Microangiopathic haemolytic anaemia, myelonecrosis, and myeloma-like presentation in metastatic cancers.

Case 1

In May 2023, a 48-year-old male presented to the Surgical Oncology Outpatient Department of our Institute with a six-week history of poor appetite, intermittent right-sided abdominal discomfort, and significant weight loss (12 Kg in the last three months). He had no family history of any cancer on the paternal or maternal side. Physical examination revealed mild conjunctival pallor, Eastern Cooperative Oncology Group score 2, and a palpable, non-tender mass in the right iliac fossa. Digital rectal examination showed a pedunculated polyp of size 1cm at the 1 to 2 O’clock position, 8cm from the anal verge. Colonoscopy showed multiple sessile polyps of sizes ranging from 4 mm to 120 mm involving the rectum, starting 5 cm from the anal verge till the transverse colon (more than 20 cm) and a non-negotiable circumferential growth in the hepatic flexure and ascending colon. Contrast enhanced computerized tomogram scan of the thorax and whole abdomen showed a heterogeneously enhancing mass lesion involving ascending colon, hepatic flexure, and proximal transverse colon for a length of 15 cm with significant mesocolic fat stranding and multiple locoregional enlarged lymph nodes, largest measuring 20 mm and no evidence of ascites, pleural effusion, or distant metastases in lungs and liver (clinical stage: CT3N2M0). His baseline laboratory evaluation revealed microcytic hypochromic anaemia (Hb; 90 g/L, ref.; 120 to 140, MCV; 80 fL (ref.; 80 to 98), neutrophilic leucocytosis [total leukocyte count (TLC); 17.6 x 10⁹/L, ref.; 4 to 11), total platelet count (Plt); 257 x 10⁹/L, 150 to 450), hypoalbuminemia (serum Alb; 1.8 g/dl, ref.; 3 to 5), normal liver and renal parameters, prothrombin time (PT), INR, activated thromboplastin time (APTT), serum carcinoembryonic antigen (CEA); and negative viral markers. He underwent right extended hemicolectomy with D2 lymphadenectomy with end ileostomy and distal transverse colon mucous fistula following a prior colonoscopic mucosal biopsy-proven histological diagnosis of intramucosal carcinoma involving ascending colon, hepatic flexure, and proximal transverse colon, along with multiple tubule-villous adenomas with dysplasia. The histopathological evaluation of the right hemicolectomy and lymph node dissection specimen revealed a pT4aN2bM0, microsatellite instable and mismatch repair deficient, mucinous adenocarcinoma in the caecum and ascending colon with extensive lymphovascular emboli (LVE). His post-operative period was unremarkable till D9, after which it had a declining course till D20 with a new onset of abdominal pain, oozing from the retroperitoneal resection site, requiring re-exploration, and later shifting to the intensive care unit due to the onset of dyspnoea, falling oxygen saturation, requiring non-invasive ventilation and later intubation. He also required frequent transfusion support with packed red cells, platelets, fresh frozen plasma, and antibiotic coverage for possible onset of sepsis-associated DIC, and finally succumbed to DIC-related complications on D24 post-surgery. Informed consent was obtained from the next of kin.

Laboratory investigation:

His complete blood count (CBC) and peripheral blood smear (PBS) evaluation on D20 post resection revealed severe Coomb negative, normocytic normochromic anaemia (Hb; 45 g/L, MCV; 99 fL, corrected reticulocyte count; 0.47%, ref.; 0.5 to 1.2%) with appearance of numerous schistocytes (>2%) and nucleated red cells (30/100 leukocytes), low normal TLC; 5 x 109/L with myeloid left shift, and severe thrombocytopenia (9 x 109/L), suggestive of a leucoerythroblastic blood picture (LEB) and MAHA. Serum biochemistry revealed raised lactate dehydrogenase (LDH) (2500 U/L, ref. < 200), SGOT (301 U/L, ref. < 40), SGPT (89 U/L, ref. < 40), alkaline phosphatase (ALP, 469 U/L, ref. < 125), jaundice [total bilirubin (TB)/direct (DB)/indirect (IB); 4.4/2.4/2.0 mg/dl], Ca2+; 10.2 mg/dl (8.5 to 11), Alb; 1.9 g/dl, and Cr; 1.7 mg/dl (0.5 to 1.2). His coagulation screening revealed raised PT/INR; 62.8 seconds/5.61, APTT; 63.7 seconds, D-dimer; 35 micrograms/L (ref.; < 0.5), and plasma fibrinogen of 3.45 g/L (ref.; 2 to 4); thus suggestive of MAHA-DIC.

