FDA Guidance to Develop Novel Molecular Diagnostic Tests for SARS-CoV-2

A laboratory advisory from the CDC:

The Food and Drug Administration (FDA) issued new guidance on February 29, 2020, for laboratories to be able to develop novel coronavirus (COVID-19) molecular diagnostics tests and begin use prior to obtaining Emergency Use Authorization (EUA). This permits laboratories that are CLIA certified and meet requirements to perform high complexity testing to start offering severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular diagnostic testing after validation is completed as outlined in the guidance. Laboratories should submit an EUA request to the FDA within fifteen business days after validation. FDA will be hosting a webinar to provide more information on March 2, 2020, at 3 pm ET.

Clinical laboratories should contact their state health departments for guidance if they have a suspected COVID-19 case specimen. Clinical laboratories should NOT attempt viral isolation from specimens collected from COVID-19 persons under investigation (PUIs). For interim guidelines for collecting, handling, and testing clinical specimens from PUIs for COVID-19, please see the CDC Coronavirus Disease 2019 (COVID-19) website.

The Forensic Pathologist as Patient Advocate

Patient advocates are simply people who care about patients as fellow human beings enough to act on that care. Forensic pathology fascinates many people, but hardly anyone realizes how strongly forensic pathologists advocate for patients.

Forensic pathologists have the responsibility of identifying human remains and determining the cause and manner of death for individuals that die suddenly and unexpectedly. Most often, we accomplish this mission by performing an autopsy. Death makes many people uncomfortable, and we’re accustomed to grim jokes about their work when meeting someone. Typically these comments carry an undertone that because decedents cannot talk, we don’t need interpersonal skills. Not only is this untrue, comments such as these provide an educational opportunity.

It is true that our patients have already died, but the relatives of our patients are very much alive. Those relatives have needs that we work to provide and questions we strive to answer. The most common question relatives have is “Why did my loved one die?” which is precisely what the pathologist is working to determine. We regularly talk with relatives of decedents that we’ve examined. We can tell family members why death occurred, including any implications that the death has for remaining members of the family. We can also help families begin to work through the social and bureaucratic requirements that death brings for those still living, such as the need to make arrangements for the disposition of the body and the need for a death certificate. (For example, after a person dies, that person’s financial accounts are frozen until a death certificate becomes available to unlock the accounts.)

Forensic pathologists work to develop a good relationship with the decedent’s relatives. Because anger and bargaining are part of grieving, conversations with relatives sometimes begin as though the relative and the pathologist are adversaries, but with time and compassion, the relationship usually transforms into a more appropriate professional relationship. A particularly important aspect of family interactions is listening to a grieving relative, because listening with care helps someone who is grieving. Attempting to build a good relationship with the decedent’s relatives does not mean that the pathologist is a blind advocate for the family. We won’t change the cause of death so that the family can reap more financial benefit from the death, for example. Lies will not help someone pass through the process of grieving in a healthy way – truth, time, and patient, loving care are the necessary therapeutic measures.

In the case of homicides, forensic pathologists advocate for the decedent by calling the death what it is and then testifying to the medical facts of that death when a suspect is tried in court. The pathologist testifies to the medical aspects of what caused death without trying to ensure that the suspect is either convicted or acquitted. Trying to sway the jury’s verdict is the work of attorneys; presenting the medical facts of why and how the decedent died is the work of the pathologist.

Forensic pathologists advocate for public health by providing an accurate cause of death. Death certificate data provide an essential component for assessing public health, and those data are an important determinant for allocation of medical research funds and for interventions to improve public health.

Like other pathologists, forensic pathologists typically do their work quietly in the background, advocating for their unique patients in their own special way. People give little thought to professional interactions with a forensic pathologist until forced to do so; in that difficult time we try to serve as best we can.

