Lung, Colon, Liver and Oral Cancer: Diagnostic Red Flags

Diagnosing lung, colon, liver and oral cancer starts with a red flag that is easy to explain away: a cough treated as tuberculosis, anaemia put down to tiredness, a liver lesion in a patient already known to be ill, a tongue ulcer expected to heal. Dr. Niti Raizada, Principal Director Medical Oncology, Fortis Hospital, Bannerghatta Road, Bengaluru, India, showed which test confirms each.

She used four routine cases to show how each red flag should be read. Together, these four cancers account for a large share of cancer deaths worldwide: lung, colorectal and liver cancer are the three leading causes. The screening schedules for each are set out in the complete guide to diagnosing common cancers and blood disorders; this article covers the diagnostic pathway once a patient presents.

Lung cancer misdiagnosed as tuberculosis

Lung cancer should be suspected when a smoker's cough, weight loss and haemoptysis do not respond to two months of anti-tuberculosis treatment. CT, PET-CT and a biopsy confirm it.

The presentation

A farmer in his early fifties had a two-month history of persistent cough, weight loss and intermittent low-grade fever, with a couple of episodes of coughing up blood (haemoptysis). He had no chest pain and no breathlessness. Dr. Raizada described this as a very common scenario in both Africa and India.

A chest X-ray showed an inhomogeneous opacity in the upper lobe of the left lung. A GeneXpert test for tuberculosis was negative, but with weight loss, haemoptysis and fever he was started on standard four-drug anti-tuberculosis treatment with pyridoxine.

The red flag: no response to treatment

After two months of treatment his symptoms had not improved. He was still coughing and still bringing up blood. At that point he was referred to Dr. Raizada's team, and a detailed history revealed what had been missed: he had smoked about 20 cigarettes a day for 25 years.

A CT scan of the thorax showed a 3.5 cm spiculated mass (a mass with irregular, spiky margins) in the left upper lobe, with no pleural effusion. The mass lay very close to the left main pulmonary artery, possibly the reason for the bleeding. Sputum smear, GeneXpert and tuberculosis culture were all negative, and the culture was negative again on repeat.

Dr. Raizada listed the red flags that, together, point strongly to malignancy:

• A spiculated mass
• Persistent symptoms
• No response to anti-tuberculosis drugs
• Abnormal activity on a PET scan

PET-CT: anatomy and activity in one scan

A PET-CT (positron emission tomography combined with CT) is both a functional and an anatomical scan: the CT shows the structure and the PET shows metabolic activity. In this patient it lit up the primary lesion in the left upper lobe and mediastinal lymph nodes (glands in the centre of the chest) on both sides.

Choosing the biopsy route

Whether the question is tuberculosis or cancer, the final word is a good tissue sample. The biopsy route depends on where the lesion sits.

• Central lesions close to a bronchus: bronchoscopy with a bronchoscopic biopsy.
• Peripheral lesions close to the chest wall: a CT-guided biopsy.
• Mediastinal lymph nodes: endobronchial ultrasound (EBUS), which lets the operator see the node from inside the airway and sample it with a needle through the bronchial wall (transbronchial needle aspiration).

In this patient both were done, a CT-guided biopsy of the lung lesion and an EBUS-guided biopsy of the mediastinal nodes, because both diagnosis and staging depended on them. The biopsy confirmed lung cancer, and the positive mediastinal biopsy made it T2N2 disease. The plan was chemoradiation.

Molecular testing is mandatory

Dr. Raizada offers molecular testing to every such patient. Targetable changes such as EGFR, ALK or ROS1 are more frequent in Asian patients: EGFR mutations alone are found in roughly a quarter of lung adenocarcinomas in India and about half in East Asia. When one is present, the cancer can be treated with tablets alone. That is why tissue is mandatory.

In her practice, molecular testing is absolutely mandatory for all adenocarcinomas and is done for squamous cell carcinoma as well. International guidelines make broad molecular testing routine for non-squamous lung cancer and recommend it more selectively in squamous disease. Increasingly, a blood test known as a liquid biopsy can also detect mutations such as EGFR and ALK and guide the choice of tablet.

