Bone marrow metastasis of gastric signet ring cell carcinoma complicated by thrombotic microangiopathy: A case report.

INTRODUCTION
The concept of thrombotic microangiopathy (TMA) syndrome was first proposed by Brain et al[1] based on clinical observations in 1962. In 1987, Murgo[2] expanded on this concept, describing cancer-associated TMA, including TMA induced by chemotherapy drugs. Clinically, TMA complications often occur in cancer patients with widespread metastases. Noteworthy, 75% of primary cancers are gastric, breast, and lung cancer[3]. Although gastric signet ring cell carcinoma (GSRC) shares a similar clinical course with gastric adenocarcinoma, it represents a distinct and more aggressive subtype of gastric cancer with lower responsiveness to chemotherapy. In China, where the incidence of GSRC is particularly high, the overall 5-year survival rate remains below 30% despite advances in surgical interventions and chemoradiotherapy[4,5].
Cancer-associated TMA is a rare and potentially fatal complication. Most patients with this syndrome experience a sudden onset of hemolytic anemia and bleeding tendencies. The symptoms of progressive malignancy often obscure the exact timing of onset, and patients can develop severe anemia within 2-4 weeks. The clinical presentation is atypical, often manifesting as bone pain, weight loss, fever, and other symptoms of bone marrow metastasis[6]. Jimenez-Andrade et al[7] and Li et al[8] reported that bone pain is the most common clinical feature, possibly because of increased intramedullary pressure from cancer cell infiltration, which leads to bone remodeling, fractures, hyperplasia, or bone marrow fibrosis. Other common manifestations of gastric cancer bone marrow metastasis include non-infectious fever, decreased red blood cells (RBCs) and platelets (PLTs), elevated alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and immature cells in peripheral blood smears[9]. Cancer-induced TMA often occurs during clinical remission. As such, many physicians delay diagnosis and treatment because they lack an understanding of its clinical features. This paper discusses a case of GSRC with bone marrow metastasis complicated by TMA. It highlights the primary management steps, including tumor treatment, bone lesion management, and hematological disease treatment, to provide a reference for the clinical diagnosis and treatment of cancer-associated TMA.

CASE PRESENTATION

Chief complaints
A middle-aged female patient was admitted with a primary complaint of "back pain for half a month, ic cancer surgery".

History of present illness
The patient returned on October 23, 2024, reporting lower back pain, prompting further evaluation (see Table 1 for the clinical timeline and disease progression analysis). An magnetic resonance imaging (MRI) on November 6, 2024, revealed lumbar degeneration, L4/5 disc protrusion, possible Schmorl's nodes at the upper edge of L3, wedge-shaped changes in T9, T10, and L5 vertebrae, possible hemangioma in L4, and abnormal signals in the thoracic and lumbar vertebrae and pelvis (Figure 1). The patient reported severe back pain with a numerical rating scale (NRS) score of 5. NRS is utilized in clinical practice for pain management in cancer patients to guide therapeutic decision-making. For scores ≤ 3, the current analgesic regimen is maintained with prioritized quality-of-life considerations. Scores ≥ 4 necessitate adjustments to analgesics or integration of non-pharmacological therapies. A post-treatment reduction in pain score by ≥ 2 points is generally regarded as clinically significant. Detailed protocols, including the NRS scoring system and the Brief Pain Inventory, are provided in Supplementary material.

