Melanocytic lesions, commonly found in 23 percent of skin biopsies, can sometimes be challenging to diagnose based on morphologic criteria alone. However, utilizing diagnostic markers can make a significant difference in the accuracy of a melanocytic lesion diagnosis.
As a dermatologist, you rely on your partnering dermatopathology laboratory to demonstrate expertise when it comes to diagnosing your melanocytic lesion cases. By understanding why diagnostic markers are ordered and examining the more prevalent types of immunohistochemical stains, you can play a greater role in providing your patients with optimal care.
Why are diagnostic markers ordered?
In a survey of 160 dermatopathologists, 99 percent indicated they ordered additional immunohistochemistry (IHC) or molecular tests out of concern for patient safety. Because melanocytic lesions can produce harmful results if a melanoma diagnosis is missed, laboratories often order diagnostic markers to make sure the results are as definitive as possible, utilizing the most reliable tests.
Medicare has released guidelines to cut costs, reduce overutilization, and ensure that orders for diagnostic markers meet medically necessary criteria. These directives indicate that “a pathologist must first review the H&E [hematoxylin and eosin] stain prior to ordering special stains or IHC.” They add that “the medical necessity for the special stain . . . must be documented in the surgical pathology report.”
The most proficient and ethical dermatopathologists avoid overbilling by ordering additional stains only when they are truly necessary.
What are the different types of markers?
Immunohistochemical stains are used to help pathologists arrive at an accurate diagnosis. As a dermatologist, it’s essential to be familiar with the stains as they will eventually end up in your report.
These antibodies are the most familiar diagnostic markers:
- S100 – The S100 protein is found in 95 percent of primary cutaneous melanomas, making it a popular stain. Diagnostic challenges can occur if the tissue was formerly frozen, had a low fixation time, or underwent enzymatic pretreatment with trypsin. S100 protein detects melanocytes, as well as neoplasms of the nerve sheath such as schwannomas.
- HMB45 – Human Melanoma Black-45 was derived from extracts of pigmented melanoma in lymph nodes. HMB-45 antibody is specific for melanocytes and exposes patterns of nevi maturation. It can also detect patchy gp100 patterns in primary cutaneous melanomas.
- MART1 – Melanoma Antigen Recognized by T Cells 1 identifies most melanocytic lesions. It is a cytoplasmic stain and can highlight the dendritic cell processes of melanocytes. It is also known as Melan A.
These markers have been discovered recently:
- MiTF – Microphthalmia Transcription Factor is a sensitive and specific marker for melanocytes. MiTF has superior sensitivity and specificity to S100 and HMB45. This is a nuclear stain and can be used to quantify pagetoid spread of melanocytes. However, other cells can express MiTF, such as macrophages, smooth muscle cells, and fibroblasts.
- SOX10 – SRY-Related HMG-Box Gene 10 is a nuclear transcription factor seen in melanocytes with a similar staining pattern as MiTF. SOX10 is also seen in nerve sheath tumors.
- PRAME – Preferentially Expressed Antigen in Melanoma is a tumor-associated antigen expressed in cutaneous melanoma, ocular melanoma, and other nonmelanocytic malignant neoplasms such as lung and breast carcinoma. The PRAME immunohistochemical stain has been shown to be diffusely positive in the nuclei of most melanoma cells and negative in most benign nevi. In addition, its specificity for malignant cells has made it a candidate for targeted immunotherapy.
Because the diagnosis of melanoma can sometimes be difficult, additional stains or second opinions are sometimes utilized.
A 2019 pathology study indicates “second opinions rendered by dermatopathologists improve reliability of melanocytic lesion diagnosis.” Utilizing digital slides from full-service dermpath labs like PathologyWatch enables multiple experts to collaborate on difficult cases simultaneously. When a dermatopathology group includes expert dermatopathologists that are trained and accustomed to a standardized laboratory process, there is no need to duplicate any ancillary staining, thereby reducing costs. Furthermore, seeking second opinions earlier in the process can help limit the number of stains required for definitive diagnosis.
Performing biopsies on melanocytic lesions will be a constant cause of concern for patients and their dermatologists. With the high stakes of melanoma and the possibilities of missed diagnoses, it is critical to know why diagnostic markers are ordered while becoming familiar with the most popular immunohistochemical stains to keep your patients safe.
