Global Study on the Accuracy of Human Epidermal Growth Factor Receptor 2-Low Diagnosis in Breast Cancer.

CONTEXT.­: Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression. Thereby, eligibility relies on an accurate diagnosis of HER2-low status defined by immunohistochemistry IHC 1+/2+ with no gene amplification. OBJECTIVE.­: To assess pathologists' accuracy and training efficacy in the diagnosis of HER2-low. DESIGN.­: Agreement rates of HER2-low scoring in breast cancer tissue were assessed between expert consensus and real-world pathologists (n = 77 from 14 countries) before and after a specific 4-hour training for HER2-low detection. Two assays were evaluated, the Ventana Pathway 4B5 CDx and the Dako HercepTest (polyclonal). Concordance of the pathologists with consensus score and efficacy of training were measured by Cohen κ, overall rater agreement, and receiver operating characteristic (ROC) curve statistics. RESULTS.­: In the Ventana 4B5 HER2-low category, baseline agreement rates were >80% but <90%. Negative percentage agreement was improved from 80.6% to 91.1% by training. In the HER2-0 category, positive percentage agreement (74.6%) was the only parameter below the 80% benchmark but was significantly improved to 89.2% after training. Training efficacy was confirmed by ROC curve analysis, which shows improvement for the identification of HER2-0 and HER2-low cases. Finally, in-depth examination of cases with discordant HER2 status disclosed specific issues of HER2-low underscoring and overscoring. CONCLUSIONS.­: The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified.

Pathology of Crooke Cells in the Human Pituitaries: A Timely Review.

Crooke cell change was first found in the regressed and suppressed corticotroph (adrenocorticotropic hormone-producing) cells, and now is known to occur in pituitary tumors. The tumor cells of this type can be recognized by morphology with immunohistochemistry, and are well known to predict aggressive behavior such as invasion and rare metastases. This is one of the representative neuroendocrine tumors in the pituitary which is now considered to have malignant potential as proposed in the pancreas and gastrointestinal tracts. It is important to emphasize the pituitary tumor pathology such as Crooke cell change for prognostication and appropriate therapies. This review article describes the evolution from the Crooke cells to Crooke cell tumors which is timely along with the Fifth WHO classification 2022 published online.

Overview of the 2022 WHO Classification of Pituitary Tumors.

This review summarizes the changes in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the pituitary gland. The new classification clearly distinguishes anterior lobe (adenohypophyseal) from posterior lobe (neurohypophyseal) and hypothalamic tumors. Other tumors arising in the sellar region are also discussed. Anterior lobe tumors include (i) well-differentiated adenohypophyseal tumors that are now classified as pituitary neuroendocrine tumors (PitNETs; formerly known as pituitary adenomas), (ii) pituitary blastoma, and (iii) the two types of craniopharyngioma. The new WHO classification provides detailed histological subtyping of a PitNET based on the tumor cell lineage, cell type, and related characteristics. The routine use of immunohistochemistry for pituitary transcription factors (PIT1, TPIT, SF1, GATA3, and ERα) is endorsed in this classification. The major PIT1, TPIT, and SF1 lineage-defined PitNET types and subtypes feature distinct morphologic, molecular, and clinical differences. The "null cell" tumor, which is a diagnosis of exclusion, is reserved for PitNETs with no evidence of adenohypophyseal lineage differentiation. Unlike the 2017 WHO classification, mammosomatotroph and acidophil stem cell tumors represent distinct PIT1-lineage PitNETs. The diagnostic category of PIT1-positive plurihormonal tumor that was introduced in the 2017 WHO classification is replaced by two clinicopathologically distinct PitNETs: the immature PIT1-lineage tumor (formerly known as silent subtype 3 tumor) and the mature plurihormonal PIT1-lineage tumor. Rare unusual plurihormonal tumors feature multi-lineage differentiation. The importance of recognizing multiple synchronous PitNETs is emphasized to avoid misclassification. The term "metastatic PitNET" is advocated to replace the previous terminology "pituitary carcinoma" in order to avoid confusion with neuroendocrine carcinoma (a poorly differentiated epithelial neuroendocrine neoplasm). Subtypes of PitNETs that are associated with a high risk of adverse biology are emphasized within their cell lineage and cell type as well as based on clinical variables. Posterior lobe tumors, the family of pituicyte tumors, include the traditional pituicytoma, the oncocytic form (spindle cell oncocytoma), the granular cell form (granular cell tumor), and the ependymal type (sellar ependymoma). Although these historical terms are entrenched in the literature, they are nonspecific and confusing, such that oncocytic pituicytoma, granular cell pituicytoma, and ependymal pituicytoma are now proposed as more accurate. Tumors with hypothalamic neuronal differentiation are classified as gangliocytomas or neurocytomas based on large and small cell size, respectively. This classification sets the standard for a high degree of sophistication to allow individualized patient management approaches.

