Introduction
The first report of hyperamylasemia associated with lung cancer was published by Weiss et al. [ 1 ]. In 1994, Petersen et al. analysed cases of resectable lung cancer and reported an incidence of hyperamylasemia of 18.6% (12 out of 70 cases) [ 2 ]. Since then, several case reports have been published, the majority of which have been adenocarcinomas, followed by small cell, adenosquamous and large cell carcinomas. One case of squamous cell carcinoma (SCC) with tissue amylase production has been reported; however, it did not present with hyperamylasemia [ 2 , 3 ]. Here, we present a case in which hyperamylasemia was caused by amylase produced by lung squamous cell carcinoma (LUSC). This report suggests that amylase production may occur in lung cancers, regardless of their histological type.
Case Report
A 74‐year‐old Japanese man presented with abdominal pain. He was diagnosed with a perforated small intestine. Preoperative evaluation revealed a 74‐mm tumour shadow obstructing the right lower lobe bronchus (Figure 1A–C ). Smoking history: 40 pack‐years (20 cigarettes/day from age 20 to 60). The patient does not consume alcohol. Occupation: office worker. No known allergies. Past medical history includes hypertension, hypothyroidism, and cerebral haemorrhage. The family history was notable for breast cancer in the mother. Following surgery, the patient was referred to a university hospital for detailed examination and treatment of a thoracic tumour with suspected lung cancer. Laboratory tests showed a white blood cell (WBC) count of 10,050/μL (neutrophils: 81.8%, lymphocytes: 12.7%, eosinophils: 0.3%, monocytes: 4.9%, basophils: 0.3%), a C‐reactive protein (CRP) level of 1.99 mg/dL and tumour markers (CYFRA: 2.1 ng/mL; squamous cell carcinoma antigen [SCCA]: 81.9 ng/mL; neuron‐specific enolase [NSE]: 5.03 U/mL; carbohydrate antigen 19–9 [CA 19–9]: 0.5 ng/mL; carcinoembryonic antigen [CEA]: 44 U/mL; sialyl Lewis‐x antigen [SLX]: 5.03 U/mL).
An endobronchial biopsy from the truncus intermedius tested positive for CK5/6 and p40 and negative for CK7 and TTF1 (Figure 2 ), resulting in a diagnosis of SCC. Pathological findings in the small intestine were consistent with those in the lung.
No brain metastases were found in brain magnetic resonance imaging. Fluorodeoxyglucose positron emission tomography (FDG‐PET) showed intense FDG uptake in the right hilar region (SUVmax 20.4). Increased FDG uptake was also observed in the right supraclavicular fossa (SUVmax 14.2), liver (SUVmax 17.7), peritoneum (SUVmax 15.7), and right ilium (SUVmax 8.1) (Figure 1D–G ). Based on a 74‐mm primary tumour (T4) with supraclavicular lymph node involvement (N3) and distant metastases involving the liver, peritoneum, small bowel, and ilium (M1c), the clinical stage was determined to be IVB (cT4N3M1c) according to the UICC TNM classification (9th edition). The patient was therefore diagnosed with stage IVB LUSC. Prior to treatment, serum amylase levels were elevated at 1693 U/L (pancreatic amylase 184 U/L), decreasing to 203 U/L following combination therapy with carboplatin, nab‐paclitaxel and pembrolizumab (Figure 3 ). The patient showed no symptoms or signs of pancreatic or salivary gland disease, as evidenced by physical findings and FDG‐PET results. AMY1 (2D4) immunohistochemistry was positive, confirming amylase‐producing LUSC (Figure 2 ) [ 2 , 3 ]. Following two courses of chemo‐immunotherapy (combination therapy with carboplatin, nab‐paclitaxel and pembrolizumab) and three courses of maintenance therapy with pembrolizumab, the primary tumour increased by 48.0% compared with that after the second course of maintenance therapy, accompanied by increased right‐sided pleural effusion and ascites; the disease was therefore assessed as progressive disease. In addition, the amylase level increased to 4054 U/L (Figure 3 ). To our knowledge, this is the first reported case of LUSC with both histological evidence of amylase production and hyperamylasemia [ 2 ]. This case provides new evidence that LUSC can produce amylase and cause hyperamylasemia.
Discussion
Hyperamylasemia associated with tumours is usually due to salivary gland‐type amylase. Therefore, when hyperamylasemia is observed in patients with lung cancer, measuring amylase isoenzymes is important. If increased salivary gland‐type amylase is detected, disorders of the salivary glands (e.g., sialadenitis or sialolithiasis) should first be ruled out. Other causes of elevated amylase, such as macroamylasemia, renal dysfunction and acute infections, should also be considered. Hyperamylasemia can also be a symptom of other malignant tumours, including ovarian, breast, prostate, colon and endometrial cancers. In this case, no abnormalities were found in the salivary glands, and other potential causes were deemed improbable. Given the positive AMY1 (2D4) immunohistochemistry result in the tumour, we concluded that the hyperamylasemia was tumour‐derived. Although the patient presented with hyperamylasemia, no specific clinical findings were identified other than deterioration of the patient's general condition due to tumour progression.
The mechanism by which tumours produce amylase is not fully understood, but several possibilities exist. First, induction signals from tumour cells may increase amylase expression, as normal cells in tissues such as the salivary glands, pancreas, lungs, tracheal epithelium and fallopian tubes constantly express the amylase gene [ 4 ], and signals involved in tumour proliferation may amplify this expression. Second, chromosomal translocations near the amylase gene region, which have been reported in multiple myeloma cell lines, may increase amylase gene expression [ 5 ]. Third, other unknown mechanisms may be involved, including idiopathic causes or hyperamylasemia associated with other diseases. Because chromosome testing was not performed in this case, the mechanism likely falls under either the first or second category.
In tumour‐induced hyperamylasemia, amylase levels often correlate with disease activity, potentially allowing more accurate assessment of the patient's condition. For example, elevated amylase levels may suggest tumour enlargement or recurrence via distant metastasis. However, the clinical differences between amylase‐producing and non‐amylase‐producing tumours, including those previously reported, remain unclear.
A limitation of this case is that the partial biopsy performed via bronchoscopy did not sample the entire tumour so components of other lung cancer subtypes may have been present.
In conclusion, this case of LUSC with hyperamylasemia that was histologically AMY1‐positive suggests that tumour‐derived amylase production may occur across a variety of lung cancer histological subtypes.
Author Contributions
Y.N. prepared all the figures and wrote the manuscript. Y.N., S.H., N.N., Y.G., N.T. and N.Y. performed the bronchoscopies, treated the patient and collected data. Y.N., Y.T. and K.I. contributed to the pathological diagnosis. Y.S. and S.N. advised on the study design and contributed to the discussion and development of the study. All the authors reviewed the manuscript.
Funding
The authors have nothing to report.
Consent
The authors declare that written informed consent was obtained for the publication of this manuscript and accompanying images and attest that the form used to obtain consent from the patient complies with the Journal requirements as outlined in the author guidelines.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
The authors thank Ms. Sakai, Ms. Shinozaki and Mr. Hoshi of the Respiratory Endoscopy Centre for their assistance with data collection.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
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