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Dr Esther Myint
Clinical Articles iconClinical 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
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Dr Stephen Birrell
Monographs iconMonographs

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
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Dr Linda Calabresi
Clinical Articles iconClinical 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
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Dr Trevor W. Beer
Clinical Articles iconClinical 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
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Dr Linda Calabresi
Clinical Articles iconClinical Articles

Poor Monitoring A Risk in Active Surveillance of Prostate Cancer

Almost three quarters of men with low grade prostate cancer may not be being adequately monitored, a recent Victorian study suggests. According to data from the Prostate Cancer Outcomes Registry – Victoria, only 26.5% of over 1600 men who had low risk prostate cancer had follow-up investigations consistent with standard active surveillance protocols in the two years after their diagnosis. Specifically, researchers were investigating whether these men adhered to the schedule that consisted of at least three PSA measures and at least one biopsy in the two years post diagnosis. While the study authors concede the clinical consequences of this shortcoming are yet unknown, the finding is still of concern. “If [these men] are not being followed appropriately according to [Active Surveillance] protocols, men may miss the opportunity to be treated with curative intent,” they wrote in the MJA. Active surveillance is increasingly the management of choice for men with low risk prostate cancer. In Victoria, 60% of men diagnosed with this grade of cancer are now managed with active surveillance, the study authors said. A major issue with active surveillance as a management option, is that the optimal timing of follow-up investigations has not been strictly defined, resulting in several different protocols and guidelines being developed worldwide.  This, in part was the impetus for the development of the Victorian prostate cancer registry, which was established in 2009 ‘to improve knowledge of patterns of care and outcomes for men diagnosed with prostate cancer.’ Currently the Australian protocol for active surveillance is based on the consensus opinion, and the three PSA tests and repeat biopsy within two years has been widely accepted as standard care. The finding that 73.5% did not receive monitoring in accordance with thisprotocol, reflected adherence levels that were among the worst when compared to similar studies around the world, and the study authors suggested the reason was likely to be multifactorial. The reasons for the non-compliance ‘may reflect patient-, clinician- and health service-related factors,” they wrote. Patients may avoid biopsy because of pain, clinicians may delay testing based on a patient’s comorbidities or health services may have fewer resources for sending reminders or pursuing patients who miss appointments, the study authors suggested. Nonetheless, efforts needed to be made to ensure men with low grade prostate cancer are not disadvantaged in terms of health outcomes if they opt to accept active surveillance as their management strategy. “To improve adherence, a multifaceted approach may be required, including an education campaign that highlights the need for men to undergo regular PSA assessment and prostate biopsy,” they concluded. Ref: MJA doi:10.5694/mja17.00559

Expert/s: Dr Linda Calabresi
Prostate gland. Male reproductive and urinary systems.
Prof Sandra Turner
Monographs iconMonographs

Modern Radiation Therapy and Hormone Therapy for Localised Prostate Cancer

This article discusses the importance of referral of patients with prostate cancer for consideration of radiation therapy if active treatment is considered.

Expert/s: Prof Sandra Turner, A/Prof Lucinda Morris
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Dr Linda Calabresi
Clinical Articles iconClinical Articles

Surviving breast cancer not the end of the story

Breast cancer survival has improved dramatically over the last few decades. Courtesy of earlier diagnosis and better treatments, five year survival has increased from 70% in the 1980s to 90%, says Melbourne medical oncologist, Dr Jacqueline Chirgwin in the latest issue of the MJA. It is little wonder then that there is now increased focus on the ongoing general health in this ever-growing population of breast cancer survivors. “Although breast cancer is worldwide the most common cancer in women, many, perhaps most patients die from other causes,” she says. Dr Chirgwin’s comments are in relation to an Australian study, published in the same issue of the journal which showed comorbid conditions are more likely to develop in women who have been diagnosed with hormone-dependent breast cancer than in women without cancer. The South Australian researchers reached this conclusion after analysing a random sample of PBS data from a cohort of women who commenced endocrine therapy at some time in the eight years from 2004 and compared that with age and sex matched controls who weren’t taking anti-cancer treatment. Conditions significantly more likely to develop in the breast cancer women included depression, pain or pain-inflammation, osteoporosis, diabetes, cardiovascular disorders and gastric acid disorders. As the study authors point out there are a number of very logical reasons why these conditions are more likely in this particular group of women. For example it is hardly surprising that someone given a diagnosis of breast cancer might subsequently develop depression and be prescribed antidepressants. Similarly a number of the cancer medications may contribute to comorbidities such as cardiovascular disease, osteoporosis and musculoskeletal pain, in addition menopausal hormone therapy is contraindicated. In addition some risk factors for breast cancer are the same risk factors for other chronic conditions such as heart disease and diabetes, namely excessive alcohol consumption, obesity and physical inactivity. And while the findings might not be all that surprising, the researchers suggest that we are missing a major opportunity to target this at-risk group in a manner which will ultimately improve their health outcome, independent of the breast cancer. “As most women diagnosed with breast cancer in Australia can now be cured, the burden of non-cancer comorbidities is becoming a major health concern for these patients, but this is still largely unrecognised. Future breast cancer research should focus on strategies that effectively respond to the burden imposed by these comorbidities,” they concluded. Ref: MJA doi:10.5694/mja17.00006 doi:10.5694/mja17.00938

