Soft Tissue Tumors with Unique Molecular Alterations: Morphological Features, Novel Immunohistochemical Markers and Molecular Testing

Faculty: Shaoxiong Chen, MD, Indiana University

Professional Practice Gap: Diagnosing soft tissue tumors is challenging, even to the experienced surgical pathologists.   Immunostaining and molecular testing are often required to arrive at a correct diagnosis. In recent years, diagnostic ancillary studies for soft tissue tumors have expanded dramatically, following the understanding of molecular mechanisms that underlie the soft tissue pathogenesis. Diagnostic immunohistochemical (IHC) surrogates for molecular alterations have improved our ability to classify soft tissue tumors accurately.  Thway, et al’s (Sarcoma 2014) report revealed that “Diagnostic agreement was seen in 250 cases (71.8%), with 57 (16.4%) major and 41 (11.8%) minor discrepancies. There were 23 cases of benign/malignant discrepancies (23.5% of all discrepancies)” by studying 348 mesenchymal neoplasms. The major diagnostic discrepancies are likely due to the lack of exposure to the update of the soft tissue diagnostic criteria and ancillary studies because progress in our understanding of the pathogenesis and diagnosis of soft tissue tumors is exceptionally rapid.

Learning Objectives:

1. Recognize the histologic features of soft tissue tumors and develop differential diagnosis based on the pattern recognition
2. Understand the role of molecular alterations in the diagnosis of soft tissue tumors
3. Apply immunohistochemistry (particularly, surrogate markers with high specificity) in classifying soft tissue tumors
4. Discuss molecular studies for rendering the accurate diagnosis if necessary.

Breast Pathology on the Precipice: Navigating Threshold Diagnoses

Faculty: J. Jordi Rowe – Cleveland Clinic

Professional Practice Gap: Threshold diagnoses in breast pathology are ubiquitous with few ancillary studies to assist in determining the best diagnosis for the patient. Threshold diagnoses are those in which it is solely the pathologist’s subjective opinion that determines the final diagnosis. Examples include pseudoangiomatous stromal hyperplasia (how much is enough?), ADH vs DCIS (there are no stains to help), atypical vascular lesion vs angiosarcoma (how to interpret finicky stains), acute and chronic inflammation from cystic neutrophilic granulomatous mastitis, ALH vs LCIS, and the list goes on.

Learning Objectives:

1. Become familiar with the spectrum of benign and malignant threshold lesions that are found in the breast.
2. Learn a practical approach to the diagnosis and evaluation of threshold lesions of the breast, taking into consideration ancillary stains and patient management.
3. Know how to identify and distinguish a threshold lesion from a breast entity with a strict set of diagnostic criteria.

Mesenchymal Tumors and Tumor-like Lesions of the Breast

Faculty: Aysegul Sahin, MD, The University of Texas MD Anderson Cancer Center

Professional Practice Gap: The mesenchymal lesions of the breast encompass a whole spectrum of proliferations from reactive lesions to benign or malignant tumors. Although uncommon, these mesenchymal lesions can be difficult to diagnose due to a variety of possible lineages, including fibroblastic, myofibroblastic, endothelial, adipocytic, myogenic, and osseocartilaginous differentiations. Additionally, biphasic tumors and metaplastic carcinomas of the breast may have a mesenchymal component, which should also be considered in the differential diagnosis. Because of their rarity, the review and guidance of how to accurately diagnose these lesions would be beneficial to the pathology community.

Learning Objectives:

1. Identify the morphologic diagnostic criteria of a variety of common and uncommon benign and malignant mesenchymal lesions of the breast
2. Learn to apply currently available IHC markers and emerging molecular techniques for the differential diagnosis of mesenchymal lesions of the breast
3. Acquire expert insights into the use of clinical and imaging features to incorporate into pathology reports to guide the best treatment recommendations

Meeting the Challenge of Interpreting Papillary Neoplasms of the Breast

Faculty: Savitri Krishnamurthy, MD, The University of Texas MD Anderson Cancer Center

Professional Practice Gap: Papillary neoplasms are commonly encountered in image guided core biopsies as well as surgical excisions of breast in academic and community surgical pathology practice.  Interpretation of  different types of mammary papillary neoplasms including benign , atypical and malignant varieties can be challenging and problematic in routine clinical practice .  Recognition of the distinct clinical, imaging and morphological criteria of the different entities of papillary neoplasms of breast together with judicious use of ancillary immunohistochemical staining and the differential diagnosis that needs to be considered will facilitate appropriate pathology reporting with implications for optimal patient management. This interactive microscopy session will provide a clear education of the histopathological and immunophenotypic features of different types of papillary neoplasms of breast including intraductal papilloma, atypical papilloma, ductal carcinoma in situ (DCIS) involving a papilloma,  DCIS, papillary type, encapsulated papillary carcinoma, solid papillary carcinoma and invasive papillary carcinoma. Classical and challenging cases of each of the different entities will be presented and discussed in the interactive microscopic session with useful tips to avoid making diagnostic errors in the interpretation of intraductal papillary neoplasms.

Learning Objectives:

1. Recognize the morphological spectrum of changes in different types of papillary neoplasms of breast including intraductal papilloma, atypical papilloma, DCIS involving a papilloma, DCIS, papillary type, encapsulated papillary carcinoma, solid papillary carcinoma and invasive papillary carcinoma in core biopsy and/or subsequent surgical excision.
2. Recognize the role of ancillary immunohistochemical stains using myoepithelial markers, high molecular weight cytokeratin and estrogen receptor immunostaining as valuable adjuncts to histopathological evaluation for definitive diagnosis of the different entities.
3. Recognize the clinical, imaging features in addition to the pathological features of the different entities belonging to intraductal papillary neoplasms for arriving at the correct diagnosis.

