Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).

Maud Menten: Pioneering Pediatric-Perinatal Pathologist, Clinician-Scientist, and "the Most Wonderful Human Being in the World".

Maud Menten was born and raised in remote regions of Canada. She obtained her MB/MD at the University of Toronto (1907/1911) and her PhD in biochemistry at the University of Chicago (1916). From 1907 to 1916, she trained at the Rockefeller Institute for Medical Research, the New York Infirmary for Women and Children, Western Reserve University in Cleveland, the Berlin Municipal Hospital in Germany, and the Barnard Free Skin and Cancer Hospital in St Louis. In 1916, she was appointed as pathologist at the Elizabeth Steel Magee Hospital, a charitable maternity hospital in Pittsburgh. She received a faculty appointment at the University of Pittsburgh (1918) and was appointed pathologist at Pittsburgh Children's Hospital (1926). In addition to being one of the first woman academic pathologists, she was likely the first perinatal, the second pediatric-perinatal, and the fourth pediatric pathologist to practice in North America. The importance of Menten's overall scientific contributions place her in the very upper echelon of 20th century pathologists. Her enzyme kinetic work resulted in the Michaelis-Menten equation, and her work in George Crile's laboratory in Cleveland provided a physiological basis for improved surgical outcomes. Her work in Pittsburgh was equally innovative, including initiating the field of enzyme histochemistry.

Dick van Velzen and the Burnside warehouse organ scandal in Nova Scotia, Canada.

Dick van Velzen practiced as a pediatric pathologist at Alder Hey Children's Hospital in Liverpool, England from September 1988 until December 1995; he then relocated to the IWK-Grace Health Centre, a children's and maternity hospital in Halifax, Nova Scotia, Canada, where he practiced until he was fired for cause in January 1998. About a year and a half later, his practice in Liverpool came under increasing scrutiny, with the initial focus on the massive collection of post-mortem pediatric organs he had accumulated for planned future research on sudden infant death syndrome. Soon, a Parliamentary Inquiry began investigating the full scope of his Liverpool practice. During the Inquiry, another organ-hoarding scandal erupted; van Velzen, when leaving Halifax after his dismissal, had put his family's personal belongings into a storage facility at Burnside Industrial Park and then did not pay bills. As his belongings were being prepared for auction, formalin-fixed organs were found, and a Canada-wide arrest warrant for disrespect for human remains was issued by the Halifax Police. While the Alder Hey scandal resulted in a 535-page-long Parliamentary Report and the Human Tissue Act, van Velzen was never charged criminally in the UK. The largely unknown story of his second organ scandal in Halifax, is related here. Although he had obtained the body parts with the consent of the parents of the child to which they had belonged, his failure to properly identify and store them traumatized parents already impacted by his organ-hoarding in the UK, traumatized additional parents in Halifax, and resulted in significant waste of public resources in investigating the case. He pled guilty to "indignity to a human body" in Canada and was fined and placed on 12 months' probation.

Eosinophilic/T-cell Chorionic Vasculitis: Its Incidence Is Increasing but It Does Not Appear to Recur in Subsequent Pregnancies.

INTRODUCTION: Eosinophilic/T-cell chorionic vasculitis (E/TCV), an incidental finding primarily in third trimester placentas, is characterized by eosinophils and CD3+ T lymphocytes infiltrating at least 1 chorionic and/or stem villous vessels. Its etiology and clinical significance are unclear. METHODS: Placental pathology reports issued by 8 pediatric-perinatal pathologists at Alberta Children's Hospital were retrieved from the lab information system (2010-2022), and candidate reports were identified using a Perl script searching for "eosinophil." Candidate diagnoses of E/TCV were validated by pathologist review. RESULTS: 38,058 placenta reports from 34,643 patients were reviewed; 328 cases of E/TCV were identified, for an overall incidence of 0.86%. Incidence increased 23% per year, from 0.11% in 2010 to 1.5% in 2021 (P < .01). This temporal change was observed for all pathologists; the incidence of identified multifocality also increased over time (P < .01). Umbilical vascular involvement was exceedingly rare. No variation in incidence was attributable to season. We received more than 1 placenta from 46 mothers with an E/TCV placental diagnosis; examination of >1 placenta did not reveal any mother with >1 E/TCV diagnosis. CONCLUSIONS: The incidence of E/TCV increased steadily over a ~12-year period and no recurrent cases were observed.

