Oncology Archives - Page 5 of 6

Oncology

Clinical Articles

Body Fat more Important than BMI in Breast Cancer

Women with a normal BMI can no longer tick off weight as breast cancer risk factor, US researchers say. According to their study, published in JAMA Oncology, it’s body fat that increases the risk even if the woman falls into a healthy weight range. The study was in fact a secondary analysis of the Women’s Health Initiative clinical trial along with observational study cohorts involving almost 3500 post-menopausal, healthy BMI women who at baseline had their body fat analysed (by DXA) and were then followed up for a median duration of 16 years. What the researchers discovered was that women in the highest quartile for total body fat and trunk fat mass were about twice as likely to develop ER-positive breast cancer. “In this long-term prospective study of postmenopausal with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancers,” the study authors spelled. Perhaps less surprisingly, the analysis also found that the breast cancer risk increased incrementally as the body fat levels increased. “We found a 56% increase in the risk of developing ER-positive breast cancer per 5-kg increase in trunk fat, despite a normal BMI,” they said. The proposed mechanism that explains why high body fat levels increases the risk of breast cancer, is much the same as the known mechanism that explains the link between obesity and breast cancer risk. People with high body fat levels tend to have adipocyte hypertrophy and cell death which means the adipose tissue is chronically although sub-clinically inflamed. This inflammation triggers the production of a number of factors including an increased ratio of oestrogens to androgens which is believed to predispose to the development of oestrogen-dependent breast cancer. Basically the study authors believe these women with high body fat but normal BMI, are ‘metabolically obese’ even though they do not fit the standard definition of obese. And while using DXA to determine body fat levels is highly accurate, such an assessment is rarely used in everyday practice. Most doctors look only at BMI measurements or they may also assess waist measurement which has variable sensitivity in terms of diagnosing excess body fat. Consequently, the researchers say, many non-overweight women who are at increased risk of breast cancer because of their high adiposity may be going unrecognised. So where does that leave us? Here the study authors were less definitive. The link between body fat and breast cancer is clear but, they say, more research is needed to determine the most appropriate management for this cohort of women with high body fat levels and normal BMI. “Future studies are needed to determine whether interventions that reduce fat mass, such as diet and exercise programs or medications including aromatase inhibitors, might lower the elevated risk of breast cancer in this population with normal BMI,” they concluded.

Reference

Iyengar NM, Arthur R, Manson JE, Chlebowski RT, Kroenke CH, Peterson L, et al. Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational Study. 2018 Dec 6. DOI: [10.1001/jamaoncol.2018.5327] [Epub ahead of print]

Expert/s: Dr Linda Calabresi

Oncology

Clinical Articles

Not Missing Ovarian Cancer

No one wants to miss ovarian cancer especially in its early stages when you have a chance of successful treatment. But should we be regularly monitoring women who have had a simple ovarian cyst detected on ultrasound, as most guidelines recommend to avoid missing this particularly deadly cancer? That is what US researchers investigated in a nested case controlled study, recently published in JAMA. The study was based on a cohort of adult women from the Kaiser Permanente Washington health care system who had had a pelvic ultrasound at some stage over a 12-year period starting in 1997, and looked at the association of the ultrasound finding with the risk of being diagnosed with ovarian cancer within three years. On analysing the data from the 72,000 women who underwent the investigation, the first finding was that ovarian cysts were very common, particularly simple ovarian cysts, occurring in more than 15,000 women. Simple cysts were detected in almost one in four women aged younger than 50, and just over one in 12 women aged 50 and over. Complex cyst structures were far less common, which is fortunate as the study also confirmed that most of the 212 women who were eventually diagnosed with ovarian cancer had a complex cyst structure on ultrasound. According to their analysis, the detection of a complex cystic ovarian mass on ultrasound increased the likelihood of cancer eight-fold, and if they were 50 or over and found to have ascites as well, the finding was practically diagnostic with the likelihood of having ovarian cancer being over 70 times greater than normal. Ultrasound detection of solid masses was not as dangerous a finding, but the one in ten association with ovarian cancer certainly warranted further investigation. But what of the women found to have a simple cyst on ultrasound? How many of them went on to be diagnosed with ovarian cancer? Well, among those aged under 50 – none! And among the older women only one – and the researchers suspect that the simple cyst found in this case was, in fact an incidental finding. As the study authors point out, this finding shouldn’t be surprising as it is well-known that ‘simple cysts are almost universally benign.’ But the majority of guidelines still recommend on-going surveillance, mainly because of a reluctance to make a definitive diagnosis on the basis of the ultrasound appearance or interpretation alone. “One of the justifications for the surveillance of simple cysts is that imaging may be inaccurate and might miss complex features,” the researchers explain. But such concerns are not warranted according to this study. What’s more, the authors suggest the constant monitoring of these benign cysts may in fact not only be useless but may cause harm. “While surveillance may not seem harmful, there is a growing realisation across all areas of medicine that unnecessary imaging is associated with morbidity, including wasted time, false-positive results, over diagnosis, unnecessary surgery and anxiety,” the study authors concluded.