Colon cancer in a young man and Lynch syndrome

A haemoglobin of 9 in a young man is a red flag for bleeding in the gut. In this case it led to colonoscopy, a diagnosis of colon cancer and testing for Lynch syndrome, an inherited cancer syndrome.

Anaemia in a young man is a red flag

A man in his late thirties went to his general practitioner because he was always tired and had recently developed abdominal pain, mostly on the right side. When the general practitioner probed the family history, he found that the patient's father and an aunt had colon cancer and another aunt had uterine cancer.

The general practitioner, whom Dr. Raizada credited for his suspicion, ordered basic tests. The haemoglobin was 9. In a woman of reproductive age, anaemia is common; in a young man, Dr. Raizada stressed, a haemoglobin of 9 is a red flag.

A stool test for hidden blood (faecal occult blood) was positive, so the patient was bleeding somewhere in the gut: the stomach, small intestine or large intestine.

Finding the source

An ultrasound of the abdomen and pelvis showed a suspicious dilated bowel loop. An upper endoscopy was normal. Colonoscopy showed an ulcerated growth in the ascending colon that was visibly bleeding, and the biopsy confirmed adenocarcinoma.

Once cancer is confirmed, two things follow: more information from the biopsy specimen, and a scan for staging.

Testing for Lynch syndrome

Immunohistochemistry on the tumour, which checks for loss of the mismatch repair proteins, pointed to Lynch syndrome. Tumours with mismatch repair deficiency show high microsatellite instability (MSI-high), and when that is found in a patient with this family history it points to a familial cancer. Lynch syndrome is confirmed by germline genetic testing.

There are recognised criteria for when to test. One of them is several members on the same side of the family with a similar pattern of cancer: colon, uterine, ovarian or gastric cancer clustering on one side should prompt testing for Lynch syndrome.

Surgery alone, and cascade testing

A PET scan showed a large mass in the colon. At surgery the disease proved localised, and no chemotherapy was needed. Dr. Raizada noted that patients with a family history and MSI-high tumours tend to do extremely well, and most are cured. Had the disease been advanced, she would have used immunotherapy. Costs for colon surgery are on the colorectal resection cost page.

What should never be forgotten is family counselling. Siblings, parents and children should all be offered testing, a process known as cascade testing. In this family, the patient's brother tested positive, had a screening colonoscopy and is doing well. More on inherited cancer risk is on the medical genetics hub.

Liver cancer (hepatocellular carcinoma) in chronic liver disease

In a patient with chronic liver disease, a liver lesion with a high alpha-fetoprotein is a spot diagnosis of hepatocellular carcinoma. When a triple-phase CT confirms it and the alpha-fetoprotein is above 400, Dr. Raizada does not require a biopsy.

The presentation

A man around sixty, a known case of chronic hepatitis B already on treatment, had had jaundice two years earlier and a previous episode of liver decompensation with ascites and portal hypertension, for which he was taking beta blockers. He went to a gastroenterologist with worsening jaundice.

An ultrasound showed multiple hypoechoic (darker than surrounding tissue) lesions in a cirrhotic liver.

The three red flags that make a spot diagnosis

Dr. Raizada's red flags for hepatocellular carcinoma (HCC):

1. A background of chronic liver disease: hepatitis B or C, alcoholic liver disease, or non-alcoholic steatohepatitis (NASH).
2. A space-occupying lesion in the liver.
3. A high alpha-fetoprotein (AFP).

With all three, she described the diagnosis as a spot diagnosis.

Triple-phase CT and LI-RADS

The key test is a triple-phase CT scan of the abdomen and pelvis, which in practice involves a scan before contrast and scans at several timed points after it. Liver cancer typically lights up brightly in the arterial phase and then "washes out", appearing darker than the surrounding liver, in the later venous and delayed phases. Radiologists grade the result with LI-RADS (the Liver Imaging Reporting and Data System). A LI-RADS 5 lesion is highly suspicious of liver cancer.

