowda VN, Gupta A, Singh N, Chowdhury N, Rao S, Kishore S, Gupta AK, Chandra H. Haematological and biochemical predictors of bone marrow metastases in non-haematological malignancies: A clinico-pathological analysis. J Med Evid [serial online] 2022 [cited 2022 Oct 5];3:123-9. Available from: http://www.journaljme.org/text.asp?2022/3/2/123/355005




  Introduction Top


Bone marrow examination has traditionally been a routine investigation for various haematological malignancies, but marrow involvement by non-haematological malignancies is a rare occurrence. Although advent of ancillary techniques such as fluorodeoxyglucose-positron emission tomography and bone scans has proven beneficial in detecting many unsuspected cases of bone metastases, few cases, especially with unknown primary or those presenting with non-specific symptoms, are still left undetected and remain a diagnostic challenge for the clinicians. In such cases, bone marrow aspiration (BMA) and trephine biopsy serve to be sensitive diagnostic tools. Bone marrow biopsy (BMB) also aids in determining the management and prognosis as it is included as a part of staging procedure in certain malignancies such as the small round cell tumours.[1],[2] Hence, bone marrow evaluation provides a rapid means of detection of metastases, thereby allowing early treatment of the patient and affecting overall survival.

The major objective of this study was to analyse the clinical presentation as well as haematological and biochemical profile of solid tumour metastases. Despite being a sensitive and effective method, bone marrow evaluation may sometimes fail to detect metastases due to a 'dry tap' or inadequate BMB and therefore needs some additional supportive parameters to provide clue towards bone marrow metastasis. In such cases, identification of those haematological and biochemical parameters which could effectively predict bone marrow metastases may serve useful by prompting the pathologists to search cautiously for abnormal cell clusters in the bone marrow or recommend a repeat procedure if the BMA or BMB are inadequate in such cases.


  Materials and Methods Top


A retrospective study was conducted in the department of pathology to include all the cases of non-haematological malignancies of bone marrow for a period of 28 months from January 2018 to April 2020, thereby excluding cases of leukaemias, lymphomas and plasma cell neoplasms from the study. Bone marrow procedure had been done in these cases in view of clinical history of bone pain, suspected bony lesions on radiology, presence of one or more cytopenias not attributable to chemotherapy, or as a part of staging procedure in a known case of malignancy. Twenty cases with a known history of malignancy without bone marrow metastases after adequate sampling were taken as controls. Clinical history of the patients was recorded. Haematological and biochemical values of the patients at the time of bone marrow procedure were noted. Haematological data included haemoglobin (Hb) levels, total leucocyte count (TLC), platelet count, absolute neutrophil count, absolute lymphocyte count (ALC), mean corpuscular volume, red cell distribution width (RDW), mean platelet volume (MPV) and platelet distribution width (PDW) which were run on the autoanalyser (LH750 Beckman Coulter Inc., California, USA) with adequate quality control. Neutrophil-to-lymphocyte ratio (NLR) was calculated for every patient. Peripheral blood smear findings were also noted in all cases. Biochemical parameters included serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Anaemia was defined as Hb value <13 g/dL in males and <12 g/dL in females. Leucocytosis was defined as TLC >11,000/uL and leucopenia as TLC <4000/uL. A platelet count <150×103/uL was counted as thrombocytopenia. BMA, imprint smears and BMB for all cases and controls were reviewed. Bone marrow procedure was performed under all aseptic precautions from the posterior superior iliac crest in all cases using Salah needle for BMA and Jamshidi needle for BMB. The aspirate and imprint smears were stained with Giemsa stain. The trephine biopsy was stained with haematoxylin and eosin after undergoing standard processing techniques comprising of fixation and decalcification. An adequacy criterion of at least 1.5 cm length was adopted for all trephine biopsies. Appropriate immunohistochemistry (IHC) was applied wherever necessary.

