Hemolytic anemia as an initial presentation of gastric signet ring cell carcinoma- a case report

Abstract

Microangiopathic hemolytic anemia (MAHA) is a rare paraneoplastic syndrome that can be an initial manifestation of advanced malignancy. This report presents the case of a 54-year-old male with symptoms of fatigue and anemia, later diagnosed with gastric signet ring cell carcinoma and bone marrow infiltration. Despite initial management with plasmapheresis and immunosuppressive therapy, the patient's condition deteriorated, highlighting the limited efficacy of these interventions in cancer-associated MAHA. The case underscores the importance of recognizing MAHA as a potential paraneoplastic syndrome, emphasizing timely diagnosis and appropriate oncological treatment to improve outcomes. Unfortunately, the prognosis remains poor in advanced disease with bone marrow involvement.

Resumen

La anemia hemolítica microangiopática (AHMA) es un síndrome paraneoplásico raro que puede ser una manifestación inicial de una neoplasia maligna avanzada. Este trabajo presenta el caso de un hombre de 54 años con síntomas de fatiga y anemia, posteriormente diagnosticado con carcinoma gástrico de células en anillo de sello e infiltración medular. A pesar del manejo inicial con plasmaféresis y terapia inmunosupresora, la condición del paciente se deterioró, destacando la limitada eficacia de estas intervenciones en la AHMA asociada al cáncer. Este caso subraya la importancia de reconocer la AHMA como un posible síndrome paraneoplásico, enfatizando la necesidad de un diagnóstico oportuno y un tratamiento oncológico adecuado para mejorar los resultados. Desafortunadamente, el pronóstico sigue siendo desfavorable en enfermedades avanzadas con infiltración medular.

Introduction

Hemolytic anemia is defined by the premature destruction of red blood cells prior to their normal 120-day lifespan and may present across a wide clinical spectrum, ranging from subclinical and compensated to acute and life-threatening¹. Hemolysis may occur intravascularly, extravascularly, or through a combination of both mechanisms, and is typically suggested by a constellation of clinical and laboratory findings including anemic syndrome, jaundice, dark urine, elevated unconjugated bilirubin and lactate dehydrogenase (LDH), reduced haptoglobin, reticulocytosis, and characteristic red blood cell morphology on peripheral blood smear^1–3. The direct antiglobulin test (Coombs test) remains central to the diagnostic approach, distinguishing immune-mediated from non-immune causes of hemolysis^1–3.

The etiological spectrum of hemolytic anemia is broad, encompassing autoimmune conditions, drug-induced reactions, membranopathies, enzymopathies, hemoglobinopathies, infections, mechanical trauma, and microangiopathic processes¹. Among the latter, microangiopathic hemolytic anemia (MAHA) — characterized by Coombs-negative hemolysis with fragmented erythrocytes (schistocytes) on peripheral smear and thrombocytopenia — warrants particular clinical attention given its association with a diverse array of underlying conditions, including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), and malignancy^4,5.

Cancer-related MAHA (CR-MAHA) is a rare but clinically significant paraneoplastic syndrome. In the largest systematic review to date, Lechner et al. analyzed 168 published cases and found that over 90% occurred in the setting of metastatic disease, with bone marrow infiltration identified in the majority of evaluable cases, suggesting that tumor-driven microvascular occlusion and endothelial injury are central to its pathogenesis⁶. Specifically, it is hypothesized that intravascular tumor emboli obstruct the microvasculature, leading to mechanical fragmentation of erythrocytes and consumptive thrombocytopenia, in a process pathophysiologically distinct from the ADAMTS13 deficiency observed in Thrombotic Thrombocytopenic Purpura (TTP)^5,6. This distinction carries critical therapeutic implications: unlike TTP, CR-MAHA does not respond to plasma exchange, and treatment must be directed at the underlying malignancy⁷.

The neoplasms most frequently implicated in CR-MAHA are gastric and breast adenocarcinomas, accounting for approximately 26% and 21% of compiled cases, respectively, followed by prostate and lung^6,8. CR-MAHA often heralds advanced disease and can be the first clinical manifestation of occult metastatic spread or signalling disease progression in previously known malignancies⁶. This syndrome carries a poor prognosis, even when systemic chemotherapy is initiated. The survival is typically measured in weeks^6,7.