Prenatal Diagnosis of Isolated Right Ventricular Non-Compaction Cardiomyopathy with an MYH7 Likely Pathogenic Variant.

Background: Noncompaction of ventricular myocardium is a cardiomyopathy that typically involves the left ventricle or both ventricles; it has often been associated with mutations in genes encoding sarcomere proteins. Little is known about isolated right ventricular noncompaction, as only a few cases have been reported. Case Report: A 30 year old G2P1 woman experienced a spontaneous fetal loss at 19 weeks and 4 days. An ultrasound examination at 19 weeks showed right ventricular and tricuspid valve abnormalities, ascites, and early hydrops. At autopsy, the right ventricular chamber was dilated with numerous prominent trabeculations and deep intrabecular recesses as well as a dysplastic tricuspid valve. Histologic examination confirmed isolated right ventricular noncompaction. Whole exome sequencing showed a likely pathogenic variant in the MYH7 gene. Conclusions: This appears to be the first report of isolated right ventricular noncompaction associated with a gene mutation as well as the first diagnosis in a fetus.

Co-occurrence of Eosinophilic/T-Cell Chorionic Vasculitis and Acute Chorionitis, Acute Chorionic Vasculitis, and Funisitis in a Term Placenta.

Eosinophilic/T-cell chorionic vasculitis was initially defined as "a new form of chorionic vasculitis characterized by an infiltrate composed primarily of eosinophils and CD3+ T lymphocytes ... [that] occurs in the absence of any evidence of chorioamnionitis." No subsequent reports have directly addressed whether histologic evidence suggestive of amniotic fluid infection should preclude its diagnosis. The case reported here describes a term placenta with mild acute chorionitis, moderate acute subchorionitis, mild acute chorionic vasculitis, and funisitis associated with multifocal eosinophilic/T-cell chorionic vasculitis. It shows unequivocally, with immunohistochemical staining, that eosinophilic/T-cell chorionic vasculitis and acute chorionic vasculitis can be seen and histologically distinguished in the same case. The paper shows how differing interpretations of inclusion and exclusion criteria by investigators have affected estimates of the incidence of this rare lesion. There is a need to harmonize diagnostic criteria; the report describes how cases with both entities can be documented carefully.

What Was Known About Childhood Diabetes Mellitus Before the Discovery of Insulin?

It has been widely reported by historians that physicians were aware of two distinct types of diabetes mellitus by the 1880s, and that these were both similar to and the direct forerunners of type 1, juvenile-onset and type 2, adult-onset diabetes. The writings of prominent specialist physicians practicing just prior to the discovery of insulin in 1921-1922 were reviewed and there is little evidence that experts believed that adult and childhood diabetes were different. In fact, more than a decade passed after the discovery of insulin before diabetes in children and adults even began to be distinguished. Childhood diabetes was exceedingly rare in the early 20th century and diabetes was believed to be primarily a chronic disease of adults. It is interesting to speculate about what might have happened if the first pancreatic extract tests had been performed on adult-onset diabetics with insulin-resistant diabetes mellitus. Clearly, the results would have been disappointing and the discovery of insulin delayed. This essay explores how the test subject decision was made. It is fortuitous that a 14 year old boy with what was unequivocally type 1 diabetes was selected to be the first insulin recipient, and the rest is history.

Workload Measurement in Subspecialty Placental Pathology in Canada.

BACKGROUND: Workload measurement is important to help determine optimal staffing and workload distribution for pathology laboratories. The Level 4 Equivalent (L4E) System is the most widely used Anatomical Pathology (AP) workload measurement tool in Canada. However, it was initially not developed with subspecialties in mind. METHODS: In 2016, a Pan-Canadian Pediatric-Perinatal Pathology Workload Committee (PCPPPWC) was organized to adapt the L4E System to assess Pediatric-Perinatal Pathology workload. Four working groups were formed. The Placental Pathology Working Group was tasked to develop a scheme for fair valuation of placental specimens signed out by subspecialists in the context of the L4E System. Previous experience, informal time and motion studies, a survey of Canadian Pediatric-Perinatal Pathologists, and interviews of Pathologists' Assistants (PA) informed the development of such scheme. RESULTS: A workload measurement scheme with average L4E workload values for examination and reporting of singleton and multiple gestation placentas was proposed. The proposal was approved by the Canadian Association of Pathologist - Association canadienne des pathologistes Workload and Human Resources Committee for adoption into the L4E System. CONCLUSION: The development of a workload measurement model for placental specimens provides an average and fair valuation of these specimen types, enabling its use for resource planning and workload distribution.