Reference

Smith-Bindman R, Poder L, Johnson E, Miglioretti DL. Risk of Malignant Ovarian Cancer Based on Ultrasonography Findings in a Large Unselected Population. JAMA Intern Med. Published online November 12, 2018. doi:10.1001/jamainternmed.2018.5113.

Expert/s: Dr Linda Calabresi

Oncology

Clinical Articles

Bowel Cancer Screening: Who, When, How?

New NHMRC guidelines put age and family history up front and centre in determining who should be screened for bowel cancer with colonoscopy and who needs iFOBT. It has been known for some time that family history can influence the risk of developing bowel cancer, Australia’s second most common cause of cancer death. But it is also known that specific, identified genetic mutations causing conditions such as Lynch syndrome or familial adenomatous polyposis are rare, accounting for less than 5% of all bowel cancers diagnosed. At most, the researchers say, this only explains half of the reasons why family history is a risk factor for bowel cancer. “The remainder of the observed increases in familial risk could be due in part to mutations in yet to be discovered colorectal cancer susceptibility genes, polygenic factors such as single-nucleotide polymorphisms, or dietary and other lifestyle factors shared by family members,” the guideline authors said in the Medical Journal of Australia. Therefore, the researchers, led by Professor Mark Jenkins, director of the Centre for Epidemiology and Biostatistics, in the University of Melbourne’s School of Population and Global Health, analysed all the available cohort studies to determine the risk of developing colorectal cancer based on age and family history. They categorised cohorts into one of three levels of risk and this determined at what age screening would be worthwhile starting and which screening method was most appropriate. The screening guidelines exclude people with a known or suspected cancer-causing genetic syndrome, as these people require much more intensive screening and should be managed in a family cancer clinic. The majority of Australians (90%) fall into the lowest risk category, category 1, which puts their risk at age 40 of developing colorectal cancer in the next 10 years at about 0.25% (one in 400). As with most other cancers age is a risk factor, so it is unsurprising that at age 50 the risk of developing this cancer has risen to 0.9%. Screening for this category 1 group should be the two-yearly iFOBT test that is currently available via the National Bowel Screening program for adults between the ages of 50 and 74 years. Interestingly, people aged 75 and older still develop bowel cancer but there have been no studies to determine the cost-effectiveness or benefit vs risk analysis of screening in this age group which is why the program and the guideline recommendations stop at 74 years. One of the differences in these new guidelines, a revision from the previous ones published back in 2005, is that people with a first degree relative who has had or has a bowel cancer at age 55 or older are still considered at average risk (category 1). However, people with this history might consider starting the iFOBT screening at a younger age (45 years), the guideline authors suggest. Category 2 includes people with a moderately increased risk of developing colorectal cancer, 3-6 times higher than average. This will mean having a first degree relative diagnosed with a bowel cancer before the age of 55 or having two first degree relatives who developed bowel cancer at any age (or one first degree and two second degree relatives). Category 2 people are recommended to have iFOBT every two years for the decade between ages 40 and 50 and then switch to five yearly colonoscopies until the age of 75. Finally, the high risk, category 3 is for all those patients without a genetic syndrome whose family history is even stronger than those people in category 2. Their risk is between 7-10 times higher than average. This includes people with at least three first-degree relatives who have been diagnosed with colorectal cancer at any age or people who have multiple relatives with the cancer including at least one diagnosed before aged 55. These high-risk people need to start screening earlier, with the guidelines recommending iFOBT every two years starting at age 35 and continuing for 10 years and then having a colonoscopy every five years between the ages of 45 and 75. Of note is that the revised guidelines have deleted the reference in the previous guidelines to starting screening 10 years before the earliest age colorectal cancer was diagnosed in a first degree relative. “There have been no studies conducted to determine the utility of beginning screening 10 years before the earliest diagnosis in the family, which was a recommendation in the 2005 guidelines and, therefore, it is not included in these guidelines,” they said. The new guidelines aim not only to more strongly define risk based on the latest evidence, but also to determine the most appropriate screening method based on that risk, taking into consideration cost-effectiveness and rationalisation of available services, in particular, colonoscopies. Reference Jenkins MA, Ouakrim DA, Boussioutas A, Hopper JL, Ee HC, Emery JD, et al. Revised Australian national guidelines for colorectal cancer screening: family history. Med J Aust. 2018 Oct 29. doi: 10.5694/mja18.00142. [epub ahead of print]