From a diagnostic standpoint, because CR-MAHA may mimic primary thrombotic microangiopathies, a high index of suspicion for underlying malignancy is essential in any patient presenting with MAHA that is atypical or unresponsive to standard therapy^4,5. Bone marrow biopsy and cross-sectional imaging assessment should be considered early in the diagnostic algorithm^5,6.

CR-MAHA in gastric cancer is exceedingly uncommon, with only a small number of cases reported in the literature, predominantly in the context of disease recurrence or metastatic spread⁸. We present a case that illustrates this rare and diagnostically challenging manifestation, highlighting the importance of early recognition of CR-MAHA as a potential harbinger of occult or progressive malignancy.

Clinical case

This clinical case refers to a 54-year-old man with a history of atrial fibrillation, epilepsy, dyslipidemia, hyperuricemia, and chronic non-active smoking (one pack per day for 8 years). His regular medication includes allopurinol 300 mg, pravastatin 10 mg, and levetiracetam 500 mg twice daily.

Approximately two months prior to the current admission, he experienced easy fatigue and palpitations lasting for one week, prompting his first visit to the emergency department, where he was diagnosed with new-onset atrial fibrillation. He underwent rate control and was started on apixaban 5 mg twice daily and bisoprolol 2.5 mg/day.

One month later, he returned to the emergency department with a one-month history of fatigue with minimal exertion, anorexia, abdominal distension, and mechanical lower back pain. He denied dyspnea, paroxysmal nocturnal dyspnea, orthopnea, weight loss, night sweats, gastrointestinal or urinary bleeding, fever, diarrhea, or vomiting.

On physical examination, the patient was calm, oriented, and had a blood pressure of 138/70 mmHg, heart rate of 100 bpm, and oxygen saturation of 100% on room air. Pale and hydrated mucous membranes were observed. Cardiac auscultation revealed achycardic arrhythmic sounds without murmurs. Pulmonary auscultation detected maintained and symmetrical breath sounds without adventitious noises. The abdomen was distended, soft, and depressible, with tenderness on palpation but without signs of peritoneal irritation. The lower limbs showed no edema or signs of deep venous thrombosis. No neurological deficits were identified. Palpation of the spinous processes was not painful, but paravertebral tenderness was elicited.

The initial laboratory evaluation highlighted a hemoglobin level of 5.0 g/dL with an MCV of 100 fL (Table 1 — Laboratory results on admission, Day 1). Given the suspicion of abdominal hemorrhage in the context of recent anticoagulation initiation, an abdominopelvic CT scan was performed. This did not demonstrate hemorrhage but revealed suspicious adenopathy formations in the perigastric, hepatic hilum, mesenteric, celiac, bilateral para-aortic, and right iliac regions, as well as thickening of the gastric wall at the level of the antrum. Complementary laboratory studies revealed a reticulocyte count of 15.4%, total bilirubin of 2.25 mg/dL, conjugated bilirubin of 0.95 mg/dL, LDH of 851 IU/L, haptoglobin of 2 mg/dL, ferritin of 3290 μg/L, a negative direct Coombs test, and a CRP of 14.45 mg/dL. In this context, a diagnosis of paraneoplastic microangiopathic hemolytic anemia was suspected, and further investigation was initiated.

Table 1.

Laboratory results on admission, Day 1.

Parameter	Patient's value
Hemoglobin (13.7-17.2 g/dl)	5 g/dl
MCV (83-98 fl)	100 fl
White Blood Cells (3.7-9.5 × 10^9/l)	4.92 × 10^9/l
Neutrophils (1.5-6.5 × 10^9/l)	2.84 × 10^9/l
Lymphocytes (1.1-3.5 × 10^9/l)	1.41 × 10^9/l
Monocytes (0.21-0.92 × 10^9/l)	0.58 × 10^9/l
Platelets (170-430 × 10^9/l)	112 × 10^9/l
Reticulocytes (0.5-1.5%)	15.40%
Creatinine (0.7-1.2 mg/dl)	0.8 mg/dl
Urea (13-43 mg/dl)	45 mg/dl
Sodium (136-145 mmol/l)	139 mmol/l
Potassium (3.5-5.1 mmol/l)	3.9 mmol/l
Chlorine (98-107 mmol/l)	105 mmol/l
LDH (135-225 UI/l)	851 UI/l
Total Bilirubin (< 1.2 mg/dl)	2.25 mg/dl
Conjugated Bilirubin (< 0.20 mg/dl)	0.74 mg/dl
Haptoglobin (40-280 mg/dl)	2 mg/dl
Ferritin (41.5-408.5 ug/l)	3 290 ug/l
Direct Coombs Test	Negative
C- Reactive Protein (< 0.5 mg/dl)	14.45 mg/dl