Uncommon Breast Lesions Every Pathologist Needs To Know About

Faculty: Stuart Schnitt, MD, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School

Professional Practice Gap: Some breast lesions are relatively uncommon and therefore infrequently encountered by most pathologists. All practicing pathologists should be aware of such lesions, but because they are uncommon many pathologists are either not aware of their existence or are not sufficiently knowledgeable about their histologic features to permit them to arrive at the correct diagnosis. As a result, lack of awareness or recognition of such lesions may result in an incorrect diagnosis, in turn resulting in improper patient management. The purpose of this course, therefore, is to educate pathologists about a number breast lesions that are either infrequently encountered or recently described or for which new information is available in order to permit the proper recognition and diagnosis of such lesions.

Learning Objectives:

1. To provide morphologic criteria for several newly recognized lesions in breast pathology
2. To emphasize the use and limitations of immunohistochemistry to assist in the diagnosis of unusual breast lesions
3. To discuss the uses and limitations of newer, molecular adjunctive tests which are being used increasingly to guide patient treatment

Inflammatory Conditions In Cardiovascular Pathology: A Practical Approach And Emerging Entities

Faculty: Chieh-Yu Lin, MD, PhD, Washington University School of Medicine in St. Louis

Professional Practice Gap: Regardless of the practice setting, pathologists may encounter variable types of cardiovascular pathology specimens, including endomyocardial biopsies from heart failure patients, temporal artery biopsies for arteritis evaluation, aortic tissue from patients with aortic dissection or aneurysm repair. These specimens can also be encountered in autopsies. Moreover, vasculitis can be present in any surgical specimen and it is critical to recognize and render the correct diagnosis to guide therapy. As the volume of cardiovascular pathology specimens is relatively low in most practices, pathologists may feel less confident when encountering these cases with subtle and overlapping histological findings. In addition, newly emerging disease entities have been identified and characterized, associated with new therapeutic agents and infections. The aim of this session is to provide a practical approach to accurately diagnose inflammatory cardiovascular conditions that carry significant clinical impact.

Learning Objectives:

1. Identify histological features and understand the diagnostic criteria of various inflammatory cardiovascular diseases.
2. Recognize overlapping and distinct features of entities in the differential diagnosis and undertake additional workup and/or purse relevant clinical correlation to render an accurate diagnosis
3. Describe the histological features and understand the pathogenesis of emerging inflammatory cardiovascular diseases.

Sonographic Clues in Pathologist-Performed Ultrasound-Guided FNA/CNB: Microscopic Diagnosis as a Multiple-Choice Exercise

Faculty: David Lieu, MD, MBA , FNA Medical Group/UCLA

Professional Practice Gap: Pathologists are often given little clinical and radiologic information when asked to interpret an FNA performed by a radiologist or clinician. Often, “left thyroid mass in a 25-year-old woman”, “neck mass in 55-year-old man”, or “right breast mass in a 48-year-old woman” is all the information that is submitted with the slides. Clinical and radiologic information are extremely helpful in narrowing the possibilities of pathologic diagnosis. They help frame mindset of the pathologist to arrive at the correct diagnosis. By knowing the most likely possibilities based on clinical and radiologic features, microscopic diagnosis is converted from an essay test (what is) to a multiple choice test (what should be). The question is transformed from “What is this mass?” to “Is this mass entity A, B, C, or D?”

Example 1: 48-year-old woman with a non-palpable irregular, spiculated, parallel, hypoechoic 1.0 cm. right breast mass at 7:00 about 3 cm. from the nipple that was BIRADS 5. The pathologist reviews the previous images, scans the patient, and locates the mass as described by the radiologist. Based on ultrasound, the possibilities on UG-FNA/CNB are invasive duct carcinoma, typically low or intermediate-grade (most likely), invasive lobular carcinoma, fat necrosis, radial scar, or granular cell tumor. It is unlikely to be a simple or complicated cyst, fibroadenoma, fibrocystic mastopathy, papillary carcinoma, or mucinous carcinoma because these entities do not have this sonographic appearance. Microscopic diagnosis is now a multiple choice test.

Example 2: 46-year-old woman with a non-palpable 8 mm. mass in the lower portion of the right thyroid that could be a parathyroid adenoma or an abnormal lymph node on sonogram according to the radiologist. The pathologist scans the patient and finds a tiny nearly anechoic mass below the right thyroid with peripheral linear echogneic foci that is suggestive of calcification. It is unlikely to be a parathyroid adenoma or lymph node. It is separate from the trachea. It could be a cyst with perpheral calcifcation based on ultrasound. The options based on ultrasound are cyst (likely), exophytic thyroid (less likely based on location, abnormal lymph node (unlikely based on location), and parathyroid adenoma (unlikely based on peripheral calcifcation and lack of polar and arcuate blood vessels on Doppler examnation). Pathologist-performed UG-FNA yields PMNs, mucus, ciliated respiratory epithelium, cartilage, and fungal hyphae. If the specimen had been submitted by a radiologist or clinician with a source listed as “neck mass”, the case would likely have been interpreted as “tracheal contamination, non-diagnostic.” Instead, the pathologist who performed the UG-FNA knew the exact location and sonographic features of the mass. It was interpreted as “consistent with origin from a bronchogenic cyst.” This diagnosis was confirmed on thoracotomy and surgical pathology.

Learning Objectives:

1. Describe normal and abnormal sonographic appearances of the thyroid, breast, salivary galnds, and lymph nodes
2. Generate a list of differential diagnoses based on the sonographic appearance of a mass
3. Examine the FNA smears and core biopsy (if performed) together with the results of any ancillary tests (IHC, flow cytometry, etc.) to choose which one on the list of differential diagnoses is correct.