Expert/s: Dr Linda Calabresi

Oncology

Clinical Articles

Detecting Liver Cancer Early

GPs can make a significant difference in curbing the rising rates of liver cancer deaths in Australia, experts say. According to an analysis of over 270 cases of newly diagnosed cases of hepatocellular cancer presenting at seven Melbourne tertiary hospitals over one year, researchers say survival rates could be improved with earlier diagnosis of cirrhosis and better adherence to recommended screening schedules among those known to be at high risk. “[T]he number of liver cancer-related deaths has been the most rapid for any cancer type in Australia over the past 40 years,” the study authors said in the MJA. And of all the types of liver cancer, hepatocellular carcinoma is by far the most common, accounting for 82%. Even though treatments are available, both curative and palliative survival remains very poor with the Australian 12-month survival rate estimated to be only 62%. In this particular study, conducted over 2012/2013 the mean survival was only 18 months. As one would expect, the patients who did better, who generally survived the longest were those whose tumours were detected at an earlier stage. These were usually the patients who were known to be at high risk of developing liver cancer and were participating in a surveillance program. But this was only 40% of the 272 cases, even though 89% would have qualified for surveillance based on their risk factors. Why was this? Well firstly, many of these people did not know they were at risk. And that’s where GPs fit in. In the study the most common risk factors for liver cancer were found to be hepatitis C infection (41%), alcohol-related liver disease (39%), hepatitis B infection (22%) and non-alcoholic fatty liver disease (14%). Many had more than one risk factor. Most telling was the finding that, even though the vast majority of patients (83%) had cirrhosis when they were diagnosed with hepatocellular carcinoma, for one third of them that was the first they knew of it. The study authors suggest clinicians need to be alert for risk factors for chronic liver disease such as excess alcohol use, chronic HCV and HBV infections and even non-alcoholic liver disease in certain groups. In these people, checking for cirrhosis is likely to be worthwhile. “An aspartate transaminase to platelet ratio index (APRI) value greater than 1.0 predicts cirrhosis with 76% sensitivity and 72% specificity, and the test is simple to undertake,” the researchers said. The other major barrier to the earlier detection of liver cancer identified in the study was the poor adherence to surveillance among those people identified as being at high risk. Researchers found patients with alcohol-related liver disease or decompensated liver disease were the least likely to get regular monitoring. A surveillance program for this particular cancer involves a 6-monthly liver ultrasound and serum alpha-fetoprotein assessment. The study authors are advocating a national hepatocellular cancer surveillance program for those who are at high risk of developing the disease, which would include all patients with cirrhosis, Asian men over 40, women over 50, Africans over 20 years of age, and patients with a family history of [hepatocellular carcinoma] without cirrhosis but with chronic HBV infections. A national program to screen for hepatocellular carcinoma amongst this particular group would be worthwhile, the researchers said, as the incidence of the cancer is high, the screening is non-invasive and inexpensive and, perhaps most importantly early detection has been shown to improve survival. However, until such a national program is developed, researchers are encouraging GPs to ensure that their at-risk patients are enrolled in a surveillance program in order to hopefully improve their health outcomes. Reference: Hong TP, Gow PJ, Fink M, Dev A, Roberts SK, Nicoll A, et al. Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study. Med J Aust [Internet]. 2018 Sep 24; 209(8): 1-7. Available from: https://www.mja.com.au/journal/2018/209/8/surveillance-improves-survival-patients-hepatocellular-carcinoma-prospective doi: 10.5694/mja18.00373

