MSK PATHOLOGY INITIATIVES INNOVATIONS REVIEW ACCOMPLISHMENTS

THE CYTOLOGY SERVICE AT MSK

1ST QUARTER 2018 consulting individuals the knowledge of) receiving glass slides. Some simple consult cases in which the patient later that their information has been received. means to review digital consult slides seeks care at MSK. Reports will be This enhancement in communication already exist; remote hosting sites generated through CoPath as usual, does nothing to speed the receipt at other institutions or in the cloud and the current billing process for glass of the slides, however. To improve already provide access to digital cases, slide consults will apply. this aspect requires the use of digital and many of us have been asked to The efforts to identify a consult pathology, such that scanned slides can provide opinions on these types of portal vendor, establish the interfaces be transmitted electronically, almost in cases. However, this remote viewing with CoPath and online systems, and real time. Under the leadership of Dr. option has a number of drawbacks: vet the security issues have consumed S. Joseph Sirintrapun and the clinical the connections can be slow, resulting nearly a year of work, but the plans are COMMENTARY informatics team (see separate article in a poor browsing experience; the now taking shape. Once active, the FROM THE DEPARTMENT CHAIRMAN on p.24), we are making great strides cases are not formally accessioned, digital consult portal will allow rapid towards a fully digital pathology consult creating a range of regulatory and access to expert MSK pathologists for portal. billing problems; the digital slides colleagues and patients anywhere in the A major part of patient care in one of his quick little grunts, indicating In general, the comfort level of are only hosted for a discrete interval world. We will have the option to grow The personal Pathology at MSK involves the review diagnostic satisfaction. I wish I could using digital slides for diagnosis has and are no longer available once the the consult practice, and for partner consult of slides from other institutions. Many break him of this trait of grunting since improved since the roll out of routine consult review has been performed. In institutions with digital scanning practice has evolved pathology consultation cases are sent it is well-known that it is the quiet pig digital scanning for archiving purposes. order to create a more formal digital capabilities, we could even consider because patients being treated at MSK that gets the most swill.” I dare say our Fellows and attendings now commonly consultation process, we have decided allowing departmental consults to be since the days of must submit outside pathology material current reports are a shade less colorful! review old material digitally. A survey to create a user interface that will allow sent digitally through the portal. For Stewart and Foote for review. These “departmental The personal consult practice has of users conducted as part of a study the consulting pathologists to upload routine diagnoses, the benefits of time consults” make up nearly 40% of our case evolved since the days of Stewart and on the operational aspects of digital digital slides and patient information efficiency along with the elimination of but it continues volume in surgical pathology, cytology Foote but it continues to represent a pathology by Drs. Matthew Hanna, through our consult portal, crossing costly glass slide shipping make this a to represent a and hematopathology. Additionally, source of fertile teaching material for Joseph Sirintrapun, and others(which the MSK firewall to be archived within very attractive option. And the ability source of fertile “personal consult” cases are sent to our fellows while offering our expert was presented recently at the 2018 our system along with all of the digital to review outside slides and have an specific expert MSK pathologists when pathologists the opportunity to extend USCAP meeting in Vancouver) found slides we are creating internally. The MSK Pathology diagnosis in the chart teaching material colleagues at other institutions need help their contributions to patient care beyond that the majority of MSK pathologists case will be accessioned as a digital prior to a new patient’s first visit will for our fellows with the interpretation, when patients the walls of MSK. Patients are becoming are comfortable using digital slides for case; additional glass slides or other create enormous downstream value would like an additional opinion, or aware of the importance of expert diagnosis especially if the glass slides materials can be added if received as well. We will provide updates on while offering our when treating clinicians hope to benefit pathology review, and increasingly the could be made available when needed. subsequently. This will allow continued the status of the consult protocol in expert pathologists from our super-specialized oncologic consults are motivated by the patient’s Thus, the department is primed to access to the digital slides for research upcoming MSK Pathology Review the opportunity pathology expertise. wish to ensure their diagnosis is as take the next step and receive digital or subsequent review, which is issues. The review of personal consult cases accurate as possible, using all available consult cases in lieu of (or in advance especially helpful for the 11% of personal - David Klimstra, MD to extend their has long been a part of our practice, advanced techniques to derive the contributions to and there are archives of these cases maximal information about prognosis from the days of Stewart, Foote, Rosai and therapeutic options. At present, patient care and other senior pathologists. The the majority of our consults are sent beyond the walls Stewart and Foote material in particular as they were 75 years ago, with glass has been collected into a teaching file, slides, paper reports, and paraffin blocks of MSK. and their consult letters offer a glimpse packaged carefully (one hopes!) and into the state of knowledge available shipped to Manhattan from far corners of at the time before the heavy reliance the globe. Cases from the US can arrive on immunohistochemistry, molecular the next day, but many overseas consults analysis, and other advanced diagnostic are delayed, especially when biological tools. Remarkably, some cases represent materials are held in Customs – a scenario entities that had not yet been described that can add days or weeks to the transit at the time they were reviewed, yet the time. The information accompanying insights based on routine microscopy the pathology material can also vary were often quite prescient. The substantially, often requiring time- consultative opinions were conveyed consuming efforts by our administrative in letters rather than formal pathology staff to retrieve basic patient or insurance reports, sometimes decorated with information. Efforts now underway seek personal remarks and humor now to streamline these processes at MSK. A regrettably considered inappropriate for web-based consult interface has already medical documents. In his 1962 letter been launched, which allows consulting about a spindle cell thymoma, Dr. Foote physicians (or patients) to enter standard wrote that he had shared the case as well information via the internet, obviating the with Dr. Stewart, who “immediately made need to initiate outside contact once the a diagnosis of thymoma, accompanied by slides are received, and also giving the

2 I MSK PATHOLOGY REVIEW I 3 Medical School. I’ve been here for 35 years and I’ve seen Dr. Rosenblum says the small size of this remarkable institution transform his team reflects cancer demographics. from the day I set foot in it. What we Compared with cancers of the lung, do is even more extraordinary now,” he breast and colon, “brain tumors just says. don’t come in those numbers, thank Dr. Bale, who hasn’t witnessed the goodness,” he says. transformation, is nevertheless finding That leaves the neuropathologists herself swept up by the enthusiasm at time for their other clinical and research (and for) the Pathology Department. interests. Dr. Rosenblum is a member “There’s so much going on here, so of the department’s Cytology Service. many great projects, ideas and people, Dr. Bale participates in the Molecular the challenge is choosing the ones to Diagnostic Service and spends time on prioritize,” says Dr. Bale. “It’s a good collaborative research with the Brain challenge to have.” Tumor Center. In addition to the studies that both neuropathologists support at MSK, Dr. Rosenblum has an interest in defining new diagnostic entities in the spectrum of glial and glioneuronal tumors. Some of this work calls for collaboration with pathologists in other parts of the country and around the world. “These tumor types are rare, so you have to pool the resources of busy and frequently consulted neuropathologists to carry out larger-scale studies,” Dr. Rosenblum says. He notes that his research, while MARC ROSENBLUM, MD AND TEJUS BALE, MD, PHD important, takes a backseat to primary patient care. However, he’s effusive genomic abnormalities, we now realize about the possibilities and progress of that there are entities that we simply both at MSK. had no idea existed before,” he says. “I may be accused of tribalism, but NEUROPATHOLOGY AT MSK The boy’s father was so grateful for Dr. Rosenblum’s commitment to Beyond diagnostic excellence, you’ll find optimism, the case that he sent a note of thanks enthusiasm and humanity after his son passed away. It’s one of DESCRIBING CNS TUMORS countless examples of admiration – By Hope Cristol from patients and clinicians alike – for Numerous central nervous system (CNS) tumors are now known to have defining Dr. Rosenblum. genetic abnormalities. Below are just some of the entities that Dr. Rosenblum “I knew of him by legend before was involved in describing and characterizing, as well as their associated genetic aberrations: Molecular diagnostics didn’t accurately classified. Dr. Rosenblum, for that – but I do try to explain just I knew him personally because everyone who meets him knows that exist when neuropathologist Marc Chief of the Autopsy Service and what is wrong.” • Papillary glioneuronal tumor (SLC44A1-PRKCA fusion) Rosenblum, MD, first began practice Director of Neuropathology, has he’s an amazing clinician, an amazing diagnostician and an all-around great • Angiocentric glioma (MYB rearrangement/fusion) some 35 years ago. Next-generation personally delivered a lot of bad news GOING THE EXTRA MILE sequencing, methylation array analysis to oncology teams as well as distraught guy,” says his neuropathology colleague • Embryonal tumor with multilayered rosettes (chromosome 19q13.42 Tejus Bale, MD, PhD. and other novel technologies have led patients and families. Ironically, that’s There are some patients with whom amplification) to more precise diagnosis, targeted part of what makes him exceptional. Dr. Rosenblum has kept in contact • Diffuse leptomeningeal glioneuronal tumor BRAF-KIAA( 1549 fusion and 1p treatments and, in some cases, better While pathologists are laboratory- for years. He cites one example of a BEYOND CLINICAL CASES deletion) outcomes. “Molecular diagnostics based physicians, Dr. Rosenblum has pediatric patient he first diagnosed provides information of taxonomic, made himself available to patients with Ewing sarcoma. That was before Dr. Bale is the only other member • Glioblastoma with primitive neuronal component of the Neuropathology team. She prognostic and predictive significance,” from his earliest days in practice. technology developed five years later • Micronodular and vacuolating neuronal tumor (MAP2K1,BRAF,FGFR joined MSK in October after completing Dr. Rosenblum says, echoing the chorus “Over the years, it hasn’t gotten any that would enable Dr. Rosenblum to alterations) of veteran colleagues who marvel at easier to explain when I’ve made a life- revisit the diagnosis. Ultimately, he a fellowship in neuropathology at • Chordoid glioma (PRKCA mutation) what’s become possible in the field. threatening diagnosis, but I think this discovered the boy had a rare cancer Brigham and Women’s Hospital, Boston He’s also not shy about discussing is a professional obligation,” he says. “I termed high-grade neuroepithelial Children’s Hospital and Beth Israel • Polymorphous low-grade neuroepithelial tumor of the young (FGFR fusions, Deaconess Hospital and a fellowship in the flipside: a recent past in which never give treatment recommendations tumor with BCOR alteration. “With BRAF mutations) cancers were less precisely and – I refer patients to bedside physicians technological advances delving into molecular genetic pathology at Harvard

4 I MSK PATHOLOGY REVIEW I 5 HERE, ALL THREE EXPERTS OFFER SHORT TAKES ON THIS POWERFUL TOOL THAT’S PRODUCING VALUABLE PATHOLOGICAL INSIGHT

PERSPECTIVES ON MASS SPECTROMETRY-BASED PROTEOMICS

The technology is emerging as an important tool in pathology and precision diagnostics

By Hope Cristol

The Pathology Department physicians and scientists who focus on mass spectrometry diagnostics are highly enthusiastic about its current and potential roles in patient care. The technology is being used to identify virtually all proteins in a cancer cell as well as examine any snowball effects occurring from abnormally expressed proteins, explains Ahmet Dogan, MD, PhD, Chief of the Hematopathology Service. He and Jessica Chapman, PhD, Director of the Clinical Proteomics Laboratory within the Pathology Department, are working on clinical assays using mass spectrometry-based proteomics.