Right side iliac crest BMA on D20 for evaluation of worsening pancytopenia yielded a scant, haemodiluted, and partly degenerated material without any visualized hematopoietic elements. Sections from the decalcified BMBx showed extensive areas of MN (> 90%) with focal osteonecrosis and new bone formation (osteosclerosis). Residual viable areas showed metastatic mucin-secreting, moderately differentiated adenocarcinomatous deposits, which on immunohistochemistry (IHC) were diffusely positive for pan cytokeratin (PanCK), CK20, and caudal type homeobox transcription factor 2 (CDX2), and negative for CK7; thus consistent with a diagnosis of metastatic colonic adenocarcinoma. [Figure 1].

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Figure 1:

(case 1) (a) Peripheral blood smear from the index case on D19 post-surgery showing presence of numerous schistocytes (black arrows) and thrombocytopenia, suggestive of microangiopathic haemolytic anaemia (MAHA) (Leishman-Giemsa stain, 400x), (b and c) Bone marrow biopsy showing extensive coagulative necrosis (myelonecrosis) with only focal viable areas (square box) (Haematoxylin and eosin stain, 40x), and associated increased reticulin fibrosis, respectively, (d) The viable areas showing metastatic adenocarcinomatous deposit (400x), (e, f and g) Immunohistochemical analysis depicting strong and diffuse positivity for pan cytokeratin, CDX2, and cytokeratin 20, respectively. Note the negative reaction for cytokeratin 7 (inset, g). These features were consistent with a metastatic colorectal adenocarcinomatous deposits in the bone marrow (400x).

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Case 2

In April 2021, a 53-year-old male was diagnosed with a poorly differentiated, pT3N3aMx, stage IIIB gastric body adenocarcinoma with LVE, peri-neural infiltration, and extra nodal extension, following which he underwent subtotal gastrectomy and Roux-en-Y gastrojejunostomy. He received two cycles of oxaliplatin and capecitabine (CapeOX) adjuvant chemotherapy followed by concurrent chemo radiotherapy (CT-RT) with tablet capecitabine and 45 Gy x 25# for one month, continued for six months. His follow-up whole body bone scan and PET-CT imaging in July 2022 showed increased osteoblastic activity and lytic lesions in the left scapula, respectively, suggestive of metastasis. He continued with tablet capecitabine for four months till November 2022. Follow-up PET-CT scan in December 2022 showed progressive disease in the left scapula with increased SUV uptake that necessitated palliative RT to the left scapula and four cycles of (CAPIRI) therapy with zolendronic acid till March 2023. His subsequent whole-body PET-CT scan in April 2023 revealed multifocal lytic and sclerotic bony lesions suggestive of metastases without any metastases in the liver, lungs, or any other organs. In May 2024, he presented with refractory bicytopenia requiring PRBC and platelet transfusion support and increasing bone pain necessitating routine hematologic and BM evaluation that showed metastases with evidence of MAHA-DIC. The patient succumbed to DIC-related complications on day 47 post-diagnosis of BM metastasis.Informed consent was obtained from the next of kin.

