As mentioned in my previous post, a diagnosis of cancer requires a positive biopsy confirmation by the pathologist. However, a negative biopsy report (where the pathologist cannot see cancer in the examined biopsy sample) must be interpreted carefully.
If an alternative specific diagnosis can be made by the pathologist (eg. tuberculosis) which clearly explains the clinical scenario, then cancer can be safely ruled out. When the entire abnormality in question has been adequately examined and no cancer is seen(for example after removing a suspicious skin mole completely), it can be concluded that there was no cancer in the first place.
Uncommonly, cancer can be missed by a preliminary biopsy – this phenomenon is known as a “false-negative biopsy”. There can be several reasons for this
- Inadequate sample. Most of the time, a very tiny sample of tissue is sufficient to diagnose cancer, and the initial goal is always to obtain a diagnosis with as little discomfort and cost to the patient as possible. Occasionally, however, the amount of tissue sample may not be sufficient to form a clear diagnosis. A fine-needle aspiration cytology (FNAC) can sometimes provide too little tissue for a clear diagnosis to be made. In the case of endoscopic biopsies, sometimes the biopsy may not be deep enough for the pathologist to demonstrate the presence of cancer. A crude example I give my patients is – most of the time a spoon of rice is sufficient to demonstrate the presence of worms in the whole bag, but if one spoon doesn’t contain worms, and if our suspicion is high, we may have to examine a cupful or even more to rule out worms in the rest of the bag
- Geographical miss. If during the biopsy, the area of abnormality was missed and a normal area was sampled. (especially likely in deep-seated and/or small tumors).
- Sampling of necrotic/inflammatory component of tumor. In rapidly growing tumors, eg sarcomas, some parts of the tumor do not get enough blood supply and die (necrose). Some tumors are known to form fluid-filled cavities within the tumor. If the biopsy happens to sample these areas of the tumor, the pathologist may not be able to see any cancer during microscopic examination. Again a crude example – tasting a tiny portion of a fruit can identify the fruit, but if parts of the fruit are rotten and we happen to taste the rotten bit, we may need to sample another non-rotten part.
- Technical issues. Obtaining the biopsy sample from the patient, storing it in the appropriate preservative, transport, processing, slicing the processed sample into micrometer thin slices, fixing each slice onto different slides, staining the fixed slide with specific dyes, examining the slide under the microscope, and if required running special tests on the slide (immunohistochemistry, etc) – there are a series of technical steps which go into reporting every biopsy. Even with all the advances in modern pathology, technical issues do crop up on occasion. Also, despite today’s cutting-edge technology, interpretation of biopsy results is subjective – in the case of rare diagnoses, most pathologists consult their in-house or external colleagues and arrive at carefully considered decisions. Standard oncology care also provides for regular clinic-pathological meetings and multidisciplinary tumor boards where difficult (if not all) cancer cases are discussed from diagnosis to treatment and beyond.
Therefore, when a biopsy report is negative for cancer but does not give a diagnosis that clearly explains the patient’s signs and symptoms, it may be wise to reassess. If the clinical suspicion for cancer is high, a repeat biopsy may be warranted, so that cancer does not get missed. It is important for patients and caregivers to understand this phenomenon of false-negative biopsy, and why their doctor may recommend a repeat biopsy procedure.