Pap Test Never Gets Old: A Potpourri of Challenging Gynecologic Cases

Faculty: Erika F. Rodriguez, MD, PhD, David Geffen School of Medicine at UCLA

Professional Practice Gap: In the United States, cervical cancer rates showed an apparent decline, with a decrease of 50% of cases from 1975 to 2012. According to the Centers for Disease Control and Prevention (CDC), the decline in deaths over the past 40 years in this disease is the “result of many women getting regular Pap tests.” Nevertheless, in recent years there has been an increase in the percentage of women in the US who are overdue for cervical cancer screening (14.4% in 2005 to 23% in 2019). Lack of screening is associated with a higher risk of developing cervical cancer. Also, a recent report on an increase in stage IV cervical cancer incidence, especially in women 40-44 years of age, demonstrates the need for continuous education on Pap test assessment and its implications for treating physicians and patients.

Although the Pap test is recognized as the most effective cancer screening test, its effectiveness is attributable to screening to prevent squamous cell carcinoma. However, the ability to recognize high-grade lesions may have decreased over time due to a decrease in the number of Pap tests performed and a decreasing number of high grade lesions and squamous cell carcinoma diagnoses. Another challenge the cytopathology community faces is the increase in non-squamous neoplasms, particularly uterine adenocarcinoma. Glandular lesions are notoriously challenging to recognize and suffer from high interobserver variability.

It is documented in the literature that high grade lesion mimics, such as atrophic smears and reparative changes, may be a source of false positives in Pap tests. Additionally, glandular lesions are challenging to identify and demonstrate a high false negative rate. Given the central role of Pap test plays in gynecological cancer screening, the constantly evolving guidelines, and changing rates of cervical cancers of various histologies, it is important to increase the tools available for trainees and practicing pathologists to develop in this central impactful area of pathology.

Learning Objectives:

1. Outline best practices in the approach of challenging Pap tests, including non-squamous lesions and cancer mimics
2. Recognize key findings of diagnostic importance in Pap tests performed in selected populations
3. Discuss diagnostic criteria and approach for glandular lesions

Head and Neck Cytology: Common, Uncommon and Rare Entities

Faculty: Zahra Maleka, MD, Johns Hopkins University School of Medicine

Professional Practice Gap: Fine needle aspiration is a well-accepted tool in the evaluation of head and neck lesions due to its minimally invasive nature, lack of scaring, and possibility of repeating the procedure whenever it is necessary. Cytology evaluation of both solid and cystic mass lesions of the head and neck provides valuable information about the cytomorphologic features of the lesion. Moreover, there is an increased demand by clinicians and surgeons to receive a definitive diagnosis in order to avoid any unnecessary aggressive procedures due to risks associated with this anatomic site.  Although metastases are the most common causes of mass lesions in the head and neck, a wide variety of both benign and malignant neoplasms including rare conditions may arise primarily in the head and neck. HPV-related oropharyngeal carcinoma, a separate entity recognized by 4th edition of the WHO Head and Neck blue book, is an excellent example of a primary head and neck carcinoma.  In addition, the cytologic findings of aspirated material can play an important role in management of the patients. The aspirated material might be utilized for molecular studies in order to detect actionable molecular alterations and subsequent targeted therapy. Familiarity of cytopathologists and pathologists with these entities is critical in rendering an accurate diagnosis. This presentation reviews cytomorphology of head and neck mass lesions, along with differential diagnosis, diagnostic pitfalls, and ancillary studies.

Learning Objectives:

1. Describe main head and neck lesions, their cytomorphologic features and the diagnostic pitfalls
2. Describe HPV-related head and neck carcinoma, its clinical presentations, variable and rare cytomorphologic features, the differential diagnosis, and the diagnostic pitfalls
3. Discuss the utility of ancillary studies such as immunohistochemistry in diagnosis of the head and neck lesions

Malignant Neoplasms of Anal Canal and Perianal Skin: A Practical Approach and HPV Status

Faculty: Dongwei Zhang, MD, PhD, Indiana University

Professional Practice Gap: Several malignant neoplasms of anal canal and perianal skin, such as neuroendocrine tumor, squamous cell carcinoma, or melanoma, show similar histologic features (e.g., basaloid or poorly differentiated), making it challenging to render accurate diagnosis. Pathologists are not familiar with some rare tumors such as Buschke-Löwenstein tumor, Paget’s disease, and mixed adenoneuroendocrine carcinoma. More and more anal malignant neoplasms are discovered to be positive for low-risk and/or high-risk human papilloma virus (HPV). Pathologists are often confused about the diagnostic value of HPV test.

Learning Objectives:

1. Utilize a practical approach to subclassify challenging anal malignant neoplasms.
2. Generate appropriate differential diagnosis of poorly differentiated carcinoma or neoplasm with basaloid features.
3. Recognize the impact of immunohistochemical studies in distinguishing mucosal vs. extramucosal anal adenocarcinoma and primary vs. secondary perianal Paget’s disease.
4. Discuss the diagnostic value of HPV test.

Renal Mass Biopsy: Building Confidence with the Familiar and Better Recognition of the New and Emerging Entities

Faculty: Bonnie Choy, MD, Northwestern University Feinberg School of Medicine

Professional Practice Gap: The use of core needle biopsy of renal masses has evolved considerably over the past few decades. There is increasing demand for tissue evaluation due to the valuable data it provides for counseling and clinical decision making. However, the workup and interpretation can be challenging to those unfamiliar with these small specimens. There is also a rapidly expanding list of new and emerging entities of renal tumors with varying biologic potentials, adding to the need for better recognition and optimization of adequacy assessment and diagnostic approach of renal lesions.

Learning Objectives:

1. Recognize the reasons for core needle biopsy of renal masses and the implications of the diagnosis on patient management and outcome.
2. Be familiar with the new and emerging entities of renal tumors in the recent 2022 WHO Classification.
3. Develop a directed approach to evaluating renal tumors to formulate a differential diagnosis and to guide immunohistochemical and molecular workup when appropriate.