Laboratory investigation:

His CBC and PBS evaluation before BM evaluation revealed severe, Coomb negative, haemolytic anaemia (Hb; 35 g/L, MCV; 91.0 fL, reticulocyte; 5%), with numerous schistocytes (10%), nucleated red blood cells (15/100 WBCs), good number of polychromatophils, and microspherocytes; neutrophilic leukocytosis (15 x 109/L), and thrombocytopenia (24 x 109/L), consistent with MAHALEB. Serum biochemistry showed hypoalbuminemia (1.8 g/dl), TB/DB/IB; 3.6/1.2/2.4 mg/dl, LDH; 654 IU/L, ALP; 231 IU/L, normal transaminases, Ca2+; 10.2 mg/dl, and creatinine; 1.2 mg/dl. His coagulation profile revealed PT/INR: 17.2 seconds/1.34, APTT: 25.0 seconds, fibrinogen: 1.11g/L, increased D-dimer: 14.30 microgram/L, thus suggestive of DIC.

Bilateral iliac crest BMA yielded haemodiluted and partly degenerated material without any visualized cellular elements. Trephine biopsy touch imprint smears showed a metastatic adenocarcinomatous deposit with both scattered osteoblasts and osteoclasts. Bombs sections showed extensive (90%) myelonecrosis with patchy areas of osteonecrosis, osteosclerosis, and extensive stromal desmoplasia. The viable areas showed metastatic signet ring adenocarcinomatous infiltrates along with evidence of LVE, which were strongly and diffusely immunopositive for PanCK, CK7, and CK20, thus confirming a metastatic gastric primary [Figure 2].

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Figure 2:

(case 2) (a) Peripheral blood smear from the index case with presence of numerous schistocytes (black arrows), nucleated red blood cells (double arrows), and severe thrombocytopenia, consistent with a diagnosis of microangiopathic haemolytic anaemia (MAHA) (Leishman-Giemsa stain, 400x), (b, c and d) Bone marrow trephine biopsy showing extensive myelonecrosis (200x), focal clusters of signet ring tumor cells (400x), and evidence of osteosclerosis (black asterix) with evidence of sinusoidal emboli (400x), respectively (Haematoxylin and eosin stain). Note, the presence of clusters of malignant epithelial cells and scattered osteoclast and osteoblasts in the trephine biopsy touch imprint smear (inset, b, Leishman-Giemsa), (e, f and g) Immunohistochemistry showing tumour cells to be strongly and diffusely positive for pancytokeratin, CK7, and CK20, respectively thus suggestive of metastatic gastric signet ring carcinoma, (h) Note the increased number of spindle to stellate shaped marrow stromal cells (double black arrows) and scattered signet ring tumor cells (thick black arrows) showing granular, cytoplasmic positivity for RANKL antibody, (e-h) Peroxidase-antiperoxidase.

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Case 3

In March 2025, a 65-year-old male with no known prior comorbidities presented with a one-month history of progressively worsening lower back pain accompanied by generalized fatigue and intermittent chest discomfort. Physical examination revealed moderate pallor, diffuse spinal tenderness on palpation, and no evidence of hepatosplenomegaly or lymphadenopathy. Spinal T2W sagittal and axial T2W image magnetic resonance imaging (MRI) image showed multiple heterogeneous signal intensity lytic-sclerotic lesions in multiple vertebral bodies with extension into the spinal canal and anterior epidural space, causing multiple vertebral body collapse [Figure 3].

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Figure 3:

(case 3) (a and b) T2W sagittal image in cervical, dorsal, and lumbar spine showing multiple heterogeneous signal intensity lesions in multiple vertebral bodies (white arrows) with extension into the spinal canal and anterior epidural space, and causing multiple vertebral bodies collapse (white asterisk), respectively.

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A provisional clinical diagnosis of CRAB-positive MM was made, and the patient was initiated on intravenous fluids, loop diuretics, intravenous tramadol, and dexamethasone (8 mg IV twice daily). Notably, this therapeutic regimen led to normalization of serum calcium levels within 48 hours of initiation. He underwent a BM evaluation to rule out MM but was diagnosed with metastatic deposits from prostate cancer. He was started on weekly single-agent cisplatin in view of poor performance status (ECOG PS4 - bedridden in view of paraparesis) at a dose of 30 mg/m² along with denosumab 120 mg for the lytic spinal bone lesions for 4 weeks. Additionally, he was started on localized RT to vertebral bone lesions (30 Gy in 5#), following which RT was withheld due to the onset of febrile neutropenia and sepsis. The patient is presently under close follow-up with supportive care. Informed verbal consent was obtained from the next of kin of the patient.

