Spontaneous tumour lysis secondary to gastric adenocarcinoma

Abstract

We present a case of a man in his 70s who presented with worsening rectal and back pain associated with weight loss, dyspnoea and brownish discolouration of urine. Physical examination noted abdominal distention and epigastric tenderness. Laboratory investigations revealed acute kidney injury, hyperkalaemia, hyperphosphataemia and hyperuricaemia. Contrast CT of the abdomen/pelvis showed multiple, low-density masses throughout the liver, suspicious for metastatic disease. Oesophagogastroduodenoscopy demonstrated a large, fungating, infiltrative and ulcerated mass in the gastric body and lesser curvature of the stomach. Surgical pathology confirmed invasive moderately differentiated gastric adenocarcinoma. He met both the laboratory and clinical criteria for spontaneous tumour lysis syndrome (STLS) as per the Cairo-Bishop criteria. He was managed with aggressive fluid hydration, rasburicase and allopurinol, resulting in improvement in his renal function and laboratory findings. STLS of solid organ tumours, especially gastric adenocarcinoma, is rare and requires early detection with timely management to ensure favourable outcomes.

Background

Tumour lysis syndrome (TLS) is an oncological emergency. TLS is commonly seen after initiation of treatment for haematological malignancies such as Burkitt’s lymphoma and acute lymphoblastic leukaemia and is rarely associated with solid tumours. Spontaneous TLS (STLS) that occurs prior to initiation of therapy is an underdiagnosed entity that is extremely rare in patients with solid tumours and is associated with poor outcomes.¹ STLS of solid tumours is associated with a worse prognosis than STLS of haematological malignancies.² The association of gastric adenocarcinoma and STLS is extremely rare with only four cases reported in the literature.^3–6 High index of suspicion, early detection and timely management are necessary to reduce the risk of organ dysfunction and fatal outcomes.

Case presentation

A man in his 70s, a former smoker, with a medical history of hypertension, hyperlipidaemia, type 2 diabetes, coronary artery disease, haemorrhoids and chronic constipation presented to the emergency department with rectal pain exacerbated with defecation. This condition was accompanied by fresh blood per rectum, worsening constipation, back pain, loss of appetite and weight loss of 24 pounds over the last 3 weeks. He reported dyspnoea on exertion and brown-coloured urine for 1 week. On examination, his vitals were stable, his abdomen was distended and epigastric tenderness was noted. Rectal examination revealed external haemorrhoids with no signs of active bleeding.

Investigations

Initial laboratory workup revealed normocytic anaemia with a haemoglobin level of 128 g/L, elevated white cell count of 11.3 x10⁹/L, elevated creatinine level of 2.59 mg/dL from the baseline level of 1.1 mg/dL, blood urea nitrogen level of 69 mg/dL, hyperkalaemia with potassium level of 6.8 mmol/L, mild hyponatraemia with sodium level of 131 mEq/L, anion gap metabolic acidosis with bicarbonate level of 17 mmol and anion gap of 14 mEq/L, hyperuricaemia (uric acid, 17 mmol/L), hyperphosphataemia (phosphorus, 5.0 mg/dL). Liver function tests revelaed aspartate aminotransferase of 97 U/L; alanine aminotransferase of88 U/L; alkaline phosphatas of 297 U/L, total bilirubin of 0.7 mg/dL and calcium level of 9.5 mg/dL. ECG showed normal sinus rhythm, with incomplete right bundle branch block. Subsequent laboratory investigations demonstrated a lactate dehydrogenase (LDH) level of 1960 U/L, carcinoembryonic antigen (CEA) level of 86.6 ng/mL and CA 19–9 level of 9119.5 U/mL.

CT of the abdomen and pelvis without intravenous or oral contrast revealed poorly defined masses throughout the liver, most of them being suspicious for metastatic disease. No signs of bowel obstruction or inflammatory changes in the surrounding tissue were noted. Chest CT without intravenous contrast showed no pulmonary parenchymal masses, infiltrate, effusion, mediastinal masses or enlarged lymph nodes. The presence of metastatic lesions in the liver coupled with the laboratory findings of hyperkalaemia, hyperuricaemia, hyperphosphataemia and elevated creatinine (acute kidney injury (AKI)) were highly suspicious for STLS.

