Autoimmune haemolytic anaemia in pancreatic adenocarcinoma: a potential paraneoplastic presentation

Abstract

While autoimmune haemolytic anaemia (AIHA) is a well-known paraneoplastic syndrome in haematological malignancies, it has been described far less in solid tumours. We hereby report the case of a 61-year-old male patient presenting AIHA related to pancreatic cancer. Investigations excluded infectious, autoimmune and toxic causes of AIHA. CT of the abdomen highlighted the presence of hypodense, infiltrating mass of the tail of the pancreas measuring 70×37×36 mm, compatible with pancreas neoplasm. Histological examination of two associated nodular lesions of the liver showed metastasis of pancreatic adenocarcinoma. The patient was started on corticosteroid without improvement of haemoglobin. Palliative chemotherapy was initiated; this led to significant improvement in haemoglobin comforting our diagnosis. This case illustrates the rare association between AIHA and pancreatic cancer. However, such association cannot be considered before excluding other, more frequent, aetiologies.

Background

Autoimmune haemolytic anaemia (AIHA) involves destruction of red blood cell mediated by the humoral immune system. AIHA aetiologies include a variety of diseases ranging from autoimmune disorders, neoplastic diseases to infection and drug-induced AIHA.¹ While AIHA is a well-known paraneoplastic syndrome in patients with haematological malignancies, it has been reported far less in solid tumours.² Majority of AIHA related to solid tumours were reported in lung, colorectal and renal tumours and Kaposi’s sarcoma.³ Pancreatic neoplasms have scarcely been identified as the cause of AIHA.

We hereby present a case of a male patient presenting both deep vein thrombosis and AIHA in whom investigations concluded to metastatic pancreatic adenocarcinoma with improvement in haemoglobin after initiation of palliative chemotherapy.

Case presentation

A 61-year-old male patient was admitted in our internal medicine department for a 3-day history of painful swelling of the left leg related to deep vein thrombosis of the popliteal and posterior tibial vein confirmed by Doppler ultrasound. He had a medical history of hypertension on ACE inhibitor and insulin-dependent diabetes. He did not smoke and denied use of illicit drugs. The patient reported fatigue and had cutaneous and conjunctival pallor. He had no fever and examination was essentially normal with no generalised lymphadenopathy and no abdominal mass or tenderness.

Investigations

Laboratory routine tests revealed evidence of inflammation: C reactive protein was elevated at 173 mg/L, erythrocyte sedimentation rate at 135 mmh^–1 along with fibrinogen serum level of 5.09 g/L (2–4 g/L). Serum protein electrophoresis showed elevated alpha 2 globulin and gammaglobulin, respectively, at 12.8 g/L (5–8 g/L) and 22.7 g/L (6–11 g/L) with low albumin serum level at 25.6 g/L. No evidence of monoclonal gammapathy was observed. Full blood count noted the presence of normocytic regenerative anaemia: haemoglobin at 86 g/L with mean corpuscular volume of 93.1 fL (80–100 fL) and reticulocyte count at 173 500/mm³. White blood cell count was normal: 8.4x10⁹/L (4-10x10⁹/L) while platelet count was moderately elevated: 636x10⁹/L (150-450x10⁹/L). The patient presented evidence of haemolysis: elevated bilirubin: 32 µmol/L (normal range: 3.4–20 µmol/L) predominantly direct bilirubin: 24 µmol/L and elevated lactate dehydrogenase: 360 U/L (normal range: 125–220 U/L). Renal and liver function tests, as well as phosphate–calcium balance, were within normal range. Direct antiglobulin test was positive for IgG. Thus, diagnosis of deep vein thrombosis associated with AIHA was retained and investigations to ascertain the cause were carried out. The patient did not report new medication intake during the last 3 months except for amoxicillin–clavulanic acid. Immunological screening did not yield positive results as antinuclear antibodies, anticardiolipin antibody, anti-β2 glycoprotein and rheumatoid factor were negative. Serology of hepatitis B and hepatitis C were also negative. Neoplastic diseases were highly suspected given the patient age and the presence of deep vein thrombosis. Upper gastrointestinal tract endoscopy showed no suspect lesions. Chest X-ray was without abnormalities. CT of the chest and abdomen was requested. It highlighted the presence of hypodense, infiltrating mass of the tail of the pancreas with heterogeneous contrast enhancement measuring 70×37×36 mm, compatible with pancreas neoplasm, associated with infiltration of the surrounding adipose tissue (figure 1). CA19-9 tumour marker serum level comforted these finding as it was elevated at 165 U/mL (normal range <30 U/mL). The patient was transferred to surgery department for removal of the pancreatic mass. However, during the procedure, two nodules were identified on the liver. Histological study confirmed liver metastasis of a well-differentiated adenocarcinoma of the pancreas (figure 2).