Laboratory investigation:

His routine CBC and serum biochemistry revealed: Hb; 55 g/L, MCV; 89 fL, reticulocyte count; 1%, TLC; 11 × 10⁹/L, Plt; 103 × 10⁹/L, urea; 95 mg/dl (17–43), Cr; 3.51 mg/dL, Ca2+; 15.51 mg/dL, phosphate; 5.36 mg/dl (2.8 to 4.5), normal liver transaminases, ALP; 169 U/L, total protein/Alb/globulin; 6.84/3.8/3.04 g/dL. His PBS examination revealed a moderate degree of normocytic normochromic anaemia, no rouleaux, scattered tear drop poikilocytes, schistocytes (1%), polychromatophils, leucocytosis with myeloid shift, and low normal platelet count; thus suggestive of LEB-MAHA. His coagulation screen showed PT/INR: 12.8 seconds/1.02, APTT: 24.8 seconds, and normal fibrinogen and D-dimer levels.

Right side iliac crest BMA yielded a difficult aspirate with the presence of clusters, pseudo-rosette-like, and aggregates of malignant small blue round cells with coarse clumped chromatin and prominent nuclear moulding, suppressing TLH, suggestive of a metastatic neuroendocrine tumour. BMBx sections revealed sheets and aggregates of metastatic malignant small blue round cells replacing haematopoiesis with areas of MN (30%), MF 2 reticulin fibrosis, and osteosclerosis. These tumour cells were strongly and diffusely immunopositive for NKX3.1, synaptophysin, chromogranin, weakly for TTF1, focally for prostate-specific antigen (PSA), and negative for CK7, CK20, and napsin. The morphologic and IHC features were consistent with a BM metastatic NET of prostatic origin, which was later corroborated by a raised serum PSA level (30 ng/ml, Ref. < 4.0).

There was no evidence of clonal plasma cells, and serum immune fixation electrophoresis was negative for monoclonal protein [Figure 4].

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Figure 4:

(case 3) (a) Peripheral blood smear (400x) showing scattered schistocytes (black arrow) suggestive of microangiopathic haemolytic anaemia (MAHA) (Leishman-Giemsa stain, 400x, (b) Bone marrow aspirate smears showing malignant cells arranged in clusters and rosette-like pattern with prominent nuclear moulding and coarse chromatin, suspicious of a neuroendocrine tumour (Leishman-Giemsa stain, 400x), (c and d) Bone marrow trephine biopsy sections showing myelonecrosis (black asterix), and residual viable tumour cells, respectively (Haematoxylin and eosin stain), (e-i) Immunohistochemical positivity of tumor cells for NKX3.1, prostate specific antigen (inset, focal), synaptophysin, chromogranin, thyroid transcription factor 1 (weak, nuclear), and negative staining for napsin, respectively, thus suggestive of metastatic prostatic neuroendocrine malignancy (peroxidase-antiperoxidase).