-Gregory G. Davis, MD, FASCP graduated from Vanderbilt Medical School and trained in pathology at Vanderbilt University Medical Center, Nashville, TN, followed by a fellowship in forensic pathology at the San Diego County Medical Examiner Office in San Diego, CA. Dr. Davis then joined the faculty at the University of Alabama at Birmingham, where he currently serves as a Professor and as Director of the Forensic Division of the Department of Pathology. Dr. Davis also serves as Chief Coroner/Medical Examiner for Jefferson County, Alabama, the county in which Birmingham is located. Dr. Davis has earned a Master of Science in Public Health from the UAB School of Public Health. His research interest is the application of epidemiology to the study and practice of forensic pathology, especially drug abuse. He has published 74 peer-reviewed manuscripts, including serving as lead author on the 2013 opioid position paper of the National Association of Medical Examiners. He is currently working as chair of a panel revising and updating the NAME opioid position paper for expected publication in 2020. He serves on the editorial boards of the Journal of Forensic Sciences and Forensic Science, Medicine, and Pathology. Dr. Davis is a Fellow At-Large Director on the Board of Directors of the American Society for Clinical Pathology.

A Trainee Abroad: One Cytopathology Fellow’s Experience at a Teaching Hospital in Rwanda

The University Teaching Hospital of Kigali (CHUK) is the largest hospital in its District of Nyarugenge and the biggest national referral hospital in the country of Rwanda, with a 565 hospital bed capacity and 6 operating theaters. It is located in the heart of the capital of the country, Kigali, contributing to its easy accessibility by patients. Rwanda is a country of over 12.5 million people, with an estimated 70.2% of the population living in a rural setting. Per the World Bank, there is an estimated 1 physician per 10,000 people in-country. The government of Rwanda is focused on elevating the country from a low-income developing nation to a middle-income country with a robust health sector capable of ensuring a healthy people with adequate healthcare access. It provides universal healthcare, at a small cost, to all Rwandan citizens who aren’t provided health insurance through employment. In Rwanda there are a total of 14 practicing pathologists, which equates to approximately 1.1 pathologists per million people in the country. In contrast, within the United States there are an estimated 60 pathologists per million people. CHUK offers an array of outpatient, inpatient, surgical, and diagnostic medical services. Inpatient and outpatient services include surgery, accident & emergency, internal medicine, mental health, anesthesiology & critical care, gynecology, pediatrics, maternal & neonatology, ear/nose/throat, ophthalmology, neurosurgery, pediatric surgery, urology, nephrology, dialysis, oncology, and dermatology. Surgical services include general surgery, general pediatric surgery, neurosurgery, orthopaedics, ophthalmology, ear/nose/throat, and obstetrics/gynecology. Diagnostic services include ultrasound, digital x-ray, CT scan, and anatomic and clinical pathology services. In its current state, the hospital has a total of 18 divisions.

There are two facets to the pathology laboratory at CHUK: the Anatomic Pathology (AP) and the Clinical Pathology (CP) laboratories. Within the AP laboratory, also known as the histopathology laboratory, all surgical specimens are grossly examined by a pathology resident and/or pathologist, prepared by a pathology resident for processing, and processed by laboratory technicians into formalin-fixed paraffin-embedded tissue placed onto glass slides. These glass slides are then reviewed by both the pathology residents and the pathologists in order to render a diagnosis, which is communicated to the clinician in order to help direct appropriate patient management. Specimens reviewed at CHUK are predominantly “in-house” specimens generated by the surgeons and clinicians functioning within the walls of the institution. “Referral” specimens are a rarity and generally consist of small biopsies. Cytopathology specimens are also processed within the AP laboratory and include a mixture of fine needle aspiration (FNA) specimens, obtained by pathology residents via superficial FNA, as well as exfoliative cytology specimens such as effusions and urines collected by “in-house” clinicians. Cervical screening conventional pap smears are a rarity. Within the AP laboratory, Diff-Quik, Papanicolaou, and hematoxylin & eosin (H&E) staining was available for slides, as well as a limited panel of special stains: PAS-D, auramine, and a modified acid-fast stain. No immunohistochemistry was available on-site, though cases could be sent for free to nearby Butaro Hospital for IHC or consultation via digital slide scanning.

Regarding my experience at CHUK, I departed the United States on a Saturday evening and reached Kigali, Rwanda by 1AM the following Monday morning. On my first day at CHUK, I was introduced to the 5 anatomic pathology staff, 9 anatomic pathology residents, and the single visiting pathologist serving as a laboratory inspector conducting a mock inspection/assessment. I was given a tour of the pathology facilities as well as the entire hospital system.