Given the imaging findings of gastric wall thickening and widespread lymphadenopathy, upper digestive endoscopy was performed on Day 4, revealing a 20 mm ulcer on the anterior wall of the antrum with slight friability on contact; gastric biopsies were collected at this time. The following day (Day 5), bone marrow aspiration and bone biopsy were performed, with aspiration yielding no morphological abnormalities.

Given the initial diagnostic uncertainty and the need to exclude a primary thrombotic microangiopathy while awaiting biopsy results, prednisolone was initiated at 1 mg/kg/day (80 mg/day) on Day 6. This approach proved ineffective: after three days, the patient showed no clinical improvement, with worsening anemia (hemoglobin 4.2 g/dL) and further elevation of hemolysis parameters (Table 2 - Laboratory results at clinical worsening, Day 9). The case was discussed with Hematology and the Intermediate Care Unit, and three sessions of plasmapheresis were performed on Days 9, 10, and 11. These were carried out without procedural complications but yielded no hematological or clinical response, reinforcing the suspicion of a non-TTP etiology.

Table 2.

Laboratory results at clinical worsening, Day 9.

Parameter	Patient's value
Hemoglobin (13.7-17.2 g/dl)	4 g/dl
MCV (83-98 fl)	108 fl
White Blood Cells (3.7-9.5 × 10^9/l)	10.83 × 10^9/l
Neutrophils (1.5-6.5 × 10^9/l)	9.36 × 10^9/l
Lymphocytes (1.1-3.5 × 10^9/l)	0.79 × 10^9/l
Monocytes (0.21-0.92 × 10^9/l)	0.66 × 10^9/l
Platelets (170-430 × 10^9/l)	23 × 10^9/l
Creatinine (0.7-1.2 mg/dl)	1.33 mg/dl
Urea (13-43 mg/dl)	126 mg/dl
Sodium (136-145 mmol/l)	135 mmol/l
Potassium (3.5-5.1 mmol/l)	4.9 mmol/l
Chlorine (98-107 mmol/l)	99 mmol/l
LDH (135-225 UI/l)	2 369 UI/l
Total Bilirubin (< 1.2 mg/dl)	3.69 mg/dl
Conjugated Bilirubin (< 0.20 mg/dl)	1.79 mg/dl
C- Reactive Protein (< 0.5 mg/dl)	7.12 mg/dl

Biopsy results became available on Day 12. Histological examination of the gastric specimen demonstrated a neoplasm of poorly cohesive cells with signet ring cell morphology, while bone marrow biopsy confirmed medullary infiltration by the same neoplastic process (Figure 1). These findings established the diagnosis of metastatic gastric signet ring cell carcinoma with CR-MAHA as its paraneoplastic manifestation.

Figure 1.

Hematoxylin and eosin staining of a gastric specimen showing simple glandular epithelium (1) and poorly cohesive neoplastic cells with signet-ring cell features (2) (×200).

Immunosuppressive therapy was promptly discontinued, and systemic chemotherapy with capecitabine and oxaliplatin was initiated on Day 13. Despite this intervention, the patient experienced progressive multi-organ deterioration and ultimately died on Day 17 of hospitalization.

Discussion

When a patient exhibits manifestations of hemolytic anemia and thrombocytopenia, the diagnosis of thrombotic thrombocytopenic purpura is invariably contemplated. Nonetheless, it is essential to acknowledge that a diverse spectrum of conditions encompassing systemic infections, autoimmune disorders, and malignancies can precipitate thrombotic microangiopathy⁸. Cancer-associated microangiopathic hemolytic anemia (CR-MAHA) is a paraneoplastic syndrome characterized by Coombs-negative hemolytic anemia with schistocytes and thrombocytopenia, representing a rare but diagnostically critical cause of hemolytic anemia⁶.