Another proponent of “mass spec” is Michael H. Roehrl, MD, PhD, GI Pathology faculty, principal investigator of a research laboratory, and Director of MSK’s Precision Pathology Biobanking Center. Dr. Roehrl uses mass spectrometry in his lab to identify and characterize proteome-level alterations of various solid tumors.

AHMET DOGAN, MD, PHD MICHAEL ROEHRL, MD, PHD JESSICA CHAPMAN, PHD

MASS SPECTROMETRY "To identify proteins that are abnormally expressed, historically we have used VS. ANTIBODY-BASED immunohistochemistry. The challenge is that you need a specific reagent for each protein. We have 20,000 proteins but only have maybe 30 or 40 well-developed reagents for each ASSAYS cancer type. Also, in many instances these reagents cannot detect normal versus abnormal Ahmet Dogan, MD, PhD proteins. Mass spectrometry-based proteomics can.

Another significant difference from other protein assays we have, like ELISA and We have 20,000 immunofluorescence, is that mass spectrometry is unbiased. With antibodies, you have to decide which ones to use. You basically see what you are looking for. With mass proteins but only have spectrometry, we’re not saying, 'Show me whether this is expressed or not'. We are saying, maybe 30 or 40 well- 'What's all in here?' developed reagents for This is redefining aspects of the field. In the case of amyloidosis, mass spectrometry has each cancer type. dramatically increased diagnostic accuracy. It’s also enabled us to identify things we didn’t even know existed. For example, LECT2 amyloidosis is now the third most common type in the United States, and we didn’t know it existed before mass spectrometry." Mass Spectrometric Ion Chromatograms of Pancreatic Cancer Image: Roehrl Lab

6 I MSK PATHOLOGY REVIEW I 7 BIOLOGICAL QUESTIONS "One of the things my lab is interested in is how cancer interacts with the immune system. Using mass spectrometry, we can ask important biological questions such as, 'What portions Michael H. Roehrl, MD, PhD of proteins in a patient’s tumor are visible or invisible to the human immune system? Why is that? How does that change over time, and how does that inform how the patient might Mass spectrometry respond to immunotherapy?' is also well suited Mass spectrometry is also well suited to proteomic response monitoring and resistance to proteomic characterization. In other words: how a patient’s cancer responds under treatment, whether response monitoring a targeted therapy is hitting the intended pathway, and how a tumor might escape from treatment. and resistance characterization. Mass spectrometry enables us to ask functional questions that we otherwise cannot address. With genomics and other nucleic acid-based assays, it is simply impossible to study dynamic changes in a signaling pathway with and without a drug. You really need to measure the protein domain directly. There are multiple methods to do that, but I think one of the most powerful – because it doesn’t rely on antibodies and it’s very sensitive – is mass spectrometry-based proteomics."

HOW MASS "A general workflow would start with a biological sample, such as tissue, fluid or blood. We SPECTROMETRY digest the proteins down into peptides using [enzymes called] endoproteinases.

WORKS Ideally, the peptides have somewhere between five and 25 amino acids. We separate these Jessica Chapman, PhD using liquid chromatography. Then they are eluted off a column into a mass spectrometer.

With a mass spectrometer, we very accurately measure the mass of the peptides. Then we You get analytical isolate peptides one at a time within the instrument and apply a little bit of energy so they bump into inert gas molecules, which results in fragmentation of the peptide backbone. information about This is a general workflow for the preparation of FFPE Immuno-Proteomics of Colon Cancer Then we measure the fragment ions to determine the peptide sequence. tissue for LC-MS analysis. First 10 m sections are cut Image: Roehrl Lab proteins with incredible and left unstained. Protein is extracted using heat and detail from this If you were to measure intact peptides, the mass could correspond to multiple sequences. sonication followed by digestion into peptides with an endoproteinase. The peptide mixture is then separated But when you fragment the peptides, you can determine the combination of amino acids technology. by LC and directly eluted into the MS. and their order. Using a protein database, you can identify which protein or group of proteins are the source of the peptide. You get analytical information about proteins with Tumor Profiling by LC-MS in a Clinical Trial incredible detail from this technology. "

Neuroblastoma Neuroblastoma Neuroblastoma Fibrolamellar HCC Fibrolamellar HCC This workflow shows the sample prep protocol for the amyloidosis assay, but the general steps are similar for many sample types. First the tissue region of interest is isolated. Then protein is extracted using heat and sonication followed by digestion into peptides with an endoproteinase. The peptide mixture is Hepatoblastoma then separated by liquid chromatography and directly eluted into the mass spectrometer. Hepatoblastoma

TUMOR PROFILING BY LC-MS IN A CLINICAL TRIAL IMAGE: ROEHRL LAB

8 I MSK PATHOLOGY REVIEW I 9

Image: Roehrl Lab TELEPATHOLOGY, ROBOTIC MICROSCOPES AND MORE

The Cytology Service at MSK continues its tradition of collaborative innovation

A schematic of LC-MS/MS data, including a base peak chromatogram showing an overview of the sample, a full scan spectrum showing By Hope Cristol all peptides that are entering the MS at one time, and the MS/MS or fragmentation spectrum from which the sequence of the peptide is determined. Peptides are then assigned to proteins using protein databases and the proteomic profile can be determined. This is an example of an amyloidosis sample, and using mass spectrometry the sub-type of the disease is determined, which assists clinicians in providing the best patient treatment.

FUTURE CLINICAL ASSAYS

Drs. Chapman, Dogan and Roehrl are using mass spectrometry-based proteomics to develop clinical assays – one of which could be in routine clinical use soon.

NEAR TERM: An amyloidosis assay that Drs. Chapman and Dogan developed is almost ready to be implemented. “The disease can be quite subtle. You may not see the cancer, but with mass spectrometry you see this abnormal protein produced by the cancer,” Dr. Dogan says.

Dr. Roehrl’s lab has recently published methods for total humoral antigen-ome profiling that will become an In the scheme of cancer care, pathologists are the As FNAB became more popular in the evaluation of assay for immune monitoring of solid tumors. physicians behind the scenes. But they, too, have teams of many types of tumors, particularly lesions of the thyroid and dedicated people behind them, enabling their important other superficial organs, Dr. Lin helped expand access to FNA work to evolve, improve and ultimately serve more patients. biopsies for non-MSK patients. To establish the FNA Biopsy MEDIUM TERM: The doctors will be looking at downstream effects of abnormal proteins: components of their Cytology Service Chief Oscar Lin, MD, PhD, is an example Clinic at the 60th Street Outpatient Center, he relied heavily on snowball effects that could be treated with drugs, particularly in lymphoma and leukemia, as well as solid of a Pathology leader who credits his team and many other Administrative Manager Allix Mazella, who played a major role tumors such as colorectal and pancreatic tumors. colleagues for the remarkable advances in cytology at MSK. in the clinic’s establishment and protocols. (Read more about Dr. Lin, however, has been a driving force for positive Allix on page 22.) He also recruited Jean-Marc Cohen, MD, to change at MSK since he joined the staff in 1999. Prior to his be the clinic’s director and enhance the service provided by LONG TERM: Global protein profiling is an ambitious project intended to identify new prognostic markers, arrival, the Pathology Department had not offered fine needle offering ultrasound-guided FNAB. diagnostic markers, therapeutic targets and drug targets. aspiration biopsies (FNAB) since the 1930s. In 2000, he re- "Our motivation to offer this service to non-Memorial In addition, Dr. Roehrl’s lab is working on “deep proteome profiling,” an assay in development that’s akin to a established the FNA service, improving the care of patients patients is that, in addition to having a biopsy done by highly broad, genome-wide panel. His team is also working on the characterization of tumor immunity. “This type of by providing same day procedures and, in many instances, trained experts, they also get the chance to be referred right same day diagnosis. away to an oncologist or surgeon at MSK. This saves valuable profiling is an assay for proteomic pathway changes,” he says. “The field of cytology has undergone many changes in time in the management of these cancer patients." the last few years. In the past, most cytology services would Besides establishing the FNA service, Dr. Lin led the focus primarily in screening pap smears. Now, more and introduction of digital technologies – primarily telepathology – more cytology specimens are not pap smears and come from in the practice of cytology. The Cytology Service is advancing many other sites, which is a paradigm change for many other the field and improving cancer care in numerous other ways institutions,” Dr. Lin says. as well.

10 I MSK PATHOLOGY REVIEW I 11 THE GROWING NEED FOR TELECYTOLOGY perform an average of 30-35 adequacy assessments every MEET THE TEAM day on the main campus using telecytology. Of course, having Rapid on-site evaluation plays an important role during a pathologist’s expertise also makes adequacy assessments FNAB and core biopsies at MSK. It enables the pathologist more accurate, reducing the need for repeat biopsies. and clinician to determine the adequacy of cellular material for initial diagnosis and whether additional samples are needed. INTRODUCING ROBOTIC MICROSCOPES MSK’s cytopathologists “Nowadays, oncologists need not only a pathological, are actively involved in morphology-based diagnosis, but also the molecular profile MSK’s expansion to regional centers has brought the both clinical work and of the tumor. The molecular profile can help guide treatment need for adequacy assessments to these locations. However, research, taking advantage in this era of personalized medicine,” Dr. Lin says. the estimated 1-2 daily biopsies performed by interventional He notes that the primary purpose of an adequacy radiologists at the regional centers doesn’t justify staffing of labs and resources for assessment is to see if the lesional material is represented in the sites with full-time cytotechnologists. Once again, immunohistochemistry, flow the biopsy obtained, thus eliminating or reducing the need telepathology offers an innovative solution. cytometry, cytogenetics for a repeat biopsy. However, he says, “We go beyond that at The Sakura VisionTek system, which involves a robotic and molecular pathology. Memorial. We will assess what potential type of tumor it is and microscope, eliminates the need for cytotechnologists onsite. THE CYTOLOGY SERVICE will triage the specimen obtained for the appropriate special Instead, interventional radiologists at the regional centers have studies required.” become certified to do some of the work previously performed INCLUDES: OSCAR LIN, MD, PHD MARC ROSENBLUM, MD As the need for rapid on-site evaluation increased – by cytotechnologists. They now prepare slides, load them Chief Attending Chief Attending (chief for Neuro) corresponding with the evolution of molecular diagnostics as into a robotic microscope and call a cytotechnologist at the well as the rise of FNAB performed across MSK sites – Dr. Lin main campus, who then reviews live images of the slides. The had several challenges to address. First, on the main campus, remote cytotechnologist is the only one who can control the there aren’t enough pathologists to perform initial adequacy microscope (via arrow keys, for example). assessments for all the cytological material collected. Second, Pathologists don’t participate in these adequacy there aren’t enough FNAB or core biopsies performed at the assessments, but they will in the future. Dr. Lin and colleagues regional sites to warrant hiring cytotechnologists there. are exploring systems that would enable the cytotechnologist Dr. Lin has either resolved or is in the process of resolving to review the images, while also sharing the images with a these shortfalls, thanks to an early-adopter mindset and cytopathologist. cutting-edge digital solutions developed and implemented There are several robotic microscope systems in use and with help from his Cytology Service team; Evangelos Stamelos, more are being added at regional campuses. The first, in 2014, manager of Pathology Information Systems; Sahussapont was deployed at MSK Westchester for Interventional Radiology CHRISTINA VALLEJO, MD JEAN-MARC COHEN, MD, FCAP NATASHA REKHTMAN MD, PHD Joseph Sirintrapun, MD, Director of Pathology Informatics; and now includes ultrasound radiology. MSK Commack’s is Attending Attending Associate Attending and others. used for both interventional and ultrasound radiology. MSK Monmouth uses the Sakura system for interventional radiology TELECYTOLOGY ON THE MAIN CAMPUS and the thoracic service. In the near future these systems will be deployed at MSK Basking Ridge, MSK Bergen County and Until a few years ago, pathologists were absent from many MSK Nassau. adequacy assessments. Instead, cytotechnologists would go to Interventional Radiology to prepare slides and determine OTHER CYTOLOGY SERVICE CONTRIBUTIONS whether the material was sufficient for pathological analysis, explains Cytology Lab Manager Dorota Rudomina. The Cytology Service has played a valuable role in the It would be impossible for a pathologist to perform utilization of molecular studies when other types of biopsies so many adequacies in multiple locations. Telecytology is don’t yield enough material. For example, sometimes core changing that. The system comes from Remote Medical biopsies procured from tumors in difficult-to-access areas (say, Technologies (RMT), and it’s based on a camera, attached close to a vital organ or large vessel) do not provide enough NARASIMHAN AGARAM, MBBS CARLIE SIGEL, MD MARCIA EDELWEISS, MD to a microscope, that live-streams specimen images to a cells for all the necessary studies. The next step would be to Associate Attending Assistant Attending Assistant Attending pathologist using a secure server. analyze the cytology material, but even that might prove to Rudomina, who played a central role in establishing be insufficient. telecytology systems at MSK, explains that the cytotechnologist What’s a pathologist to do, then, if an additional biopsy is still required to be present in Interventional Radiology to is needed but ill-advised because of the tumor’s location? Dr. prepare slides and show the cells of interest to the pathologist. Lin’s team now has an enhanced protocol for just this dilemma. Once a slide is on the microscope stage, the cytotechnologist “We developed a method to use cytology material that calls a pathologist using the Vocera system: a secure, wireless, used to be discarded after processing. This is the so-called mobile communication platform, like a “mini walkie-talkie,” she ‘residual material,’ which includes supernatant obtained after says. The pathologist then logs into the system and reviews the cells are separated for analysis,” Dr. Lin says. high-resolution images of the slides from a laptop, desktop His team, in collaboration with the Molecular Diagnostics or mobile device. Service, have assessed over 80 cases to date using this The RMT system allowed the Cytology Service to method. “We are now able to save certain patients from RAJMOHAN MURALI, MBBS, MD DARREN BUONOCORE, MD JENNIFER SAUTER, MD dramatically reduce the number of pathologists required for another procedure that could put them at risk for serious Assistant Attending Assistant Attending Assistant Attending the high volume of adequacy assessments. Physicians now complications.”