All statistical analyses were done using IBM SPSS Statistics for Windows, version 20.0, Armonk (NY, USA). The results were analysed using the independent sample t-test to assess statistically significant difference between the cases and control values with 95% confidence intervals. P < 0.05 was considered to be statistically significant. In addition, a receiver operating characteristic (ROC) curve was used to calculate sensitivity, specificity, likelihood ratio (LR) and area under curve to evaluate the usefulness of a particular variable as a predictive marker of bone marrow metastasis. A cut-off value for each parameter was determined so as to obtain the most optimum values of sensitivity and specificity. This study is a retrospective study using stored slides, blocks, available data and records of patients available in department of pathology and laboratory medicine and does not have any ethical issues; however, the same has been applied before the institutional ethics committee for exemption.


  Results Top


Of the total 1538 bone marrow procedures done in our institute between January 2018 and April 2020, 22 cases (1.4%) showed bone marrow infiltration by solid tumour. Of these, 12 cases underwent bone marrow procedure as a staging protocol for management of a histologically proven malignancy, 3 were clinically diagnosed as multiple myeloma and the remaining had bone marrow examination done due to abnormal blood counts. Bone marrow procedure was done from unilateral site in all the seven clinically unsuspected patients. Remaining 15 cases had undergone bilateral bone marrow examination. A dry tap in BMA was obtained in six cases, whereas eight cases had diluted aspirates. Atypical cells could be seen in the BMA of only 4 cases (18%). However, imprint smears were available for all the cases and revealed the neoplastic cells in 20 cases (90%) [Figure 1] and [Figure 2]. Bone marrow biopsies were adequate in all the cases ranging in size from 1.5 to 2.2 cm in length. The clinico-haematological profile and biochemical profile of all the cases with bone marrow metastases are shown in [Table 1]. The age of the patients with bone marrow metastases ranged from 3 to 84 years (median: 36.5), with six cases belonging to paediatric age group. The demographic profile of the cases and controls is summarised in [Table 2]. Most common chief complaints of the patients comprised back pain and difficulty in walking (72%), followed by weight loss and anorexia (64%), and breathlessness and generalised weakness (45%). Other complaints included fever and primary organ-specific symptoms such as lower urinary tract symptoms, haematuria and cough. [Table 2] shows the primary malignancy in all the patients, most common being the Ewing's sarcoma. The histological type of malignancy was determined by the characteristic morphology on BMB and confirmed by appropriate IHC [Figure 1] and [Figure 2] which was decided after correlating with the clinical complaints and the radiological investigations of the patients. However, in two cases, primary site could not be established.
Figure 1: Bone marrow and immunohistochemistry findings in a case of breast adenocarcinoma (a-d). (a) Aspirate smear showing clusters of neoplastic cells (×400, Giemsa), (b) Trephine biopsy showing sheets and tubules of atypical cells (×400, haematoxylin and eosin), (c) Tumour cells showing strong cytoplasmic positivity for mammaglobin and (×400, DAB), (d) Gross cystic disease fluid protein-15 (×400, DAB)

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Figure 2: Bone marrow and immunohistochemistry findings in a case of Ewing's Sarcoma (a-d). (a) Imprint smear displaying clusters of small round cells (×400, Giemsa), (b) Trephine biopsy showing diffuse infiltration by tumour cells (×400, haematoxylin and eosin), (c) Tumour cells showing strong membranous positivity for CD99 and (×400, DAB), (d) Diffuse nuclear positivity for FLI-1 (×400, DAB)

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Table 1: Clinico-haematological and biochemical profile of the cases with bone marrow metastasis

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Table 2: Clinical features and primary malignancy of the patients

