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The Power of Gene Expression Profiling

sponsored by Castle Biosciences

Gene expression profiling (GEP) is becoming an important tool in cancer diagnosis and prognosis. In melanocytic lesions, GEP can be particularly helpful in differentiating benign from malignant lesions. GEP measures the RNA expression level of targeted genes known to have differential expression in benign versus malignant tissue. A computer-generated algorithm analyzes these expression levels to classify the lesion as likely benign or likely malignant. 

The results of GEP, therefore, can aid both in achieving a definitive diagnosis and guiding appropriate patient care in difficult to diagnose melanocytic lesions. Etan Marks, DO, board certified in AP/CP, hematopathology and dermatopathology, affiliated with Skin Pathology Associates, Delray Beach, and Aaron Farberg, MD, double board-certified dermatologist and Mohs surgeon affiliated with Bare Dermatology and with Baylor Scott & White Health, are two specialists who have integrated the Castle Biosciences MyPath Melanoma GEP test into their practices. Here, they share insights on when and how GEP testing should be used, as well as its impacts on collaboration and, ultimately, patient care. 

In what situations do you use GEP testing?

Marks: The situations I have found to be most appropriate for GEP testing are when the clinical features are consistent with melanoma, but the histologic features are ambiguous. Maybe there’s a little bit of pagetoid spread. Maybe there’s simply pleomorphism or rare mitotic figures. Regardless, the definitive criteria for melanoma – which would typically make me confident – are just not there. GEP testing helps to resolve the ambiguity among all of these various factors. 

I’ve created my own algorithm – and I’m sure other people have as well – of when it’s appropriate to use GEP testing. The basic principle is this: Only use it when you’re going to know what to do with either a negative or a positive result. If you order something, you have to be willing to use the results. It’s very similar to an immunohistochemical stain, in that it is a piece of information that will either build or break down your case for whatever diagnosis you are considering. 

Farberg: There are many instances where I’ll order GEP testing for a melanocytic neoplasm. For example, if I biopsy a lesion that I am highly suspicious of being melanoma, and the pathology is benign, then I’ll use GEP testing to resolve the mismatch. Another example is when the diagnosis is ambiguous, such as in the case of a moderately dysplastic nevus, as I would need more clarity on the malignant potential of that type of lesion.

In what ways does GEP testing impact treatment?

Marks: What we’re trying to accomplish with GEP testing is the ability to get rid of an ambiguous diagnosis to determine how to treat these lesions in the best possible way. It allows the pathologist to be more definitive – and even provides an opportunity for the pathologist to have a conversation with the clinician – so that the appropriate treatment can be applied. 

Farberg: GEP testing provides a more accurate understanding of a melanocytic lesion. I biopsied the lesion because I had a concern for malignant potential. If histopathology does not provide a confident answer, then additional information from GEP is necessary. 

It’s important for management plans to integrate GEP results, while also considering histopathologic features, laboratory information, and clinical features. The same GEP result could have a different clinical impact for a patient, depending on the specific nature of the testing situation. For example, in a dysplastic nevus with unusual features, a benign GEP result could indicate that the patient may benefit from a narrow reexcision, instead of a wide local excision. In the same clinical scenario, if the GEP result is malignant, the test result may be integrated into the diagnostic evaluation to arrive at a definitive diagnosis of invasive melanoma or melanoma in situ. 

Having the most accurate understanding of the malignant potential of a melanocytic neoplasm allows for the best management discussion and more appropriate treatment management decisions. More data allows a collaborative decision-making process between a dermatologist and the patient. 

How does GEP testing affect collaboration between dermatologists and dermatopathologists?

Marks: Communication allows you to take into account more of the clinical perspective than just what’s on the slide. There’s an old school of thought in which the slide is all that should be diagnosed by the dermatopathologist, and the dermatologist should take that into consideration with regard to how to treat patients.

But I learned a more integrated approach, in which you take the clinical perspective into account when you’re looking at the slide, which is what the GEP test can encourage in some instances. You can give much more clinically relevant information to your dermatologist, and give more definitive guidance on the malignant potential of the lesion. So it’s much more collaborative in that way, and you are taking some of the decision burden off of the dermatologist.

What has been the impact of this increased collaboration?

Marks: I feel that clinical input can be especially valuable with ambiguous lesions. I only see a picture, and sometimes I want to know how worried the dermatologist is about this clinically, or whether they just need me to do as much workup as I can. When you do get this valuable input, it can help you modify how extensive your workup is, which is why I like the collaborative approach. 

Farberg: Greater communication between the pathology lab, the dermatology clinic, and patients is the best way to determine treatment strategy for ambiguous melanocytic lesions. With nonphysician providers performing increasing numbers of skin biopsies, particularly in underserved areas where dermatology services are limited, this has become more important than ever. 

It is work, and it requires more time and effort. But, this is what is best for our patients. We know that collaborative healthcare leads to improved outcomes. This is no different, and, by working together, we’re able to better help our own patients. 

How is incorporating GEP testing into your workflow valuable? 

Marks: Whereas I used to have more ambiguous diagnoses, GEP has allowed me to be more definitive. For example, in the case of a compound melanocytic proliferation with unusual features that looks atypical and lacks the definitive features of melanoma, I still can’t exclude a melanoma. In those situations, I might order NGS testing but, unless it shows certain mutations, the results won’t necessarily be conclusive. Now, I’m able to use a GEP test after that – and nine times out of ten it will provide a definitive diagnosis. 

Farberg: Incorporating GEP testing into the clinical workflow is important as it increases reliability, and helps avoid mistakes – such as misdiagnosis – or delays in treatment. Similar to a pilot’s workflow for takeoff and landing, doctors use similar regimented workflows to avoid mistakes. 

Our dermatopathology colleagues are experts, and they are able to accurately diagnose melanocytic neoplasms. However, there are some lesions that are simply difficult to diagnose, and require additional investigation and data to determine the most appropriate treatment for the patient. GEP testing offers additional accurate, objective, and clinically actionable information for these difficult-to-diagnose lesions.

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