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Literature review

We did a PubMed/MEDLINE-based literature search using various structured terms and text words without language restriction on the occurrence of MAHA and BM metastasis in association with solid (epithelial) cancers, and CRAB-like manifestations/presentations in non-myelomatous cancers published in the English literature from 1st January 2000 to 31st December 2024. Following search items were used for literature search: “bone marrow metastasis, MAHA, solid cancer/colorectal/gastric”, “myelonecrosis, MAHA, and epithelial cancer”, “thrombotic microangiopathy in cancer”, “microangiopathic haemolytic anaemia in metastatic solid malignancies”, “cancer associated MAHA”, “CRAB in bone marrow metastases,” “CRAB positive cancers mimicking myeloma,” “CRAB in metastatic solid malignancies/cancers,” “CRAB symptoms in lymphoma/leukemia”, “CRAB symptoms in metastatic solid malignancies”, etc.. We included all isolated case reports, case series, or systematic reviews with detailed clinicohematological, biochemical, and coagulation profiles (wherever available), and therapeutic outcome data for our review. Reference lists of relevant papers were also screened manually for additional cases. We excluded duplicate cases or cases in which there was insufficient reporting of clinical data of individual patients. We also excluded all those published reports that described cases with co-existent metastatic solid cancers and MM from our review in order to avoid bias. The detailed data pertaining to MAHA in metastatic colon and gastric cancers are presented in Table 1,^[4-28] and those about CRAB in non-myelomatous cancers are presented in Table 2.^{[3, 29-31]}

MAHA in solid epithelial cancers:

The largest review by Lechner and Obermeier (N = 168, epithelial; 154, lymphomas; 14) reported a higher prevalence of MAHA in concurrent (81%) than recurrent cancers (19%). [1] The common reported epithelial cancers were those from the stomach (N = 44), breast (N = 36), prostate (N = 23), lungs (N = 16), unknown primaries (N = 12), and abdominal/? gastrointestinal tract (N = 10). More than 90% of MAHA cases had metastatic disease; 81% had BM infiltration, and a variable degree of TTP or HUS-like features that occurred in 11 (7%) and 26 (17%) of cases, respectively. MAHA occurred as the sign of recurrence, commonly in gastric, breast, and prostate cancers (N = 23/80), with a time gap of MAHA-associated recurrence to first diagnosis ranging from 3 to 13 years (7 months to 13 years for stomach, 6 months to 10.5 years for breast, and 14 months to 12 years for prostate). MAHA-associated cancers who received therapy (surgery with or without chemotherapy, CT) had a better median overall survival (MOS) than those who didn’t [4 (0.5 - 31) vs. 0.5 (0.5 - 84) months, respectively, log rank p > 0.05]. The MOS was 10.5 (95% CI: 2 – 26), 5 (0.5 – 15), 4 (0.5 – 31), 3.5 (2 – 9), and 3 months (0.5 – 2) for MAHA associated cancers of prostate (N = 15), lungs (N = 13), breast (N = 26), unknown primary (N = 11), and stomach (N = 34), respectively.^[1]

Ducos et al. reviewed the 17 cases of cancer-MAHA-TTP (2001-2012) and compared their features with 20 idiopathic TTPs.^[2] The median delay between cancer diagnosis and MAHA was 27.5 days (range: 4 to 92 days) with a high prevalence of BM metastasis (12/17, 71%). Compared with idiopathic subgroup, cancer subjects were older (p = 0.007), and were more likely to have respiratory symptoms (p < 0.0001), bone pain (p = 0.002), anorexia/weight loss (p < 0.0001), thrombocytopenia (p = 0.02), late onset MAHA-DIC, and high mortality (12/17 died, p = 0.002) whereas the former was more likely to have neurological symptoms (p = 0.05) and be benefitted by plasmapheresis than cancer sub group.^[2]In a review by Van Bunderen et al^[16], older age, male gender, advanced malignancy, breast cancer, and the presence of necrosis in the tumour specimen were independent factors significantly related to the occurrence of DIC. Patients with DIC had a reduced survival, even when grouped by tumour stage, compared with patients without DIC.^[16]