History of past illness
The patient experienced hematemesis in July 2023 and underwent further gastroscopy, which revealed gastric cancer. A multi-slice spiral computed tomography (CT) scan performed revealed localized thickening with enhancement of the gastric wall, liver cysts, small lymph nodes in the hepatogastric space, slightly enlarged retroperitoneal lymph nodes, and suspected digestive tract lesions. On July 31, 2023, fiberoptic gastroduodenoscopy revealed chronic atrophic gastritis and multiple gastric ulcers, with pathology confirming adenocarcinoma (signet ring cell carcinoma; Figure 2). The patient underwent total gastrectomy with esophageal-jejunal Y-shaped anastomosis on August 7, 2023. Subsequent postoperative pathology suggested that the adenocarcinoma was moderately to poorly differentiated, and the ulcer type was infiltrative. The tumor measured 5 cm × 5 cm × 0.8 cm with subserosal layer invasion. Histopathological examination revealed no lymphovascular invasion, perineural invasion, or involvement of proximal/distal margins. Metastatic involvement was detected in 11 of 31 dissected lymph nodes, including 10/26 in the lesser curvature, 1/2 in the suprapyloric region, and 0/3 in the infrapyloric region. Postoperatively, the patient received two cycles of adjuvant S-1 therapy (60 mg orally twice daily on days 1-14). Subsequently, six cycles of combination chemotherapy were administered (oxaliplatin 180 mg intravenous infusion on day 1 + S-1 capsules 60 mg orally twice daily on days 1-14, repeated every 3 weeks) between December 10, 2023, and April 18, 2024. Myelosuppression developed as a treatment-related adverse effect but resolved following the administration of granulocyte colony-stimulating factor. Maintenance therapy with S-1 (60 mg orally twice daily on days 1-14 every 3 weeks) was continued until September 10, 2024.

Personal and family history
The patient had no personal or family history of tumours.

Physical examination
Physical examination revealed the following: Body mass: 60 kg; temperature: 36.6 °C; pulse: 72 per minute; respiratory rate: 18 minute-1; and blood pressure: 16.67/9.60 kPa. The patient also had anemia, mild jaundice, scattered petechiae on the back, and a 10 cm surgical scar on the abdomen.

Laboratory examinations
Fiberoptic gastroduodenoscopy on July 31, 2023, revealed chronic atrophic gastritis and multiple gastric ulcers, with pathology confirming adenocarcinoma (signet ring cell carcinoma). Postoperative immunohistochemistry revealed Ki-67 (30%+), Her-2 (0), AE1/AE3 (+), CK7 (+), CDX2-88 (+), CK20 (few+), CEA (-), MUC6 (few+), MUC5AC (few+), and P53 (diffuse+). Lauren's classification was the mixed type. Blood tests yielded the following results: Hemoglobin (Hb): 72 g/L; white blood cell (WBC): 5.5 × 109/L; PLT: 25 × 109/L; RBC: 2.51 × 1012/L; CA199: 20.3 U/mL; alpha-fetoprotein: 3.78 IU/mL; CEA: 80.04 ng/L; CA-125: 15.6 U/mL; CA-153: 9.7 U/mL; blood ammonia (dry): 23.79 μmol/L rising to 32.39 μmol/L; urine routine: Hematuria (3+), proteinuria (3+); stool routine: Occult blood (+-++); ALP: 421 U/L, total bilirubin (TBil): 112.8 μmol/L, direct bilirubin (DBiL): 19.7 μmol/L, indirect bilirubin (IBIL): 93.1 μmol/L, creatinine (Cr): 43 μmol/L, LDH: 790 U/L; coagulation profile: Prothrombin time (PT): 31.4 seconds, fibrinogen (FIB): 0.6 g/L, activated partial thromboplastin time (APTT): 71.4 seconds, and D-DI: > 20 μg/mL. Other tests, including procalcitonin, peripheral blood abnormal cells, blood culture, folic acid, vitamin B12, plasma ADAMTS13 activity and inhibitor levels, and hemolysis tests, were unremarkable (Table 2). Bone marrow flow cytometry, immunophenotyping, and karyotype analysis, as well as peripheral blood smears, bone marrow morphology, and bone marrow biopsy were also conducted (Figure 3). Color Doppler ultrasound of the limbs showed no significant abnormalities, while a head CT revealed right frontal lobe hemorrhage, right frontotemporal subdural hematoma, and brain herniation.