Dermatologists understand the concern and danger patients face when biopsies reveal melanoma. Since almost 7,000 Americans are predicted to die from melanoma in 2020, and some therapeutic regimens for advanced disease are contingent upon molecular tumor markers, clinics must take an active role in accelerating the molecular testing process.
Dermatologists can benefit from a baseline understanding of molecular testing. By identifying why molecular tests are ordered, exploring the most common forms of testing, and examining the testing workflow, dermatologists can help to ensure their patients receive life-saving care.
Why are molecular tests ordered?
When a diagnosis of advanced melanoma occurs, molecular diagnostic testing is critical to revealing opportunities for targeted therapies and immunotherapies. Targeted therapies treat melanoma by inhibiting genetic driver mutations. One of the most commonly mutated genes in melanoma is BRAF, which affects about 50 percent of all melanoma cases. Mutations in the BRAF gene produce a protein that can cause cancerous cells to grow and divide. In addition, tumors with certain BRAF mutations are sensitive to targeted therapy with BRAF and MEK inhibitors, which is associated with prolonged survival. Another commonly mutated gene in melanoma is NRAS, which can also be targeted by MEK inhibitors.
Melanomas with mutations in the C-KIT gene are less common but can also be tested for. Typically, C-KIT melanomas occur on the palms, hands, feet, or mucosal areas like the mouth. Some targeted therapies, such as imatinib, can be utilized in tumors with C-KIT mutations.
Immunotherapy utilizes the body’s own immune system to treat melanoma tumors. A biomarker called tumor mutational burden has been associated with response to immunotherapies. Tumor mutational burden can be determined by certain types of molecular testing.
Molecular testing is recommended for at-risk patients with stage 3 and stage 4 metastatic melanoma. While stage 3 can suggest satellite tumors or multiple lymph nodes matted together, stage 4 indicates cancer has spread to other areas of the body, such as the liver, soft tissue, spinal cord, or lungs. A patient in either stage can expect surgery, targeted therapy and/or immunotherapy, and possible radiation treatment.
What are the most common forms of testing?
When testing detects cutaneous malignant melanoma in the early localized stage, patients have a five-year survival rate of 99 percent. However, a belated diagnosis that results in cancer spreading to regional or distant locations can reduce the five-year survival rate to as little as 25 percent.
Molecular testing is most commonly performed on a sample of the patient’s melanoma tumor. Testing procedures are often determined by what is covered by the patient’s insurance. Next-Generation Sequencing (NGS) performs full characterization and provides the most genetic information. This highly sensitive test can identify mutations in melanoma tumor tissue simultaneously in BRAF and hundreds of other genes, including NRAS and C-KIT. Some NGS tests can also measure tumor mutational burden, a biomarker for response to immunotherapy.
Real-time polymerase chain reaction (RT-PCR) is another form of molecular testing that detects the most common mutations (hot spot mutations) in a gene. While PCR testing specializes in low numbers of gene targets, it can offer faster turnaround time for results when only one or a few genes are of interest. NGS testing can simultaneously detect mutations across thousands of target regions. Either of these genetic tests is optimal for BRAF mutation analysis.
What is the molecular testing workflow?
Traditionally, oncologists handle molecular testing. However, dermatologists can speed up the process by requesting the tests from their dermatopathology lab partner, which should have protocols to manage and report mutation tests. Experienced full-service dermatopathology labs like PathologyWatch stay up to date on the latest molecular testing processes. In addition to managing tests for dermatology clinics, the academic-level dermatopathologists at PathologyWatch also manage testing for oncologists.
Once the laboratory makes the melanoma diagnosis, EMR integration is a reliable way to share fast and accurate results with the dermatologist, who is an integral part of the patient’s care team. After receiving the results, the dermatologist can refer the patient to an oncologist, who will start life-saving treatment based on the molecular testing results.
Though representing only 1 percent of all skin cancers, melanoma’s ability to spread to other parts of the body makes it highly lethal. As a dermatologist, knowing why molecular tests are ordered, understanding the different types of testing, and being aware of the testing workflow can help you get your patients the prompt treatment they require.
Sometimes, seeing is believing.
This is never more true than when discussing a treatment plan for a medical condition. “Communicating the importance of medical evidence and a balanced representation of options is the first step toward accelerating patient engagement in shared decision making,” concluded the groundbreaking discussion paper Communicating with Patients on Health Care Evidence.