Expert/s: Dr Linda Calabresi

Oncology

Clinical Articles

The link between sebaceous gland tumours and colon cancer.

A case report A 56-year-old patient presents with a smooth, round, slightly scaly lump on the forehead, 2mm in maximum dimension. The clinical diagnosis was query basal cell carcinoma and it was excised. Microscopic findings were of sebaceoma and following immunohistochemistry staining shows loss of nuclear positivity of the DNA mismatch repair enzymes MSH2 and MSH6, which is usually associated with high-degree microsatellite instability (MSI), and raises the possibility of Muir Torre syndrome associated tumour. The patient underwent investigations, including colonoscopy, and was found to have a fungating lesion in the sigmoid colon. The patient had a left-sided hemicolectomy and the microscopic findings were of a moderately differentiated adenocarcinoma. It also has the same loss of nuclear positivity of the DNA mismatch repair enzymes MSH2 and MSH6, which further raises the possibility of Muir Torre syndrome associated tumour. Discussion Not all skin cancers are straight-forward and some can be associated with internal malignancies or visceral cancers. Skin cancers can be syndromic; they can occur together and characterise a particular abnormality or condition and Muir Torre syndrome (MTS) is a good example. Syndromes are mostly inherited as autosomal dominant traits. MTS is characterised by the development of sebaceous tumours, often multiple, in association with visceral neoplasms, usually gastrointestinal carcinomas. MTS is found as a variant of the autosomal dominant disorder, hereditary non-polyposis colorectal cancer (HNPCC), with tumours demonstrating microsatellite instability (MSI) and germline mutations in the DNA mismatch repair genes MutS homolog MSH2 and MLH1. Muir Torre syndrome This syndrome was first noted by Muir et al in 1967 and Torre in 1968 and is defined by the occurrence of a sebaceous neoplasm and internal malignancy in the absence of other predisposing factors. Cancers of the gastrointestinal and genitourinary tracts are the most common, with colorectal cancers often occurring at or proximal to the splenic flexure, contrary to most sporadic colorectal cancers. The skin lesions which develop in MTS include sebaceous adenoma, sebaceoma and sebaceous carcinoma. Multiple keratoacanthomas (with or without areas of sebaceous differentiation) are seen in some cases and reticulated acanthoma with sebaceous differentiation. Multiple sebaceous tumours and sebaceous tumours occurring before the age of 50 years are strong indicators of the syndrome. The cutaneous tumours may precede or follow the direct manifestation of the visceral cancer and may occur sporadically in family members. The visceral tumours behave less aggressively than would be expected from the histologic findings and this is particularly true for tumours with MSI. Detection of MSI in cutaneous neoplasms may form the basis of a non-invasive screening technique for hereditary non-polyposis colon syndrome (also known as Lynch syndrome), of which the Muir Torre syndrome is regarded as an allelic variant and represents 1-2% of cases with Lynch syndrome. MTS is inherited as an autosomal dominant trait. Mutations in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 have been found in these patients. Recommendations in Muir Torre syndrome - Consider MTS in patients presenting with a sebaceous neoplasm. Immunohistochemistry examination of tumours for MLH1 and MSH2 protein can be used as a screening test to identify patients. -Individuals with or at risk of MTS or HNPCC should have: 1) Colonoscopy every 1-2 years, beginning at age 20–25, or 10 years younger than the youngest age at diagnosis in the family is strongly recommended. 2) Annual history and physical examination, including a complete skin examination and urinalysis, as well as periodic endometrial sampling and/or transvaginal ultrasound for women.
General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

