How accurate is exfoliative cytology ('skin scrape' cytology) for diagnosing basal cell carcinoma and other skin cancers in adults?

Why is improving the diagnosis of skin cancer important?

There are a number of different types of skin cancer. The most common is basal cell carcinoma (BCC). BCC is a localised cancer that can grow and destroy the skin around it. They rarely spread into the body like other cancers can. Very small or superficial low-risk BCCs can generally be treated with treatments such as creams rather than surgery, while it is better to surgically remove BCCs that are more likely to grow and spread. Radiotherapy (a treatment where radiation is used to kill cancer cells) can also be used if BCCs are very large or cannot be removed by surgery. Cutaneous squamous cell carcinoma (cSCC) is also usually a localised skin cancer. In a small proportion of cases it can spread to other parts of the body, so the best treatment is to remove it using surgery. Melanoma is one of the most dangerous forms of skin cancer as it has a higher potential to spread to other parts of the body, and so it is vital to recognise it and remove it early. If people with BCC do not receive the correct diagnosis (known as a false negative test result), their treatment can be delayed, making the surgical procedure more complicated. Diagnosing BCC when it is actually something else (a false positive result) may result in unnecessary treatment, surgery or other investigations and can cause the patient stress and anxiety. If BCC is incorrectly diagnosed in an individual who actually has an cSCC or melanoma, effective treatment can be delayed and this might lead to a greater chance that the cSCC or melanoma spreads to other organs in the body, which can be very serious.

What is the aim of the review?

The aim of this Cochrane Review was to find out how accurate a technique called 'exfoliative cytology' is for diagnosing skin cancer. Researchers in Cochrane found nine studies to answer this question. Nine studies were concerned with the diagnosis of BCC, two with the diagnosis of cSCC and one with the diagnosis of melanoma.

What was studied in the review?

Exfoliative cytology means scraping the surface of a possible skin cancer with a knife and then spreading a small layer of the scrape onto a glass slide so that the cells in the scrape can be stained and looked at under a microscope. It is less invasive than skin biopsy and quick to perform, with results available immediately. This could save patients an additional clinic visit to receive skin biopsy results.

What are the main results of the review?

The review examined nine studies with a total of 1655 lesions (a mole or area of skin with an unusual appearance in comparison with the surrounding skin) that were given these final diagnoses*: 1120 BCCs, 41 cSCCs and 10 melanomas.

For identifying BCC, seven studies show the effect of using exfoliative cytology to confirm BCC in lesions that doctors already suspected were BCCs. In a group of 1000 such lesions, of which 860 (86%) actually do have BCC, then:

- an estimated 853 people will have an exfoliative cytology result confirming that a BCC is present. Of these 14 (1.6%) will not actually have a BCC (false positive result);

- of the 147 people with an exfoliative cytology result indicating that no BCC is present, 21 (14%) will in fact actually have a BCC (false negative result).

One study compared the accuracy of exfoliative cytology to using a hand-held microscope (dermoscopy) for making a diagnosis of BCC but used a different method of removing cells and included patients with a higher risk of melanoma than found in the other eight studies.

There was not enough evidence to determine the accuracy of exfoliative cytology for diagnosing cSCC or melanoma.

How reliable are the results of the studies of this review?

The small number of studies included in this review, poor description of how patients were selected to be included in the study, and limited information on how the test results were used to make diagnoses, reduces the reliability of our results.

The studies did not explain how patients had been referred to have the exfoliative cytology test. Most important of all, the test was only used in people in whom doctors had already diagnosed a BCC just by looking at the skin lesion. In other words, the test was being used to confirm a doctor's diagnosis. Most studies did not include enough people with skin lesions that are similar in appearance to a BCC to be sure that this test correctly identifies a BCC. This may cause exfoliative cytology to appear more accurate than it would be in actual practice.

Who do the results of this review apply to?

Studies were conducted in the UK, across Europe and in Australia. Study authors rarely described patient characteristics, such as age and location of the lesion. The percentage of people included in the studies with a final diagnosis of BCC ranged from 18% to 90% (nine studies). For cSCC it was 4% and 18% (two studies), and for melanoma it was 5% (one study). It was not possible to tell from the studies how clinicians had decided that study participants had lesions that could be a skin cancer.