12 I MSK PATHOLOGY REVIEW I 13 interested in. Perhaps significantly, the only award I got in non-cancer conditions, so we’re looking to generate preclinical INSIGHTS FROM THE RESEARCH LAB OF medical school was for the top grade in pharmacology, which data to show that this could be an attractive therapeutic made the choice of going into pathology seem paradoxical option for further development in sarcomas that otherwise MARC LADANYI but now maybe it makes more sense!” lack good drug targets.” In a recent conversation with MSK Pathology Review, he The veteran pathologist talks about his lab’s focus on spoke about some of the latest work from his lab, as well as SARCOMA DRUG SCREENS therapeutic strategies – and why he doesn’t own a Bentley how he stays on top of the ever-evolving field. Dr. Ladanyi has worked with MSK’s core facilities and By Hope Cristol DRAWING FROM MSK-IMPACT other teams to do large drug screens in several sarcomas. A few years ago, they screened a library of more than 300,000 Dr. Ladanyi’s research team fluctuates between 8-10 chemical compounds for growth inhibition of Ewing sarcoma people. The work is largely driven by observations from human cells. The researchers identified a novel type of proteasome cancer genomic studies, more recently including MSK-IMPACT. inhibitor that did the job, selectively inhibiting Ewing sarcoma In lung cancer, the researchers have done functional cells by inducing apoptosis. studies of cell lines harboring mutations of both NF1 and “The running joke in the lab at the time was that the patent RASA1. In a paper published in 2017 in Clinical Cancer Research, on this novel proteasome inhibitor was going to pay for my they reported that concurrent RASA1 and NF1 loss-of-function first Bentley,” Dr. Ladanyi says. “Then we got scooped by a mutations function as lung cancer drivers. The mutations also group at the Karolinska, so no Bentley for me.” define a genetic subset of non-small cell lung cancer that may Dr. Ladanyi adds that his research team has collaborated respond to a MEK inhibitor such as trametinib. on similar screens for other sarcomas, including malignant His team is also looking at novel resistance mechanisms rhabdoid tumor, and they’re pursuing several interesting to different kinase inhibitors in lung cancer. Many of these leads. Much of this work has been done with MSK pediatric resistance mechanisms are first observed through MSK- oncologist Neal Shukla, MD. IMPACT testing in patients with recurrence of disease while on kinase inhibitor treatment. KEEPING UP WITH ADVANCES The sarcoma work largely focuses on Ewing sarcoma, synovial sarcoma and desmoplastic small round cell tumor Dr. Ladanyi joined MSK in 1987 as a fellow, obviously well (DSRCT). The team has been researching these sarcomas for before molecular pathology transformed the field. How has he some time. (Dr. Ladanyi’s lab, together with that of the late stayed on top of it all, and for so long? William Gerald, originally identified the EWSR1-WT1 fusion in “One thing you realize when you’ve been around for a DSRCT). Now, the researchers hope to use new insight about while is that you’re like a witness to history. The way you keep the genomics of these tumors to develop better treatment up with advances is that you’re there when the advances are approaches. made,” he says. He adds that he and other pathologists at MSK have kept EXPLORING THERAPEUTIC NUCLEIC ACIDS up with the field in a general sense by collectively being ahead of the curve in different ways. “It helps to be at an institution Speaking of applying genomics to treatment approaches, where every day you are having scientific conversations that the team has explored modified oligonucleotides as drugs to will take place at most other institutions only several years inhibit certain genes, particularly fusion genes and others that later. And this ties in with what might be the best scientific may be of therapeutic interest. career advice I ever read: always seek out and talk to people “I think it’s a promising area,” Dr. Ladanyi says. “There are who are smarter than you are.” already a handful of oligonucleotide-based drugs for some

MARC LADANYI, MD RESEARCH ROUNDUP

These are just a few of Dr. Ladanyi’s notable research papers published in 2017 and 2018:

Marc Ladanyi, MD, is one of the most recognizable names only Drs. Victor Reuter and Marc Rosenblum having been here • New England Journal of Medicine: “Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.” in pathology at MSK. That’s because in this era of molecular longer.) • Nature Medicine: “Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 diagnostics, the Chief of the Molecular Diagnostics Service is In addition to his clinical duties overseeing Molecular patients.” central to many of the department’s major initiatives, including Diagnostics, Dr. Ladanyi also has a research lab that works in • Precision Oncology: “Plasma DNA-Based Molecular Diagnosis, Prognostication, and Monitoring of Patients With EWSR1 MSK-IMPACT. the areas of sarcomas and thoracic malignancies. Dr. Ladanyi holds the endowed William J. Ruane Chair “What’s maybe unexpected is that so much of the work Fusion-Positive Sarcomas.” in Molecular Oncology and his name has been on over 400 in my research lab is focused on novel therapeutic strategies,” • Clinical Cancer Research: “RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking- research papers published during his three decades of service Dr. Ladanyi says. “The cliché would be that a pathologist Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition.” to the Department. (He is the third most senior attending, with doesn’t work on therapies, but that in fact is what we’re most • Cell: “Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.”

14 I MSK PATHOLOGY REVIEW I 15 cloning. Some of her earlier A LEADER IN SARCOMA RESEARCH discoveries include the EWSR1- CREB1 fusion in gastrointestinal Cristina Antonescu, MD, talks about the discoveries from her lab clear cell sarcoma, EWSR1-POU5F1 and the people who help make them possible in soft tissue myoepithelial tumors, and WWTR1-CAMTA1 in epithelioid By Hope Cristol hemangioendothelioma. More recently, her team established a highly efficient pipeline for novel gene fusion discovery that includes whole transcriptome RNA sequencing and FusionSeq bioinformatic algorithms. Using this method, the researchers described more than 20 novel translocations in the past eight years, such as:

• NAB2-STAT6 in solitary fibrous tumors • MIR43-NOTCH in malignant glomus tumors • VGGL2-related fusions in congenital gene discovery. Dr. Antonescu is also FUNDING THE LAB spindle cell rhabdomyosarcoma pleased to have new team member Yumi • FOS and FOSB-related fusions Fujisawa, who is focusing on cell culture Dr. Antonescu’s first American in epithelioid hemangioma and genotyping. Cancer Society research grant in 2004 Over the years, Dr. Antonescu has enabled her to start her lab. Subsequent After thorough validation, these mentored international investigators government funding through either new genetic alterations have now been with a special interest in sarcoma sarcoma-related Program Project incorporated as routine molecular pathology and molecular biology, such or SPORE mechanisms have been diagnostic markers at MSK and as Antoine Italiano and Francois Le instrumental for her work. However, beyond. In addition, they pave the way Loarer (Bordeaux, France), Costantino she is especially grateful for the for additional research on potential Errani (Bologna, Italy), John Huang and extramural funding she receives. Dr. therapeutic targets. Karen Kao from Taiwan. Antonescu says it has been essential to “Additionally, my lab serves as keep the lab growing. Specifically, she SUPPORTING ROLES a valuable resource for mentoring mentions contributions from The GIST and assisting some of the junior Cancer Research Fund, Angiosarcoma Dr. Antonescu takes great pride members of our department, such Awareness, Team Luke, Shuman Fund, in her research lab team. Lei Zhang, as Narasimhan Agaram, MBBS, with Cycle for Survival (an MSK fundraiser involved in running the fluorescence in various sarcoma subtypes, Sarah for rare cancers, in partnership with CRISTINA ANTONESCU, MD situ hybridization, has worked in the lab Chiang, MD, with characterization Equinox), and others. for more than 12 years and developed of new gene fusions in endometrial “As the research lab is expanding, hundreds of novel probes to validate and stromal sarcomas, Nora Katabi, MD, taking on new endeavors and screen the new fusions. Yun Shao (Peter) in the molecular characterization of methodologies, one consistent task Sung is the group bioinformatician. A salivary gland tumors, and Natasha for the near and long term future is to Cristina Antonescu, MD, Director of in the pathogenesis of gastrointestinal is lengthy. However, she shares these team member for many years, Peter has Rekhtman, MD, PhD, in undifferentiated ensure a constant flow of grants and Bone and Soft Tissue Pathology, is one stromal tumors (GISTs) and molecular recent highlights from her lab – and established a reliable RNA sequencing thoracic tumors with SMARCA4 funding to support these activities,” Dr. of several veterans of the Pathology characterization of novel fusion genes, expresses gratitude for the people and data analysis pipeline for novel fusion abnormalities,” Dr. Antonescu says. Antonescu says. Department: She joined the faculty in activating mutations or gene copy groups behind her success. 1999 after completing her fellowships number changes. in oncologic pathology and sarcoma The sarcoma research program KEY DISCOVERIES research at MSK. As a clinician, her at MSK, to which she has contributed role is to establish accurate pathologic greatly, has made numerous important One major focus of Dr. Antonescu’s SPORE RESEARCH HIGHLIGHT diagnosis, grading and staging. But she discoveries. It’s also been recognized lab is the discovery of new genetic Dr. Antonescu is Director of the Pathology Core for the National Cancer Institute’s SPORE in soft tissue sarcoma. She is just as passionate about and dedicated as a leader in sarcoma research by the abnormalities in sarcomas for improved also serves as the clinical co-leader of a project exploring the mechanisms of KIT signaling and imatinib resistance in to her role as a scientist. National Cancer Institute (NCI), which classification and diagnosis. Before the GIST. Since 1999, Dr. Antonescu has served has supported MSK with Soft Tissue era of next-generation sequencing, she as the Director of the Pathology Core Sarcoma Program Project Grants for used standard molecular techniques, About half the GIST patients who benefit from imatinib will eventually become resistant to it, and few other treatments are available. Dr. Antonescu and colleagues are exploring the pathways involved in imatinib-resistant GIST for the Sarcoma Program Project. She nearly 30 years. such as RACE (Rapid Amplification of and conducting preclinical investigations in hopes of finding new options for these patients. started her own lab in 2004. Key areas of Dr. Antonescu’s expertise runs deep cDNA Ends) and FISH (fluorescence her research are KIT oncogenic signaling and her list of research achievements in situ hybridization) for positional