This research found that 80 percent of patients want their provider to tell them the full truth about their diagnosis even though it may be unpleasant. Around 70 percent of people surveyed want their provider to share the risks associated with each option. But how can a healthcare provider share clear, definitive information for their patients who are often unfamiliar with terminology and find it difficult to fully comprehend the ramifications of the diagnosis?
The answer is simple: Provide a visual aid.
The aforementioned study published by the Institute of Medicine of the National Academies examined the effects of using visual aids as part of the patient’s decision-making on treatment plan options. Researchers found that when patients are given decision aids—such as educational booklets, DVDs, or interactive tools—to help them make treatment choices, they are more knowledgeable and satisfied with their care.
If visual aids prove beneficial for patients to better understand their diagnoses and the necessary treatment plan, then let’s discuss the three exciting ways digital pathology acts as an effective decision aid for patient care and heightens the quality of care delivered.
1. Encourages Patient Engagement
At PathologyWatch, we utilize the collaborative capabilities of digital technology as it provides full access to a patient’s test slide through our EMR. And that information can also be shared with a patient to assist in the decision-making process for designing a treatment plan.
In many cases, patients are better able to understand their diagnoses when they can see the pathology associated with their cases. This isn’t just about delivering information to a patient. Instead, as our dermatology clients attest, it invites a personal conversation that centers around a patient’s concerns and goals for treatment.
Typically practiced in breast cancer cases, for example, shared decision-making (SDM) provides a collaborative strategy for a patient and the healthcare provider to discuss medical options. Most consumers (95 percent) believe it is important that doctors tell them about the results of medical research when making treatment decisions. By pairing the patient’s values and priorities with the physician’s expertise, both parties can talk about the best possible option.
2. Provides Faster Results
Experts predict that the global number of new cancer cases will rise by 70 percent over the next two decades. This means pathology labs will need to find ways to accommodate the increase in demand through cost-saving efficiency and diagnoses.
“Digitizing your workflow is not simply a question of upgrading your lab’s hardware and IT,” says Ivo Van den Berghe, MD. “It’s also about rethinking your ways of working. . . . Digital pathology replaces the subjective nature of manual slide inspection under the microscope.”
Digital transformation also creates more efficiency. “In the old situation, a lab assistant would have to manually sort and archive 300 tissue samples each day,” Van den Berghe says. “Now the samples are sorted and archived automatically. This saves our lab assistants a lot of time.” Such expediency means doctors can meet with their patients sooner, armed with visual test results, and discuss more timely treatment plan options that can improve the recovery rate.
3. Provides a Comprehensive Perspective
In cases where the diagnosis involves a rare condition, digital pathology can make it possible for doctors to tap into expertise available throughout the world for a comprehensive understanding of an irregular case. “We’re connecting with laboratories worldwide to get a better understanding of rare tumors and how to treat them,” Van den Berghe says. “Digital pathology enhances clinical confidence in our findings by delivering the right result the first time.”
Patients trust their doctor to deliver accurate results. With digital pathology, they can get their results quickly, participate in shared medical decisions, and potentially benefit from a more comprehensive perspective of their diagnosis and ideal treatment options.
Critical values are defined as “laboratory results that indicate a life-threatening situation for the patient.” Because of their demanding nature, the appropriate healthcare professional must be notified urgently of a critical value.
In the field of dermatopathology, the College of American Pathologists defines a critical value as a critical diagnosis such as “a medical condition that is clinically unusual or unforeseen and should be addressed at some point in the patient’s course.”
All laboratories, including dermatopathology labs, are required to exercise effective communication when it comes to reporting critical diagnoses and must have a written protocol in place. This is in accordance with laboratory regulations outlined by CLIA (Clinical Laboratory Improvement Amendments; CLIA ’88) and the Joint Commission (TJC) National Safety Goals.
Dermatology clinics should understand what qualifies as a critical or a significant unexpected diagnosis. By examining how labs identify and manage critical diagnoses, defining the referring provider/lab partnership, and understanding how results are shared, we can expedite treatment and improve patient care.
Management of Critical Diagnosis in the Lab
Immediate and decisive action is required in the dermatopathology lab to identify and report critical diagnoses to the dermatologist as soon as possible. Every dermatopathology laboratory should have a written protocol outlining the diagnoses that are considered critical. In most instances, a new diagnosis of invasive melanoma is considered a critical diagnosis, as well as a life-threatening diagnosis such as staphylococcal scalded skin syndrome, graft versus host disease, or toxic epidermal necrolysis. Unalarming in appearance, each of these skin disorders could lead to serious health complications if not treated quickly.