MAHA in colon cancer

There were 20 isolated reports of MAHA in colorectal cancer that included 16 males and 4 females with ages ranging from 37 to 79 years. In six (30%) cases, this marked the recurrence of CRC with a time gap ranging from 6 months to 13 years from first diagnosis; and in the remaining 14 (70%) cases, this occurred concurrently with the diagnosis of CRC. Seven were right-sided, nine were left-sided, and the remaining four occurred in the transverse colon with a signet ring and/or mucinous histology. Back pain with or without associated bleeding manifestations and cytopenia (s) [anaemia with thrombocytopenia;12/20 (60%), pancytopenia (4/20, 20%)] dominated the clinical presentation. Leukoerythroblastic peripheral smear was noted in eight (40%) cases, whereas two (10%) had evidence of circulating tumour cells in the peripheral blood (carcinocythemia).^[16,17] Schistocytes were present in the peripheral smear in 12 (60%) cases, leading to a diagnosis of MAHA, whereas a coagulation profile suggestive of DIC was evident in 10 (50%) cases. Coomb-negative haemolytic anaemia with raised serum LDH was observed in 14/20 (70%) cases. Of note is the fact that a raised serum ALP (> 200 IU/L) was noted in 10 of 11 cases where it was performed (200 to 1000 U/L in four, > 1000 U/L in six), and this was corroborated with mixed sclerotic-lytic bone lesions described in most cases on radiological evaluation (not presented in the table). BM evaluation showed metastasis in all cases, and the extent of marrow involvement ranged from focal to extensive and five have evidence of MN. None of these cases of MAHA other than that reported by Saad et al were attributable to the Oxaliplatin based chemotherapeutic drugs.^[5] The MOS of this cohort was 8.8 months (min, 0.2 months, max.; 10 months, 95% CI: 2.7 - 14.9). MAHA complicated with DIC was associated with inferior MOS than those without (6.4 vs. 9.4 months, respectively, log rank p = 0.39) [Figures 5a-b].

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Figure 5:

(a) Median overall survival in microangiopathic haemolytic anaemia (MAHA) associated colorectal cancer. (b) Note the impact of MAHA with (blue line) or without (green line) associated disseminated intravascular coagulation (DIC) on the same. Note: Data extrapolated from 20 sporadic cases published in the literature.

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Naito et al^[13] (2014) in their review of 27 CRCs with BM involvement reported a male predominance with dominant rectal primaries with aggressive histology. The overall survival of their cohort was less than 100 days, whereas folinic acid, fluorouracil, and oxaliplatin (FOLFOX) or folinic acid, fluorouracil, and irinotecan (FOLFIRI) based therapy improved the survival outcome. Moreover, early initiation of DIC-directed therapy, such as recombinant human soluble thrombomodulin (rhTM) in addition to CT, was effective in other studies.^{[9, 13]}

MAHA in gastric cancer:

The largest series systematic review and case control study by Lam and colleagues^[1,22] revealed that MAHA-GC had a male preponderance and younger age (50 to 55 years) at presentation compared to those with non-MAHA-GC. In up to 90% of cases, MAHA occurred concurrently with metastatic disease that frequently involved bone (producing mixed lytic-sclerotic bone lesions), BM, and lymph nodes; conspicuously bypassing the portal circulation and sparing the liver. In up to 30% cases, MAHA occurred as a sign of relapse following a tap lapse ranging from 7 months to 13 years (median, 7 years). DIC was reported in a higher proportion of subjects (86%), whereas TTP was reported in 14% of patients. BM examination, wherever performed for evaluation of cytopenias, revealed metastatic disease in up to 65 to 85% cases with or without evidence of MN, and the extent of marrow involvement did not correlate with the severity of MAHA-DIC. Bone pain, weight loss, raised serum ALP and LDH, and associated coagulation abnormalities were characteristic. Patients with MAHA-GC had a significantly inferior median overall survival (MOS) compared to those with non-MAHA-GC [1.7 (95% CI: 0.9-2.6) vs. 7 months (95% CI: 6-9), log rank p < 0.01]. In multiregression analysis, MAHA (hazard ratio [HR] 3.28, p < .01) and receiving no treatment (HR 3.57, p < .01) were associated with a significantly increased risk of mortality.^[23-28]