New and Emerging Renal Cell Carcinomas: An Algorithmic Pattern-Based Approach to their Diagnosis

Faculty: Manju Aron, MD, Keck School of Medicine of USC

Professional Practice Gap: Over the past several decades there has been an exponential increase in the number of subtypes of renal cell carcinomas (RCC), many of which have been included in the WHO 2022 classification as new or emerging entities. With this expanding spectrum of RCC it has become a daunting task for many of the trainees and pathologists, to accurately identify these subtypes, many of which are characterized by distinct molecular alterations with potential implications for optimal clinical management, prognostication, selection of targeted therapies and identification for genetic testing.

The accurate classification of many of these tumors is often challenging because of their relative rarity and morphological overlap with the more common subtypes of RCC. The unfamiliarity of the practicing pathologist with these entities and the morphological and immunohistochemical (IHC) profiles that can help differentiate them from the more common subtypes of RCC, further impedes the identification of these RCC.

This interactive microscopy course, through the illustration of classic cases, will help familiarize the attendees with the distinct morphologic features of these RCC, and emphasize the role of immunohistochemistry and molecular testing in the diagnosis and differentiation of these RCC subtypes from their more common morphologic mimics. It is hoped that upon completion of this course, the attendees will feel greater confidence in accurately reporting these tumors, thereby positively impacting patient management

Learning Objectives:

1. Describe the morphological features of the newer and emerging entities of renal cell carcinoma as per the WHO 2022 classification system.
2. Distinguish these entities from their morphologic mimics using immunohistochemical stains and or molecular studies where required.
3. Effectively communicate the clinical significance of these tumors to the treating urologist/oncologist

Neuroendocrine Differentiation in the Setting of Prostate Cancer

Faculty: Samson Fine, MD, Memorial Sloan Kettering Cancer Center

Professional Practice Gap: The spectrum of neuroendocrine differentiation in the setting of prostate cancer has become a ‘hot topic’ with the rise of neuroendocrine lesions in both the prostate and metastatic sites post-androgen deprivation/hormonal therapy. As clinical standards of care bring potent next-generation anti-androgens earlier in the prostate cancer disease course, including the neoadjuvant setting, the spectrum of lesions that a practicing pathologist may reasonably encouter is expanding. While most pathologists can recognize small cell/neuroendocrine carcinoma as seen in other organs, more subtle histologies and their clinical import and/or implications for further management are less well recognized.  This interactive microscopy session will share experience and practical tips on assessment of these challenging lesions and the clinical context in which they occur.

Learning Objectives:

1. Recognize morphologic features associated with all WHO categories of neuroendocrine differentiation in the setting of prostate cancer
2. Gain awareness of morphologies which indicate intermediate states between high grade adenocarcinoma and small cell/NE carcinoma and how to use IHC/molecular testing to best classify such lesions
3. Accurately report the nature of neuroendocrine differentiation, such that clinicians can make accurate management decisions (e.g., prostatic adenocarcinoma with single cell NE IHC marker labeling (no platinum-based chemotherapy) v. small cell/neuroendocrine carcinoma (yes platinum-based chemotherapy)

Fine Lines in Endometrial Pathology: Difficult Distinctions with Big Clinical Impact

Faculty: Amy Joehlin-Price, MD, Cleveland Clinic

Professional Practice Gap: Endometrial biopsies are one of the most common gynecologic specimens, and correct clinical management depends immensely on proper pathologic diagnosis. Endometrial samples, however, can have subtle findings that change clinical management drastically. Occasional errors that make the biggest clinical impact include incorrect assignment of primary tumor site, missing subtle or poorly-sampled carcinomas, and confusing high grade endometrial carcinomas with low grade endometrial carcinomas and vice versa. Using a series of 10 cases, along with several cases for comparison, this interactive microscopy session will examine these three clinically important pitfalls to allow pathologists to deal with subtle endometrial sample finding with confidence.

Learning Objectives:

1. Describe findings in endometrial tumor samples that require work up for other primary tumor sites, such as the cervix or ovary.
2. Explain small volume findings in both benign and malignant biopsy samples that lead to clinical treatment differences.
3. Correctly classify biphasic carcinomas where the differential diagnosis includes both high and low grade endometrial carcinomas.
4. Recognize less common carcinoma histologies, including gastric-type and mesonephric-like carcinomas, and include appropriate immunohistochemistry and histologic details in reports for these carcinomas.

Approach to Intraoperative Consultations of Ovarian Lesions – Diagnostic Pearls and Clinical Implications of the Frozen Section Diagnosis

Faculty: Luis Blanco, Jr., MD, Northwestern University Feinberg School of Mecicine

Professional Practice Gap: Given their location deep in the pelvis and the risk of peritoneal seeding, ovarian lesions are difficult to biopsy pre-operatively and are therefore a common specimen received for intraoperative consultation. Ovarian lesions are challenging enough on permanent H&E sections.  They are even more challenging to diagnose during intraoperative consultations, when numerous factors come into play during a time sensitive procedure that will directly determine the next steps in surgery.  These include gross examination, accurate sampling especially in tumors with heterogeneity, and the patient’s clinical history.  In addition, ovarian lesions can range from benign to borderline to malignant, and can be categorized as epithelial, sex cord-stromal, germ cell, or metastatic, leading to an overwhelming number of possibilities.  Further, depending on the practice setting, a non-GYN expert may be assigned to the case, and inadequate knowledge of the consequences of diagnosis may lead to under- or over-treatment.

Learning Objectives:

1. Develop a practical diagnostic approach to intraoperative assessments of ovarian lesions received for frozen section consultation.
2. Recognize the key diagnostic features of the spectrum of ovarian neoplasms:  benign vs. borderline vs. malignant, and epithelial vs. sex-cord stromal vs. germ cell vs. metastatic.
3. Describe the various options for reporting the intraoperative consulation findings of ovarian lesions.
4. Discuss the implications and consequences of the frozen section diagnosis of ovarian lesions for each category.