16 I MSK PATHOLOGY REVIEW I 17 COMING SOON ROLLING OUT THE REPORTS Dr. Zehir hopes to roll out integrated reports to the INTEGRATED Hematopathology Service team later this year. The team currently has a version of an integrated report, but it lacks REPORTS the automation and searchability of the model Dr. Zehir’s team is developing. By next year, the multitude of reports for a “They add results and add their interpretive commentary, given patient could be synthesized into a but it’s all plain text. If you want to search for a specific patient single, searchable file later, it’s kind of impossible,” Dr. Zehir says. Dr. Reuter agrees that it’s smart to start with Hematopathology. “If you think about it, the overwhelming By Hope Cristol majority of hematopathology [biospecimens] are triaged to different laboratories: immunohistochemistry, flow cytometry, if there’s bone marrow that will be read, and also the bone marrow aspirate,” he says. “Those are all different reports being done on the same patient at pretty much the same time, and [an integrated report] brings those together and provides interpretation.” If the tool works as well as expected, it will be implemented across Pathology – hopefully by next year. But Dr. Reuter sees no reason why such a powerful tool couldn’t be exported to other departments across the institution. Dr. Zehir, too, envisions the project having broad reach. “I There’s a basic workflow for clinical pathology at MSK: look at the integrated reporting project as a stepping stone A patient comes in for surgery or a biopsy, the sample goes to to better prospectively collect clinical data and to share it pathologists, tests are performed, reports are written. There with the institition with a more structured way,” Dr. Zehir says. might be four reports for a patient. There might eventually AHMET ZEHIR, PHD AND VICTOR REUTER, MD be 94. The treating physician must go through the pathology reports whenever there’s a new addition, extract the most salient information and make proper treatment decisions. forming the sentence for them, and they can just enter positive only to the patient, but also the patient’s family, starting a It’s an increasingly big lift given the rise in available genomic or negative findings,” Dr. Zehir says. chain of events that may lead to genetic counseling. With an information. Another advantage for pathologists is that the data for integrated report, all this information would be at physicians’ Ahmet Zehir, PhD, Director of Clinical Bioinformatics, the integrated reports will be searchable. For the first time, it fingertips in a single document. is leading an effort to integrate the pathology reports for will be a simple task to identify a cohort of patients who are each patient. “This way the treating physician only looks at positive for a certain biomarker. one report with pertinent results instead of going through multiple reports and trying to summarize the information in A HYPOTHETICAL CASE their minds,” Dr. Zehir says. More than merely merging pathology reports, the Dr. Reuter offers a hypothetical example of integrated integrated reports will also synthesize critical values and reports in action. “Let’s say that I have looked at a renal tumor provide pathologists’ interpretation of genomic and clinical that is extremely aggressive. I have performed a lot of ancillary data. studies, but at the end of the day I really cannot classify it, beyond calling it renal cell carcinoma, type unclassified, a term BENEFITS FOR PATHOLOGISTS which exists in the WHO classification of tumors,” Dr. Reuter says. Victor Reuter, MD, Vice Chair of Pathology, is a key He sends the tumor for molecular analysis and a week collaborator in this initiative, but he modestly describes his later finds out it has a mutation of the fumarate hydratase role as representing the department and its pathologists. “My (FH) gene. number one goal is making sure that this tool is user friendly,” Dr. Reuter continues, “Wouldn’t it be logical for me he says. to integrate into the pathology report that this renal cell Automation will be essential, of course, to ensure the new carcinoma, unclassified type, we now know has a mutation reports are a boon and not a burden to pathologists. The good in the FH gene, which has been associated with familial news on that front is that Dr. Zehir and his team are making diseases?” automation a priority. As an example: Today, pathologists type The renal cell carcinoma is still morphologically sentences to describe the results of immunohistochemistry unclassifiable, but with genomic information, there’s more to assays for specific biomarkers. “We can automate this by the story. That mutation that might be clinically relevant not

18 I MSK PATHOLOGY REVIEW I 19 technological developments in the last decade, researchers Dr. Reis-Filho’s team focuses on the analysis of the genetic RESEARCH SPOTLIGHT can now decode the entire genome of a tumor quickly and features of rare cancer types. “Tumors from each of the rare inexpensively, searching for molecular alterations that cause cancer types, unlike common malignancies, are much more normal cells to become cancerous. homogeneous, have simpler genomes, and are often driven by a single highly recurrent driver alteration,” says Dr. Reis-Filho. Distinguishing between driver genetic changes and passenger “It is as if these are biological outliers.” genetic changes is by no means trivial. Through large-scale studies of common types of cancer, including the analysis His group has reasoned that if these tumors are homogeneous of over 20,000 patients using MSK-IMPACT, most of the in their genetic make-up, then by sequencing a handful of driver mutations have been identified. These driver genetic tumors from each rare cancer type, their driver genetic alterations in common cancer types can be used to subclassify alterations can be identified. By using this approach, Dr. Reis- the tumors into distinct biological and clinical subtypes. Filho and colleagues have identified:

JORGE REIS-FILHO, MD, PHD

THE DIRECTOR OF EXPERIMENTAL PATHOLOGY HIGHLIGHTS SOME OF HIS LAB’S LATEST DISCOVERIES By Hope Cristol OTHER RESEARCH HIGHLIGHTS

There’s always something coming out of Dr. Reis-Filho’s lab, which has 11 team members. Stay tuned for publications on: Jorge Reis-Filho, MD, PhD, Director of Experimental Pathology, genomics, we can not only push the boundaries of what we is one of the few members of the Pathology Department who know, but also change patients’ lives,” Dr. Reis-Filho says. • New driver genetic alterations in rare cancer types is exclusively dedicated to research. His work focuses on two Here, he offers a snapshot of recent projects from his lab. • Liquid biopsy-based monitoring of breast cancers. areas: the molecular underpinning of rare cancers, particularly breast cancers, and characterization of intratumor genetic DISCOVERING NEW DRIVERS • Intratumor genetic heterogeneity and single cell sequencing analysis of breast cancer precursors heterogeneity in breast cancers. Genetic analysis of tumors is a lynchpin of cancer research “By combining traditional pathology with cutting edge as well as of precision medicine. Given the unprecedented

20 I MSK PATHOLOGY REVIEW I 21 A NEW MUTATION affecting the gene PRKD1 that defines subset of these tumors that are low-grade, have an indolent RESEARCH ON DCIS says. “In other tumors, multiple clones within a DCIS can polymorphous low-grade adenocarcinomas of the salivary clinical behavior, and are driven by specific driver genetic become invasive.” glands alterations that render them different from most triple- In the area of intratumor genetic heterogeneity, Dr. Reis- This has several implications. First, the research suggests negative cancers. These tumors have rather esoteric names, Filho emphasizes his team’s research on ductal carcinoma DCIS is already a genetically advanced disease – that there are The COMBINATION OF MUTATIONS affecting IDH2 and PI3K- such as adenoid cystic carcinomas, secretory carcinomas, in situ (DCIS), specifically its progression to invasive breast already many genetic alterations to begin with. Second, this pathway genes that defines a vanishingly rare form of breast mucoepidermoid carcinomas and polymorphous low-grade cancer. heterogeneity may cause important challenges in identifying cancer called solid papillary carcinoma with reverse polarity adenocarcinomas. However, their identification is more than The researchers developed single cell sequencing methods biomarkers that predict tumor behavior. Third, DCIS will a mere academic exercise. that can be applied to samples of formalin fixed, paraffin progress differently among different patients. A SUBTYPE OF TRIPLE-NEGATIVE BREAST TUMOR, “Our work has actually brought histology back to the embedded DCIS tissue. They observed that intratumor genetic “We need to understand the biology of each DCIS if we adenomyoepithelioma, that has recurrent driver alterations of forefront of the analysis of triple-negative cancers. Identifying heterogeneity can be present as early as DCIS. This is contrary are to be able to manage these patients optimally,” he says. the oncogene HRAS these subtypes now has clinical implications,” Dr. Reis-Filho to the previous belief that tumors acquire heterogeneity later says. in their evolution. In addition, Dr. Reis-Filho’s work on rare forms of triple- “In some cases, indeed there is a selection of specific negative breast cancers has resulted in the identification of a subclones from DCIS to invasive breast cancer,” Dr. Reis-Filho

Q: What brought you to Memorial Sloan When I started in the Cytology Service within Pathology, I Q: What do you find most gratifying about Kettering four years ago? helped to create and manage our Fine Needle Aspiration working in Pathology? Biopsy Clinic. This service improves access to non-MSK While earning my MPH in Healthcare Management, I knew I patients who seek convenient appointments with an MSK Although I don’t always interact with patients, I am wanted to go into hospital administration because it would pathologist. fortunate to be able to connect my day-to-day projects and afford me the opportunity to manage operations and improve performance improvement initiatives to their experience here. Q & A processes to directly benefit patient care. I also have a I also standardized the process for the transportation of I find it very rewarding knowing that an effort to reduce the WITH ALLIX MAZZELLA personal connection to Memorial Sloan Kettering as several specimens from satellite locations. Before I revamped this time it takes to deliver a specimen from the OR to Pathology, relatives have been treated here. Of note, my grandmother workflow, each site followed its own process for sending for example, can directly impact and enhance their care. I am was diagnosed with stage IV breast cancer in the ’80s. She samples to us. Now, all facilities use the same Pathology also grateful to work with such a wonderful and supportive went on to live another 35 years and always maintained that transport log and leak-proof tote bag for forwarding samples team of pathologists, fellow managers and staff. Everyone in this hospital saved her life. When the opportunity to apply for to the Main Campus. These samples are then reconciled our department is truly dedicated to MSK’s mission, and I feel an administrative fellowship at MSK presented itself during against the transport log once they are received in central inspired to be surrounded by such enthusiasm. grad school, I was overjoyed by the prospect of fulfilling my accessioning. professional aspirations and working for an organization that Q: What might your colleagues be surprised to meant so much to my family and me. Q: What are you responsible for in your current learn about you? role? I think many of my colleagues already know this, but I love Q: You've moved through the ranks at MSK I manage non-technical operations for the Surgical Pathology to write (and eat!). When I first finished college, I toyed with from Administrative Fellow in Hospital and Cytology services. I ensure that accessioning, transcription the idea of going to journalism school or becoming a food Administration to Administrative Coordinator and other administrative support roles are adequately staffed. critic. Years ago, I wrote freelance restaurant reviews for New in Pathology to Administrative Manager in I’m also responsible for making sure that my staff follow York Magazine, Not For Tourists and a book that features Pathology. What accomplishments are you established protocols and are trained on new processes. restaurants with local and sustainable menu options called especially proud of? Clean Plates. I don’t write reviews any more, but I still do a Together with pathologists and other managers, I identify whole lot of eating! areas of improvement within our operations and will create Prior to working in Pathology, I created a tool to collect and and implement new workflows to improve efficiency. For analyze data from both MSK and the Hartford HealthCare example, I am now in the process of looking for an IT solution Cancer Institute. These findings were ultimately used to so that we can use technology to better track samples sent to identify both gaps and similarities in the way both institutions the Main Campus before they are entered in our Laboratory practice cancer care as part of the MSK Cancer Alliance Information System. Process improvement projects often initiative. I also worked with the Integrative Medicine Service affect other departments, and I therefore collaborate closely to develop a mechanism to collect and evaluate patient- with other services if Pathology plans to roll out a new reported outcomes. This helped the service establish workflow that will involve their staff. baselines and improve effectiveness of their therapies and ADMINISTRATIVE MANAGER treatment modalities.

