Should we rename low risk cancers?BMJ 2019; 364 doi: https://doi.org/10.1136/bmj.k4699 (Published 23 January 2019) Cite this as: BMJ 2019;364:k4699
- 1UCSF Carol Franc Buck Breast Care Center, San Francisco, CA, USA
- 2Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK
- Correspondence to: L J Esserman , M Varma
Yes—Laura J Esserman
No medical diagnosis evokes such universal fear as one with the word “cancer.” It is a compelling argument that ethics alone require us to use a strict definition of the word to avoid unnecessary harm to our patients—psychological, physical, and financial—from unnecessarily invasive investigation and treatment.1
The clinical definition of cancer describes a disease that, if untreated, will grow relentlessly and spread to other organs, killing the host. What we routinely refer to as cancer today is a disease marked by heterogeneity, varying in metastatic potential from ultralow (<5% chance of progression over two decades) to extremely high (>75% chance of progression over one to two years). Many thyroid, prostate, and breast cancers are ultralow risk lesions.
Today, a “breast cancer” diagnosis encompasses a range of conditions, from tumours with high risk of early recurrence, which are most likely to need cytotoxic and biological therapies; through those with risk of late recurrence, which is best mitigated with hormonal therapy; to those with ultralow risk and for which breast cancer specific survival of 10 years (even without systemic therapy) is 100%.2 Clearly, a condition that is indolent or rarely metastasises is not a cancer as clinically defined.
Diagnosis requires the same microscopic interpretation that has been in place for decades. In the past, it was not possible to reliably identify lesions with negligible risk. Today, genomic tests inform our understanding of the risk and timing of recurrence, but we have yet to use them to change how we define cancer. Molecular classifications and other hallmarks of ultralow risk lesions are being investigated.1
The increased incidence of ultralow risk cancers is the direct result of modern screening programmes.34 Ultralow risk prostate cancers (Gleason 3+3 tumours, with metastasis-free survival rates of 98% at 10 years5) are so common that prostate specific antigen screening has fallen from favour. As many as 35% of screen detected breast cancers may also fall into the ultralow risk category6; 25% of all “cancers” detected are ductal carcinoma in situ (DCIS) (up from 3% in 1985 before screening). Yet DCIS is rarely, if ever, lethal. Despite 60 000-70 000 women in the US having DCIS removed every year for over a decade, rates of invasive cancer continue to rise.7 And over time, the risk of developing a cancer is as much bilateral as it is unilateral, suggesting that DCIS should be considered a risk factor rather than a focal lesion amenable to surgical removal.89
Low and intermediate grade DCIS could be reclassified as “indolent lesions of epithelial origin” (IDLE),10 without the word carcinoma.
The ethical imperative to relabel lesions that are ultralow risk is not only about sparing patients the unnecessary physical and psychological trauma of a cancer diagnosis and the attendant fears of recurrence or side effects of treatment. De-escalation of treatment is appropriate but has proved extremely difficult for low risk breast lesions (for example, eliminating radiation after lumpectomy for hormone positive, node negative tumours in postmenopausal women or observing low grade DCIS) as well as Gleason 6 prostate cancers (active surveillance). This is because it is difficult to encourage patients to wait and watch once they have been told they have cancer.11
Women with low risk DCIS, most of whom will live long and productive lives without any intervention, are being rushed to the operating room, precipitating a lifetime of anxiety. Instead, we should offer the option of trials of active surveillance. Radiation after lumpectomy or mastectomy is still the standard for hormone positive invasive cancer in postmenopausal women, although three randomised trials (the first in 2005) found that lumpectomy and endocrine therapy alone should suffice.1213
Finally, the failure to remove minimally lethal disease from the denominator in trials masks the signal of effective treatments and impedes our efforts to find more tailored therapies or screening approaches for the people most likely to benefit. Progress in personalised medicine depends on harnessing advances in molecular medicine and artificial intelligence to identify people at risk of consequential cancers and focusing our screening and prevention efforts on maximising impact and minimising harm.