Imaging examinations
On July 31, 2023, fiberoptic gastroduodenoscopy revealed chronic atrophic gastritis and multiple gastric ulcers, with pathology confirming adenocarcinoma (signet ring cell carcinoma; Figure 2). An MRI on November 6, 2024, revealed lumbar degeneration, L4/5 disc protrusion, possible Schmorl's nodes at the upper edge of L3, wedge-shaped changes in T9, T10, and L5 vertebrae, possible hemangioma in L4, and abnormal signals in the thoracic and lumbar vertebrae and pelvis (Figure 1). Immunotyping flow cytometry of bone marrow biopsy showed abnormal expression of granulocyte differentiation antigen in 38.5%, nucleated red blood cell population in 23.2%, and no significant abnormalities observed in the rest, as well as peripheral blood smears, bone marrow morphology, and bone marrow biopsy were also conducted (Figure 3). Color Doppler ultrasound of the limbs showed no significant abnormalities, while a head CT revealed right frontal lobe hemorrhage, right frontotemporal subdural hematoma, and brain herniation.

FINAL DIAGNOSIS
Postoperative pathology revealed GSRC, with bone marrow metastasis and secondary TMA confirmed by clinical presentation, laboratory tests, and imaging.

TREATMENT
The patient received intermittent blood transfusions, including 17.5 units of leukocyte-depleted red blood cells and 10 therapeutic doses of PLTs after admission. The following medications were administered: Recombinant human thrombopoietin to increase PLT count, human FIB (2 g) to improve coagulation, methylprednisolone sodium succinate (80 mg/day) to control hemolysis, carbazochrome sodium sulfonate for hemostasis, compound glycyrrhizin and ursodeoxycholic acid tablets for liver protection, mosapride citrate to promote gastrointestinal motility, omeprazole for gastric acid suppression, ceftazidime combined with ornidazole to control infection, zoledronic acid for bone protection, and tramadol hydrochloride sustained-release tablets (100 mg per os every 12 hours) and morphine (3 mg intravenous injection quaquedie) for pain management. Fluid and nutritional support were also provided. Due to pancytopenia caused by tumor infiltration of the bone marrow, further chemotherapy was considered unsuitable to avoid the risk of severe myelosuppression. Although plasma exchange in the intensive care unit was recommended, the family chose to pursue palliative care instead. In summary, inpatient management followed stratified organ-system approaches targeting core pathological mechanisms (Table 3).

OUTCOME AND FOLLOW-UP
The patient ultimately died on December 2, 2024, due to a brain hemorrhage and herniation.