There were two aspects to my primary job at CHUK: teaching the residents cytopathology and microscopic review of all live cytopathology cases received in the laboratory. Regarding resident education, there were four ways in which I interacted with the residents during my time to facilitate cytopathology education: lectures, multi-headed microscope unknown slide sessions (unknown case conference where I provided the residents with cases they had never seen before), multi-headed microscope “stump the chump” unknown slide sessions (where the residents presented me with unknown cases I had never seen before), and interactive practicals where we performed various hands-on aspects of cytopathology and general pathology practice.

In respect to lectures, I delivered a total of eight 1.5 hour powerpoint-based lectures covering the following topics: breast cytology, thyroid cytology, lymph node cytology, salivary gland cytology, urine cytology, effusion cytology, peritoneal washing cytology, and frozen section pathology (frozen section lecture presented as a combined effort with Dr. Raina Flores). For unknown slide sessions in which I presented cases to the residents, we had 6 sessions covering the following topics: breast, thyroid, salivary gland, urine, conventional pap, and cerebrospinal fluid. We completed a total of 5 “stump the chump” sessions, where residents gave me slides that I had never seen before and we discussed each case and its work-up as well as its associated differential diagnosis or final pathologic diagnosis at the multi-headed microscope. Topics covered included: breast, thyroid, salivary gland, lymph node, and effusions. Finally, with the assistance of “in-house” pathologists, I helped conduct 2 hands-on practicals with the residents: the first regarding fine needle aspiration technique and slide smearing technique (with Dr. Claire Nadyisaba) and the second regarding performance of frozen section intraoperative consultations using Leica CM1850 cryostats and cow liver (with Dr. Raina Flores).

The second of my duties, live cytopathology case review, was also performed at the multi-headed microscope with the residents each afternoon. On a given day, we would typically receive somewhere between 1 and 4 FNA consultations for which the residents would go to FNA clinic and perform the procedure. The laboratory also received various aspirated and exfoliative cytology specimens, such as pleural effusion and ascites fluids, from clinicians within the hospital system. In total, we reviewed 51 cytopathology cases together at the microscope. 27.5% were neoplastic, with 7.8% being malignant and 2% being lymphoma. 56.8% of cases were negative for malignancy, with 21.5% being inflammatory/infectious. In total, 9.8% of cases were interpreted as “atypical” and 5.9% of cases were non-diagnostic. Of the 51 cases, 21 (41.2%) were FNA consultations that I attended and the resident performed.

On my final day of work, I provided the residents with a 41-page cytology knowledge assessment (in PDF format) to complete at their leisure. This test covered the following topics: cervical and vaginal cytology (19 questions), urine and bladder cytology (11 questions), effusion cytology and peritoneal washings (13 questions), cerebrospinal fluid cytology (12 questions), breast cytology (8 questions), thyroid cytology (17 questions), salivary gland cytology (13 questions), and lymph node cytology (11 questions). Within the document, an answer key with associated detailed explanations was provided so it could serve as a learning aid/study guide for the trainees.  On my last workday, the residents were asked to evaluate their experience with the Cytopathology Module/Course. A total of 7 of 9 residents completed the evaluation. Regarding preparation and organization of different topics, all residents found the quality of the powerpoints to be “very good” or “excellent”. The quality of the practical sessions was rated as “good,” “very good” or “excellent by all residents and the entire module was given an overall rating of “very good” or “excellent” by all of the residents. The majority of residents felt their time was used effectively during this module and that the venues for theoretical and practical learning were appropriate. In the free-text areas for additional comments, suggestions for improvement included a longer duration (at least 4 weeks) of the module, more hands-on practical time, the opportunity for residents to present information, and more microscopy sessions. For additional topics to be covered, respiratory cytology was suggested. In overarching comments regarding their module experience, the residents felt the module was well-prepared, the teaching sessions were well-organized, and that the course was interesting and helpful.