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On analysis of haematological parameters, anaemia was seen in all 22 cases (100%), while leucocytosis was present in only 6 cases (27%). Leucopenia was noted in a single patient only (4.5%). Thrombocytopenia was observed in 16 cases (72%). Peripheral smear examination revealed leucoerythroblastic blood picture in 7 cases (32%), microcytic hypochromic red blood cells in 4 cases (18%) and macrocytic anaemia and haemolytic blood picture in 2 cases (9%) each. Normocytic normochromic blood picture was observed in the remaining 7 cases (32%). The mean values of the different haematological and biochemical parameters in the cases and controls and a comparative difference between the two with respect to bone marrow metastases are represented in [Table 3]. A statistically significant difference was observed in the values of MPV, ALC, NLR and LDH between the cases and the controls. ROC curve analysis showed that of all the parameters, MPV, NLR and LDH had a significantly higher sensitivity and specificity with a high LR in determining bone marrow metastasis [Table 4]. A comparison between ROC curves of these three parameters is illustrated in [Figure 3]. MPV < 8.1 fL had 63% sensitivity and 90% specificity in cases with bone marrow metastasis as compared to the controls with no evidence of bone marrow metastasis, with a LR of 6.3. NLR >3.5 could detect bone marrow metastasis with 77% sensitivity and 85% specificity. Furthermore, an NLR >4.7 has a 100% specificity for predicting bone marrow metastasis. In the biochemical parameters, serum LDH Value >452 U/L carried 68% sensitivity and 90% specificity in diagnosing solid tumour metastasis, with an LR value of 6.8.
Figure 3: Plot showing receiver operating characteristic curves for mean platelet volume, neutrophil-to-lymphocyte ratio and lactate dehydrogenase. All the three curves show high area under the curve

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Table 3: Comparison of Haematological and biochemical parameters between the cases and controls

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Table 4: ROC curve analysis of the Haematological and the biochemical parameters

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  Discussion Top


Bone marrow evaluation is the most useful and accurate technique for demonstrating bone marrow metastases of non-haematological malignancies. Infiltration of bone marrow by solid tumours is a rare occurrence. In our study, only 1.4% of all the bone marrow procedures accounted for solid tumour metastases over a period of 28 months. Evaluation of BMA and trephine biopsy specimens is being utilised increasingly over the past few decades to determine the accurate stage of certain malignancies.[1],[2] In our study, bone marrow involvement aided the clinicians in upstaging the tumour and planning the management accordingly in 12 cases (54%). However, the major diagnostic utility of the bone marrow examination was evident in those cases where a primary malignancy was completely unsuspected (32%) or an initial diagnosis of multiple myeloma was being worked upon (14%), thereby providing valuable information to the clinicians. Importance of a meticulous bone marrow evaluation has also been described in literature, especially in cases where bone marrow metastasis is the initial presentation of solid tumours.[1],[2],[3],[4] Although bone marrow examination is quite sensitive in detection of metastases, the adequacy of the material obtained proves to be a major limiting factor at times. A 'dry tap' in BMA, where no material is aspirated despite multiple attempts or a scanty non-diagnostic yield is obtained, may result from extensive bone marrow fibrosis or hypercellularity in a metastatic involvement of bone marrow. In such cases, imprint smear examination proves beneficial in detecting the atypical cells which might otherwise be missed out.[5],[6] In the present study, tumour cells could be picked up in only 18% of the BMA smears, whereas 14 aspirates were either diluted or a dry tap. However, imprint smears helped in identifying malignancy in 90% of the cases. Gupta et al. reported the diagnostic utility of BMA in 76% of BMA and 97% of imprints in non-haematological disorders.[6] Therefore, a careful and diligent preparation of imprint smears is necessary for accurately replicating core biopsy findings and increasing the sensitivity of diagnosing metastases. Similarly for BMB, the length of the biopsy is a crucial factor for assessing the adequacy. The WHO (2016) recommends a minimum length of 1.5 cm for BMB to be adequate enough for evaluating any neoplasm.[7] The size criteria ensure precise detection of even those lesions which tend to involve the bone marrow focally, especially metastatic tumours. In our study, the trephine biopsies were adequate and revealed the atypical cells in 100% cases. This is consistent with the findings in other studies which have reported the diagnostic superiority of BMB over BMA in cases of solid tumour metastases.[5],[6],[8] In addition, bilateral bone marrow examination has been advocated to increase the diagnosis of marrow involvement in many haematological and non-haematological malignancies and was done in 15 cases (68%) in our study.[9]