Winner's curse: The sad aftermath of the discovery of insulin.

Every young researcher dreams of making a great discovery, but few achieve it. If they do, success does not guarantee happiness. There is little satisfaction in discovering something if others get the credit, and those who achieve fame must face the 'winner's curse' of living up to their reputation. Few discoveries have been more dramatic than the isolation of insulin which, as Michael Bliss said, resembled a secular miracle. And yet, as he also pointed out, this great discovery brought little happiness to those who made it. Some were sidelined, and Banting and Best were saddled with the winner's curse. Here, we look at the ways in which a great discovery can haunt its discoverers.

Vitelline Vessel Remnant-Derived Funisitis Is a Sensitive and Specific Predictor of Histological Evidence of Amniotic Fluid Infection.

BACKGROUND: 4-11% of umbilical cords contain vitelline vessel remnants (VVRs). A recent study has described neutrophilic inflammation arising from VVRs and suggested an association with amniotic fluid infection (AFI). METHODS: During routine placental pathology sign-out over a six month period, we identified 70 cords with VVRs. HE-stained sections were re-examined for "VVR-derived funisitis," which was classified as low or high grade/stage based upon whether neutrophils were present only in Wharton's jelly near the VVRs or whether neutrophils were also present near the cord's amniotic surface. The same placentas were also examined for histologic evidence of AFI (maternal response = acute chorionitis or chorioamnionitis vs. fetal response = chorionic vasculitis, umbilical vasculitis, or funisitis vs. both). RESULTS: Neutrophilic inflammation arising from VVRs was present in 54.3% (38/70); 15 and 23 lesions were low and high grade/stage, respectively. "VVR-derived funisitis" was strongly associated with histological evidence of AFI elsewhere in the placenta. Its overall sensitivity and specificity were 0.94 and 0.88; when VVR-derived funisitis was high grade/stage or diagnosed in the third trimester, specificity rose to 1.0. CONCLUSION: "VVR-derived funisitis" has a strong association with histological evidence of AFI.

Kurt Aterman, MUDR, MB, BCh BAO HONS, DCH, MRCP, PhD, DSc, FRCPath: "A Small Man With a Very Large Cerebrum and a Soul to Match".

Kurt Aterman was raised in the Czech-Polish portions of the former Austro-Hungarian Empire during World War I and the interwar period. After completing medical school and beginning postgraduate pediatrics training in Prague, this Jewish Czech physician fled to England as a refugee when the Nazis occupied his homeland in 1939. He repeated/completed medical training in Northern Ireland and London, working briefly as a pediatrician. Next, he served in the Royal Army Medical Corp in India, working as a pathologist. After the war and additional pathology training, he spent the next decade as an experimental pathologist in Birmingham, England. After completing a fellowship with Edith Potter in Chicago, Aterman spent the next 2 decades as a pediatric-perinatal pathologist, primarily working in Halifax, Canada. Fluent in many European languages, he finished his career as a medical historian. Aterman published extensively in all 3 arenas; many of his pediatric pathology papers were massive encyclopedic review articles, accurately recounting ideas from historical times. Aterman was a classical European scholar and his papers reflected this. Aterman was one of the founding members of the Pediatric Pathology Club, the predecessor of the Society for Pediatric Pathology. This highly successful refugee's writings are important and memorable.

Diffuse Subamniotic Calcification: A Novel Pattern of Placental Calcification.