Once identified as critical or significant, the laboratory is responsible for documenting how and when the results are communicated with the dermatology clinic. If the diagnosis is shared over the phone, there should be a record of who made and received the call. In addition to ensuring the clinic accepts and understands the results, the lab keeps a record to comply with existing laboratory regulations.
The Referring Provider/Lab Partnership
When a clinic and laboratory form a new partnership, the dermatologist and lab open communication lines to clarify the types of results they define as urgent or critical.
Though 75 percent of laboratories have a written policy for handling critical and significant unexpected diagnoses, clinics need to ensure their lab’s processes meet the needs of patients and practices (for instance, if a dermatologist establishes that he or she wants a notification for melanoma in-situ as well as invasive melanoma, or for unexpected cases of Tinea spp). By communicating regularly regarding cases, mutual trust will develop over time between the lab and the clinic.
Sharing Urgent Results
The most crucial step in the critical diagnosis process comes when the dermatologist shares the results with patients and points them towards treatment. The urgency is real, as the rate of survival decreases 5 percent for patients with stage I melanoma treated between 30 and 59 days compared with those treated in the first 30 days after diagnosis.
To ensure fast and precise action, it is helpful when labs share critical values directly to the EMR in addition to a phone call. Full-service dermpath labs like PathologyWatch transfer results and digital images electronically, enabling clinics to correlate with dermatopathologists instantly. At the same time, accessing the diagnosis in the EMR makes it easy for dermatologists to quickly share the results with patients on a tablet or laptop, reducing worrisome waiting periods.
Whenever a dermatology clinic sends a batch of request sheets to the lab, there are chances for revealing critical diagnoses. By clarifying what constitutes a critical value, defining the referring physician/lab partnership, and examining the best way to share results, you can increase optimal treatment and recovery for patients.
Dermatology clinics carry the responsibility of providing patients with correct test results from dermatopathology laboratories. With 9,500 Americans diagnosed with skin cancer every day, the weight of managing pathology orders and results is critical to ensure every patient’s diagnosis is received and shared in an organized, accurate, and timely manner.
Experienced dermatologists know there’s more involved in processing pathology results than sending out request forms and waiting for results to return. By being proactive, defining the lab’s responsibilities, evaluating paper and electronic workflows, and exploring the advantages of an EMR interface, you can ensure your dermatology clinic provides optimal quality of care to your patients.
The Clinic’s Responsibility
Patients hold their dermatology clinics accountable for sharing biopsy results, which means it is up to the providers and their staff to receive, organize, and deliver pathology results directly to patients. While it takes an average of 12 years of schooling and training to become a dermatologist, it only takes a few moments to lose a patient’s trust.
Labs return their reports to clinics through various channels, including fax, web portal, courier, and mail. The dermatology practices keep track of these results and share them with their patients. Proactively opening the communication lines between the clinic and the lab is the best way to make sure nothing slips through the cracks. By checking in with the lab frequently to follow up on cases, a dermatologist can stay on top of any delays or missing reports while answering questions that may help to produce more definitive diagnoses.
According to Tammie Ferringer, MD, open communication between the clinic and the lab is “totally appropriate and should occur.” The dermatopathologist advises, “Calling is absolutely acceptable, and it is usually easier to get ahold of a dermatopathologist than a lot of dermatologists because they’re seeing patients constantly.”
The Lab’s Responsibility
The dermatopathology lab is obligated to deliver case results and alert the clinic of any unexpected or urgent diagnoses. Labs deliver their diagnoses using documented communications, keeping records of faxes, correspondence, and deliveries. However, the lab’s obligation stops once the clinic receives the results. The dermatology practice coordinates and shares the results with their patients.
Dermatology clinics have the option of sending requests and receiving diagnoses via traditional paper or electronically. Even though 70.2 percent of dermatologists report using an EHR in their practice, many still prefer to use paper when communicating with labs.
One disadvantage of paper is the task of matching outgoing orders with incoming results. With some dermatology practices seeing 40–50 patients per day, managing a paper workflow can create a bottleneck and impact the time to deliver results to patients.
Current events also point towards electronic records as a safer solution for clinics to consider. “We’re in the era of social distancing, so it’s time to embrace EMRs and other technologies that make it safer for us to do our jobs,” notes Mark D. Kaufmann, MD, FAAD. “This will help us be responsible in the COVID-19 era, as well as create new efficiencies in terms of billing and coding.”