What are the implications of this review?

No research has been done using exfoliative cytology to diagnose a skin cancer when a patient is first seen by a doctor. The results of this review suggest that exfoliative cytology can help to confirm BCC in patients with skin lesions that a doctor already suspects of being a BCC. This test could be useful for patients with BCCs that need non-surgical treatments, such as radiotherapy, where a tissue diagnosis is needed before the treatment can be given.

How up-to-date is this review?

The review authors searched for and used studies published up to August 2016.

*In these studies, biopsy was the reference standard (means of establishing the final diagnosis).

Authors' conclusions: 

The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity. Since decisions to treat low-risk BCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality prevent us from drawing strong conclusions to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis.

Read the full abstract...
Background: 

Early accurate detection of all skin cancer types is essential to guide appropriate management, reduce morbidity and improve survival. Basal cell carcinoma (BCC) is usually localised to the skin but has potential to infiltrate and damage surrounding tissue, while cutaneous squamous cell carcinoma (cSCC) and melanoma have a much higher potential to metastasise and ultimately lead to death. Exfoliative cytology is a non-invasive test that uses the Tzanck smear technique to identify disease by examining the structure of cells obtained from scraped samples. This simple procedure is a less invasive diagnostic test than a skin biopsy, and for BCC it has the potential to provide an immediate diagnosis that avoids an additional clinic visit to receive skin biopsy results. This may benefit patients scheduled for either Mohs micrographic surgery or non-surgical treatments such as radiotherapy. A cytology scrape can never give the same information as a skin biopsy, however, so it is important to better understand in which skin cancer situations it may be helpful.

Objectives: 

To determine the diagnostic accuracy of exfoliative cytology for detecting basal cell carcinoma (BCC) in adults, and to compare its accuracy with that of standard diagnostic practice (visual inspection with or without dermoscopy). Secondary objectives were: to determine the diagnostic accuracy of exfoliative cytology for detecting cSCC, invasive melanoma and atypical intraepidermal melanocytic variants, and any other skin cancer; and for each of these secondary conditions to compare the accuracy of exfoliative cytology with visual inspection with or without dermoscopy in direct test comparisons; and to determine the effect of observer experience.

Search strategy: 

We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We also studied the reference lists of published systematic review articles.

Selection criteria: 

Studies evaluating exfoliative cytology in adults with lesions suspicious for BCC, cSCC or melanoma, compared with a reference standard of histological confirmation.

Data collection and analysis: 

Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Where possible we estimated summary sensitivities and specificities using the bivariate hierarchical model.

Main results: 

We synthesised the results of nine studies contributing a total of 1655 lesions to our analysis, including 1120 BCCs (14 datasets), 41 cSCCs (amongst 401 lesions in 2 datasets), and 10 melanomas (amongst 200 lesions in 1 dataset). Three of these datasets (one each for BCC, melanoma and any malignant condition) were derived from one study that also performed a direct comparison with dermoscopy. Studies were of moderate to poor quality, providing inadequate descriptions of participant selection, thresholds used to make cytological and histological diagnoses, and blinding. Reporting of participants' prior referral pathways was particularly poor, as were descriptions of the cytodiagnostic criteria used to make diagnoses. No studies evaluated the use of exfoliative cytology as a primary diagnostic test for detecting BCC or other skin cancers in lesions suspicious for skin cancer. Pooled data from seven studies using standard cytomorphological criteria (but various stain methods) to detect BCC in participants with a high clinical suspicion of BCC estimated the sensitivity and specificity of exfoliative cytology as 97.5% (95% CI 94.5% to 98.9%) and 90.1% (95% CI 81.1% to 95.1%). respectively. When applied to a hypothetical population of 1000 clinically suspected BCC lesions with a median observed BCC prevalence of 86%, exfoliative cytology would miss 21 BCCs and would lead to 14 false positive diagnoses of BCC. No false positive cases were histologically confirmed to be melanoma. Insufficient data are available to make summary statements regarding the accuracy of exfoliative cytology to detect melanoma or cSCC, or its accuracy compared to dermoscopy.

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