Dr. Jeffrey North discusses diagnosing difficult tumors that have conflicting histopathologic criteria, including advanced testing methods and the importance of risk stratification.
Jeffrey North, MD, Managing Director & Associate Professor of Pathology and Dermatology, The University of California, San Francisco
“Many tumors that we look at under the microscope have very distinct features when they’re benign or when they’re malignant, and there’s a long list of things we look for when we evaluate a melanocytic tumor. So when we see many of the features that support malignancy, we can make a definitive diagnosis of melanoma,” said Jeffrey North, MD, who presented “Ancillary Tests in Melanocytic Neoplasia” at the 2022 Hawaii Dermpath Conference.
“However, there are some tumors in the melanocytic world where you’ll see conflicting criteria. They have some features that look malignant, and then they have some features that actually support a benign diagnosis. And so, what do you do with those when you have these conflicting criteria?”
According to Dr. North, sometimes interpretation limitations require more testing.
“…the tried-and-true immunostains that we have such as p16 and various proliferative markers, as well as some new ones such as PRAME [PReferentially expressed Antigen in Melanoma] are quite helpful and sometimes they can tip the balance and give you a definitive diagnosis….”
However, immunostains won’t always provide that confirmation, said Dr. North.
“And what do you do at that point? Well, you can certainly send it out for a consultation to another center. You can give a descriptive diagnosis and say, ‘it could be this or it could be that.’”
Or you can take it a step further and use molecular tests to understand the tumor at the genetic level, said Dr. North.
“…just like there are histopathologic findings of malignancy, there are genetic findings of malignancies that differentiate melanoma from a nevus.”
While the vast majority of nevi do not have chromosomal gains or losses, melanomas do, said Dr. North.
“These selective gains and losses are an evolutionary method that malignancies use to grow and proliferate and so they can be found as a distinguishing feature between nevi and melanoma…. So that’s one way you can look at the question ‘is this a benign tumor or is this a malignant tumor?’ by just looking at the genome, looking to see if genomic instability is evident and you’ve lost your normal diploid, two copies of each chromosome in the tumor cells.”
Next generation sequencing techniques can also be used to examine multiple potential mutation sites, said Dr. North.
“It’s pretty common in basically all types of melanocytic tumors from all the different families, although the mutations can involve different genes.”
Those mutations can be found in the MAP kinase pathway, tumor suppressor genes, and other regulatory genes. Telomerase involvement and telomere preservation also play a role, said Dr. North.
“There’s a bunch of different genes that you can build a panel for. And with next generation sequencing, you can look for all the possible mutations that you might find in the various types of melanocytic tumors. … you can then combine that with the chromosomal copy number changes—gains or losses in chromosomes—which can also be inferred from the sequencing data in next generation sequencing.”
Together, these can provide a complete picture of the genetic makeup of the tumor in question, including the mutation or mutations driving tumor growth, said Dr. North.
“Most benign nevi have a single driver mutation and that’s it. They don’t have any other genetic damage. When you only have that single mutation, your other mechanisms of cancer prevention in your cells can hold that neoplasm back and prevent it from becoming a melanoma.”
However, multiple mutations take a toll on cellular defenses and can lead to melanoma transformation, said Dr. North.
“So the more genetic events—the more mutations you accumulate in these tumors—the more of a genetic pattern of melanoma emerges. And especially when you combine that with chromosomal gains and losses, you can really have a powerful view of the genetics of this tumor and whether it genetically looks like a melanoma or whether it looks genetically benign.”
Risk Stratification
While next generation sequencing can be a helpful tool in making a definitive diagnosis, it’s complicated, said Dr. North.
“The turnaround time, it can be weeks to sometimes a month, you know, depending on where it’s done, how quickly the block material is obtained, and whether it was seen at a different lab first and then has to be sent to another lab for testing.”
It’s also an expensive test that insurance may not cover.
“And then you have to weigh that with, what implications will that make for your treatment? If you have a small melanocytic tumor, which even if it was melanoma was probably not going to be aggressive or high risk, well, it may not actually be worth the resources and money to pursue that molecular testing.”
Which is why risk stratification is important for these tumors, said Dr. North.
“…if this is a pretty low-risk tumor, we almost never do very extensive molecular testing because, you know, the chance that it’s going to cause any trouble down the road is just very, very low. And in most people’s opinions, I would think the costs don’t warrant the small extra bit of information you might glean when the treatment is going to be pretty similar either way.”
It’s different for situations in which there is a chance of spread and you really need to know if it’s a malignant or benign tumor, said Dr. North.
“If this is a tumor that has extended deeply into the dermis, and has basically developed a significant chance of spreading to your lymph nodes and elsewhere in your body, then you know that stakes are higher… and you really want to know, ‘do we have a malignant tumor here or do we have a benign tumor here?’ because that will decide whether this patient should have lymph node biopsies and possibly neoadjuvant therapy with systemic treatments that have potentially very bad side effects.”
Disclosure: Dr. North is a consultant for Kiniksa Pharmaceuticals, Advinow Medical, and Enspectra.