Figure 1.

Abdominal CT highlighting the presence of hypodense, infiltrating mass of the tail of the pancreas measuring 70×37×36 mm.

Figure 2.

Pancreatic adenocarcinoma proliferation in the hepatic parenchyma (200×).

Treatment 

Patient was initiated on corticosteroid at the dose of 1 mg/kg/day of prednisone. However, he presented very unstable diabetes with severe ketoacidosis requiring continuous high dose of intravenous insulin. Thus, we decided to reduce corticosteroid to 40 mg of prednisone daily (0.5 mg/kg/day) after 2 days. Given the presence of hepatic metastasis, patient was addressed for palliative treatment with chemotherapy. He received a combination of 5-fluorouracil, folinic acid and cisplatin. Treatment protocol was as follow: bolus of leucovorin 200 mg/m², 5-fluorouracil bolus 400 mg/m² on day 1, followed by 5-fluorouracil 2400 mg/m² 48 hours infusion and cisplatin 50 mg/m² on day 2. Cycles were repeated every 14 days. He was put on long-term low-molecular weight heparin for treatment of deep vein thrombosis.

Outcome and follow-up

As for AIHA, although no significant response was noted on corticosteroid, we witnessed an improvement in haemoglobin after initiation of chemotherapy. The patient did not receive red blood cell transfusion. At the follow-up visit before initiating the third cycle of chemotherapy, haemoglobin was at  108 g/L. Reticulocyte count was at 54 000/mm³ and lactate dehydrogenase serum level had decreased to 240 U/L while bilirubin level returned to normal range: total serum bilirubin at 14 µmol/L. The patient is now undergoing the third cycle of palliative chemotherapy with stable level of haemoglobin.

Discussion

We hereby report the case of an elderly patient presenting AIHA in whom investigations pointed to an asymptomatic pancreatic cancer with hepatic metastasis. AIHA in our patient required thorough investigations before linking it to concomitant pancreatic cancer as similar cases have rarely been reported.

Paraneoplastic syndromes refer to symptoms or laboratory abnormalities not directly induced by local or metastatic tumour growth. These syndromes could be related to ectopic production of biological substances or immune-mediated reactions.⁴ It is a rather well-known yet uncommon manifestation in solid tumours with nervous system dysfunction being the most documented syndrome.^{5 6} Cancer-associated haematological manifestations include AIHA, anti-FVIII antibodies, antiphospholipid antibodies and autoimmune thrombocytopenia among others.^{6 7} AIHA is typically observed in lymphoproliferative disorders.^{2 8} AIHA reports in solid tumours, except for ovarian dermoid cyst, are few and this holds especially true for pancreatic cancer.^{3 9}

Puthenparambil et al compiled a report of 52 cases of AIHA related to solid tumour, out of which only one case was linked to pancreatic cancer in 1955.^{3 10} Other solid tumours associated with AIHA were essentially lung, kidneys and colorectal cancers and Kaposi syndrome.³ In addition to previously cited case, AIHA related to pancreatic cancer was reported, to our knowledge, in only another case of a 71-year-old man presenting pancreatic adenocarcinoma with demyelinating neuropathy and AIHA, confirming the rarity of such paraneoplastic syndrome.¹¹

AIHA can be characterised into warm and cold-reactive antibodies with warm AIHA being the most predominant.¹² Linking AIHA to solid tumour requires excluding others possible underlying diseases such as drug intake, infections, autoimmune diseases and haematological malignancies.¹ In fact, in a study of 1083 patients with solid tumours, only 1.29% presented paraneoplastic syndrome out of which only 14% were associated with AIHA.⁷ Our patient underwent such investigations which yielded no positive results.

Deep vein thrombosis is a well-known complication of neoplastic diseases. Pancreatic cancer is associated with the highest risk of venous thromboembolism.¹³

Since solid tumor-related AIHA is very rare, treatment is not well-defined. First-line therapy of AIHA usually consists of corticosteroid with varying results.¹⁴ However, most patients require undergoing therapy for the underlying malignancy to effectively observe improvement of haemoglobin.¹⁵ In our report, improvement of haemoglobin was obtained after chemotherapy for pancreatic cancer. This response further comforts our diagnosis of cancer-related AIHA. It has been suggested that such response in haemoglobin and haemolytic activity could also be a monitoring parameter in such patients indicating response or even relapse of related tumour.¹⁵

Learning points.

• This case reports an exceedingly rare association between pancreatic adenocarcinoma and autoimmune haemolytic anaemia (AIHA).

• Linking AIHA to solid tumour is challenging and physician must not overlook other causes, far more frequent, that can be associated with cancer.

• Although conventional treatment of AIHA, mainly steroids, may yield some results; treatment of the underlying tumours remains the cornerstone therapeutic care.