Benign, Malignant or Something in Between? Demystifying Ovarian Borderline Tumours

Faculty: M. Herman Chui, MD, Memorial Sloan Kettering Cancer Center

Professional Practice Gap: Classification of the malignant potential and histologic subtype of ovarian tumors has important implications for treatment and prognosis. There are several areas that are diagnostically challenging, and general pathologists are not familiar with the precise contemporary criteria, including distinction of mucinous borderline tumor from confluent/expansile mucinous carcinoma, serous borderline tumor with microinvasion versus foci of low-grade serous carcinoma and classification of extraovarian implants (Seidman et al 2004).

Learning Objectives:

1. Explain the histologic features and molecular pathogenesis distinguishing the major histologic subtypes of ovarian borderline tumors
2. Compare and contrast the spectrum of lesions from benign to malignant across the different epithelial subtypes of ovarian tumors
3. Discuss the histologic features distinguishing non-invasive implants from invasive carcinoma
4. Provide illustrative examples of common diagnostic dilemmas pertaining to ovarian borderline tumors

Ovarian Germ Cell Tumors: Looking Beyond the Varied Morphology

Faculty: Tricia Murdock, MD, Johns Hopkins Medicine

Professional Practice Gap: 1) For grading purposes of immature teratomas, assessing the immature neuroepithelium in an ovarian teratoma is a perpetual problem, both quantitatively and qualitatively. Another challenge is recognizing a somatic type CNS-like tumor arising in a teratoma and differentiating from immature neuroepithelium.
2) Identifying tumors arising in ovarian teratomas versus a primary or secondary tumor to the ovary is particularly challenging. Although there are no specific diagnostic criteria for determining primary versus secondary tumors (i.e., mucinous neoplasms), there are clinicopathologic clues. Additional information on how to appropriately sign out with advice for notes and differential diagnosis will be provided.
3) Germ cell tumors, particularly yolk sac tumors (YST), may mimic other epithelial ovarian tumors. Recognizing the varied YST morphology and appropriate immunohistochemical stains is imperative.

Learning Objectives:

1. The learner will be able to identify immature neuroepithelium in ovarian teratomas and be able to provide a grade for the immature teratoma.
2. The learner will be able to identify tumors arising in ovarian teratomas and discuss the differential diagnosis (including primary versus secondary tumors).
3. The learner will be able to recognize the various morphologic patterns of yolk sac tumors, especially the patterns that overlap with epithelial ovarian tumors. The learner will be able to discuss the immunohistochemical profile of yolk sac tumors versus the epithelial tumors.

Frozen Section Diagnoses in Head and Neck Pathology: Diagnostic Pearls and Clinical Implications

Faculty: Qihui (Jim) Zhai, MD, Mayo Clinic College of Medicine and Science, Mayo Clinic Florida

Professional Practice Gap: Frozen section interpretation is a critical component of daily practice for most surgical pathologists in hospital setting. Diseases of the head and neck region could be difficult to diagnose due to the complex anatomy and the wide histological spectrum. Rendering an accurate intraoperative diagnosis is often challenging and stressful considering the time limitation, freezing artifacts, and the immediate resulting surgical impact. Trainees and general pathologists may not have extensive exposure to head and neck pathology particularly to the intraoperative consultations. This course will demonstrate real cases that were encountered in daily practice, including those from squamous mucosa, salivary glands, neck, thyroid, and parathyroid. Clinical setting will be offered. Frozen section slides will be presented and discussed, with the focus on the diagnostic pitfalls and pearls. Intraoperative implications will be discussed. An analytic approach and immediate surgical relevance will be the theme of this practical course.

Learning Objectives:

1. Identify differential diagnoses of squamous mucosal lesions and evaluation of the resection margins by separating squamous carcinoma from its mimickers
2. Define the classification of salivary gland tumors, using an algorithmic approach to analyze major diagnostic features such as the low power growth pattern, tumor cell types, cytologic atypia, etc. Pleomorphic adenoma, oncocytoma, Warthin tumor, mucoepidermoid carcinoma, adenoid cystic carcinoma, polymorphous adenocarcinoma, salivary duct carcinoma, myoepithelial carcinoma, secretory carcinoma, etc.
3. Distinguish a benign primary cystic lesion from a metastatic well-differentiated squamous carcinoma in a neck lymph node, including HPV-positive type
4. Understand frozen section diagnostic implications, pitfalls, and pearls in thyroid nodules and parathyroid glands

EBV+ Immune Deficiency-related Lymphoproliferative Lesions; Review & New Paradigm

Faculty: Jennifer Chapman, MD, University of Miami, Miller School of Medicine

Professional Practice Gap: Immune deficiency  / dysregulation (IDD)-related lymphoproliferative disorders (LPDs) are under-recognized, clinicopathologically and biologically unique lesions that are difficult to identify and classify in clinical practice.  IDD-related LPDs range from hyperplasias to polymorphic lesions to aggressive lymphomas and their clincial approach is unique due to their IDD-related biology and treatment responses. These lesions have undergone a paradigm shift in terms of their naming classification and organization in the upcoming 5th edition WHO classification of hematolymphoid tumors.

Learning Objectives:

1. Review the oncogenic nature of EBV, in particular when host immunity is compromised allowing EBV to express its full genome.  Review viral-derived antigens exhibiting homology to human antiapoptotic molecules, signal transducers and cytokines, which promotes EBV infection, cell immortalization, and transformation.
2. Discuss the classification and naming system for EBV-positive immune deficiency-related lymphoproliferative lesions, including the new classification and naming paradigm recommended by the upcoming 5th edition WHO classification.
3. Study several well characterized examples of EBV positive immune deficiency related lymphoproliferative disorders and lymphomas, ranging from reactive hyperplasias to aggressive lymphomas.
4. Special focus on poylmorphic lesions and ways to resolve the differential diagnosis of EBV+ mucocutaneous ulcer, EBV+ polymorphic lymphoproliferative disorder, EBV+ classic Hodgkin lymphoma and EBV+ diffuse large B cell lymphoma.