DISCUSSION
Clinically, TMA is not an independent disease but a complication of various conditions[1]. Several factors, such as infections, connective tissue diseases, immune complex diseases, and the use of anticancer drugs are potential causes of TMA. Therefore, the diagnosis of cancer-associated TMA should exclude disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, hemolytic anemia, and chemotherapy-related TMA[10-12]. The most significant laboratory abnormalities in TMA are hematological changes, which include severe hemolytic anemia with Hb < 5 g/dL, and the presence of abnormal red blood cell morphology in peripheral blood smears, such as elliptocytes, teardrop cells, spherocytes, and schistocytes, which show poor response to transfusion therapy. Murgo[2] noted that increased schistocytes in the blood smears of patients with metastatic cancer strongly suggest TMA. Peripheral blood smears can exhibit increased reticulocytes and nucleated red blood cells, with a characteristic decrease in PLT count[13], often as low as 7 × 109/L. In this case study, the patient had erythroid hyperplasia and normal megakaryocytes. Bone marrow flow cytometry and immunophenotyping ruled out malignant hematological diseases. The patient's plasma had regular ADAMTS13 activity with negative inhibitors. The patient also did not meet the diagnostic criteria for TTP, specifically the "pentad" of symptoms, further ruling out TTP as a diagnosis[14]. In the present case, the patient manifested clinical features partially overlapping with TTP, including thrombocytopenia and microangiopathic hemolytic anemia. However, the exclusion of TTP was strongly supported by normal ADAMTS13 activity (> 10%) and undetectable inhibitors[13,15]. Current evidence indicates that approximately 95% of acute idiopathic TTP cases exhibit severe ADAMTS13 deficiency (< 10% activity), with 75%-90% demonstrating inhibitory IgG antibodies[16,17]. The close correlation between ADAMTS13 antigen levels and enzymatic activity (r = 0.93) further strengthens diagnostic validity, and in this patient, both parameters remained within normal ranges[17]. Notably, while atypical TTP secondary to collagen vascular diseases or medications may occasionally present with preserved ADAMTS13 activity, such cases typically lack inhibitors and show poor response to rituximab therapy[15,18]. Regarding hematological malignancies exclusion, comprehensive flow cytometric analysis of peripheral blood and bone marrow specimens revealed no clonal cell populations or aberrant immunophenotypes. These findings, combined with normocellular morphology, effectively ruled out paroxysmal nocturnal hemoglobinuria and leukemia-associated microangiopathy[19]. Currently, epidemiological data has shown that among TMA patients with normal ADAMTS13 activity, approximately 60% are ultimately diagnosed with alternative etiologies such as infection-related, drug-induced, or pregnancy-associated microangiopathy rather than TTP or hematological malignancies[15]. Although ADAMTS13-specific circulating immune complexes have been documented in 39%-47% of TTP cases, these complexes are invariably associated with significantly reduced protease activity - a biochemical profile discordant with the current patient's laboratory findings[20,21]. The standardized ADAMTS13 activity assay (e.g., fluorescence resonance energy transfer-based methodology) demonstrates exceptional diagnostic specificity, with normal results providing robust exclusion criteria for classical TTP[16,17]. Concurrently, negative flow cytometry outcomes substantiate the exclusion of clonal hematopoietic disorders, directing diagnostic consideration toward non-malignant TMA subtypes[19]. This multimodal laboratory approach, when integrated with clinical manifestations, establishes a comprehensive framework for differential diagnosis in TMA. Gajendra and Sharma[9] reported that approximately 10% of patients exhibiting such characteristics may have cancer cell infiltration in the bone marrow. In this case study, bone marrow biopsy revealed areas of necrosis and fibrosis with unclassified cells. Further analysis of cell morphology revealed the possibility of "signet ring cells", which was consistent with the patient's gastric cancer pathology from a year earlier. Bone marrow metastasis of gastric cancer was suspected based on the MRI findings of multiple T2FS high-signal lesions in the thoracic and lumbar vertebrae and pelvis and the "dry tap" phenomenon during bone marrow aspiration.
Noteworthy, there were laboratory changes associated with hemolysis, including a sharp increase in IBIL, elevated reticulocyte count, and increased LDH, during the clinical treatment of the patient. However, the Coombs test was negative, and no other hemolysis-related abnormalities were detected. The patient also showed significant elevations in DBiL and total bilirubin. However, abdominal color Doppler ultrasound and other imaging studies did not reveal liver or biliary tract abnormalities. Although the association of this result with underlying liver disease or consumptive coagulopathy remains uncertain, autoimmune hemolytic anemia was definitively ruled out in this patient. Although a few TMA patients may present with azotemia, renal failure is not a characteristic of cancer-associated TMA and is more commonly associated with TTP[14]. In this case study, the patient's renal function was normal before admission and remained stable during the first week of hospitalization. The patient's serum Cr decreased during the terminal stage of the disease, primarily attributed to malnutrition and reduced intake, consistent with previous research findings[22]. In contrast, the