Firming the Foundation: Pathology, Rare Melanomas, and Moving the Field Forward

When Dr. Priyadharsini Nagarajan talks about her work at MD Anderson Cancer Center, her energy and excitement could light up any room. That’s because Dr. Nagarajan – a pathologist who specializes in skin (called a ‘dermatopathologist’) – sees her work as critical to creating a firm foundation for all subsequent care that a patient receives. “Pathology is the center of everything, from your initial diagnosis to determining which treatments you are a good candidate for,” says Dr. Nagarajan. “Our job is to tell the rest of your care team what they are treating, so a wrong diagnosis means the wrong treatment. It’s that important.”

Pathology, defined as the science of cause and effect of disease, is a branch of medicine responsible for diagnosing conditions by closely examining samples of body tissue in a laboratory setting. Every time you have a biopsy, bloodwork, or surgery performed for a suspected cancer, a highly trained pathologist will carefully evaluate the sample to provide a detailed report.

For melanoma, pathologists – or in this case a dermatopathologist – are involved well before any decisions on treatment can be made. For melanoma, your dermatologist (or another type of doctor) will perform a biopsy when they identify a suspicious lesion or area of concern. That sample is placed in a fixative immediately to preserve it and sent to a lab where it is processed into paraffin (wax) blocks, and cut into very thin slices. These tissue slices are stained with special dyes, usually “hematoxylin and eosin (H&E)” dyes, closely examined under a microscope, and then stored. Samples are legally required to be stored for ten years, but many are kept for longer. In some cases, additional studies evaluating the presence of specific proteins and/or gene products may be needed for diagnosis.

“I don’t think patients or even many of my colleagues understand what it is that we do,” says Dr. Nagarajan. “There is no magic black box that spits back results. It takes a team of people– sometimes as many as 20 or more – working in concert to get you the results you need to make informed decisions about your care.”

For a suspected melanoma, the pathologist will first diagnose what it is that they are looking at. In skin, a lot of things look very similar to the naked eye, so it’s important that they start with fresh eyes and at square one. Is it an insect bite, a rash, or something more nefarious? If the sample is a tumor, pathologists will then determine if the sample is malignant, meaning cancer, or if it’s a harmless (benign) growth. If the sample is cancer, the pathologist will then determine what type of cancer is in front of them, which is needed to inform future treatment.

Dr. Nagarajan is particularly interested in mucosal melanoma, a rare melanoma subtype. Mucosal melanoma affects the mucosal tissue or wet surface linings in the body including the eyes, nasal cavity, sinuses, mouth, throat, bronchi, the gastrointestinal tract, vagina, rectum, anus, urethra and other areas. Mucosal melanoma accounts for about 1 to 2% of all melanoma diagnoses in the United States and is not believed to be caused by exposure to the sun or other sources of ultraviolet radiation.

“Our goal in treating melanoma is to make it a chronic condition, that you can live with for many years, if not decades, with a high quality of life,” says Dr. Nagarajan. “To some extent, with cutaneous melanomas, we’ve achieved this, but for rare subtypes – that develop in areas not exposed to the sun – this hasn’t happened yet.”

One of the biggest challenges for patients facing rare melanoma subtypes is delayed diagnosis. When melanoma is detected at its earliest stages it is easier to treat, often with surgery alone. However, once it has metastasized – or spread through the body – treatment becomes much more difficult. More than 30% of all patients with mucosal melanoma already have metastatic disease at diagnosis compared to less than 10% for patients with cutaneous melanoma.^{1, 2, 3}

Experts believe the delayed diagnosis is related to the rarity of mucosal melanoma. In addition, the signs and symptoms of early-stage mucosal melanoma such as bleeding, pain, or a noticeable mass mimic those of far more common and benign conditions such as hemorrhoids and nasal polyps. Finally, while all melanomas form in melanocytes – the pigment-producing cells that give our skin its color – several mucosal melanomas are not pigmented at all.

“I tell everyone to go to their checkups and to talk to their doctor if something doesn’t feel right,” says Dr. Nagarajan. “A biopsy is the only way to rule out mucosal melanoma if you have hemorrhoids or even nasal polyps that won’t go away after six to 12 months. These things look benign until it’s too late.”

Mucosal melanoma is currently diagnosed and staged using criteria developed for cutaneous (skin) melanoma. However, definitive evidence supporting this use is lacking. Doctors rely on clear diagnosis and staging guidelines to determine the correct treatment plan for the patient in front of them, but if the underlying guidelines are not derived or well-defined to this tumor subtype, it is difficult to stage the patients appropriately, which ultimately affects a patient’s care plan.

“As a physician-scientist, I want to know if we can use the same criteria to diagnose mucosal melanomas or do we need to modify them, if we can use the same treatments to treat them, and I want to find out how well the tumors respond to these treatments,” says Dr. Nagarajan.

As part of her research, Dr. Nagarajan is also looking for biomarkers that can help predict which mucosal melanomas are most likely to be aggressive and those that can help determine which treatments are most likely to work.

However, the rarity of these melanomas presents its own challenge. “My biggest hurdle is not the lack of clinical resources, but the lack of pathological specimens and sometimes follow-up,” she says. Put simply, Dr. Nagarajan doesn’t have the samples she needs to do this work. She has identified approximately 250 anorectal melanomas among patients referred to MD Anderson Cancer Center over a period of 26 years. Of this, only 160 had accompanying complete medical records and follow-up information. However, pathology samples (paraffin blocks or tumor) were only available for about a quarter of these samples – dramatically limiting Dr. Nagarajan’s analysis.

The lack of preserved tissue samples is slowing the pace of not only Dr. Nagarajan’s work, but that of all researchers focused on rare cancer subtypes. When it comes to research, “tissue is the issue,” she says.

To accelerate research into rare melanoma subtypes, MRA will soon launch the RARE Registry, a new direct-to-patient effort to advance research focused on acral and mucosal melanomas. Through the registry, MRA hopes to gain critical insight into the risk factors, treatment histories, and unique experiences of patients facing these subtypes to drive research forward.

Click here to be the first to know when MRA's RARE Registry launches later this year!

Using the easy-to-use RARE mobile app or web portal, participants will provide information about their demographics, diagnosis, treatment history, lifestyle, and quality of life factors. All information collected by the registry will be de-identified and made available through an open-access portal that will give clinicians and researchers the information they need to inform and advance future research efforts. In the future, patients will also be able to share samples of their stored tumor specimens – allowing for genomic analysis of the mutations present in the sample.

In the meantime, researchers like Dr. Nagarajan are making do with the specimens they have while scouring for more patients willing to share their tumor samples.

“We are still taking the early steps when it comes to treating mucosal melanoma, but we are moving so fast that we’ll be there very soon,” says Dr. Nagarajan. “Patients with cutaneous melanoma have a bright future today and I’m sure we’ll do the same thing for patients with mucosal melanoma too.”

Click here to be the first to know when MRA's RARE Registry launches later this year!