22 I MSK PATHOLOGY REVIEW I 23 SIX MAJOR BENEFITS OF THE PCP, WHICH MAY BE AVAILABLE AS A PILOT BY THE END 6 KEY BENEFITS OF THIS YEAR OF THE PATHOLOGY CONSULT PORTAL

The groundbreaking initiative will 1 IT BUILDS A BETTER PATHWAY FOR SECOND OPINIONS. expand and improve access to MSK pathologists Dr. Sirintrapun’s concept behind the PCP is to create an infrastructure so that outside institutions, patients, or anyone else who wants a second opinion can scan By Hope Cristol glass slides and upload them securely. This will eliminate potential problems of physically transporting slides, such as loss, delay, and damage. Another key is for the PCP to deeply integrate with the anatomic pathology laboratory information system (AP-LIS). Dr. Sirintrapun’s vision is for the PCP to emerge as the primary pathway for rendering all opinions on outside pathology cases. 5 IT ESTABLISHES THE BENCHMARK FOR DIGITAL PATHOLOGY CONSULTATION. 2 IT STREAMLINES BECOMING AN MSK PATIENT. Dr. Sirintrapun notes that a few other institutions have If you are interested in a second opinion and your case implemented pathology consultation portals with digital is uploaded for review, you officially become an MSK slide scanning technology. None thus far is built for patient. Through the PCP, this simplification for patients large-scale adoption and utilization. “To further clarify, proves a significant advance by leveraging automated none eases the burden for patients in registration, none mechanisms for patient registration. deeply integrates with the AP-LIS, and none is built to handle more than a few cases per week,” Dr. Sirintrapun 3 IT BOLSTERS BONDS WITH MSK CANCER ALLIANCE says. The PCP at MSK will be built to handle thousands MEMBERS. of uploads per week and feature tools that make the MSK is committed to strengthening relationships with notificatio“n, reporting and communication between the three members of the MSK Cancer Alliance: Hartford parties simple. HealthCare Cancer Institute, Lehigh Valley Health Network and the Miami Cancer Institute at Baptist 6 IT SHINES A SPOTLIGHT ON PATHOLOGISTS. Health South Florida. Already positioned to streamline Patients often choose an oncologist, a surgeon or a patient registration, the PCP can offer customized hospital based on reputation. Selecting a pathologist? "expedited lanes" for Alliance Member patients. That’s uncommon – but perhaps not for much longer. "What this portal has an opportunity to do is make 4 IT CREATES A GLOBAL PRESENCE. pathologists the driver of patients coming to MSK," Dr. Once operating at full scale, the PCP expands Sirintrapun says. "If you're a patient somewhere else and Pathology's reach not only domestically but also have concerns about your diagnosis, you can ask your internationally. “There's an unlimited need for expert doctor to upload a consultation to our portal. It changes opinion outside the U.S.," Dr. Sirintrapun says, the paradigm for how pathology is regarded across emphasizing the profound shortage of pathologists in hospitals and institutions." Asia, Africa, South America and even Europe.

S. JOSEPH SIRINTRAPUN, MD

S. Joseph Sirintrapun, MD, the affable Director of Pathology Informatics, is leading MSK's future Pathology Consult Portal (PCP) – what he calls a moonshot. When the PCP goes live, “it will be a marvel of technical and human factors engineering,” he says.

On the back-end, the PCP is a complex integration of teams, tools and technology. On the front end, Dr. Sirintrapun says he “aspires for pathologists to discover and embrace a simple, intuitive engine that enables digital slide-based consults to flow in from anywhere.”

24 I MSK PATHOLOGY REVIEW I 25 MSKCC@USCAP 2018

PLATFORMS: Pathology. Lobular Carcinoma Katabi, Ghossein – Endocrine Rosenblum, Antonescu – Bone In Situ Displays Intra-Lesion Pathology. Outcome of Non- and Soft Tissue Pathology. NUT Alex, Nafa, Zehir, Arcila, Lin – Genetic Heterogeneity and Clonal Invasive Follicular Variant of Carcinoma: A Midline Shift- Cytopathology. Residual Cytology Evolution in the Progression to Papillary Thyroid Carcinoma [NI- Identification of a Subset of Material for the Detection of Invasive Disease EFVPTC] with Oncocytic Features Undifferentiated Soft Tissue Targetable Genetic Alterations by and Visceral Tumors Defined by Next Generation Sequencing: An Gopalan, Al-Ahmadie, Chen, Lewis, Kumar, Arcila, Roshal, NUTM1 Gene Fusions Institutional Experience *** Sirintrapun, Tickoo, Reuter, Xiao – Hematopathology. PHF6 Fine – Genitourinary Pathology. Mutations Define A Subgroup Shahi, Travis, Jungbluth, Alex, Zehir, L. Wang, Nafa, Neuroendocrine Differentiation of Mixed Phenotype Acute Ladanyi, Sauter – Pulmonary Hameed, Ladanyi – Bone in the Setting of Prostate Cancer: Leukemia with Aberrant T-cell Pathology. Comparison of MTAP and Soft Tissue Pathology. Contemporary Assessment of 76 Differentiation *** Immunohistochemistry (IHC) with Clinical Genomic Sequencing Consecutive Cases from a Single p16/CDKN2A Deletions/Loss and of 72 Pediatric and Adult Institution Lewis, Soslow, Delair, K. Park, Utility of MTAP and BAP1 IHC in Osteosarcomas Reveals Murali, Hollmann, Arias-Stella, the Diagnosis of Malignant Pleural Distinct Molecular Subsets with Gupta, Benayed, Arcila, Zehir, Hameed, Benayed, Ladanyi, Mesothelioma (MPM) *** Potentially Targetable Alterations Berger, Ladanyi, S. Dogan – Jungbluth, Antonescu, Chiang – *** Pathobiology. TERT Promoter Gynecologic Pathology. ZC3H7B- Soslow – Gynecologic Mutation and Amplification: A BCOR High Grade Endometrial Pathology. Clinicopathologic Antonescu – Gynecologic Pan-Cancer Study on 20,184 Stromal Sarcoma: A Report of 17 Characterization of Endometrial Pathology. Clinicopathologic, Tumors Profiled by Clinical Cases of a Newly Defined Entity Carcinomas with More Than One Immunohistochemical, and Genomic Sequencing *** Molecular Classifying Feature Molecular Characterization of 30 Montecalvo, Alex, Sauter, J. Uterine Perivascular Epithelioid Hanna, Reuter, Fine, Agaram, Chang, Jungbluth, Ladanyi, T. Wang, Askan, Zehir, Bhanot, Neoplasms Hameed, Klimstra, Sirintrapun Antonescu, Travis, Rekhtman – Klimstra, Basturk – Pancreas – Informatics. Implementation of Pulmonary Pathology. Pulmonary Pathology. Mass-Forming Basturk, Klimstra – Pancreas Digital Pathology Offers Clinical BRG1 (SMARCA4)-Deficient Intraductal Neoplasms of Pathology. Pancreatobiliary and Operational Increase in Undifferentiated Neoplasms the Biliary Tract Comprise Maljunction-Associated Efficiency and Cost Savings *** Represent An Exceptionally Morphologically and Genetically Gallbladder Cancer is as Common Aggressive Type of Sarcomatoid Distinct Entities *** in the West as in the East, Hechtman, Vakiani, Klimstra, Carcinoma: Clinicopathologic and Shows Distinct Clinicopathologic Shia – Gastrointestinal Pathology. Genomic Evidence Supports A Turashvili, Soslow, Chiang – Characteristics and Offers an Pathologic Patterns of Anti-PD-1 Link to Non-Small Cell Carcinoma Gynecologic Pathology. Whole Invaluable Model for Reflux- Induced Colitis *** Genome DNA Methylation Associated Physio-Chemical Profiling Distinguishes High Grade Carcinogenesis J. Chang, Arcila, Montecalvo, Muller, Jungbluth, Ladanyi, Endometrial Carcinomas *** Benayed, Borsu, Travis, Sauter – Pulmonary Pathology. Chen, Gopalan, Fine, Tickoo, Ladanyi, Rekhtman – Pulmonary Prominent Expression of Negative Zeng, Brogi, Turashvili, Ross, Sirintrapun, Berger, Reuter, Pathology. Next Generation Immune Checkpoint Regulator Berger, Weigelt, Reis-Filho, Wen Al-Ahmadie – Genitourinary Sequencing and Clinicopathologic VISTA in Malignant Pleural – Breast Pathology. Assessing Pathology. Molecular Profiling of Analysis of 101 Pulmonary Invasive Mesothelioma (MPM) *** Tumor Infiltrating Lymphocytes Screenshot of the PCP digital Viewer Urothelial Papilloma and Inverted Mucinous Adenocarcinomas and Genomic Alterations n Papilloma of the Bladder Focusing on Comparison Among Peng, Delair, Sirintrapun, Chen, Pre-Treatment Core Biopsy and Molecular Subtypes *** Chen, Al-Ahmadie, Fine, Tickoo, Correlation with Response to Cotzia, Benayed, Soslow, Reuter, Gopalan – Genitourinary Neoadjuvant Chemotherapy *** Antonescu, Ladanyi, Chiang Jia, Al-Ahmadie, Fine, Gopalan, Pathology. Pathologic – Gynecologic Pathology. Sirintrapun, Tickoo, Reuter, Characterization of Speckle-Type POSTERS: Undifferentiated Uterine Chen – Genitourinary Pathology. POZ Protein (SPOP)-Mutated MAJOR COLLABORATION Sarcomas Represent Morphologic and Molecular Prostate Carcinoma *** Alex, Travis, Rekhtman, Underrecognized High Grade Characterization of Renal Buonocore, Sauter – Pulmonary Like any important project at MSK, the Pathology Consult Portal involves multiple teams and players, including Endometrial Stromal Sarcoma Medullary Carcinoma: A Study of Reis, Gopalan, Chen, Fine, Pathology. Histologic Features Pathology Senior Project Manager Jennifer Samboy, as well as: 18 Cases *** Tickoo, Sirintrapun, Reuter, Predictive of Response to PD-1 Cotzia, Berger, Ladanyi, Al-Ahmadie – Genitourinary Blockade in Patients with Non- Ghossein, Antonescu, S. Dogan Jia, Al-Ahmadie, Fine, Gopalan, Pathology. PD-L1 Expression small Cell Lung Carcinoma *** PATHOLOGY PATHOLOGY IT HOSPITAL IS – Head and Neck Pathology. Sirintrapun, Tickoo, Reuter, Chen in Urothelial Carcinoma with Genetic and Histologic – Genitourinary Pathology. Clear Divergent Differentiation, Antonescu – Head and Neck LEADERSHIP Spectrum of SMARCB1-Deficient Concordance Among Three John Philip, Senior Project Manager Cell Renal Cell Carcinoma with Pathology. Adamantinoma-Like Evan Stamelos, Pathology Systems Carcinomas of the Head and Neck Prominent Papillary Architecture: Antibodies Ewing Sarcoma of Salivary Glands Victor Reuter, MD, Vice Chair Manager Precision Oncology Including Sinonasal Tract, Thyroid A Rare Morphologic Variant Pathology Department and Skin Supported by Molecular Evidence Rekhtman, Travis – Pulmonary Antonescu – Pediatric Vincent Lu, Administrative Janet Mak, Vice President, *** Pathology. Spread Through Pathology. Specificity of BCOR Meera Hameed, MD, Service Chief Coordinator Applications Favazza, Soslow, Delair Air Spaces (STAS) Correlates Immunohistochemistry in Surgical Pathology – Gynecologic Pathology. Jelloul, Khattar, Jungbluth, with Prognosis in Lung Pediatric Renal Neoplasia Janice Schacter, IS Manager Clinical Outcomes of Patients Lu Wang, Y. Zhang, A. Dogan Neuroendocrine Tumors (LNET) with Tumor Displacement into David Klimstra, MD, Chairman DATACENTER – Hematopathology. MHC Arias-Stella, Ladanyi, S. Dogan Pathology Department Fallopian Tubes in Patients Class II Transactivator (CIITA) Roehrl – Informatics. Computer – Head and Neck Pathology. Treated by Robotically-Assisted SECURITY Abnormalities Are Frequent in Science Approaches to Extract Pathogenic SMARCA4 Mutations Miroslav Trunec, Manager, Hysterectomy for Newly B-cell Lineage Lymphomas and Immunohistochemistry (IHC) in Head and Neck and Thyroid Server Technologies Diagnosed Endometrial Cancer Are Associated with Loss of MHC Results from Surgical Pathology Carcinomas are Rare *** Mike Piscitelli, Security Analyst *** Class II (MHCII) Full Text Reports Using Machine Learning and Natural Language Arias-Stella, Lewis, Benayed, Giri, Weigelt, Reis-Filho – Breast Expression *** Processing (NLP) Techniques Soslow, Antonescu, Ladanyi,