Aggressive Lymphoma Mimics: A Practical Approach to Avoid Diagnostic Pitfalls

Faculty: Ji Yuan, MD, PhD, Mayo Clinic

Professional Practice Gap: Reactive lymphoid proliferation may resemble aggressive lymphomas clinically, radiologically, morphologically, phenotypically, and genetically. Patients may present with diffuse lymphadenopathy and splenomegaly with B-symptoms, significantly overlapping with those with lymphomas. Histologically, reactive lymphoproliferation could show a dense infiltrate with large cell cytology, effacement of the normal architecture, necrosis, an aberrant phenotype, and occasional clonal gene rearrangements and genetic abnormalities (1-8). These features certainly pose diagnostic pitfalls for pathologists to misdiagnosis as an aggressive lymphoma. Previous studies of lymphoma consultation in academic centers have reported variable rates of discordance between referral and final diagnosis with a potential impact on patient care ranging from 2% to 17% (9-14). Reactive/benign lesions misdiagnosed as lymphoma were one of the most frequently discrepancies, accounting for 4-30% of the cases with discordances (9-14). These aggressive lymphoma mimics, named as “tumor-like lesions with B- or T-cell predominance” have been introduced in the upcoming 5th WHO classification (15), to acknowledge the importance of recognition of these entities.

Learning Objectives:

1. Explain the pitfalls and challenges in the diagnosis of aggressive lymphoma mimics
2. Recognize histological and phenotypic features of aggressive lymphoma mimics
3. Learn a practical approach using appropriate ancillary studies to differential the mimics from aggressive lymphoma

Secrets of the Spleen: An Overview of Practical Splenic Pathology

Faculty: Dennis O’Malley, MD, NeoGenomics Laboratories, Inc.

Professional Practice Gap:Most pathologists are unfamiliar with spleen pathology based on: 1) rarity of the samples, 2) a broad range of pathology [hematopathology, soft issue pathology, vascular pathology, myeloid disease, reative conditions] and 3) many unusual conditions. Experience with a range of these lesions allows the practicing pathologist to confidently assess the category, important underlying biology and proper categorization of the pathologic processes.

Learning Objectives:

1. Investigate the physiologic functions of the spleen as they are expressed by histopathology
2. Understand the distribution of pathologic processes of the spleen based on separate anatomic compartment
3. Assay hematolymphoid disorders of the spleen
4. Discuss the range of vascular and stromal pathology of the spleen

Histiocytic and Dendritic Cell Neoplasms

Faculty: Zenggang Pan, MD, PhD, University of Colorado Anschutz Medical Campus

Professional Practice Gap: Histiocytic and dendritic cells neoplasms (HDCNs) are rarely encountered by hematopathologists and surgical pathologists. They have a broad range of clinical presentations, morphologic and immunophenotypic features, and molecular genetic background. In addition, HDCNs often closely resemble non-hematopoietic neoplasms, which may lead to misinterpretation albeit extensive workup. Moreover, HDCNs can be transdifferentiated from B-cell or T-cell lymphomas. Therefore, it is challenging, particularly for surgical pathologists and trainees, to identify the essential morphologic features, generate differential diagnosis, and initiate effective workup.

Learning Objectives:

1. Identify the characteristic morphologic features of histiocytic and dendritic cell neoplasms
2. Generate differential diagnosis based on morphology and propose effective initial workup
3. Understand the algorithm to diagnose histiocytic and dendritic cell neoplasms, based on necessary clinical data, imaging studies, morphology, immunostains, and molecular genetic assays
4. Recognize the phenomenon of transdifferentiation and molecular genetic background

How to Avoid Pitfalls in Diagnosis of T-cell Lymphoma

Faculty: Nidhi Aggarwal, MD, University of Pittsburgh School of Medicine

Professional Practice Gap: Peripheral T-cell lymphoma is a heterogenous group of neoplasms that are difficult to diagnose. According to one study from 2016 about 13% of the cases of reported T-cell lymphomas when reviewed centrally were diagnosed incorrectly including about 5% that represented disorders other than those arising from T-cells (1).  Common pitfalls involve differential diagnosis between reactive versus neoplastic lesions. Unlike B-cells where kappa and lambda staining can be used as a surrogate for clonality, CD4:CD8 ratio can be altered in reactive conditions as well. More recently, the use of TRBC1 as a flow marker is proving to be useful in the diagnosis of T-cell lymphomas of αβ type (2). Normal T and NK -cell populations exist that lack or show diminished expression of some pan T-cell markers (3), expansion of these populations can be seen in reactive and neoplastic conditions. The knowledge of the pattern of expression of pan T-cell antigens on various normal T and NK -cell populations essential in order to understand aberrant expression.  In addition, molecular studies done to establish clonality such as TCR gene rearrangement studies can be positive in non-neoplastic states and may not lineage specific (4) further adding to the complexity of T-cell neoplasms especially in a background of autoimmune diseases. Furthermore, T-cell lymphomas may mimic other malignancies including Hodgkin lymphomas (5), and sometimes non-hematopoietic neoplasms. Anaplastic large cell lymphoma may express PAX5 (6) and cases of Hodgkin lymphoma that lack PAX5 expression have been described. Small cell variant (7) and ALK negative variants of this disease may be particularly difficult to diagnose. Markers of follicular helper T-cells may be expressed in other conditions (8). Lastly, characterization and classification even when T-cell lymphoma is diagnosed may be challenging. Recent studies focussing on mutational analysis may help in some cases (9).