patient exhibited prolonged PT, APTT, and decreased FIB. The patient's score ranged between 6 and 9 based on the Chinese Disseminated Intravascular Coagulation Scoring System, meeting the diagnostic criteria for DIC[23]. DIC plays a significant role in regulating the microvascular changes associated with cancer-related TMA. Though DIC is a relatively common complication of metastatic cancer, the degree of TMA observed in this case was not a typical feature of DIC[24]. Of note, the types of primary cancers that cause DIC differ from those that cause TMA. Pancreatic cancer is the most common tumor associated with DIC, while gastric cancer is the leading cause of TMA[25]. Moreover, the processes of DIC and TMA are not parallel. Despite the improvement in DIC symptoms following heparin therapy, the hemolytic process continued to worsen. This suggests that the coagulation abnormalities were primarily driven by cancer-associated TMA. Notably, intracranial hemorrhage is a common complication, typically presenting as a terminal event. In this case, the patient died due to a brain hemorrhage and herniation.
TMA may be an early manifestation of various malignancies, particularly gastric malignancies[3]. Herein, we summarize the following clinical features for the diagnosis of cancer-associated TMA based on domestic and international literature: (1) Hemolytic anemia unresponsive to steroids; (2) Presence of immature red and WBCs in peripheral blood; (3) Rapid decrease in PLT count with bleeding manifestations; (4) Hypercoagulable and hypofibrinolytic state; (5) Bone marrow biopsy showing necrosis and fibrosis; (6) Imaging studies (X-ray, CT, positron emission tomography-CT) showing signs of metastatic cancer; and (7) Pathological evidence of metastatic cancer in tissue biopsies. The pathogenesis of TMA remains unclear, and its clinical presentations are diverse. Diagnosis primarily relies on bone marrow aspiration and biopsy[26]. Noteworthy, bone marrow necrosis and fibrosis further impair hematopoietic function and exacerbate anemia and related symptoms. Surgical treatment of gastric cancer may improve prognosis, but its effectiveness is limited. Supportive treatments, such as plasma exchange and immunoglobulin therapy, are necessary because the response to anticancer drugs is not immediate. Timely symptomatic support and appropriate chemotherapy for gastric cancer may be effective. In this case study, the patient's overall condition was poor, rendering them unable to tolerate chemotherapy. In this case of gastric signet-ring cell carcinoma with bone marrow metastasis complicated by TMA, the decision to withhold low-dose or metronomic chemotherapy was based on critical hematological parameters (Hb < 50 g/L, PLT count < 20 × 109/L) and demonstrated chemoresistance. Current clinical evidence indicates that PLT counts below 50 × 109/L constitute an absolute contraindication for cytotoxic therapy due to exponentially increased hemorrhagic risk, particularly in TMA patients where endothelial injury may be exacerbated by chemotherapeutic agents[15,19]. The observed resistance to capecitabine and S-1 (tegafur/gimeracil/oteracil) aligns with data showing 38%-52% primary chemoresistance rates in metastatic gastric cancer, with persistent administration potentially inducing drug-associated TMA through direct endothelial toxicity[18,27]. Plasma exchange was prioritized based on its dual mechanistic benefits in TMA management: (1) Removal of ultralarge von Willebrand factor multimers and complement activation products (C5b-9), which drive microvascular thrombosis even in ADAMTS13-sufficient TMA subtypes[16,20]; and (2) Clearance of tumor-derived procoagulant factors including tissue factor and cancer procoagulant, shown to achieve PLT recovery in 52% of gastric cancer-associated TMA cases[17,28]. Notably, 30% of malignancy-related TMA cases exhibit alternative complement pathway dysregulation, a pathophysiological subset particularly responsive to plasma exchange therapy[21,29]. The therapeutic rationale was further strengthened by pharmacokinetic considerations: The 5-7 days clinical window following plasma exchange allows for potential bone marrow recovery prior to implementing targeted therapies (e.g., anti-vascular endothelial growth factor agents), while continued chemotherapy would likely perpetuate the TMA cycle through drug-microenvironment interactions[16,27]. This approach adheres to international guidelines that prohibit chemotherapy in severe thrombocytopenia (< 50 × 109/L), where even metronomic regimens increase life-threatening hemorrhage risk to 67%[15,19]. Steroid therapy is typically ineffective but may be considered if the primary cancer is steroid-sensitive. Cancer-related TMA exhibits uniformly poor outcomes (median survival < 30 days), with mortality primarily attributable to terminal complications: Bone marrow necrosis, hematopoietic system failure, and DIC. In future, it is imperative to develop treatment plans that can reduce the tumor burden and inhibit the hemolytic process, thereby improve the prognosis.

CONCLUSION
Cancer-associated TMA (metastatic gastric signet-ring carcinoma) has an extremely poor prognosis (< 30-day median survival), driven by bone marrow necrosis and DIC. Diagnosis requires bone marrow biopsy. Cytotoxic chemotherapy is absolutely contraindicated with PLTs < 50 × 109/L due to hemorrhage risk. Plasma exchange is the priority intervention (approximately 52% PLT recovery). Steroids are generally ineffective. Reducing tumor burden is critical for outcome improvement.

ACKNOWLEDGEMENTS
The authors sincerely thank the participant for his willingness to participate in this study.