Expert/s: Dr Esther Myint

Oncology

Monographs

Mammographic Breast Density: A New Era for Breast Cancer Screening and Prevention

This article discusses how high mammographic breast density lowers the sensitivity of breast cancer screening and increases breast cancer risk.

Expert/s: Dr Stephen Birrell

Oncology

Clinical Articles

Improving the Odds for Childhood Cancer Survivors

Surviving childhood cancer is a major win in anyone’s language. However, it is well-known, that even as adults these survivors are at an increased risk of dying before the age of their cancer-history-free peers. Now, it would appear, these people can do something about managing that Damocles sword. According to a recent study published in JAMA Oncology, regular vigorous exercise in early adulthood is associated with a lower risk of mortality in adult survivors of childhood cancer. And the study authors believe the finding could have a significant impact, given the numbers of children that now survive cancer. “These findings may be of importance for the large and rapidly growing population of adult survivors of childhood cancer at substantially higher risk of mortality due to multiple competing risks,” they said. The study was a multicentre cohort analysis of data from over 15,400 adults who had had cancer diagnosed at one of number of paediatric tertiary hospitals in North America before the age of 21. Interviews were conducted at baseline (median age at almost 26 years) at which, among a range of other parameters, levels of exercise were assessed. These patients were then followed for up to 15 years (median follow-up 9.6 years). Overall, after adjusting for chronic health conditions and treatment exposures the researchers found an inverse association between exercise and all-cause mortality. More compelling was the analysis of a subset of almost 5700 survivors, which showed that increased exercise over an eight-year period was associated with a 40% reduction in all-cause mortality compared with low levels of exercise. Of course, the critical question is what constitutes vigorous or increased exercise? How much exercise does a person need to do to qualify for this benefit? The question these patients were asked was ‘on how many of the past seven days did you exercise or do a sport that made you sweat or breathe hard?’ This was considered vigorous exercise, and the mortality benefit was seen in people who exercised to this level for at least 60 minutes a week. But the benefit was not entirely dose-dependent. It appeared that vigorously exercising for about an hour a day, five days a week (eg a brisk 60 min walk) was the most advantageous in terms of mortality, beyond that the benefit was attenuated. It is well known that, in the general population, regular exercise reduces all-cause and cause-specific mortality, however there are much fewer studies looking at its benefit among cancer survivors, especially younger-age cancer survivors. “To this end, our findings….significantly extend the current evidence base and arguably provide the best available epidemiological evidence to support the endorsement of exercise for cancer survivors,” the study authors said. Ref: JAMA Oncology doi10:1001/jamaoncol.2018.2254

Expert/s: Dr Linda Calabresi

Oncology

Clinical Articles

Melanoma vs Spitz Naevi in Children

Melanoma is rare in childhood, representing no more than 2% of all skin melanomas. Diagnosis is often delayed because melanoma is unsuspected, partly due to differences in presentation and its rarity. The diagnosis is made with trepidation by pathologists, since the vast majority of childhood skin lesions are benign. Establishing the true prevalence of juvenile melanoma is complicated by a number of factors, one being the definition of childhood or juvenile. Many studies use a cut-off age of 19 years, but this is not consistent. Cancer registry data may also be unreliable due to misclassified Spitz naevi, for example.