Two primary patterns of placental calcification have been described, each with distinctive pathophysiology and clinical relevance. We report a novel pattern of diffuse subamniotic calcification. It occurred in a 25-week placenta involved by recurrent chronic histiocytic intervillositis (CHI) associated with severe intrauterine growth restriction (IUGR) and intrauterine fetal demise (IUFD). This was the mother's third stillbirth related to CHI, despite treatment with intravenous immunoglobulin (IVIG), prednisone, low-molecular-weight heparin, and acetylsalicylic acid (ASA). On placental examination, the majority of the fetal surface was calcified. This variably formed a continuous band or dispersed calcium microparticles. Electron microscopy demonstrated associated electron dense deposits highly suggestive of immune complex deposition. CHI explains recurrent IUGR and stillbirth, but has not been associated with calcification or immune complex deposition. We hypothesize IVIG therapy may have caused immune complex deposition and subsequent dystrophic calcification, supported by its rare association with immune complex deposition disorders in the kidney. Identification of additional cases with this pattern of calcification, with additional studies on fresh tissue including immunofluorescence, electron microscopy and mass spectrometry, may aid in elucidating the underlying pathophysiology and clinical significance of this unusual lesion.

Daniel Smith Lamb (1843-1929): A window into the early histories of the Army Medical Museum and Howard University Medical School.

U.S. Army doctor Daniel Smith Lamb was a significant figure in the history of American pathology during its formative years. For 55 years (1865-1920), Lamb performed hundreds of autopsies in and around Washington, D.C. and personally collected over 1,500 gross pathology specimens for the Army Medical Museum. His work began at the close of the Civil War and continued on through World War I, contributing substantially to gross pathological and histological studies that documented wartime pathology, thus further contributing to the training of Army doctors. Specimens he collected also include material from autopsies he conducted on President James Garfield, his assassin Charles Guiteau, and other historical figures. Under the auspices of the Army Medical Museum, he conducted autopsies across the city of Washington for the museum's collection, many of which survive to this day at the National Museum of Health and Medicine. He served under 12 U.S. Army Surgeons General and 11 Museum Curators and was noted to be a steadying influence during a time of constant leadership changes at that institution. Lamb was known throughout Washington, D.C. as an advocate of medical education for African-Americans and women. While working at the Museum, he simultaneously served for 46 years as professor of anatomy at Howard University (1877-1923). He wrote seminal histories of the institutions with which he was associated and in so doing also contributed significantly to the study of the history of medicine.

Prevalence, Morphology, Embryogenesis, and Diagnostic Utility of Umbilical Cord Vitelline Vascular Remnants.

The objective of this study is to better understand embryonic vitelline vascular remnants in the umbilical cord, to assess their prevalence, to categorize their morphology, and then finally to describe and assess inflammation arising from these structures. During routine placental sign out, the author noted the presence or absence of vitelline vessel remnants for 1 year; when present, he assessed their histologic patterns and noted whether there were neutrophils marginating from the remnants and into the adjacent Wharton's jelly and whether there was any other evidence of amniotic fluid infection in sections of placental disc, membranes, or cord. All cord sections with vitelline vessel remnants were immunostained for CD15 to document any infiltrates, to highlight patterns of infiltration, and to evaluate whether mild cases of umbilical phlebitis were associated with these lesions and were at risk of being missed. Vitelline vessel remnants were present in 4.2% of placentas examined. There were 5 vitelline vessel remnant histologic patterns identified providing insight into the vitelline vessel circulation. Funisitis, primarily neutrophilic, arising from vitelline vessel remnants was present in 70.3% of the 37 cords with vitelline vessel remnants. The presence of vitelline vessel remnant funisitis documents continued active circulation in these vascular structures, and vitelline vessel remnant funisitis was associated with the presence of other placental histological evidence of amniotic fluid infection in 53.8% of cases. The author also reviews normal embryology and the pathology of vitelline vessel remnants.

Discordance of Twin Placentas for Multifocal Eosinophilic/T-cell Chorionic Vasculitis.

Eosinophilic/T-cell chorionic vasculitis (ETCV) is an idiopathic placental lesion characterized by chorionic vasculitis composed predominantly of eosinophils and CD3+ T lymphocytes. It usually presents as a unifocal lesion, but a subset have multifocal involvement. We report 4 Di-Di and 2 Di-Mo twins sharing fused placental discs with discordant circulatory involvement by multifocal ETCV. The findings are difficult to explain by sampling alone. The limitation of ETCV to 1 fetus's vascular territory in monozygotic twin pregnancies is difficult to explain but could provide insights into the fetal immune system and the etiology of ETCV.