Finally, though not within the confines of my assigned “duties”, I also spent a portion of each day acting as “consultant” to the on-site pathologists for challenging surgical pathology cases, offering opinions as able for various lesions that were challenging to classify on H&E morphology alone. I also served as a “second reviewer” for new malignant diagnoses being rendered in the laboratory, offering my name to be included in the report as a board certified pathologist who has laid eyes on the case and agrees with the interpretation. Examples of some interesting surgical pathology cases I saw in “consultation” included Wilms tumor (nephroblastoma), cystic partially differentiated nephroblastoma (CPDN), pleomorphic xanthoastrocytoma (PXA), sinonasal undifferentiated carcinoma, basaloid moderately-differentiated carcinoma of the uterine cervix, high-grade large cell lymphoma of the cervical lymph node, high-grade squamous intraepithelial lesion of the vulva arising within a condyloma acuminatum, and low-grade papillary urothelial carcinoma of the bladder. I also attend a single Tumor Board Multidisciplinary Conference with two residents and 1 staff pathologist in which a resident presented a case of mucinous moderately-differentiated adenocarcinoma of the colon transmurally invading adjacent ileum. It was interesting to hear the clinicians, pathologists, and radiologists interact in addressing quality of care, efficiency of care, and clinical decision-making. The time of initial presentation to the time of surgery was greater than 1 year for this patient.

My time spent at CHUK in Kigali, Rwanda was an invaluable experience. The work setting granted me the opportunity to expand my role as an academic educator. I was offered the opportunity to present as many lectures as possible to the resident trainees, participate as the leader of multi-headed microscope slide sessions, serve as a spearheading physician in laboratory services expansion efforts, and work as an ‘attending’ physician overseeing trainees’ performance of FNAs. It was an experience that demanded personal growth, via the assumption of roles that I am not privy to as a post-graduate medical education trainee in the United States. Additionally, I was exposed to a cytopathology and surgical pathology workload for a patient population quite dissimilar from the community I am used to serving. With limited ancillary testing capabilities, I returned to a more “pure” form of rendering pathologic diagnoses, based on H&E morphology alone rather than on the synthesis of cyto- and/or histomorphologic appearance coupled with various ancillary diagnostic testing data points. In conclusion, this was an experience that expanded my understanding of the ways in which I can be useful as a board certified anatomic and clinical pathologist interested in incorporating medical mission work into my clinical practice. Beyond arriving in countries without expansive pathology laboratory systems and simply doing the work, I can also pursue opportunities where I can help educate and shape burgeoning in-country pathologists who will then go on to have productive, hopefully decades-long careers in their country, serving their countrymen. This trip certainly expanded my understanding of the role of a “visiting” pathologist. This experience was made possible by the ASCP Trainee Global Health Fellowship Award. Thank you so much to the ASCP, Dr. Dan Milner, Alpa Pandya, and the CHUK pathology department for helping to facilitate this opportunity!

Image 1. Dinner with CHUK pathologists and pathology residents
Image 2. Frozen section training with CHUK pathology residents
Image 3. CHUK laboratory medicine building
Image 4. CHUK hospital
Image 5. CHUK hospital entrance
Image 6. Small “downtown” area near CHUK hosptial–Kwibuka (“to remember”) memorial in remembrance of the 25th anniversary of the Rwandan genocide.
Image 7. Overlooking Kigali.
Image 8. Ferry ride to various neighborhoods in Kigali

-Kelsey McHugh, MD is a board certified anatomic and clinical pathologist, with cytopathology subspecialty certification, who is currently completing gastrointestinal, hepatic, and pancreatobiliary pathology subspecialty training. She anticipates graduating from the Cleveland Clinic Gastrointestinal, Hepatic, and Pancreatobiliary Pathology Fellowship in June 2020, after which she will remain at the Cleveland Clinic as a staff pathologist beginning July 2020.

Respiratory Protection in the Days of the Novel Coronavirus

In the peak of the flu season we might see many people wearing masks in physician offices and hospitals. In the news today, as the 2019 Novel Coronavirus (SARS-CoV-2) continues to spread, we see many images of people wearing different types of respirators, some are N95 respirators and others are surgical masks. Not all experts agree on the efficacy of these pieces of personal protective equipment in the face of viruses, but if you’re going to use them, it is important to know how, when and why.