Expert/s: Dr Linda Calabresi
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Dr Linda Calabresi
Clinical Articles iconClinical Articles

PPIs Increase Risk Of Stomach Cancer

Looks like there is yet another reason to rethink the long-term use of proton pump inhibitors. And this one is a doozy. According to a new study, recently published in the BMJ journal, Gut, the long-term use of PPIs is linked to a more than doubling of the risk of developing stomach cancer. And before you jump to the reasonable conclusion that these patients might have had untreated Helicobacter Pylori, this 2.4 fold increase in gastric cancer risk occurred in patients who had had H.pylori but had been successfully treated more than 12 months previously. What’s more, the risk increased proportionally with the duration of PPI use and the dose, which the Hong Kong authors said suggested a cause-effect relationship. No such increased risk was found among those patients who took H2 receptor antagonists. While the study was observational, the large sample size (more than 63,000 patients with a history of effective H.pylori treatment) and the relatively long duration of follow-up (median 7.6 years) lent validity to the findings. The link between H.pylori and gastric cancer, has been known for decades. It has been shown that eradicating H.pylori reduces the risk of developing gastric cancer by 33-47%. However, the study authors said, it is also known that a considerable proportion of these individuals go on to develop gastric cancer even after they have successfully eradicated the bacteria. “To our knowledge, this is the first study to demonstrate that long-term PPI use, even after H. pylori eradication therapy, is still associated with an increased risk of gastric cancer,” they said. By way of explanation, the researchers note that gastric atrophy is considered a precursor to gastric cancer. And while gastric atrophy is a known sequela of chronic H. pylori infection, it could also be worsened and maintained by the profound acid suppression associated with PPI use and this could be why the risk persisted even after the infection had been treated. Bottom line? According to the study authors, doctors need to ‘exercise caution when prescribing long-term PPIs to these patients even after successful eradication of H. pylori.’ Ref: Gut 2017; 0:1-8. Doi:10.1136/gutjnl-2017-314605

Expert/s: Dr Linda Calabresi
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Shomik Sengupta
Clinical Articles iconClinical Articles

Always Investigate Haematuria

Bladder cancer affects almost 3,000 Australians each year and causes thousands of deaths. Yet it often has a lower profile compared to other types of cancer such as breast, lung and prostate. The rate at which Australians are diagnosed with bladder cancer has decreased over time, which means the death rate has fallen too, although at a slower rate. This has led to an increase in the so called mortality-to-incidence ratio, a key statistic that measures the proportion of people with a cancer who die from it. For bladder cancer this went up from 0.3 (about 30%) in the 1980s to 0.4 (40%) in 2010 (compared to 0.2 for breast and colon cancer and 0.8 for lung cancer). While the relative survival (survival compared to a healthy individual of similar age) for most other cancers has improved in Australia, for bladder cancer this has decreased over time.

Who gets bladder cancer?

Australia’s anti-smoking measures and effective quitting campaigns have led to a progressive reduction in smoking rates over the last 25 years. This is undoubtedly one key reason behind the observed decline in bladder cancer diagnoses over time. Environmental risk factors are thought to be more important than genetic or inherited susceptibility when it comes to bladder cancer. The most significant known risk factor is cigarette smoking. Bladder cancer risk also increases with exposure to chemicals such as dyes and solvents used in industries like hairdressing, printing and textiles. Appropriate workplace safety measures are crucial to minimising exposure, but the increased risk of occupational bladder cancer remains an ongoing problem. Certain medications, such as the chemotherapy drug cyclophosphamide, and pelvic radiation therapy have also been linked to bladder cancer. Patients who have had such treatment need to be specifically checked for the main symptoms and signs of bladder cancer, such as blood in urine. Men develop bladder cancer about three times as often as women. In part, this may have to do with the fact that men are exposed more to the risk factors. Conversely, women have a relatively poorer survival from bladder cancer compared to men. The reasons for this are unclear, but may partly relate to difficulties in diagnosis.
Read more – Interactive body map: what really gives you cancer?

How is bladder cancer diagnosed?