ABCDE + ABCDD

ABCDE criteria help to identify adult melanoma clinically (Asymmetry, Border irregularity, Colour variation, Diameter >6mm, Evolution). Many melanomas in childhood are non-pigmented (> 50% of 65 recent cases from Victoria). Additional ABCD criteria have been suggested in children: Amelanotic, Bleeding bump, Colour uniformity, De novo, any Diameter to facilitate earlier recognition. Children more often present with advanced disease due to diagnostic delay, reported in 50-60% of patients.

Childhood Melanoma in WA

A recent WA study with the WA Melanoma Advisory Service (WAMAS) identified 95 melanomas in patients 19 years or younger over a 14-year period. Three patients died from melanoma. The majority of tumours, 75%, occurred between ages 13 and 19 years, similar to other studies. In all populations, juvenile melanoma is much less common before puberty. Delayed diagnosis was evident with 21 of 23 patients presenting with Clark level 4 or 5 melanomas with Breslow thickness >1mm in 65%. A family history of melanoma was seen in 17%. A study this year in Victoria revealed 65 melanomas during a 19-year period, with seven fatalities. A decrease in juvenile melanoma has been seen in WA despite an increasing population. In Queensland, a substantial decline occurred between 1997 and 2010, attributed to safer sun exposure practices since the 1980s.

Prognosis

The outlook for childhood melanoma mirrors that in adults being primarily based on stage and Breslow thickness. The exceptions are tumours with spitzoid features. These show appearances resembling Spitz naevi and, although often metastasising to local nodes, are less frequently lethal. Prognostication is complicated by the fact that occasional examples behave aggressively and some spitzoid melanomas in case series may be misdiagnosed Spitz naevi.

Treatment

Complete excision, as in adults, is required. Further investigations and treatment should be decided in conjunction with expert advice. Treatment of advanced melanoma is progressing rapidly and possible eligibility for clinical trials means that patients will get the best opportunities for positive outcomes with personally tailored, up-to-date guidance. It is recommended that all melanoma diagnoses in childhood are reviewed by pathologists with expertise in melanocytic lesions. Referral to a multidisciplinary team is valuable to ensure correct diagnosis and to optimise treatment and advice to patients and families.

Sophie Spitz’s ‘Juvenile Melanoma’

Pathologist Sophie Spitz described 12 unusual ‘juvenile melanomas’ in 1948. Follow-up showed benign behaviour, despite microscopy suggesting melanoma. These lesions are now called Spitz naevi. Although typically childhood lesions, they can occur in adults, reducing in frequency with age. Diagnosis clinically and microscopically can be challenging. Lesions may clinically resemble pyogenic granulomas, haemangioma or dermatofibroma. While most are correctly identified pathologically, some are misdiagnosed as melanoma. Conversely, a leading cause of litigation in pathology is underdiagnosis of melanoma as Spitz naevus. Distinction between Spitz naevi and melanoma may be extremely difficult or even impossible. In these histologically ambiguous tumours inter-observer agreement is notoriously poor. There is now a move away from traditional benign versus malignant divisions with suggestions that a histological continuum exists between Spitz naevi at one end and Spitzoid melanoma at the other. Indeterminate lesions may be labelled Spitzoid tumours of uncertain malignant potential (STUMP) with a guarded prognosis.

Improving pathological diagnostic accuracy

Treatment and prognostication of childhood melanoma requires accurate diagnosis which can be enhanced by experience and consultation between pathologists. Molecular studies such as FISH and aCGH may assist in ambiguous cases, but such methods are still in development and not uniformly available. However, molecular techniques will ultimately lead to more accurate diagnosis, prognostication and tailored treatment for children with melanoma. References available on request

General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

Expert/s: Dr Trevor W. Beer