Learning Objectives:

1. Evaluate a case of T-cell lymphoma with differential diagnosis.
2. Use ancillary studies to refine the differential diagnosis.
3. Be aware of the controversies in the literature about various entities and how best to formulate a report.
4. Review genetic information that may help in further diagnosis.

Histopathological Challenges in Adult Cholestatic Liver Injury: Identifying the Etiology From Liver Biopsy

Faculty: Lan Peng, MD, UT Southwestern Medical Center

Professional Practice Gap: Cholestasis is a common clinical symptom. Pathologist often receive liver biopsy (often rush biopsy) from cholestatic patients. Liver biopsy is performed to obtain a definitive diagnosis of cause, to exclude potential etiologies, or simply to assist in development of a differential diagnosis.  Diseases with specific histological features include biliary obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, rejection and graft-versus-host disease. However, there are other  causes, such as viral hepatitis including COVID-19, sepsis, drug-induced liver injury, paraneoplastic cholestasis. Some of the histological features of cholestasis are nonspecific. Hence, cases-based review will help pathologists and trainees develop sound knowledge of the pathology of cholestasis, be aware of the board differential diagnosis, and identify the etiologies. The pathologist is also cautioned not to overinterpret the cholestatic liver biopsy and to apply rigorous criteria for specific causal diagnoses.

Learning Objectives:

1. Identified and describe the different pattern of cholastatic liver injury (acute vs chronic; extrahepatic vs intrahepatic);
2. Learn practical approaches in Interpretation of cholestatic liver injury;
3. Explain the possible etiologies, and narrow down the differential diagnosis;
4. Discuss the findings with clinician and help clinical decision-making;
5. Be prepared for unusual and problem cases.

Liver Tumors: Judicious Use Of Immunohistochemical And Genomic Tools To Unravel The Mysteries Of Neoplastic Liver Lesions

Faculty: Sanjay Kakar, MD, University of California San Francisco

Professional Practice Gap: The diagnosis of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA)/metastatic adenocarcinoma and hepatocellular adenoma are the leading areas that cause problems in biopsy diagnosis for practicing pathologists. The WHO 2019 classification introduced new variants of HCC and iCCA that can closely mimic other tumors. With advancing radiology techniques, smaller lesions are being targeted necessitating judicious use of immunohistochemistry. Characteristic molecular changes have been described in a variety of liver tumors and have become an essential tool in the diagnostic armamentarium for poorly differentiated tumors.

Learning Objectives:

1. Recognize the histologic variants of hepatocellular carcinoma and intrahepatic cholangiocarcinoma
2. Distinguish hepatocellular carcinoma and cholangiocarcinoma from benign mimics and metastatic tumors
3. Formulate appropriate immunohistochemical panels for specific clinicopathologic settings
4. Become cognizant of the appropriate use of genomic testing for the diagnosis of liver tumors

Liver Allograft Pathology: How to Issue a Clinically Useful Report

Faculty: Kiyoko Oshima, MD, PhD, Johns Hopkins University School of Medicine

Professional Practice Gap: Liver allograft pathology has an important role in managing patients who underwent a liver transplant.  However, pathologists are often not familiar with the precise diagnosis of transplant-specific entities such as acute rejection, atypical, delayed onset rejection, chronic rejection, or humoral rejection. In addition, knowledge of clinical medicine including surgical complications or clinical strategies for patient management is imperative to issue a clinically useful report to guide a patient’s care.  Pathologists often lack knowledge of the clinical side as well.

Learning Objectives:

1. Recognize the morphology of typical and atypical acute cellular rejection, chronic rejection and humoral rejection
2. Understand histology related to complications including vascular and biliary anastomotic strictures or insufficiency
3. Develop knowledge related to clinical management of patients with a history of liver transplantation

Pediatric Non-Neoplastic Liver Pathology: A Concise Overview for the Practicing Pathologist

Faculty: Juan Putra, MD, Boston Children’s Hospital

Professional Practice Gap: The indications for liver biopsy in children are evolving as current knowledge of etiologies, noninvasive biomarker alternatives, and treatment options in this age group are expanding. Pediatric liver biopsies may be encountered in both general and subspecialty sign-out settings. Depending on the institution, pathologists often have limited exposure to pediatric liver biopsies during their training.

Torbenson et al. (PMID: 30857968) evaluated extramural consultation for challenging liver pathology cases in adults, and noted that 61% of the cases sent for expert consultation were non-neoplastic liver disease. Similarly, pediatric non-neoplastic liver disease poses many diagnostic challenges for the practicing pathologists, particularly general pathologists in the community setting.

Learning Objectives:

1. List different conditions associated with neonatal cholestasis and describe histologic features which may be helpful to distinguish one from another.
2. Characterize the histologic findings of pediatric fatty liver disease and describe other conditions which may manifest as hepatic steatosis in the pediatric population.
3. Recognize pathologic features of several inherited metabolic liver disorders.

Nuances in Pediatric Gastrointestinal Pathology Biopsy Interpretation: What is Your Gut Feeling?

Faculty: Archana Shenoy, MD, Nationwide Children’s Hospital – The Ohio State University

Professional Practice Gap: Pediatric gastrointestinal biopsies pose distinct diagnostic challenges in contrast to adult gastrointestinal biopsies. The spectrum of diagnoses encountered in early childhood are often unique. A subset of these entities may have overlapping morphologic features with commonly diagnosed entities in adults, however, in the pediatric age group clinical associations differ. Further, underlying syndromic associations are important to recognize.  A review published by Putra et. al, highlights the need to have a different diagnostic approach in the interpretation of pediatric gastrointestinal biopsies in comparison to adults (Surg Pathol Clin. 2020 Sep;13(3):399-411). Timely diagnosis is critical in ensuring appropriate clinical diagnosis, medical and surgical management as well as an evaluation by genetics when indicated.