Dr. Raizada's rule is that when the triple-phase CT confirms liver cancer and the AFP is above 400, a biopsy is not required. International guidelines (AASLD and EASL) go further and accept typical imaging alone as diagnostic in a cirrhotic liver.

In this patient, the scan showed a hyperenhancing lesion with typical LI-RADS 5 features and an AFP of 540, so no biopsy was needed.

Treating the background disease

The hepatitis B viral load was high, so antiviral treatment was started. The liver function tests were deranged, including the prothrombin time and INR, which reflect the liver's synthetic function, and his Child-Pugh score (a grading of liver function) was B. A staging scan showed no spread to the chest or bones.

How staging decides treatment

A spot diagnosis is not the end of the workup. Staging is based on tumour size, number of lesions, vascular invasion and liver function, and the stage decides treatment. The options are:

• Local ablative therapy, which destroys the tumour in place
• Surgical resection
• Liver transplant, for disease limited to the liver that is not suitable for resection
• Systemic therapy, where there is any vascular involvement, since those patients are not candidates for local treatment

Costs are on the liver cancer surgery cost page and the liver transplant cost page.

Surveillance depends on the person doing the scan

Ultrasound is a subjective, operator-dependent test. Asked in the masterclass Live Discussion about monitoring chronic liver disease, Dr. Raizada called the radiographer's skill very important: if the skill is not good, lesions can be missed. If there is any doubt on ultrasound, a triple-phase CT or a multiphasic MRI or CT should be done immediately.

Bleeding is the hidden danger

Liver cancer comes with coagulopathy, and the risk of bleeding is very high. In any patient with chronic liver disease, not only those with cancer, Dr. Raizada checks PT, PTT and INR from the first visit. Any bleeding tendency is treated with vitamin K and, if needed, blood products. Because these patients also tend to have low white cell and platelet counts, she recommends blood counts and a clotting profile on a regular basis. For her, the key in every case is the right diagnosis at the right time.

Oral cancer: the tongue ulcer that does not heal

A tongue ulcer that has not healed, with everted edges, a hard base or enlarged neck nodes, needs an incisional biopsy. In this case it showed squamous cell carcinoma.

The presentation

A farmer in his fifties who chewed tobacco and drank alcohol had a non-healing ulcer on the right side of his tongue for two months. It was painful, but not severely, which is why he came late; by the time he did, the pain had made swallowing difficult. Dr. Raizada noted that constant irritation from a tooth can also lead to tongue cancer, not only tobacco.

On examination there was an ulcerated mass of about 3 by 2 cm on the right lateral border of the tongue, with irregular, everted edges and an indurated (hardened) base. There were enlarged lymph nodes in the neck.

Diagnosis and staging

An incisional biopsy, which removes a portion of the lesion, showed moderately differentiated squamous cell carcinoma. A scan after the biopsy measured the lesion at 3.2 by 2.1 cm with a depth of invasion of 6 mm. Fine needle aspiration of the neck node confirmed squamous cell carcinoma there too. The stage was T2N1.

Treatment

The patient had definitive surgery. If the surgery goes well, Dr. Raizada considers him cured of his cancer. Costs for tumour removal are on the tumour excision cost page.

Dr. Raizada considers examining the mouth and neck mandatory for clinicians in every patient. The warning signs patients should report are any red patch, any white patch, or a thickened, stiff area of the lining of the mouth, as in oral submucous fibrosis.

Diagnosing lung, colon, liver and oral cancer: the common thread

In each case the decisive move was simple: questioning a diagnosis that was not responding, taking a family history, ordering a basic blood count, or examining the mouth. For a comparable organ-by-organ view of warning signs from a surgical oncologist, see Dr. Rajesh Kumar Jain's article on early warning signs of cancer; Dr. Nithin S.G.'s cancer warning signs checklist by type covers symptoms across cancer types. The same logic, applied to a bleeding patient, is how Dr. Raizada diagnoses acute promyelocytic leukaemia, and the same discipline governs the workup for breast, ovarian and cervical cancer. More on cancer care across specialties is on the oncology hub.