Clinically, the most frequent complaint of the patients in our study was that of back pain associated with disabled movements in 72% of the patients. This finding was similar to studies done by Chandra et al. and Wong et al.[10],[11] Although bone marrow metastasis is known to occur in many solid tumours, the most common primary tumours that metastasise to bone marrow are lungs, breast, stomach and prostate.[12],[13],[14] Overall, the most frequent primary malignancy in the present study was Ewing's sarcoma (31.8%) followed by breast carcinoma (13.6%). 2 cases (9.1%) of adenocarcinoma each from prostate, lung and gastrointestinal tract were noted. Anner and Drewinko however reported metastasis from neuroblastoma (48.2%) as the most frequent occurrence followed by Ewing's sarcoma (35.5%).[14] Gupta et al. observed gastric adenocarcinoma to be the most common primary tumour.[6] In our study, metastatic adenocarcinomas from various primary sites were evident on histology of trephine biopsy in 9 cases (40.9%). However, despite an extensive radiological and immunohistochemical analysis, the primary site could not be established in two cases. The haematological parameters in cases of bone marrow metastases usually reveal one or more cytopenias.[1],[3],[4] In our study, anaemia and thrombocytopenia were documented in 100% and 72% of the cases, with the leucocyte count being within normal range in most patients (mean 8.9×109/L). This was quite similar to the observations of Ozkalemkas et al., who reported anaemia and thrombocytopenia in all of their cases. In fact, one of the main reasons for bone marrow evaluation in their study was unexplained cytopenias in cases of unsuspected non-haematological malignancies. They also concluded that presence of leucoerythroblastic blood picture and microangiopathic haemolytic anaemia should trigger a necessity of bone marrow evaluation.[1] In the present study, leucoerythroblastic blood picture was observed in 32% cases, while haemolytic anaemia was recorded in 9% of cases only. Delsol et al. reported leucoerythroblastosis in 44% of the patients with bone marrow metastases and considered this haematological finding as a consistent feature of solid tumour metastases.[15]