OSHA’s Respiratory Protection standard (1910.134) provides information about requirements for staff who may potentially be exposed to airborne pathogens. These requirements include specific instructions for choosing the proper respirator, for providing fit-testing, and for user training. The College of American Pathologists (CAP) also expects labs to determine the risk of airborne pathogen exposure for each employee, and they require labs to have a plan which outlines engineering and work practice controls that reduce exposure potential.

The purpose of a respirator is to protect the employee from contaminated or oxygen-deficient air. Therefore, two classes of respirators are common; air-purifying respirators which use filters to remove contaminants from the air you breathe, and atmosphere-supplying respirators which provide clean air from an uncontaminated source. These types of respirators can also be classified further as tight-fitting or loose-fitting.  Tight-fitting respirators need a tight seal between the respirator and the face and/or neck of the user in order to work properly. For now, let’s focus on the air-purifying respirators which are in high demand these days as a potential 2019-nCoV pandemic looms.

In the laboratory, N95 respirators are probably the most commonly-used respirators, often used for protection against tuberculosis and other airborne pathogens. These respirators filter out 95% of airborne pathogens that are 0.3 microns or larger. While the exact size of the 2019-nCoV is not yet known, most coronaviruses are slightly larger than 0.1 microns. Does that mean a N95 respirator (recommended by the CDC) will not offer protection from the coronavirus? Not necessarily.

According to biosafety expert Sean Kaufman (www.saferbehaviors.com), the filter in the N95 respirator works three ways- through interception, impaction, and diffusion. Interception collects larger particles which are blocked by mask fibers, and impaction collects larger particles which have too much inertia to be moved around the filter fibers. Diffusion occurs as smaller particles are bombarded with larger air molecules and are pushed against filter fibers. Most of the bacteria or virus particles are removed from the airstream making the respirator quite useful and protective (HEPA filters on a Biological Safety Cabinet work in much the same way).

Employees who may need to wear a tight-fitting respirator as part of their job are required to have fit-testing every year. This is required by OSHA, and contracted employees (such as pathologists) should be fit-tested as well. Employees who may need such respirators would be those who work in microbiology labs, cytology techs who participate in patient procedures, and others. Labs should perform a risk assessment for each job category to determine the type and level of potential harmful airborne exposure.

Procedure masks, such as those handed out when people suspect they have the flu, are not technically considered respirators. Often, the person who is sick will wear these masks in order to prevent the spread of droplets when coughing or sneezing. They can protect others in the area, but they do not protect the user from harmful airborne pathogens or vapors.

Can these surgical masks be useful for the healthy public when a coronavirus is present? Sean Kaufman says “yes. If you wear a surgical mask in a potentially contaminated environment (on a commuter bus, for example),” Kaufman says, “it can keep you from touching your nose or mouth- two major routes of entry for viruses. Behaviorally speaking, these masks do offer some protection.”

Knowing when and why you use a respirator is vital, but knowing how to use it is important as well. Tight-fitting respirators should never be used without fit-testing to make sure the correct size is being used. Otherwise, the protection offered will be limited. Make sure your staff is properly trained and protected to work in environments where the air is not safe to breathe, and teach others about the usefulness of respirators when the flu and other viruses are lurking!

Dan Scungio, MT(ASCP), SLS, CQA (ASQ) has over 25 years experience as a certified medical technologist. Today he is the Laboratory Safety Officer for Sentara Healthcare, a system of seven hospitals and over 20 laboratories and draw sites in the Tidewater area of Virginia. He is also known as Dan the Lab Safety Man, a lab safety consultant, educator, and trainer.

EUA for 2019-nCoV Test

On February 4th, the FDA announced an Emergency Use Authorization for the CDC’s 2019 Novel Coronavirus real-time RT-PCR Diagnostic Panel. Here’s the press release:

Audience: Clinical Laboratory Professionals

Subject: Laboratory Update: Information about Emergency Use Authorization for  2019 Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel

Level: Laboratory Update

This message is to ensure that clinical laboratories are aware that CDC has developed a new laboratory test kit called the CDC’s 2019 Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel, for use in testing patient respiratory specimens for 2019-nCoV. On February 4, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to enable emergency use of the test kit in the United States. All EUA documents are available on the FDA website.