26 I MSK PATHOLOGY REVIEW I 27 Chiang, Jungbluth – Gynecologic Delair, Weigelt – Gynecologic Jelloul, Yabe, Y. Zhang, A. Histopathology of Pancreatic Montecalvo, Rekhtman, Sigel, Werneck Krauss Silva, Vyas, Basturk, Jungbluth, Askan, Rekhtman, Natasha (American Pathology. Novel PLAG1 Gene Pathology. Hotspot TERT Dogan, Xiao – Hematopathology. Cancer in Patients with Germline Travis – Pulmonary Pathology. Basturk, Klimstra, Tang – Klimstra, Shia – Gastrointestinal Society for Cytopathology): Rearrangement Distinguishes Promoter Mutations in Adult- Extramedullary Plasmablastic Mutations in Ataxia-Telangiectasia Micropapillary and Solid But Cytopathology. Cytologic Pathology. Immunohistochemical Current Concepts in Lung Cancer Uterine Myxoid Leiomyosarcoma Type Granulosa Cell Tumors of Transformation of Plasma Cell Mutated (ATM) Gene Not Lepidic Components Features of Well-Differentiated (IHC) and In-Situ from Other Uterine Myxoid the Ovary as Potential Drivers of Myeloma: Clinicopathologic Study Correlate with Worse G3 Pancreatic Neuroendocrine Hybridization (ISH) Analysis Shia, Jinru: (Evening Specialty Mesenchymal Tumors *** Progression of 10 Cases *** Klimstra, Ghossein, Katabi Prognosis in 1522 Invasive Tumors *** of Common Hepatocellular Conference – GI Pathology): Case – Head and Neck Pathology. Predominant Nonmucinous Lung Markers in Gastrointestinal 3 Askan, Shia, Basturk – Pancreas Fine, Al-Ahmadie, Chen, Jungbluth, A. Dogan – Misdiagnosed Myoepithelial Adenocarcinoma (LADC) Sirintrapun, Fuchs – Informatics. Adenocarcinomas with Hepatoid Pathology. Expression of Gopalan, Sirintrapun, Tickoo, Hematopathology. In Situ Protein Carcinoma of Salivary Gland: Generation of Realistic (in silico) Differentiation *** Soslow, Robert (Evening Calretinin, Marker of Mesothelial Reuter – Genitourinary Pathology. Expression Analysis of B-cell A Challenging and Potentially Murali, Chiang, Delair, Histopathologic Images Using Specialty Conference – GYN Differentiation, in Pancreatic Impact of Zone of Origin in Maturation Antigen (BCMA) Significant Pitfall Soslow, K. Park – Gynecologic Generative Models Based on Vyas, Hechtman, Vakiani, Pathology): Case 4 Ductal Adenocarcinoma: A Anterior-Dominant Prostatic Pathology. Gastric-type Cervical Deep Neural Networks Klimstra, Shia – Gastrointestinal Potential Diagnostic Pitfall Tumors: Long-Term Biochemical Jungbluth, Ghossein, Katabi Kumar, Lewis, Roshal, A. Dogan Adenocarcinoma in Small Biopsy Pathology. In Colorectal Tang, Laura: Hot Topics in Recurrence-Free Survival in an – Head and Neck Pathology. – Hematopathology. Hairy Cell and Cytology Specimens Sirintrapun, Gopalan, Al- Carcinoma (CRC), True Tumor Pathology 01 - GI Pathology – Basturk, Weigelt, Askan, Lu Anatomically Well-Annotated Expression of Cancer Testis Leukemia Expresses Programmed Ahmadie, Chen, Fine, Tickoo, Cell Staining for PD-L1 is TNM in 2018: Problems in Daily Wang, Arcila, Pareja, Reis- Series Antigen PRAME, PD-L1 and PD-1 Death 1 (PD-1): A New Diagnostic Muthukumarana, K. Park, Soslow, Reuter, Yagi – Informatics. Three- Uncommon and Occurs in Practice Filho, Klimstra – Pancreas in Salivary Duct Carcinoma Marker *** Chiang – Gynecologic Pathology. Dimensional Morphology of the Sporadic Microsatellite-Instable Pathology. Sclerosing Epithelioid Grabenstetter, Brogi, Wen – BCOR Expression in Mullerian Prostate by MicroCT Tumors with Loss of MHC-I *** COURSES: Mesenchymal Neoplasms of the Breast Pathology. Oncotype DX Jungbluth, Ladanyi – Bone Ladanyi – Techniques. Adenosarcoma: A Potential Pancreas Recurrence Score in Multifocal/ and Soft Tissue Pathology. Determination of MLH1 and Diagnostic Pitfall *** Soslow – Gynecologic Wen, Weigelt, Reis-Filho – Breast Multicentric Ipsilateral Invasive SETD2 Mutation is a Recurrent MGMT Promoter Methylation Pathology. SWI/SNF-Deficient Pathology. Clonal Evolution in Practical Molecular Diagnostics Benayed, Ho, Ladanyi, Hameed – Breast Carcinomas Secondary Alteration in Synovial Status Using the Illumina High- Pareja, Brogi, Weigelt, Reis-Filho Undifferentiated Endometrial the Progression from Ductal for the Practicing Surgical Bone and Soft Tissue Pathology. Sarcoma Associated with Loss of Throughput Methylation EPIC – Breast Pathology. Solid Papillary Carcinomas are Highly Aggressive Carcinoma in Situ to Invasive Pathologist- Maria Arcila Comprehensive Detection of Guo, Alex, Lin – Cytopathology. the H3K36ME3 Histone Mark (850k) Platform Carcinomas with Reverse and Resistant to Conventional Ductal Carcinoma Known Fusion Genes in Sarcomas Impact of the Paris System for Polarity (Solid Papillary Breast Chemotherapy Surgical Pathology and and Discovery of Novel Fusion Reporting Urinary Cytology Jungbluth, Lezcano, Busam Lewis, Yao, Y, Zhang, Roshal, Carcinomas Resembling the Tall Werneck Krauss Silva, Al- Cytopathology of the Pancreas Partners by a Clinical Targeted Atypical Urothelial Cells Category – Pathobiology. Cancer Xiao – Hematopathology. Cell Variant of Papillary Thyroid Soslow- Gynecologic Pathology. Ahmadie, Chen, Gopalan, and Ampulla - Olca Basturk RNA Sequencing Assay at a Major Cancer Center *** Testis Antigen PRAME is Myeloid Neoplasms with Features Neoplasms) Harbor Recurrent Loss of Claudin-4 Expression is Sirintrapun, Tickoo, Reuter, Abundantly Expressed in of Both Myelodysplastic/ Mutations Affecting IDH2: A Common in Undifferentiated/ Fine – Genitourinary Pathology. Molecular Advances in Bhanot, Roehrl – Quality Gupta, Aron, Cheville, Hansel, Metastatic Melanoma and Other Myeloproliferative Neoplasm Validation Study Dedifferentiated Endometrial Microscopic Bladder Neck Gynecologic Pathology: An Assurance. The Precision Lowenthal – Genitourinary Malignancies with Ring Sideroblasts Carcinomas Invasion Re-Visited: Correlation Update for the Anatomic Pathology Biobanking Pathology. Female Urethral and Thrombocytosis and Pareja, Edelweiss, Wen, with Tumor Topography, Staging Pathologist - Britta Weigelt Center (PPBC) Experience at Carcinoma: Analysis of 29 Cases Jungbluth, Roehrl – Quality Myelodysplastic Syndrome with Jungbluth, Weigelt, Reis-Filho T. Wang, Vakiani, Hechtman, and Grading *** International IBBL Biobank and Proposal for a New Staging Assurance. Carrier-Based Del (5q) – Breast Pathology. HMGA2 Sigel – Gastrointestinal MODERATORS: Proficiency Testing System. *** Multi-Tissue Block (CBMTB) Rearrangement in Breast Pathology. Histoarchitectural Yagi, Hameed – Bone and Soft of Normal Tissues as On-Slide Lu, Hameed – Bone and Soft Adenomyoepitheliomas Lacking Pattern Does Not Distinguish Tissue Pathology. Whole Block (Pancreatobiliary Pathology Bhanot, Roehrl – Quality Gupta, Chen, Al-Ahmadie, Quality Control for Automated Tissue Pathology. Histone HRAS and PI3K Pathway-Related IDH1 Mutant Intrahepatic Imaging in Bone Tumors Society): Olca Basturk, Co- Assurance. The Rapidly Growing Sirintrapun, Fine, Berger, Immunohistochemical Staining H3K36M Mutation and Gene Mutations Cholangiocarcinomas from Non- Moderator Role of Pathology in Clinical Trials Tickoo, S. Dogan, Reuter, Procedures Trimethylation Patterns in IDH1 Mutant Controls *** LECTURES: at a Major Cancer Center Gopalan – Genitourinary Chondroblastoma Pareja, Wen, Katabi, Brogi, (Platform Presentations – Breast Pathology. TERT Copy Number K. Park, Soslow – Gynecologic Weigelt, Reis-Filho – Breast Tickoo – Genitourinary Pathology. Basturk, Olca (Pancreatobiliary Pathology): Timothy D’Alfonso, Buonocore, Lin, Cohen – Alterations, Promoter Mutations Pathology. Clinical Outcomes Matsuda, Hanna, Grabenstetter, Pathology. Pleomorphic Adenoma Acquired Cystic Disease- Pathology Society): Genomic Co-Moderator Cytopathology. Misleading and Rearrangements in of HPV-Associated and Brogi – Techniques. Developing and Mucoepidermoid Carcinoma Associated Renal Cell Carcinoma Profiling of Intraductal Clinical Significance of Bethesda Adrenocortical Carcinomas: Unassociated Endocervical an Efficient Approach for the of the Breast are Underpinned by (ACKD-RCC)-Like Cysts Pancreatobiliary Neoplasms (Platform Presentations – Category IV for Thyroid Nodules Clinicopathologic and Molecular Adenocarcinomas (ECAs) Assessment of Tumor Extension Gene Fusions Brogi, Edi: (Evening Specialty Pathobiology): Snjezana Dogan, Analysis of 62 Cases *** Support the IECC Classification by Ex Vivo Imaging of Breast Tickoo, Chen, Reuter – Conference – Breast Pathology): Co-Moderator Busam – Dermatopathology. Specimens: A Pilot Study Using Roehrl – Informatics. The Big Genitourinary Pathology. Case 4 Genetic Overlap Between Primary Gupta, Zarei, Sukov – K. Park, Soslow – Gynecologic X-Ray Tomosynthesis with Data Opportunity in Research Challenges in Pathologic Staging (Platform Presentations – Dermal Melanoma and Cutaneous Genitourinary Pathology. Clear Pathology. International Histopathologic Correlation *** Biobanking: Design and of Renal Cell Carcinoma: An Chen, Ying-Bei: Diagnostic Cytopathology): Oscar Lin, Co- Melanoma Metastases Cell Renal Cell Carcinomas Endocervical Adenocarcinoma Development of a Web-Based Interobserver Variability Study of Approach to Renal Tumors with Moderator with PDGFRA/ KIT (4q12) Co- Criteria & Classification: Mirsadraei, Chen, Reuter, Lin Application to Unify and Connect Urologic Pathologists Papillary Architecture: Updates Chiang, Cotzia, Hechtman, amplification and PDGFRB (5q32) Validation and Interobserver – Cytopathology. Cytological Biospecimen Information and to Using 2016 WHO Classification *** Denotes fellow contribution. Jungbluth, Murali, Soslow, Amplification. *** Reproducibility Characteristics of Hereditary Overcome Data Silo Challenges Turashvili, Chiang, Delair, Benayed, Ladanyi, Antonescu Leiomyomatosis and Renal Cell K. Park, Soslow, Murali – DeLair, Deborah (International Italics indicate MSK fellow. – Gynecologic Pathology. NTRK H. Zhang – Breast Pathology. K. Park, Soslow – Gynecologic Carcinoma (HLRCC)-Associated Roehrl, Hameed, Matsuda, Gynecologic Pathology. BRAF Society of Gynecological Fusions Define a Novel Uterine FOXK2 is A Novel Oncogene in Pathology. Silva-type Patterns of Renal Cell Carcinomas *** Murray, Brogi – Informatics. Mutations and Expression of Anti- Pathology): The IMPACT of Sarcoma Subtype with Features Breast Cancer Invasion and Correlates [Tumor The Roles of Micro-Computed BRAF-V600E (VE1) in Low-Grade Next Gen Sequencing Panels in of Fibrosarcoma *** Size, Lymph-vascular Invasion, Montecalvo, Alex, Sauter, J. Tomography (CT) in Breast Serous Tumors of the Ovary *** Gynecological Cancer Hajiyeva, Edelweiss – Breast and Lymph Node Metastasis] in Chang, Ladanyi, Antonescu, Pathology *** Cotzia, Al-Ahmadie, Chen, Pathology. Frozen Section of HPV-Unassociated Endocervical Travis, Rekhtman – Pulmonary Turashvili, Murali, Soslow Ghossein, Ronald (Endocrine Gopalan, Sirintrapun, Tickoo, Sentinel Lymph Nodes in 702 Adenocarcinomas Pathology. SMARCA4 (BRG1) Rosenblum – Neuropathology. – Gynecologic Pathology. Pathology Society): New TNM Reuter, Fine – Genitourinary Breast Cancer Patients Treated Deficiency in Lung Carcinomas Clinicopathologic Features Prognostic Value of Staging in Thyroid Cancer Pathology. Grade Group 2 with Neoadjuvant Chemotherapy K. Park, Turashvili – Gynecologic Correlates with Poor of Anaplastic Myxopapillary Clinicopathologic Variables in Prostate Cancer with Poorly *** Pathology. Morphologic Patterns Differentiation and Aggressive Ependymomas Synchronous Endometrial and Hechtman, Jaclyn: Identifying Formed Glands Alone on Needle of Secondary Involvement of Clinical Behavior *** Ovarian Carcinomas: Metastases the Rare: Evolving Diagnostics Biopsy: Histologic Features and Hanna, Grabenstetter, Ross, the Uterine Cervix by Non- S. Dogan, Zehir, Ladanyi – or Independent Primary Tumors? Standards in Characterizing Pathologic Outcomes at Radical Tan – Breast Pathology. Invasive Gynecologic Neoplasms *** Montecalvo, Rekhtman, Katabi, Endocrine Pathology. NKX2-1 *** Cancer Prostatectomy *** Lobular Carcinoma with an Ghossein, Antonescu, Travis – Amplification is Associated Unusual Immunophenotypic Khattar, Jelloul, Y. Zhang, Pulmonary Pathology. Thoracic with Aggressive Features in a Vanderbilt, Zehir, Arcila, S. Hechtman, Jaclyn: Peculiar Delair, Soslow, Chiang, K. Park, Profile *** Arcila, Lu Wang, A. Dogan Hyalinizing Clear Cell Carcinoma: Subset of Differentiated Thyroid Dogan, Ladanyi – Techniques. Polyps: Diagnostics of Less Murali, Weigelt – Gynecologic – Hematopathology. t(14;18) A Series of 3 Cases Carcinomas of Follicular Cell Mining Large Panel Hybrid Common Colorectal Lesions Pathology. Integration of Jameel, Brogi, Ross, Weigelt, Negative Inguinal Follicular Origin Capture-Based Clinical Next and Awareness of Their Clinical Massively Parallel Sequencing Reis-Filho, Wen – Breast Lymphoma is Characterized by Montecalvo, Rekhtman, Travis Generation Sequencing Data Associations and Immunohistochemistry for Pathology. Targeted Next Genetic Abnormalities of 1p36/ – Pulmonary Pathology. Clinical Shia – Gastrointestinal Pathology. for Novel Virus Pathogen-tumor the Classification of Prospectively Generation Sequencing Analysis TNFRSF14 and 16p/CREBBP Significance of Morphological Are Enterocolic Mucosal Mast Cell Associations Based on Mapping Katabi, Nora: Hot Topics in Collected Endometrial Cancers of Metaplastic Breast Carcinoma Regions *** Patterns of Micropapillary Lung Aggregates Clinically Relevant of Off-Target Reads to Viral Pathology 01 – Head & Neck into Prognostically Relevant *** Adenocarcinoma: Classical and in Patients Without Suspected Genomics *** Pathology – Head & Neck Subgroups Klimstra – Pancreas Pathology. Filigree Patterns Systemic Mastocytosis? Pathology-New and Improved