Oesophagogastroduodenoscopy (EGD) (figure 1) and colonoscopy were conducted to localise the primary tumour. It revealed a large, fungating, infiltrative and ulcerated mass, extending from the gastro-oesophageal junction, along the lesser curvature to the antrum and gastric body, involving 100% of the lumen circumference with evidence of stigmata of recent bleeding. Colonoscopy revealed non-bleeding, non-thrombosed internal haemorrhoids and otherwise normal findings. The specimen obtained by cold forceps biopsy, identified as invasive, moderately differentiated adenocarcinoma (figure 2A), was positive for human epidermal growth factor receptor 2 (HER-2) (figure 2B).

Figure 1.

Oesophagogastroduodenoscopy: large, circumferential fungating, infiltrative and ulcerated mass in the stomach with stigmata of bleeding.

Figure 2.

(A) Biopsy specimen of gastric body mass showed the features of invasive, moderately differentiated adenocarcinoma. (B) Immunohistochemical studies showed positive staining for HER-2 receptor.

Differential diagnosis

Given the laboratory findings of anaemia, hyperkalaemia, hyperphosphataemia, hyperuricaemia and AKI, in addition to CT findings of multiple low-density masses suspicious for metastasis, led to the clinical suspicion of TLS. The patient had no history of chemotherapy. The patient met both the laboratory and clinical criteria for TLS according to the Cairo-Bishop criteria (table 2) and was diagnosed with STLS. Transaminitis was likely due to hepatic metastasis, as noted on CT.

Given the patient’s history of smoking, high-grade intrathoracic malignancy such as small cell carcinoma or lymphoma was suspected. However, chest CT did not reveal any intrathoracic masses. EGD revealed a large gastric mass, and a biopsy confirmed the diagnosis of gastric adenocarcinoma (figure 2A). Rectal examination under anaesthesia revealed a large anterior midline fissure, which likely contributed to the rectal pain.

Treatment

Initial management included therapy with insulin, dextrose and kayexalate for hyperkalaemia. As STLS was suspected, the patient was started on rasburicase at 1.5 mg intravenously and allopurinol at 300 mg in addition to aggressive fluid resuscitation. While awaiting the biopsy results, his creatinine, potassium, phosphorus and uric acid levels improved. The laboratory data trends are shown in table 1.

Table 1.

Laboratory data trends during hospital stay

	Creatinine (mg/dL)	Potassium (mmol/L)	Phosphorus (mg/dL)	Calcium (mg/dL)	Uric acid (mg/dL)	LDH (U/L)
Day of admission	2.59	6.8
Day 1 of hospitalisation	2.02	5.2	5.0	9.4	17.7	1940
Day 2	1.20	5.3	3.1	9.1	9.8	1573
Day 3 (After rasburicase)	0.83	4.8	2.0	8.7	6.9	1479
Day 7	0.87	4.4	3.6	8.7	8.6	1733
Day of discharge (day 9)	0.83	4.4	3.4	8.9	8.9	1880

LDH, lactate dehydrogenase.

Biopsy results confirmed HER-2 positive status (figure 2B), showing invasive, moderately differentiated adenocarcinoma (figure 2A). Diuretics (furosemide) were used to treat volume overload from aggressive hydration. When his laboratory data showed improvement, intravenous fluids were stopped, and he was discharged on allopurinol at 300 mg daily.

Outcome and follow-up

The patient was followed up at the oncology clinic and was started on FOLFOX6+trastuzumab protocol for HER-2-expressing metastatic gastric carcinoma and gastro-oesophageal junction carcinoma.⁷ He received 5-fluorouracil (5000 mg loading and 400 mg/m² on day 1), leucovorin (860 mg on day 1) and oxaliplatin (200 mg on day 1), followed by trastuzumab (600 mg on day 2). He continued to take allopurinol at 300 mg daily. Laboratory results at 8 weeks after four cycles of treatment revealed creatinine level of 0.62 mg/dL, potassium level of 3.4 mg/dL, uric acid level of 4.6 mg/dL and LDH level of 232 U/L. Unfortunately, despite appropriate chemotherapy, his disease continued to progress. He opted for hospice care approximately 1 year later and passed away a few months later.

Discussion

TLS is an oncological emergency that occurs secondary to massive lysis of the tumour cells. It is typically noted in haematological malignancies and is triggered by cytotoxic therapy.⁸ Rapidly growing tumours including high-grade lymphomas such as Burkitt lymphoma and acute lymphoblastic leukaemias are well-known tumours that are predisposed to TLS.² TLS is rarely observed in solid tumours and is restricted to a few case reports and case series.⁹ When TLS occurs spontaneously, without prior intervention such as chemotherapy or radiation, it is termed as STLS, accounting for 15% of all TLS cases.^{8 10} STLS is extremely rare in patients with solid tumours. A recent systematic review reported 64 cases of STL of solid tumours.¹

Rapid lysis of the tumour cells leads to the release of intracellular contents including nucleic acids, phosphorus and potassium into the bloodstream. The nucleic acids are catabolised into xanthine, hypoxanthine and uric acid by the enzyme xanthine oxidase, leading to the characteristic findings of hyperkalaemia, hyperuricaemia, hyperphosphataemia and hypocalcaemia.