The test kit will be available for ordering today from the International Reagent Resource (IRR). Formerly, U.S. diagnostic testing for 2019-nCoV was only being conducted at CDC; however, the FDA EUA and distribution of the tests will allow 2019-nCoV testing to take place at laboratories designated by CDC.  This includes U.S. state and local public health laboratories and Department of Defense (DoD) laboratories.

Clinical laboratories should NOT attempt viral isolation from specimens collected from 2019-nCoV persons under investigation (PUIs). For interim guidelines for collecting, handling, and testing clinical specimens from PUIs for 2019-nCoV, please see the CDC 2019 Novel Coronavirus website

The FDA website lists current EUA assays, and also includes a link to terminated EUA assays. Each pathogen-specific EUA includes the device-specific Letter of Authorization, fact sheets, and manufacturer instructions/package inserts. These documents are updated when amendments are made (e.g., additional specimen types, extraction methods, procedural clarifications), so check the website routinely to ensure your laboratory staff members have the most up-to-date information.

Additional Resources

If you have any questions, please contact LOCS@cdc.gov.

Patient Interaction

Medical school councilors have good intentions in mind when they steer medical students who realize that direct patient care isn’t their strong suit into pathology. But I am different kind of pathologist – the one who sees (or talks to) patients every day. I am a member of unique subspecialty – Transfusion Medicine – which is the most patient-centric subspecialty of all pathology subspecialties. And, contrary to the popular wisdom, I like seeing patients.

Don’t get me wrong though, my heart and soul still live in the lab, deeply rooted in understanding test performance, troubleshooting and quality control. But direct patient care helps to put all the work I have done in the lab into a perspective.

One program that became especially dear to my heart is our chronic RBC exchange program for the kids and adults with sickle cell anemia who have high risk of developing serious complications from the disease, such as stroke, acute chest syndrome, and severe iron overload. As an apheresis physician I see these patients quite frequently due to the nature of the program – chronic RBC exchanges every 4 to 6 weeks. This also means that I quickly had to learn quite a lot not only about managing the exchanges, but also about patients’ success and failures, spend time explaining to parents the benefits of the program and engaging them to maintain compliance with rigorous schedule. The work is not immediately rewarding. All the adjustments I do to the plan of care show changes in lab values in a month or two at best. But it is not entirely about numbers. Another aspect that makes this program special is when you notice that the kids you treat are doing better at school, have less ED visits and overall live a more fulfilling life.

Sometimes the patient interaction is not as direct as in the case of the sickle cell RBC exchange program. For example, being part of the obstetric team that cares for the patient with severe hemolytic disease of fetus and newborn is also extremely rewarding. And the more challenging clinical question is the more rewarding it is in the end. Just this summer we had a patient who developed an antibody to very high frequency antigen that is present in 99.7% of the population and finding the right donor for intrauterine transfusion involved quite a few people in at least 3 cities.  When all the pages, phone calls, emails, and personal conversations between me and residents, obstetricians, anesthesiologists, pediatricians, and blood suppliers result in a positive outcome for mom and baby – I feel elated. And who wouldn’t?! That is why I enjoy what I do!

-Aleh Bobr MD is currently the medical director of blood bank and tissue services at University of Nebraska Medical Center in Omaha, NE. He did his residency in Anatomic and Clinical pathology and Fellowship in Transfusion Medicine at Mayo Clinic Rochester, MN. Prior to that he did his post-doctoral research fellowship in Immunology with focus on dendritic cell biology at University of Minnesota and Yale University. He received his medical degree from Vitebsk State Medical University in Vitebsk, Belarus. Current interests include application of apheresis, platelet refractoriness.