28 I MSK PATHOLOGY REVIEW I 29 The QUALITY IMPROVEMENT FAIR at MSKCC is an annual institution-wide event hosted by the Division of Quality and Safety showcasing various improvement efforts and initiatives across the institution.

THE PURPOSE OF THE FAIR IS TO:

Create awareness of various projects and initiatives occurring across the Center

Improve collaboration among colleagues

Educate staff on quality and safety principles and guidelines

Emphasize patient safety and quality of care as top priorities among senior leadership and across the Center

Celebrate the hard work of our staff in their continual efforts in maintaining a safe environment for our patients

The Department of Pathology was featured with three projects under the leadership of Sarah Cook Virgo, Brian Murphy and Tessara Baldi.

“PATHOLOGY CONSULTATIONS: EMPOWERING USERS, IMPROVING TURN AROUND TIME AND EMBRACING THE DIGITAL AGE” Sarah Cook Virgo

“DNA EXTRACTION FROM NAIL CLIPPINGS: DIAGNOSTIC MOLECULAR PATHOLOGY LABORATORY” Tessara Baldi

“AUTOMATED STORAGE AND RETRIEVAL OF CLINICAL DNA SAMPLES IN THE DEPARTMENT OF MOLECULAR PATHOLOGY” Brian Murphy

30 I MSK PATHOLOGY REVIEW I 31 “PATHOLOGY CONSULTATIONS: EMPOWERING USERS, IMPROVING TURN AROUND TIME AND EMBRACING THE DIGITAL AGE” “AUTOMATED STORAGE AND RETRIEVAL OF CLINICAL DNA SAMPLES IN THE DEPARTMENT OF MOLECULAR PATHOLOGY” Sarah Cook Virgo Brian Murphy