The Cairo-Bishop criteria, which is a modified version of Hande and Garrow’s classification, is used to diagnose TLS.^{11 12} Laboratory TLS is defined by the presence of at least two abnormal laboratory values of uric acid, potassium, phosphate and calcium 3 days before or 7 days after the initiation of chemotherapy. Clinical TLS is defined as laboratory TLS and any one or more of the following: creatinine >1.5 times the upper limit of the reference range, cardiac arrhythmia, seizure or sudden death.¹¹

The Cairo-Bishop criteria are summarised in table 2.

Table 2.

Cairo-Bishop criteria for laboratory diagnosis of tumour lysis syndrome

Variable	Value	Change from baseline
Uric acid	≥476 µmol/L (8 mg/dL)	25% increase
Potassium	≥6.0 mmol/L (or 6 mEq/L)	25% increase
Phosphorus	≥2.1 mmol/L (6.5 mg/dL) for children or ≥1.45 mmol/L (4.5 mg/dL) for adults	25% increase
Calcium	≤1.75 mmol/L (7 mg/dL)	25% increase

Changes in two or more laboratory variables are required within 3 days before or 7 days after cytotoxic therapy.

The risk factors for the development of TLS and STLS can be divided into host-related and tumour-related factors. Host-related factors include underlying impaired renal function, dehydration, elevated uric acid level and exposure to nephrotoxic agents.² Tumour-related factors include tumour type such as lymphoma, high cell turnover rate, large tumour burden, metastasis, disseminated disease, compression of the genitourinary tract by the tumour and elevated serum LDH level.² Hepatic involvement is a strong risk factor for TLS and STL of solid tumours and predicts a poor prognosis.^{1 13} In a recent systematic review, 75% of the patients with STL of solid tumours showed hepatic involvement, indicating the role of hepatic involvement in the development of STLS. We performed a systematic search of Medline and Embase to identify cases of STL of gastric adenocarcinoma and found only four cases in the literature (table 3).

Table 3.

Published case reports of spontaneous tumour lysis syndrome of gastric adenocarcinoma

Author	Age/sex	Presenting complaint	Primary tumour with metastasis	Laboratory values*	Treatment	Outcome
Woo et al3	36/M	Abdominal fullness and pain	Gastric adenocarcinoma with paratracheal, aorticopulmonary, paraaortic, aortocaval, peripancreatic and multiple hepatic masses	Creatinine: 2.9 Potassium: 5.6 Phosphorus: 6.9 Calcium: 7.0 LDH: 13 924 Uric acid: 16.9	Hydration, alkalisation, allopurinol, diuretics, haemodialysis followed by chemotherapy	Died
Salmón-González et al4	79/M	Epigastric pain, asthenia and postprandial vomiting	Gastric adenocarcinoma with perigastric, hepatic and pancreatic ganglionic metastasis	Creatinine: 2.07 Potassium: 6.2 Phosphorus: 7.8 Calcium: 6.8 LDH: 1773 Uric acid:14.6	Hydration and hydroelectrolyte correction	Died
Goyal et al5	51/M	Generalised weakness, nausea, vomiting and oliguria	Gastric adenocarcinoma with metastasis to the left lobe of the liver, the L-4 vertebra and the right adrenal gland and multiple enlarged mesenteric lymph nodes	Creatinine: 11.4 Potassium: 5.3 Phosphorus: 15.2 Calcium: 8.9 LDH: 568 Uric acid:27.9	Hydration, allopurinol and haemodialysis	Survived
Chen et al6	62/M	Weakness, decreased appetite, epigastric pain, right flank pain, constipation and weight loss	Gastric adenocarcinoma with metastasis to the left ureter and peri gastric and greater omental lymphadenopathy	Creatinine: 4.94 Potassium: 5.32 Phosphorus: 6.8 Calcium: 9.5 LDH: 353 Uric acid:8.74	Hydration, alkalisation, antibiotics and diuretics	Died

*Laboratory values for creatinine, potassium, phosphorus, calcium and uric acid are presented in mg/dL and LDH in IU/L.