High-risk pituitary adenomas and strategies for predicting response to treatment.

High-risk pituitary adenomas are aggressive. They show clinical and imaging features similar to those of carcinomas, including infiltration of the surrounding brain structures, but lack cerebrospinal or systemic metastases. In addition, they display distinct behavior, including tendency for fast growth and frequent recurrences, which are difficult to control. The term "high-risk" adenoma was first introduced in the 4th edition of the World Health Organization Classification of Endocrine Tumors in 2017. Five defined adenoma types belong to this category, including sparsely granulated somatotroph, lactotroph in men, Crooke cell, silent corticotroph, and plurihormonal PIT-1 positive adenomas. The morphological and immunohistochemical characteristics of high-risk adenomas are herein described in detail. In addition, the clinical features and the treatment options are presented. This review focuses on predictive markers assessed by immunohistochemistry, which help clinicians to design the appropriate treatment strategies for high-risk adenomas. Somatostatin receptor status predicts effectiveness of postsurgical treatment with somatostatin analogs, and MGMT expression predicts response to treatment with temozolomide. This comprehensive review presents the clinical and pathological features of high-risk pituitary adenomas, underlines the contribution of immunohistochemistry, and emphasizes the leading role of pathology in the design of optimal clinical management.

JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

Molecular, functional, and histopathological classification of the pituitary neuroendocrine neoplasms.

In 2017, WHO published an updated classification of the pituitary adenomas according to the lineages defined by the transcription factors, PIT1, SF1 and TPIT. Nomenclature of the pituitary tumors follows the mature cell types such as somatotroph (GH), lactotroph (LH), thyrotroph, corticotroph, and gonadotroph (FSH, LH). Null cell adenomas are defined by the absence of expression of any hormones and transcription factors. Not infrequently, the pituitary adenomas are invasive to the adjacent structures and are designated as aggressive adenomas. Knosp grading is often used to define the aggressiveness of the tumor. Sparsely granulated somatotroph adenomas and Crooke cell corticotroph adenomas are representative aggressive adenomas. Recently, genomics regarding various adenomas have been clarified, such as GNAS for somatotrophs and USP8 for corticotrophs. Familial pituitary adenomas are another aspect which has been clarified such as MEN1, Carney's complex, familial isolated pituitary adenoma and McCune-Albright syndrome. The pituitary adenomas often produce GH or PRL, hormones of PIT1 transcription factor. It has been agreed that the pituitary adenomas share the characteristics of neuroendocrine neoplasms. The terminology of pituitary neuroendocrine tumor has been discussed. This review article covers various aspects of pituitary adenomas.

Digital/Computational Technology for Molecular Cytology Testing: A Short Technical Note with Literature Review.

This short article describes the method of digital cytopathology using Z-stack scanning with or without extended focusing. This technology is suitable to observe such thick clusters as adenocarcinoma on cytologic specimens. Artificial intelligence (AI) has been applied to histological images, but its application on cytologic images is still limited. This article describes our attempt to apply AI technology to cytologic digital images. For molecular analysis, cytologic materials, such as smear, LBC, and cell blocks, have been successfully used for targeted single gene detection and multiplex gene analysis with next-generation sequencing. As a future perspective, the system can be connected to full automation by combining digital cytopathology with AI application to detect target cancer cells and to perform molecular analysis. The literature review is updated according to the subjects.

Survey of surgical resections for neuroendocrine liver metastases: A project study of the Japan Neuroendocrine Tumor Society (JNETS).

BACKGROUND/PURPOSE: Hepatic resection is considered the treatment of choice for neuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study was to collect real-world data regarding hepatic resections for NELM. METHODS: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative details, pathological findings, and patient outcomes were investigated. RESULTS: A total of 222 patients were enrolled from 30 institutions. The primary tumor site was the pancreas in 58.6%, and the presentation of NELM was synchronous in 63.1% of the cases. Concomitant resection of the primary tumor and liver metastases was performed for 66.4% of the synchronous metastases, and the 90-day morbidity and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2 resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence after R0/1 resections. However, the patients were treated using multiple modalities after R2 resection or recurrence, and the overall survival rate was relatively favorable, with 5-year and 10-year survival rates of 70.2%, and 43.4%, respectively. Univariable and multivariable analyses identified the tumor grading (G3) of the primary tumor as a significant prognostic factor for both the recurrence-free and overall survivals. CONCLUSIONS: The present data confirmed the safety of the surgical resection of NELM. Although recurrences were frequent, the survival outcomes after resection were favorable when a multi-disciplinary treatment approach was used.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

Histopathology and Cytopathology of Neuroendocrine Tumors and Carcinomas of the Breast: A Review.