At present, unlike other cancers such as breast cancer that can be picked up on mammograms, bladder cancer can’t be diagnosed at the stage where there are no symptoms. The usual symptoms that lead to the diagnosis of bladder cancer are blood in the urine (haematuria) or irritation during urination, such as frequency and burning. But symptoms are quite common and, in most instances, caused by relatively benign problems such as infections, urinary stones or enlargement of the prostate. So, the key to bladder cancer diagnosis is for suspicious symptoms to be quickly and appropriately assessed by a doctor. Haematuria, in particular, always needs to be considered a serious symptom and investigated further. Up to 20% of patients with blood in the urine will turn out to have bladder cancer. Even if the bleeding occurs transiently, this could still be the first symptom that leads to the earliest possible diagnosis of bladder cancer. It shouldn’t be ignored, since delayed diagnosis of bladder cancer is known to worsen treatment outcomes. Unfortunately, delays in investigation of blood in urine are well known to occur and particular subgroups such as women and smokers tend to experience the greatest delays. Recent studies from Victoria and West Australia have shown how some Australian patients have significant and concerning delays in investigation of urinary bleeding. Multiple factors contribute to such delays, including public perception and anxiety, lack of referral from general practitioners and administrative and resourcing limitations at hospitals. Patients reporting blood in their urine should be referred for scans such as an ultrasound or computerised tomography (CT) to assess the kidneys. They should also have their bladder examined internally (cystoscopy) using a fibre-optic instrument known as a cytoscope. Cystoscopy, a procedure usually performed by urologists (medical specialists of urinary tract surgery), remains the gold standard for diagnosing bladder cancer. Although diagnostic scans can help detect some bladder cancers, they have significant limitations in detecting certain types of tumours.

What happens if cancer is detected?

If a bladder cancer is noted on cystoscopy, it is removed and/or destroyed using instruments that can be passed into the bladder alongside the cystoscope. These procedures can be carried out at the same setting or subsequently, depending on available instruments and anaesthesia. The cancerous tissue removed is examined by a pathologist to confirm the diagnosis. This also provides additional information such as the stage of the cancer (how deep it has spread) and grade (based on appearance of the cancer cells), which help determine further management.

Are there any new developments?

Given that cystoscopy is an invasive procedure, there has been considerable effort to develop a non-invasive test, usually focusing on markers in the urine that can indicate the presence of cancer. To date, none of these have been reliable enough to obviate the need for cystoscopy.
Read more: Can we use a simple blood test to detect cancer?
Additionally, to enhance the ability to detect small bladder cancers, cystoscopy using blue light of a certain wavelength (360-450nm) can be combined with the administration of a fluorescent marker (hexaminolevulinate) which highlights the cancerous tissue. While this approach does lead to the detection of more cancers, the resulting clinical benefit remains uncertain. The ConversationAt present, immediate and appropriate investigation of suspicious symptoms, especially haematuria, using a combination of radiological scans and cystoscopy, remains the best means to diagnose bladder cancer in an accurate and timely manner. Shomik Sengupta, Professor of Surgery, Eastern Health Clinical School, Monash University This article was originally published on The Conversation. Read the original article.
Expert/s: Shomik Sengupta
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Dr Linda Calabresi
Clinical Articles iconClinical Articles

If In Doubt Cut It Out

New guidelines suggest excising a changing skin lesion after one month As with facing an exam where you haven’t studied, or finding yourself naked in a public place – missing a melanoma diagnosis is the stuff of nightmares for most GPs. In a condition where the prognosis can vary dramatically according to a fraction of a millimetre, the importance of early detection is well-known and keenly felt by clinicians. According to new guidelines published in the MJA, Australian doctors’ ability to detect classical melanomas early has been improving as evidenced by both the average thickness of the tumour when it is excised and the improved mortality rates associated with these types of tumours. Unfortunately, however the atypical melanomas are still proving a challenge. Whether they be nodular, occurring in an unusual site or lacking the classic pigmentation, atypical melanomas are still not being excised until they are significantly more advanced and consequently the prognosis associated with these lesions remains poor. As a result, a Cancer Council working group have revised the clinical guidelines on melanoma, in particular focusing on atypical presentations. The upshot of their advice? If a patient presents with any skin lesion that has been changing or growing over the course of a month, that lesion should be excised. The Australian guideline authors suggest that in addition to assessing lesions according to the ABCD criteria (asymmetry, border irregularity, colour variegation, and diameter >6mm) we should add EFG (elevated, firm and growing) as independent indicators of possible melanoma. “Any lesion that is elevated, firm and growing over a period of more than one month should be excised or referred for prompt expert opinion,” they wrote. In their article, the working group do acknowledge that it is not always a delayed diagnosis that is to blame for atypical melanomas being commonly more advanced when excised. Some of these tumours, such as the nodular and desmoplastic subtypes can grow very rapidly. “These subtypes are more common on chronically sun-damaged skin, typically on the head and neck and predominantly in older men,” the authors said. However, the most important common denominator with melanomas is that they are changing, they concluded. A history of change, preferably with some documentation of that change such as photographic evidence should be enough to raise the treating doctor’s index of suspicion. “Suspicious raised lesions should be excised rather than monitored,” they concluded. Ref: MJA Online 9.10.17 doi:10.5694/mja17.00123

Expert/s: Dr Linda Calabresi

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