LDH, lactate dehydrogenase; M, male.

All four patients presented with metastasis, and three of them had hepatic metastasis, similar to our patient, indicating a heavy tumour burden.^{3 4 6} The elevated uric acid levels cause renal endothelial cell dysfunction, inflammation and precipitation of uric acid crystals in the renal tubules, resulting in acute uric acid nephropathy and AKI.^{2 14–16} Rapid potassium release into the circulation coupled with inadequate excretion from the kidneys secondary to AKI predisposes patients to hyperkalaemia leading to muscle cramps, cardiac arrhythmia and cardiac arrest.¹⁷ Malignant cells have high concentrations of phosphorus, and their release into the circulation leads to hyperphosphataemia and increases the calcium-phosphate product, resulting in the deposition of calcium phosphate crystals in various organs, including the renal tubules, further worsening the renal function and AKI.¹³ Utilisation of calcium in the above processes leads to hypocalcaemia, predisposing individuals to tetany, seizures, psychiatric disturbances and cardiac arrhythmias.⁸ In patients with STLS, rapidly proliferating tumour cells reuse the released phosphorus, unlike tumour cells, after chemotherapy; therefore, hyperphosphataemia is less common in those with STLS than in those with TLS.^{11 18} However, a recent systematic review of STL of solid tumours by Verghese et al reported high mean phosphate levels,¹ possibly because earlier studies on STLS included many patients with haematological malignancies that have higher proliferative rates and growth kinetics than solid tumours; hence, further studies are required to determine the role of phosphate levels in STLS of solid tumours.^{1 2}

Aggressive hydration is the cornerstone of the prevention and treatment of TLS and STLS. The goal is to improve renal perfusion, preserve the glomerular filtration rate, maintain adequate urine output to prevent the precipitation of uric acid and calcium phosphate crystals, and avoid obstructive uropathy.² Patients should receive intravenous fluid at 2–3 L/m² per day, and the urine output should be monitored closely to maintain it in the range of 80–100 mL/m²/hour. Diuretics may be used to enhance urine output but are contraindicated in the presence of hypovolaemia or obstructive uropathy.¹⁹ Loop diuretics are preferred as they may assist with potassium excretion. Electrolyte abnormalities, such as hyperkalaemia, hyperphosphataemia and symptomatic hypocalcaemia, should be managed according to standard treatment guidelines.

Rasburicase, a recombinant form of urate oxidase that rapidly breaks down serum uric acid, is effective in preventing and treating hyperuricaemia associated with TLS and effectively lowers the requirement for haemodialysis.²⁰ Rasburicase can cause haemolysis in patients with glucose 6-phosphate deficiency and is contraindicated in these patients.^{21 22} Allopurinol reduces uric acid levels by inhibiting xanthine oxidase, the enzyme responsible for the conversion of xanthine and hypoxanthine to uric acid.²³ However, it does not affect preexisting uric acid levels and requires several days to lower hyperuricaemia. Allopurinol also has the potential to cause the accumulation of xanthine and hypoxanthine that can crystallise and precipitate in the renal tubules, resulting in obstructive uropathy.²¹ Thus allopurinol is beneficial for prophylaxis of TLS and is ineffective in treatment of established TLS. Haemodialysis is indicated in patients who develop severe oliguria or anuria, intractable fluid overload, persistent hyperkalaemia or hyperphosphataemia-induced hypokalaemia and in those who fail to respond to medical therapy.²² STL of solid tumours is associated with high mortality rates. A literature review of STLS reported that 17 out of 26 patients with solid tumours died⁸; another systematic review reported a mortality rate of 60.9% due to STLS in patients with solid tumours. The incidence and mortality rates of STLS in patients with solid tumours are unclear owing to the lack of large-scale studies.¹ Early recognition and treatment of solid tumours are essential to improve the outcomes of patients with STLS.

Learning points.

• Spontaneous tumour lysis syndrome (STLS) is a rare but important oncological emergency that requires early detection and management.

• A high index of suspicion for STLS is necessary for patients with solid tumours with a high tumour burden, hepatic involvement and concurrent renal disease.

• Appropriate laboratory and imaging diagnostic investigations should be performed when STLS is suspected.

• Despite the uncommon association between gastric adenocarcinoma and STLS, this rare association can rarely happen.

• Vigilant monitoring and aggressive management are the cornerstones of treatment of STLS and are essential for reducing organ dysfunction and improving outcomes.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).