Hyping Technology with Opinions rather than Facts

I often have an argument or discussion with my spouse about facts versus opinions. Although both concepts represent information, my brain is mostly concerned with facts as a scientist and a problem solver. My spouse, having spent years in the hospitality, banking, and real estate business, is “all about the customer,” with success rooted largely in recognition of and alignment to their opinions. In my current role as CMO at ASCP where we have “concierge customer service” as one of our principles, I have adapted to listening, understanding, and operationalizing the opinions of a diverse group of individuals. However, when it comes to science, I feel that it is important to remain with facts until the point where science runs out of answers, and we have to guess about something. Where I run into trouble is that I have the opinion that people who do not understand the facts should not necessarily espouse their opinions. Someone once said an expert is someone who knows everything about a topic as well as everything that is wrong about a topic—referring to common misunderstandings that flow through our common knowledge. Opinions are like belly buttons—everyone has one, but some are cleaner than others.

When it comes to journalism, I am unfortunately a purest. I just want the facts. I was, therefore, a bit taken aback by a New York Times article discussing an innovative technology in neurosurgery for intraoperative consultations for brain tumors. My visceral negative response emerged from the surgeon discussed in the article owning part of the company that built the device for the study. My secondary  concerns stem from the article discussing intraoperative consultations done by pathologists and, yet, not a single pathologist was interviewed for the article. But the biggest concern I had which made me delve deeper into the topic  was the enormous number of inaccurate facts or complete untruths presented in the article. It is hard to say it wasn’t poor journalism but, as a scientist, I had to go to the source.

The scientific article in question was “Near real-time intraoperative brain tumor diagnosis using stimulated Raman histology and deep neural networks” published on Jan 6, 2020. The New York Times article, “A.I. Comes to the Operating Room” was published the same day. I read the article myself, and when it didn’t quite pass my sniff test, asked three of my colleagues who are experts in this area to also read the paper and the news report. Jane Brock, a breast pathologist who is truly an innovative thinker and dreams of the day when pathologists can study tissue immediately with confocal laser imaging and rapid molecular testing—part of her research—said of the technology, “this is a great paper and a great microscope.” She further mentioned how brain is ideal because it is homogenous, easily flattened, and amenable to artificial intelligence (AI) review because of the limited parameters needed to be evaluated for clinical decision making intraoperatively. “This is definitely the future of pathology—getting rid of frozen sections in favor of fresh tissue imaging,” Dr. Brock said. “It also means you can take tissue for research/molecular diagnostics, image it, and not waste it just by imagining it [on frozen section]. The time savings are huge.” It was exciting to hear Dr. Brock’s enthusiasm for the technology conceptually and how it could be a boon for pathologists’ ability to consult during surgery.

Dr. Rebecca Folkerth,  a surgical neuropathologist for more than 20 years before she became the neuropathologist for the Office of the Medical Examiner of New York, had some concerns about the science in the paper and the maturity of the technology to replace a consultation with a pathologist today. “The questions asked [in the paper] were of necessity extremely basic, and hardly represent the real world as encountered in the operating room and neuropathology laboratory,” said Dr. Folkerth. She was concerned in the news article with the statement “Final pathologic diagnosis is increasingly driven by molecular rather than morphologic criteria.” “That is actually true for a minority of nervous system lesions, such that the ‘gold standard’ for diagnosis remains ‘macroscopic (gross) pathology’ [essentially imaging] and ‘cytologic and histoarchitectural features’ as well as clinical and laboratory findings. In other words,” concluded Dr. Folkerth, “the training and experience of a physician [pathologist] is what allows the synthesis of all data points to arrive at a comprehensive interpretation.” With regard to the immediate application to real world practice, Dr. Folkerth said, “It is telling that no ‘gliosis/treatment effect’ cases were analyzed [because] distinction of post-treatment changes from a neoplastic process in the brain is one of the most difficult encountered in clinical neuropathology.” Other cellular processes that occur in the brain were also not in the study. “A glaring omission of this paper,” Dr. Folkerth concluded, “were the consequences of the errors in ‘predicting diagnosis’. Were these ‘class A’ [leading to radical changes]?” In the article, the surgeon states that neuropathologists “hate frozen sections” which Dr. Folkerth says is simply not true. Perhaps the author should have interviewed an actual neuropathologist for this piece. Both Dr. Brock and Dr. Folkerth had concerns about the practicality of the technology where Dr. Brock felt it was currently “too expensive” (relative to current practice which provides more information across the spectrum of neuropathology) while Dr Folkerth was not clear who this process could work in smaller or decentralizes or underserved surgical settings (as the new article suggests) without a lower cost. Dr. Folkerth agreed with Dr. Brock, however, that this technology “may well represent a revolution in intraoperative decision-making and outcome.”