CRAB-like features in solid cancers

CRAB-like features at ‘initial presentation’ are uncommonly reported in the literature.^[3,29-31] Review of 27 sporadic published reports suggests that such a phenomenon is not uncommon in non-myelomatous haematolymphoid malignancies (N = 21) compared to bone or BM metastases in epithelial cancers (N = 6). CRAB occurred frequently in the setting of diffuse large B-cell lymphoma (DLBCL) and rarely with other lymphoproliferative neoplasms, with a median age at diagnosis of 58 years (range: 16 to 78) without any gender predilection.^[3] Generalized bone pain, backache, and fatigue were the most common initial manifestations, whereas bone lesions (N = 22/27, 81.4%) were frequently destructive, lytic, or lytic-sclerotic in nature, and involved multifocal (both appendicular and axial skeleton) sites. Serum Ca2+, Cr, and Hb ranged from 10.5 to 20.3 mg/dl [median; 14.8 mg/dl, severe (≥ 14) among 13/27, 48%], 1.2 to 8.5 (median; 2.5, ≥ 1.5 in 13), and 50 to 120 g/L (median; 101). Surprisingly, serum ALP levels were evaluated among 6/27 cases (22.2%, all greater than 150 IU/L). None other than the index case had evidence of MAHA on PBS examination. While eight of the associated CRAB had an unfavourable out (relapse and/or death) following supportive and definitive cancer-directed therapies, the remainder had a stable clinical course.^{[3, 29-31]}

A single-centre large retrospective analysis (2012-2015) from Thailand^[32] comparedtheclinicoradiological and laboratory characteristicsbetween subjects with bone metastasizing solid epithelial cancers (N = 450) (common primaries: lungs, liver, prostate, breast) and MM (N = 136). Other than age and gender (p > 0.05), two sub-group differed significantly from each other regarding Ca²⁺ (9.21 ± 1.28 vs. 9.81 ± 1.64 mg/dl, respectively), blood urea nitrogen [14 (11 to 21) vs. 19 (12 to 30) mg/dl], Cr [0.9 (0.7 to 1.2) vs. 1.3 (0.8 to 2.3) mg/dl], Hb (111.7 ± 21. 6 vs. 93.7 ± 23. 6 g/L), abnormal bone lesions on plain X-ray films (lytic/mixed lytic-sclerotic vs. pure lytic), raised ALP [138 (96 to 262) vs. 86 (63 to 120) IU/L] (all p < 0.001), and lactate dehydrogenase [239 (178 to 347 vs. 201 (142 to 245) IU/L, p = 0.06). On multivariate fractional polynomial regression analysis, only three parameters, such as raised Cr, globulin, and ALP, were significant indicators that distinguished metastases from MM with excellent discriminative ability (area under the curve: 0.90 [95% CI 0.86– 0.93].^[32] Another large study by an Italian group^[33] reported that solid tumours with ≥ 3 sclerotic bone lesions had significantly higher ALP levels (306.3 ± 582.5 vs. 123.8 ± 79.8 IU/L, respectively, p < 0.008) compared to those with MM, irrespective of their age, gender, ISS, and Durie Salmon staging. The values were higher for bone metastases from prostate (365.9 IU/L, p = 0.002) compared to those from lungs (142.8 IU/L, p = 0.030), and other tumours with lytic lesions (p < 0.05).^[33]

The mechanisms of malignancy-associated MAHA, bone lesions, and hypercalcemia are complex and likely to be of multifactorial origin. It is postulated that interaction between tumour cells and the monocyte-macrophage system plays a crucial role in the production of tissue factors and secretion of cytokines such as tumour necrosis factor alpha, interleukin 1, and interleukin 16, which in turn, promotes fibrinolysis and MAHA-DIC in cancer.^[34] It is of interest to note that cancer cells, destined to bypass portal circulation-liver, have more propensity to express RANKL that drives them toward bone and BM metastases via RANK-RANKL pathways.^[35] This RANK-RANKL mediated osteoclast activation produces localized bone lysis, which, along with ectopic production of parathyroid hormone-related peptide (PTHrP),is postulated to be the main mechanism of cancer-related hypercalcemia.^[35-37]