Learning Objectives:

1. Discuss histologic features of common and rare entities encountered on pediatric gastrointestinal biopsies with relevant syndromic associations
2. Identify ancillary tests that would assist diagnosis on small tissue biopsies
3. Generate differential diagnoses and recognize diagnostic pitfalls

Pediatric Type Lymphomas and Lymphoid Proliferations Associated with Immune Dysfunction Syndromes

Faculty: Shunyou G0ng, MD, PhD, Ann & Robert H. Lurie Children’s Hospital of Chicago

Professional Practice Gap: Pediatric type lymphomas are unique and rare lesions described and/or recognized not long ago, thus generally not familiar to practicing pathologists and pathology trainees. Distinguishing these lymphomas from benign lesions or more aggressive lymphomas is crucial for clinical management and counseling. On the other hand, several immune dysfunction syndromes primarily seen in children may present with benign lymphadenopathy nearly indistinguishable from malignant lymphoma. Particularly, these patients have significantly higher risk of developing malignant lymphoma than general population. Correct diagnosis of these pediatric type lymphomas and lymphoid proliferations associated with immune dysfunction syndromes is challenging and requires an integrated approach comprising morphologic evaluation, utilization of appropriate immunohistochemical stains and genetic studies, and clinicopathological correlation. A delay in diagnosis of these cases is common, causing anxiety in clinicians, patients, and families. Due to the rarity of these rare lesions, such specimens are commonly sent to academic institutions for consultation. As an academic pathologist entirely devoted to pediatric hematopathology, I receive and review many challenging cases in this category each year. By doing so I am fortunate to closely follow the rapid advances in disease biology and continuously update knowledge on the classification and diagnostic approaches that emerged following the 2016 revised 4th edition of WHO classification of tumors of hematopoietic and lymphoid tissues. I hope to share these updates and experiences with my fellow pathologists and/or pathology trainees at USCAP meeting

Learning Objectives:

1. Identify the morphologic, immunophenotypic and molecular/genetic features of the selected lymphoid lesions.
2. Perform focused differential diagnosis and select the relevant tests for further work-up.
3. Recognize the importance of correlating morphology with axillary studies and clinical information in reaching the correct diagnosis.

That Isn’t Peculiar, It’s Normal!: Time to Get Acquainted with the Histologic Features of Developing Fetal Organs and Not Miss Useful Clues to Certain Pathologies

Faculty: Chrystalle Carreon, MD, Boston Children’s Hospital/Harvard Medical School

Professional Practice Gap: Outside of non-academic pediatric and perinatal centers, within or outside of the US, the microscopic evaluation of fetal and neonatal tissues at pediatric and perinatal autopsies or surgical pathology sign-outs are considered the responsibility of general pathologists. However, the lack of volume and constant exposure to the such cases makes it difficult to remember the key histologic features in these special types of tissues, which could result in erroneous overinterpretation of normal findings or missing a key pathologic finding that could trigger a work-up to arrive at a more specific diagnosis.

Learning Objectives:

1. Correctly identify the different fetal organs by histology and be able to estimate the approximate gestational age (early, mid, late), as well as develop competency in judging whether the findings are within the normal spectrum or pathologic.
2. Enhance confidence in diagnosing and reporting fetal and neonatal organ findings in a systematic manner,
3. Understand the clinical significance of certain abnormal findings, particularly those that could be syndrome-associated.

The Challenging Lesion in the Lung – A Practical Approach to not so Common Pulmonary Lesions

Faculty: Anja Roden, MD, Mayo Clinic

Professional Practice Gap: Pathologists are in general familiar with non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). However, while less common, there is a broad variety of neoplasms that can occur as primary neoplasms in the lung. Some of those neoplasms may mimic SCLC or NSCLC making their diagnosis challenging, specifically on small biopsies. The diagnosis of these mimickers is important because some of those are benign, others behave more aggressive than NSCLC. Patients with some of these neoplasms such as SMARCA4-deficient undifferentiated tumor or NUT carcinoma also may have the option to participate in clinical trials and should be treated differently than NSCLC or SCLC. Other lesions are morphologically distinct but since they are less common, pathologists are often unfamiliar with those and uncomfortable signing them out.   In addition, the distinction from metastatic disease is important and needs to be considered. Furthermore, there are a few neoplasms that have been recently added to the 2021 WHO such as bronchiolar adenoma/ciliated muconodular papillary tumor and SMARCA4-deficient undifferentiated tumor; pathologists are not always familiar with them and know the implications and importance of their diagnosis.

Learning Objectives:

1. To recognize lesions that have been recently introduced in the 2021 WHO
2. To identify less common primary lung lesions
3. To utilize proper immunostains for the diagnosis of primary lung neoplasms
4. To recall molecular and cytogenetic studies that may be helpful in the distinction of some lung lesions

Why Do All Lungs Look the Same at Autopsy? Untangling the Alveolar Web

Faculty: Aliya Husain, MBBS, University of Chicago

Professional Practice Gap: Multiple articles in the recent literature have re-focused our attention on significance of evaluating pulmonary pathology in the light of COVID19 pandemic. However, expertise and training in interpretation of changes seen due to superimposed pre-mortem complications is lacking. The vast majority of textbooks focus on interstitial pneumonias and other benign conditions based on biopsies and resections and do not show how to differentiate from additional changes seen at autopsy. I see this specifically in our residents and fellows as I sign out autopsy lungs with them.

Learning Objectives:

1. Describe acute and organizing phases of lung injury at autopsy and differentiate from organizing pneumonia
2. Explain how acute changes mask the findings of interstitial and other lung diseases
3. Discuss effects of aspiration, resuscitation, pre-terminal drug therapy, heart failure on the lungs