Interfacing the EMR
Working with a lab that interfaces electronically with a dermatology clinic’s EMR introduces a new level of streamlined reliability. In an instant, office staff can see which orders are still outstanding and which diagnoses are ready to be reviewed and shared with patients, with some interfaces using color codes to flag new or urgent results.
In addition to simplifying sorting, searching, and managing requests, an EMR interface, like the one provided by PathologyWatch, includes immediate access to whole-slide images and access to academic-level dermatopathologists. PathologyWatch makes it easy to pull up digital images and review them independently or with the patient.
Your dermatology clinic moves quickly to ensure your patients receive accurate results with an acceptable turnaround time. If you take time to evaluate your practice role, understand the lab’s obligation, compare paper and electronic workflows, and consider an EMR interface, you’ll find ways to improve the management of pending specimen lists and report distribution to serve your patients better.
It is essential for dermatology clinics to partner with a pathology lab that can effectively meet supply management and specimen transportation demands. With the number of active pathologists decreasing by 17.53 percent in recent years, the pressure is on to keep slides moving out the door with confidence.
By maintaining an adequate inventory of specimen containers, knowing how to prepare samples and request forms for shipping, and learning about transportation options, your practice can ensure that your tissue samples reach the pathology laboratory safely and on time.
When a dermatology clinic aligns with a pathology laboratory, it is the lab’s responsibility to keep the practice stocked with specimen containers to preserve and deliver tissue samples. These containers must be freely available to help practices return timely and accurate results to their patients.
Wide-mouth specimen containers carry 10 percent neutral buffered formalin. With approximately 18 months of shelf life, formalin is a liquid fixative that preserves the tissue while enhancing the appearance under the microscope.
Specimen containers come in various sizes to meet the dimensions of small biopsies and large surgical samples. The tissue is sealed inside the container, and the patient’s name, age, sex, and other identifiers are recorded on the clear container’s label. Then, the material is placed in a biohazard bag and packaged to be picked up.
Request Forms and Shipping Bags
The clinic attaches the required documentation to the specimen using the request forms supplied by the pathology lab or, if applicable, automatically generated within the EMR. Because specimen mislabeling occurs in 0.2 to 0.3 percent of all laboratory cases, this step requires strict attention.
The request form provides details about the patient and the specimen, including the sample’s type and location, biopsy date, patient details, clinical information, medical reference numbers, and insurance information. Because not all laboratories can bill every insurance, dermatology clinics often are required to work with multiple labs that offer different insurance coverage.
When everything is in order, the request form and specimen container are enclosed in secure shipping bags and readied for transport. Should additional bags, request forms, or specimen containers be needed, the pathology laboratory should make it easy to place orders online or by phone.
The lab is tasked with picking up specimens from the dermatology clinic and delivering them safely to the pathology laboratory. As Mayo Clinic Laboratories states, “Specimens must be packed and shipped properly for accurate testing, which helps ensure that patients receive optimal treatment.”
To alleviate risk and ensure the highest diagnostic quality, couriers should be trained in safety and the handling of hazardous waste while complying with HIPAA and OSHA regulations. However, couriers can only transport specimens to local labs, sometimes limiting dermatology clinic access to only local dermatopathologists. Also, couriers typically don’t offer electronic tracking to keep clinics apprised of their location.
Using medical material supply chain services from UPS and FedEx gives dermatology clinics easy access to respected pathology authorities outside of their region. This includes academic-level reads from the specialists at PathologyWatch, who can use digital pathology to collaborate with experts worldwide. UPS and FedEx offer advanced tracking, so clinics always know their patients’ samples’ exact location. With proven reliability and contingency plans, they provide reassurance that the specimens will reach the lab.
For optimal specimen tracking and security, clinics are recommended to create a tracking log of all specimens placed within a package. A copy of this log should be placed within the package as a shipping manifest. A vigilant laboratory will ask for this information, which will allow them to immediately verify the successful transportation of the specimens sent. If there is a discrepancy between the shipping manifest and the materials received, the clinic can be immediately notified, and the specimen can be recovered. While electronic orders can also help in this process, the best practice is to include a shipping manifest within the package.
Developing dependable supply management and specimen transportation to share tissue samples with the lab is critical in running a successful dermatology clinic. Having a reliable reserve of specimen containers, request forms, and shipping supplies, while understanding the advantages of different transportation options, can ensure specimens are packed and shipped correctly and safely for accurate testing.