An important objective of this study was to determine the haematological and biochemical parameters which could possibly predict the event of bone marrow metastases in cases of non-haematological malignancies. At times, the neoplastic infiltration in the bone marrow may be quite indistinct such that the cells may not be distinguished on histomorphology alone. In these cases, use of appropriate IHC markers or even molecular studies facilitates adequate visualisation of the malignant cells.[9],[16] However, in few cases, even after the application of ancillary techniques, bone marrow metastases may not be detected, especially when the involved lesion is very focal. In such instances, a knowledge of haematological or biochemical predictive variables could hint the pathologist to consider a careful second examination of the bone marrow. In the present study, a statistically significant difference was observed between the cases with bone marrow metastasis and the controls with uninvolved marrow with respect to MPV, ALC, NLR and LDH. On ROC curve analysis, an MPV value <8.1 fL had a specificity of 90% and a high LR in predicting bone marrow metastasis. The exact reason for a decreased platelet volume in bone marrow metastases is unknown, yet it has been proposed that thrombopoietin production by marrow stromal cells may be affected due to interaction with metastatic cells which results in deranged maturation of the megakaryocytes and hence influences the platelet volume.[17] According to Aksoy et al., MPV <7.4 fL showed a sensitivity of 82.7% and a specificity of 89.6% for bone marrow metastasis.[18] Although the mean values of ALC were significantly different (P < 0.001) between the cases and the controls, the specificity and LR derived from the ROC curve analysis were not significant. However, NLR >3.5 showed a moderate sensitivity (77%) and a good specificity (85%), with a high positive LR in predicting bone marrow metastasis. Higher neutrophil counts and lower lymphocyte counts in the cases with bone marrow metastasis as compared to the controls resulted in higher NLR. A relation between systemic inflammation and tumorigenesis is well known. Tumour cells stimulate release of granulocyte-colony stimulating factor which triggers neutrophilia, thereby promoting tumour growth and angiogenesis through production of various cytokines. On the other hand, lymphocytes play an important role in providing anti-tumour immunity.[19],[20],[21] Caliskan and Korkmaz recorded a higher NLR in patients with bone metastases as compared to those without bone metastases.[20] Similarly, Wang et al. reported that a high NLR (>3) was independently associated with worse prognosis in patients with malignant bone metastases.[21] Serum LDH >452 U/L showed a 90% specificity and LR of 6.8 for bone marrow metastases in our study. This was in concordance with other studies which also demonstrated the positive correlation of serum LDH values with marrow involvement by metastases.[1],[22],[23] Hamrick and Murgo concluded that patients with normal serum LDH along with normal bone scans had <5% chance of marrow involvement.[22] Other variables such as anaemia, thrombocytopenia, elevated RDW, PDW and ALP have also been shown to indicate bone marrow metastases in various studies; however, no such correlation was seen in our study.[1],[11],[23] The limitation of the study has been a small number of cases and inclusion of a spectrum of malignancies. Furthermore, this was an exploratory study, with the controls being taken by convenience sampling. This study needs to be validated by a larger study to confirm the diagnostic accuracy of MPV, NLR and LDH as well as study the correlation of tumour type and the prognosis of the patient with the various haematological and biochemical parameters.


  Conclusion Top


Metastatic involvement of bone marrow by solid tumours is an uncommon phenomenon and mandates a careful bone marrow examination aided by a judicious use of IHC panel in arriving at a diagnosis. Parameters such as MPV, NLR and serum LDH not only serve as rapid and easily available methods to predict the occurrence of bone marrow metastases but also warrant a meticulous search for the presence of neoplastic cells to avoid a misdiagnosis.

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Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Ozkalemkas F, Ali R, Ozkocaman V, Ozcelik T, Ozan U, Ozturk H, et al. The bone marrow aspirate and biopsy in the diagnosis of unsuspected nonhematologic malignancy: A clinical study of 19 cases. BMC Cancer 2005;5:144.  Back to cited text no. 1
    
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Xiao L, Luxi S, Ying T, Yizhi L, Lingyun W, Quan P. Diagnosis of unknown nonhematological tumors by bone marrow biopsy: A retrospective analysis of 10,112 samples. J Cancer Res Clin Oncol 2009;135:687-93.  Back to cited text no. 12
    
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Kucukzeybek BB, Calli AO, Kucukzeybek Y, Bener S, Dere Y, Dirican A, et al. The prognostic significance of bone marrow metastases: Evaluation of 58 cases. Indian J Pathol Microbiol 2014;57:396-9.  Back to cited text no. 13
[PUBMED]  [Full text]  
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Anner RM, Drewinko B. Frequency and significance of bone marrow involvement by metastatic solid tumors. Cancer 1977;39:1337-44.  Back to cited text no. 14
    
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Nagahisa H, Nagata Y, Ohnuki T, Osada M, Nagasawa T, Abe T, et al. Bone marrow stromal cells produce thrombopoietin and stimulate megakaryocyte growth and maturation but suppress proplatelet formation. Blood 1996;87:1309-16.  Back to cited text no. 17
    
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Aksoy S, Kilickap S, Hayran M, Harputluoglu H, Koca E, Dede DS, et al. Platelet size has diagnostic predictive value for bone marrow metastasis in patients with solid tumors. Int J Lab Hematol 2008;30:214-9.  Back to cited text no. 18
    
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Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet 2001;357:539-45.  Back to cited text no. 19
    
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[PUBMED]  [Full text]  
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    Figures

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