A change in nomenclature would lead to a change in what researchers investigate and what clinician investigators report. This will allow more focus on conditions that directly affect women’s health and reduce the considerable toll from breast cancers, which lead to more than 40 000 deaths a year in the US alone.
Overtreating people who are not at risk of death does not improve the lives of those at highest risk. The refinement of the nomenclature for cancer is one of the most important steps we can take to improve the outcomes and quality of life of patients with cancer.
Removing the cancer label from low risk tumours1 requires knowledge of the natural course of the tumour to ensure that patients are not undertreated. However, biopsies provide information about only the tiny fraction of the tumour sampled. To be sure that the tumour lacks unsampled higher risk components would require complete excision.
In practice, it is impossible to determine the natural course of any low risk tumour because excision for definitive diagnosis alters its natural course, precluding knowledge of how the tumour would have behaved if left untreated. This uncertainty could also lead to underestimation of the frequency of overdiagnosis as some “cured cancers” would not have progressed even if untreated.
It has been suggested that Gleason score 3+3=6 prostate cancer should be recategorised as a non-cancer because none of the men who had such tumours in radical prostatectomy specimens subsequently developed metastasis.14 However, a diagnosis of Gleason score 6 prostate cancer can be established only after radical prostatectomy because over 30% of men with biopsy diagnosis of Gleason 6 cancer have unsampled higher grade tumour in the prostate gland.15 It would not be helpful to inform a patient experiencing complications after radical prostatectomy that he did not have cancer because the specimen showed that the tumour was Gleason score 6. Renaming cancers would also affect patients who had had radical therapy before the new terminology was adopted due to their perception of having had unnecessary major treatment for a non-cancerous condition.
Alternative terminology may also induce confusion and anxiety. It has been recommended that some low risk thyroid carcinomas should be recategorised as tumours of “uncertain malignant potential.”16 However, such a term could be misinterpreted as indicating that the pathologist is uncertain whether the tumour is benign or lethal.
A non-cancerous label could affect the level of support for which the patient is eligible, although this may be less important in low risk tumours. However, removing the cancer label would not prevent serious psychosocial and financial consequences if accompanied by a recommendation for protracted follow-up, as is the case for active surveillance for prostate cancer.17
Education is key
Rather than focusing on semantics, the key is to educate everyone from the healthy public to health professionals about the meaning of a diagnosis of cancer. When pathologists make such a diagnosis, they are classifying the tumour type and not necessarily indicating the outcome of that particular tumour, which would also depend on other factors such as tumour grade and stage. In contrast to a 5 cm papillary thyroid cancer that has a substantial risk of metastasis, a 0.5 cm papillary thyroid cancer is likely to be entirely harmless once removed but could progress to a clinically significant tumour if left untreated. A diagnosis of thyroid cancer is thus analogous to a diagnosis of lung infection, which includes viral bronchitis that requires no treatment; bacterial pneumonia that is generally easily cured if treated promptly with antibiotics; as well as severe infections such as severe acute respiratory syndrome (SARS), with considerable risk of mortality.
Continuum of risk
New terminology often leads to confusion, so an alternative approach would be to recalibrate thresholds for the diagnosis of cancer.18 There is a misconception that benign and malignant are biologically distinct, when in reality there is a continuum of increasing risk from benign to good prognosis to bad prognosis. The minimum risk threshold to distinguish benign from good prognosis cancer is arbitrary, with a low threshold resulting in overdiagnosis (and overtreatment) and a higher threshold risking underdiagnosis (and undertreatment).
An alternative approach would be to raise this arbitrary risk threshold for the pathological diagnosis of cancer so that some very low risk cancers are categorised as benign. If the public were educated that benign signifies very low risk rather than no risk at all, then anxiety inducing labels could be avoided. Recently, the World Health Organization renamed a subtype of kidney cancer as multilocular cystic renal neoplasm of low malignant potential because it has not been reported to recur or metastasise.19 Since these tumours have a benign outcome, an alternative approach would be to expand the pathological spectrum of benign multilocular renal cyst to include this type of tumour.
Creating new entities risks confusion, so public education about the nature of cancer must be the priority.
Competing interests: Both authors have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; externally peer reviewed.