Pioneer in Pediatric Pathology: William A (Bill) Newton Jr (1923-).

William A (Bill) Newton Jr practiced pediatric pathology and hematology/oncology at Children's Hospital of Columbus, Ohio, for over 40 years starting in 1952. Newton was an original member of the Pediatric Pathology Club, which preceded the Society for Pediatric Pathology, and was its president from 1968 to 1969. He published important independent observations in pediatric pathology, helped establish systematic cooperative pediatric tumor pathology review by experts, became an acclaimed expert on the diagnosis of rhabdomyosarcoma, was a critical contributor to many pediatric oncology clinical trials, made important early contributions to tumor banking in pediatrics, and trained numerous pediatric pathology and pediatric oncology fellows. Finally, he concluded his career as a humanitarian, leading important volunteer work aimed at improving pediatric cancer care in China. This most interesting pediatric pathologist was simultaneously a Brigadier General in the U.S. Army. Bill Newton's life and career, which is reviewed in detail here, should be of immense interest and an inspiration to the Pediatric & Developmental Pathology readership.

Early history of transylvania medical college: The saga of a disputed autopsy precipitating a duel and grave robbing.

At the beginning of the 19th century, there were only five medical schools in America. The Medical Department of Transylvania University in Lexington, Kentucky, was the first in the West; however, it had few students or faculty until it was restructured in 1815. In 1817-1818, three of its faculty members (Benjamin Dudley, Daniel Drake, and William Richardson) quickly developed a highly dysfunctional relationship. Dudley tried to have Richardson fired, with Drake blocking this. Drake then criticized Dudley's performance of a coroner's autopsy, resulting in both parties publishing derogatory comments about each other. Dudley then challenged Drake to a pistol duel but Drake, not believing in dueling, declined. Richardson, wanting to defend his friend's honor, accepted the challenge and was mortally wounded in August 1818. Dudley, a prominent surgeon, saved his life. Both Dudley and Richardson were important Kentuckian Freemasons and the brotherhood felt compelled to punish them for un-Masonic behavior. Drake left and started his own medical school in Cincinnati in 1819, in direct completion with and destabilizing Transylvania's school. This saga is dissected in the context of the bizarre history of dueling as part of the Code of Honor by which gentlemen in the Old South often resolved their differences. The essay analyzes the autopsy dispute and reviews politics within the medical school, the University, and newer competing medical schools. Transylvania's medical school was recognized as one of the best in the US during the first half of the 1800s, but by 1859, it had permanently closed its doors. Clin. Anat. 32:489-500, 2019. © 2019 Wiley Periodicals, Inc.

From shame to fame: The improbable career of the great anatomist-surgeon D. Hayes Agnew.

David Hayes Agnew began his career as a country doctor in rural Pennsylvania in 1838. After a 3-year diversion as a partner in a large ironworks business that went bankrupt in 1846, Agnew, seriously in debt, returned to the medical profession in Cochranville, PA, hoping to focus on surgery. Recognizing that he needed to improve his knowledge of anatomy, he purchased cadavers from Philadelphia and dissected at home in his spare time. When he was finished dissecting, he covertly moved bodies to a nearby pond so he could later collect skeletons after eels had removed the remaining soft tissues. This worked well until Agnew and the townspeople found out that a local fisherman, known for selling the most delicious eels, fished exclusively from this pond. Agnew was asked to leave Cochranville and he moved to Philadelphia, where he purchased the Philadelphia School of Anatomy and worked as a surgeon at Blockley Hospital. During the Civil War, he became renowned for his ability to manage gunshot wounds. Agnew was upwardly mobile in Philadelphia, becoming one of America's most prominent 19th-century academic surgeons. When President James Garfield was shot by an assassin, Agnew was called to care for him. When he retired from his position as the John Rhea Barton Professor of the Principles and Practice of Surgery at the University of Pennsylvania, the medical students hired the famous American realist painter, Thomas Eakins, to produce The Agnew Clinic, which became one of the artist's two most important paintings. Clin. Anat. 32:661-671, 2019. © 2019 Wiley Periodicals, Inc.