“DNA EXTRACTION FROM NAIL CLIPPINGS: DIAGNOSTIC MOLECULAR PATHOLOGY LABORATORY” Tessara Baldi

32 I MSK PATHOLOGY REVIEW I 33 pancreatic neuroendocrine tumours Ladanyi M, Berger MF, Solit DB, Shia J, Saltz P, Normanno N, Scarpa A, Reis-Filho JS, FACULTY PUBLICATIONS (PanNETs) and poorly differentiated L, Schultz N. Clinical sequencing defines the Rodon J, Swanton C, Andre F. The European pancreatic neuroendocrine carcinomas genomic landscape of metastatic colorectal Society for Medical Oncology (ESMO) (PanNECs): concepts, issues and a practical cancer. Cancer Cell 2018; 33: 125-136. precision medicine glossary. Ann Oncol diagnostic approach to high-grade (G3) 2018; 29: 30-35. cases. Histopathology 2018; 72: 168-177. Yang Q, Bavi P, Wang JY, Roehrl MH. Andry C, Duffy E, Moskaluk CA, McCall Gao J, Heins ZJ, Gross BE, Kelsen DP, Zhang Murali R, Delair DF, Bean SM, Abu-Rustum Immuno-proteomic discovery of tumor Zheng J, Hernandez JM, Doussot A, S, , Remick D. Biobanking – Roehrl MHA L, Strong VE, Schattner M, Gerdes H, Coit NR, Soslow RA. Evolving roles of histologic Turashvili G, Brogi E, Morrow M, Dickler tissue autoantigens identifies olfactomedin Bojmar L, Zambirinis CP, Costa-Silva B, Budget and the role of pathology biobanks DG, Bains M, Stadler ZK, Rusch VW, Jones evaluation and molecular/genomic profiling M, Norton L, Hudis C, Wen HY. Breast 4, CD11b, and integrin alpha-2 as markers of van Beek EJAH, Mark MT, Molina H, Askan in precision medicine. Acad Pathol 2017; 8: DR, Molena D, Shia J, Robson ME, Capanu in the management of endometrial cancer. carcinoma with 21-gene recurrence colorectal cancer with liver metastases. J G, , Gonen M, Kingham TP, Allen 4. Basturk O M, Middha S, Zehir A, Hyman DM, Scaltriti JNCCN 2018; 16: 201-209. score lower than 18: rate of locoregional Proteomics 2017; 168: 53-65. PJ, D’Angelica MI, DeMatteo RP, Lyden D, Askan G, Bagcı P, Hameed M, Basturk M, Ladanyi M, Rosen N, Ilson DH, Berger recurrence in a large series with clinical Jarnagin WR. Extracellular matrix proteins , , Taylor BS, Solit DB, Schultz N. O. Dedifferentiated liposarcoma of the MF Tang L O’Reilly EM, Lee JW, Lowery MA, Capanu follow-up. BMC Cancer 2018; 18: 42. Yang Q, Roehrl MH, Wang JY. Proteomic and carcinoembryonic antigen-related cell gastroesophageal junction. Turk J Pathol Genetic predictors of response to systemic M, Stadler ZK, Moore MJ, Dhani N, Kindler profiling of antibody-inducing immunogens adhesion molecules characterize pancreatic 2018; 34: 104-107. therapy in esophagogastric cancer. Cancer HL, Estrella H, Maynard H, Golan T, Segal A, Yaeger R, Chatila WK, Lipsyc MD, Hechtman in tumor tissue identifies PSMA1, LAP3, duct fluid exosomes in patients with Disc 2018; 8: 49-58. Salo-Mullen EE, Yu KH, Epstein AS, Segal JF, Cercek A, Sanchez-Vega F, Jayakumaran ANXA3, and maspin as colon cancer pancreatic cancer. HPB (Oxford) 2018; in Begg CB, Ostrovnaya I, Geyer FC, M, Brenner R, Do RK, Chen AP, Tang LH, G, Middha S, Zehir A, Donoghue MTA, You markers. Oncotarget 2018; 9: 3996-4019. press. Papanastasiou AD, Ng CKY, Sakr RA, Jordan EJ, Lowery MA, Basturk O, Allen PJ, Kelsen DP. Phase 1 trial evaluating cisplatin, D, Viale A, Kemeny N, Segal NH, Stadler Bernstein JL, Burke KA, King TA, Piscuoglio Yu KH, Tabar V, Beal K, Reidy DL, Yamada gemcitabine, and veliparib in 2 patient ZK, Varghese AM, Kundra R, Gao J, Syed A, Yates LR, Seoane J, Le Tourneau C, Siu LL, S, Mauguen A, Orlow I, Weigelt B, Seshan Y, Janjigian Y, Abou-Alfa GK, O’Reilly EM. cohorts: Germline BRCA mutation carriers Hyman DM, Vakiani E, Rosen N, Taylor BS, Marais R, Michiels S, Soria JC, Campbell VE, Morrow M, Reis-Filho JS. Contralateral Brain metastases in pancreatic ductal and wild-type BRCA pancreatic ductal breast cancers: Independent cancers or adenocarcinoma: Assessment of molecular adenocarcinoma. Cancer 2018; 124: 1374- metastases? Int J Cancer 2018; 142: 347- genotype–phenotype features—an entity 1382. 356. with an increasing incidence? Clin Colorectal Cancer, 2018; in press. Park K, Roma A. Pattern based classification of endocervical adenocarcinoma: A Cornelis F, Petre EN, Vakiani E, Klimstra D, review. Pathology 2018; 50: 134-140. 1ST QUARTER 2018 PROMOTIONS Durack J, Gonen M, Osborne JR, Solomon Kao YC, Fletcher CDM, Alaggio R, Wexler SB, Sofocleous CT. Immediate post- L, Zhang L, Sung YS, Orhan D, Chang ablation FDG-injection and corresponding WC, Swanson D, Dickson BC, Antonescu Rimawi MF, De Angelis C, Contreras A, standardized uptake value is a surrogate CR. Recurrent BRAF gene fusions in a Pareja F, Geyer FC, Burke KA, Herrera S, biomarker of local tumor progression after subset of pediatric spindle cell sarcomas: Wang T, Mayer IA, Forero A, Nanda R, Goetz thermal ablation of colorectal carcinoma Expanding the genetic spectrum of tumors MP, Chang JC, Krop IE, Wolff AC, Pavlick AC, liver metastases. J Nucl Med 2018; in press. with overlapping features with infantile Fuqua SAW, Gutierrez C, Hilsenbeck SG, Li fibrosarcoma. Am J Surg Pathol 2018; 42: MM, Weigelt B, Reis-Filho JS, Kent Osborne 28-38. Domínguez-Vigil IG, Moreno-Martínez AK, C, Schiff R. Low PTEN levels and PIK3CA Wang JY, Roehrl MH, Barrera-Saldaña HA. mutations predict resistance to neoadjuvant Kim J, Geyer FC, Martelotto LG, Ng CK, The dawn of the liquid biopsy in the fight lapatinib and trastuzumab without Lim RS, Selenica P, Li A, Pareja F, Fusco N, against cancer. Oncotarget 2018; 9: 2912- chemotherapy in patients with HER2 over- Edelweiss M, Kumar R, Gularte-Merida R, 2922. expressing breast cancer. Breast Cancer Res Forbes AN, Khurana E, Mariani O, Badve S, Treat 2018; 167: 731-740. Vincent-Salomon A, Norton L, Reis-Filho Drilon A, Laetsch TW, Kummar S, DuBois JS, Weigelt B. MYBL1 rearrangements and Roehrl MHA. The promise of precision SG, Lassen UN, Demetri GD, Nathenson M, MYB amplification in breast adenoid cystic pathology. The Pathologist 2017; 32: 22-25. Doebele RC, Farago AF, Pappo AS, Turpin carcinomas lacking the MYB-NFIB fusion B, Dowlati A, Brose MS, Mascarenhas L, gene. J Pathol 2018; 244: 143-150. Roxburgh CS, Shia J, Vakiani E, Daniel T, Federman N, Berlin J, El-Deiry WS, Baik Weiser MR. Potential immune priming of C, Deeken J, Boni V, Nagasubramanian R, Liu Y, Gaisa MM, Wang X, Swartz TH, Arens the tumor microenvironment with FOLFOX Taylor M, Rudzinski ER, Meric-Bernstam F, Y, Dresser KA, Sigel C, Sigel K. Differences chemotherapy in locally advanced rectal Sohal DPS, Ma PC, Raez LE, Hechtman JF, in the immune microenvironment of anal cancer. Oncoimmunology 2018; in pess. Benayed R, Ladanyi M, Tuch BB, Ebata K, cancer precursors by HIV status and LAETITIA BORSU, PHD TRAVIS HOLLMANN, MD, PHD AHMET ZEHIR, PHD Cruickshank S, Ku NC, Cox MC, Hawkins association with ablation outcomes. J Infect Salo-Mullen EE, Lynn PB, Wang L, Walsh Associate Attending Associate Attending Assistant Attending DS, Hong DS, Hyman DM. Efficacy of Dis 2018; 217: 703-709. M, Gopalan A, Shia J, Tran C, Man FY, Larotrectinib in TRK fusion–positive cancers McBride S, Schattner M, Zhang L, Weiser in adults and children. NEJM 2018; 378: 731- Lowery MA, Kelsen DP, Capanu M, Smith SC, MR, Stadler ZK. Contiguous gene deletion of 739. Lee JW, Stadler ZK, Moore MJ, Kindler HL, chromosome 2p16.3-p21 as a cause of Lynch Golan T, Segal A, Maynard H, Hollywood E, syndrome. Fam Cancer 2018; 17: 71-77. Hoang L, Chiang S, Lee C. Endometrial Moynahan M, Salo-Mullen EE, Do RKG, Chen stromal sarcomas and related neoplasms: AP, Yu KH, Tang LH, O’Reilly EM. Phase II Sayeed S, Xing D, Jenkins SM, Weisman New developments and diagnostic trial of veliparib in patients with previously PS, Buehler D, Warmke L, Park K, considerations. Pathology 2018; 50: 162-177 treated BRCA-mutated pancreas ductal Schoolmeester JK. Criteria for risk adenocarcinoma. Eur J Cancer 2018; 89: stratification of vulvar and vaginal smooth Hu ZI, Shia J, Stadler ZK, Varghese AM, 19-26. muscle tumors: An evaluation of 71 cases Capanu M, Salo-Mullen E, Lowery MA, Diaz comparing proposed classification systems. LA, Mandelker D, Yu KH, Zervoudakis A, Martin ML, Zeng Z, Adileh M, Jacobo A, Li Am J Surg Pathol 2018; 42: 84-94. Kelsen DP, Iacobuzio-Donahue CA, Klimstra C, Vakiani E, Hua G, Zhang L, Haimovitz- DS, Saltz LB, Sahin IH, and O’Reilly EM. Friedman A, Fuks Z, Kolesnick R, Paty PB. Sigel CS, Krauss Silva VW, Reid MD, Evaluating mismatch repair deficiency in Logarithmic expansion of LGR5+ cells in Chhieng D, Basturk O, Sigel KM, Daniel TD, pancreatic adenocarcinoma: Challenges and human colorectal cancer. Cell Signal 2018; Klimstra DS, Tang LH. Well differentiated recommendations. Clin Cancer Res 2018; 24: 42: 97-105. grade 3 pancreatic neuroendocrine tumors 11326-1336. compared with related neoplasms: A Murali R, Grisham RN, Soslow RA. The roles morphologic study. Cancer Cytopathol 2018; Janjigian YY, Sanchez-Vega F, Jonsson P, of pathology in targeted therapy of women in press. EFSEVIA VAKIANI, MD PHD MIKHAIL ROSHAL, MD Chatila WK, Hechtman JF, Ku GY, Riches with gynecologic cancers. Gynecol Oncol Associate Attending Associate Attending JC, Tuvy Y, Kundra R, Bouvier N, Vakiani E, 2018; 148: 213-221. Singhi AD, Klimstra DS. Well-differentiated

34 I MSK PATHOLOGY REVIEW I 35 This year, there were at least FOUR teams representing the Department of Pathology for Cycle for Survival. 100% of your donations will fund pioneering research led by Memorial Sloan Kettering to benefit people worldwide, who are facing rare cancers. Thank you for your continued support! For those interested in joining or donating, please contact our team captains:

PATHOLOGY PEDALS Sarah Cook Virgo: [email protected]

PATHOLOGY WARRIORS Amanda Beras: [email protected]

PPBC-BANK THIS! Jessica Kenney: [email protected]

ROB LOVES LAX Lorraine Corsale: [email protected]

36 I MSK PATHOLOGY REVIEW I 37 UPCOMING COURSES

http://mskcc.org/neoplasticdiseases.com

2ND QUARTER 2018

THE HISTORY OF PATHOLOGY AT MEMORIAL SLOAN KETTERING CANCER CENTER

RESEARCH PROFILE: SARAH CHIANG, MD

GENITOURINARY PATHOLOGY TEAM

RESEARCH PROFILE: NORA KATABI, MD

CYTOGENETICS TEAM

RESEARCH PROFILE: JACKIE HECHTMAN, MD