INVESTIGATING SUSPECTED CANCER
Whether the patient has been picked up by a screening programme or has presented to their doctor with worrisome symptoms, the next step is to carry out further tests to confirm or exclude the diagnosis. Diagnosis is usually based on a tissue sample (biopsy) of the affected organ, preceded by clinical examination by a doctor, imaging, and blood tests. Ideally, cancer would be investigated using non- invasive imaging tests. In practice, in almost all cases the diagnosis needs to be confirmed by examining a tissue sample in the laboratory. Imaging is a key to deciding where and how to obtain tissue. Modern cross-sectional imaging either with X-rays – computed tomography, or CT, scans – or using magnetic resonance imaging (MRI) can give remarkably detailed pictures of internal organs and suspected tumours. However, even the best imaging is unable to show with certainty whether a mass is cancerous and also, even if the diagnosis of cancer is highly likely, exactly what sort of cancer. Occasionally the imaging is sufficient. For example, an elderly, frail, life-long heavy smoker with suspected lung cancer on a chest X-ray and who is unfit for any treatment may be spared the discomfort of a confirming biopsy. One or two other scenarios may also not require a biopsy – patients with extensive cancer deposits in bone (a common site of spread for prostate cancer) on imaging and a grossly elevated serum prostate-specific antigen (PSA) can be reliably diagnosed as having widespread prostate cancer with no biopsy. The illustrations show specimen scans of cancer in the breast (Figure 1) and secondary tumour deposits in the lung and liver (Figure 2). In all of these cases, the abnormalities are evident. However, even for radiologically obvious lesions such as these, a biopsy is generally required to determine the exact cancer type and hence the appropriate treatment.
The pathologist assesses small tissue samples taken, for example, via a needle – biopsies. Occasionally, for example in renal cancer, the initial material may be from a surgically removed organ, such as the diseased kidney. Mostly, this is done by mounting very thin slices of the removed tumour on slides and then carrying out a range of stains which highlight particular features of interest. The stained slides are then examined by the pathologist using a microscope. A commonly used stain is haematoxylin and eosin (usually called H&E) which highlights the various components of the cell such as the nucleus. Increasingly specialized stains are used which help further characterize a tumour. An example would be staining for the oestrogen receptor in breast cancer which helps predict the response of cancer to both chemotherapy and hormone therapy. There are a rapidly growing number of available tests, mostly based on monoclonal antibodies (which are also increasing rapidly as a form of treatment). In addition, tests can also be done to look for changes in the expression of particular genes or to look for the presence of particular mutations or rearrangements in chromosomes.
The primary question for the pathologist is: ‘is it cancer?’ If the answer is ‘yes’, then secondary questions include the specific type – in other words, in which organ did it start and which subtype. In addition, cancers are graded in terms of aggressiveness, typically on a scale of one (low) to three (high). Some cancers, for example, prostate cancer, lymphoma (cancer of the lymph glands), and sarcomas (cancers of the connecting and structural tissues such as bone, muscle, or cartilage), have different grading systems, but the same principles apply. All of these systems are based on the size and shape of the cancer cells and how they compare to the normal cells in the organ in which they originated.
More recently, and increasingly, additional subclassification is based on molecular markers present on cancer. These can be defined as characteristic features based on excessive levels of particular markers either in a tumour itself or circulating in the blood (or sometimes present in urine). Probably the best-known example of a molecular marker is HER2 in breast cancer. This was initially described as a marker of poor outcome in breast and ovarian cancer by Dr Denis Slamon from UCLA in the late 1980s. This led to the development of the drug trastuzumab (Herceptin), intended to target cells with excessive amounts of the protein (termed over-expression). Landmark trials, initially in patients with advanced disease and subsequently in newly diagnosed patients, showed that the drug significantly improved outcomes for the 25% of women with tumours with high levels of the HER2 protein. Staining tumour samples for HER2 expression thus gives important information about prognosis (treatment outcomes) and also helps guide the choice of treatment.
The other major role for the pathologist in cancer care is the assessment of specimens resulting from surgical removal of organs containing cancer. In addition to the questions posed above, which will be reassessed with the larger specimen, the pathologist is also addressing issues such as:
- is a tumour confined to the organ that has been removed at surgery?
- are the surgical resection margins (the edges of the specimen) free of a tumour?
- is there spread to other associated structures such as lymph glands?