In the largest systematic review to date, Lechner et al. analyzed 168 published cases of CR-MAHA and found gastric carcinoma to be the most frequently implicated neoplasm, accounting for approximately 26% of cases⁶. The median age at presentation is approximately 50 years, consistent with our patient's age,^9,10 and a slight male predominance has been reported in gastric cancer-associated cases, also in keeping with the present case. Importantly, over 90% of cases occurred in the setting of metastatic disease, and bone marrow infiltration was identified in the majority of evaluable patients, as observed in our case, suggesting that carcinomatous myelophthisis is central to the pathophysiology of CR-MAHA⁶.

The present case is of particular interest in that the hematological syndrome emerged concurrently with, rather than following, the oncological diagnosis, representing an overlapping presentation in which CR-MAHA served as the initial clinical manifestation of an otherwise occult metastatic process.

The underlying mechanism of CR-MAHA is not fully elucidated; however, the prevailing hypothesis involves intravascular tumor emboli causing microvascular occlusion, endothelial injury, and consequent mechanical fragmentation of erythrocytes and consumptive thrombocytopenia through microthrombus formation in small vessels^4,6. A retrospective study by Berger et al., conducted between 2012 and 2019, identified eight patients with gastric adenocarcinoma and a clinical diagnosis of hemolytic anemia with schistocytes, further highlighting the rarity and severity of this presentation¹⁰.

Distinguishing CR-MAHA from primary thrombotic microangiopathies, particularly TTP, can be challenging, especially when the underlying malignancy is not yet known^4,5. However, this distinction is crucial, as it determines whether plasma exchange should be initiated empirically or deferred in favor of a more targeted oncological workup. Several features may raise suspicion for CR-MAHA over TTP: the absence of neurological involvement, the presence of constitutional symptoms, imaging findings suggestive of malignancy, disproportionate elevation of LDH, and the absence of severe ADAMTS13 deficiency^5,7. In cases where CR-MAHA is suspected, bone marrow biopsy should be pursued early in the diagnostic algorithm, as medullary infiltration by tumor cells is both common and diagnostically confirmatory^4,6. In our patient, bone marrow biopsy on Day 5 combined with gastric biopsy, ultimately established the diagnosis, albeit after empirical treatment had already been initiated.

Initial management of unexplained MAHA and thrombocytopenia typically involves plasma exchange, given the hematological emergency posed by TTP, which carries high mortality if left untreated^4,10. In our patient, plasmapheresis was initiated on Day 9 following failure of prednisolone, in keeping with standard practice for undifferentiated thrombotic microangiopathy. However, once CR-MAHA is established, plasma exchange, corticosteroids, and other immunosuppressive therapies confer no proven benefit⁷. The cornerstone of treatment is directed therapy against the underlying malignancy, and systemic chemotherapy should be initiated as promptly as possible once CR-MAHA is confirmed⁷. Regarding the role of rituximab, this agent may only be considered in lymphoma-associated thrombotic microangiopathy, where a B-cell mediated mechanism is implicated, with no evidence in solid tumor-related CR-MAHA⁷. Other emerging approaches, including eculizumab and targeted anti-VEGF therapies, have been explored in isolated case reports but lack sufficient evidence to support routine clinical use⁷.

CR-MAHA carries a profoundly poor prognosis. Berger et al. reported a median overall survival of 10.3 weeks in patients with gastric cancer-related CR-MAHA who received chemotherapy, underscoring that even active oncological treatment rarely alters the short-term outcome in the context of disseminated disease with bone marrow infiltration¹⁰. In our patient, death occurred on Day 17 of hospitalization, consistent with the dismal prognosis reported in the literature, despite the timely initiation of capecitabine and oxaliplatin following histological confirmation of the diagnosis.

Conclusion

This case therefore reinforces several practical messages for the clinician: CR-MAHA should be suspected early in any patient presenting with Coombs-negative hemolytic anemia and thrombocytopenia alongside constitutional symptoms or imaging findings suggestive of malignancy; bone marrow biopsy should be performed promptly when the diagnosis is suspected; lack of response to plasmapheresis after one to two sessions should itself heighten suspicion for an underlying neoplasm; and goals-of-care conversations, including early palliative care planning, should be initiated without delay, given the median survival of weeks even with active treatment.

Ethical considerations

Written informed consent for publication was obtained from the patient (or legal representative), and all potentially identifiable information was removed or masked.