Lastly, I spoke with Dr. Jason Hornick, who in addition to be an internationally renowned surgical pathologist, has been in charge of quality of intraoperative consultations at one of the premiere hospitals in the US. The “frozen section [procedure] does not often take longer than 30 minutes, and is not often ‘far less accurate’ than in the study,” Dr. Hornick began. “The rates of significant discordance between intraoperative diagnosis and the final diagnosis in published surveys (for all of surgical pathology) are generally less that 1.5%.” Dr. Hornick (and I) agree that the surgeon quoted in the article is bashing the practice of pathology without any accuracy to his statements. He is not quoting facts and he is not quoting opinions. He is simply saying things that are wrong and not supported by data or years of experience. Dr. Hornick also mentioned that the cost of frozen sections are trivial compared with the cost of this technology and, as pointed out by Dr. Folkerth, the pathologists’ intraoperative consultation is much broader than just reviewing a slide for signs of tumor. Dr. Hornick said it best: “The expert consultation provided intraoperatively by the pathologist to the surgeon is not restricted to making an accurate diagnosis; pathologists are uniquely suited to integrating the patient’s clinical history, imaging, prior pathology, and surgical findings to assist the surgeon in making surgical decisions.” He concluded, “The intraoperative consultation is not a laboratory test; it is a consultative opinion by an expert physician who often understands the patient’s disease better than the surgeon.”

With these three experts’ views including their clarification of the facts and their opinions, it seems pretty clear, in my opinion, that this news article is presenting an inappropriate picture of the practice of pathology and making claims about this technology which are not, in fact, accurate or fair. What struck me, however, was the comment by the surgeon that when he was working with pathologists, he may only ask two questions because of the very long time for the frozen section but with this technology he can ask six or seven questions and get the answers really quickly. If this surgeon needed to know the answers to those question, that is, if they were mission critical to patient care, why didn’t the surgeon work with the pathology team and demand higher quality and faster turnaround time rather than investing time and money in a novel, expensive technology (from which he profits) which can only provide a fraction of the answers that a pathologist can provide? Unless the technology completely replaces a pathologist—which it doesn’t seem to be able to do—the pathologists and frozen section labs still have to be available. Thus, costs are increased, not decreased. The only parameter for increased value for the patient would appear to be time savings; however, most clinicians and pathologists would agree that the value to a patient of a two-minute AI read versus less than 20-minute intraoperative consultation is minimal compared with the cost difference.

But outside of all of this, as the entire field of pathology faces pressure from technologies—largely driven by non-pathologists—we have to realize that pathologists’ consultations, whether intraoperative or on permanents, are a tool of quality directly for the patient. If a surgeon is able to perform a surgery and discard tissue, use a system from which he/she profits, or depends solely on a computer algorithm informed by a couple of hundred cases, where is the quality check for the patient? How do we know that was tumor that was removed? Pathologists are paid to perform intraoperative consultations and ASCP works very hard to ensure that pathologists are not only fairly paid for their work but that their involvement occurs whenever it can improve quality and care for the patient. Dr. Folkerth alone has seen thousands of cases on intraoperative consultation for neuropathology and the collective knowledge of currently living neuropathologists would be millions of cases. If such knowledge were captured by an AI across the full spectrum of neuropathology, the technology would truly be remarkable. But you can’t have such integration of knowledge without involving pathologists.

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-Dan Milner, MD, MSc, spent 10 years at Harvard where he taught pathology, microbiology, and infectious disease. He began working in Africa in 1997 as a medical student and has built an international reputation as an expert in cerebral malaria. In his current role as Chief Medical officer of ASCP, he leads all PEPFAR activities as well as the Partners for Cancer Diagnosis and Treatment in Africa Initiative.