Neuroendocrine tumors (NET) and carcinomas (NEC) of the breast are rare diseases, but NEC has attracted attention in both cytopathology and surgical pathology because of its specific management and prognosis. Fine-needle aspiration biopsy (FNAB) cytology can make the diagnosis in many cases particularly with high-grade NEC, with definitive diagnosis based on histopathology and immunohistochemistry. This review describes the characteristics of the disease based on the WHO classification 2012 and recent literature and -includes discussion related to the International Academy of Cytology Yokohama System of Reporting Breast FNAB -cytology.

The International Academy of Cytology Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytopathology.

The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.

Phase II Trial of Trastuzumab and Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Salivary Duct Carcinoma.

PURPOSE: Clinical evidence demonstrating the effectiveness of systemic therapy for advanced salivary duct carcinoma (SDC) is lacking because of the disease's rarity. We assessed the efficacy and toxicity of trastuzumab plus docetaxel in patients with locally advanced and/or recurrent or metastatic human epidermal growth factor receptor 2-positive SDC. PATIENTS AND METHODS: This was a single-center, single-arm, open-label, phase II study in Japan. The patients received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Docetaxel 70 mg/m2 was administrated every 3 weeks. The primary end point was the overall response rate; the secondary end points included the clinical benefit rate, progression-free survival, overall survival, and toxicity. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry (Identification No. UMIN000009437). RESULTS: Fifty-seven eligible patients with SDC were enrolled. The overall response rate was 70.2% (95% CI, 56.6% to 81.6%), and the clinical benefit rate was 84.2% (95% CI, 72.1% to 92.5%). Median progression-free and overall survival times were 8.9 months (95% CI, 7.8 to 9.9 months) and 39.7 months (95% CI, not reached), respectively. The most frequent adverse event was anemia (52 patients [91%]), followed by a decreased WBC count (51 patients [89%]) and neutropenia (50 patients [88%]). The most frequently observed grade 4 adverse event was a decreased neutrophil count (34 patients [60%]). Grade 3 febrile neutropenia was reported in eight patients (14%). No grade 2 or greater adverse events of heart failure or left ventricular ejection fraction decline to less than 50% occurred. CONCLUSION: Our data show encouraging efficacy of trastuzumab plus docetaxel therapy in patients with human epidermal growth factor receptor 2-positive SDC, with a manageable toxicity profile.

A Groundbreaking Work Which Laid the Foundation for Mass Screening in Cervical Cytology in Japan.

This commentary discusses the impact of a milestone article on the accuracy of cervical smears for detecting cancer back in the developmental and transforming era of the cytological detection of atypical and malignant cells. The study served in the establishment of cancer screening in Japan which has contributed greatly in decreasing mortality from cervical cancers.

A Case Report: Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm with Aggressive Neuroendocrine Component.

Mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) is defined as mixed epithelial neoplasms composed of both neuroendocrine and nonneuroendocrine components with variable proportions for each component. Neuroendocrine component can show morphological features including well- or poorly differentiated neuroendocrine neoplasms and nonneuroendocrine component can present different tumor types depending on the site of origin. Recently, studies of tumors have shown that MiNENs are not as rare as our traditional belief, due to the wide application for immunohistochemistry. However, our knowledge of MiNENs is still limited. There is no universal consensus about nomenclature, classification, and guideline of treatment. Hereby, we would like to present a case report of gastric MiNEN with aggressive neuroendocrine component to contribute a small part towards common understanding of gastric MiNENs.

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity.

Trastuzumab-containing therapy is a standard of care for patients with HER2+ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity.

Experts' opinion: Recommendations for retesting breast cancer metastases for HER2 and hormone receptor status.

The human epidermal growth factor receptor 2 (HER2) and hormone receptor status of recurrent breast cancer may change between the tumor and metastases from negative to positive and vice versa, potentially affecting the treatment regimen. Retesting of metastases may therefore be crucial to allow appropriate selection of patients for whom targeted therapy is indicated; however, retesting is not routinely performed. This article recommends that metastases be retested for HER2 and hormone receptor status and provides practical guidance on when and how to retest, as agreed by a panel of expert pathologists with extensive experience of HER2 and hormone receptor testing.

A rare case with a solitary fibrous tumour of the colon and an epithelioid angiomyolipoma of the kidney.

Solitary fibrous tumour is a soft tissue tumour composed of a subset of fibroblast-like cells and frequently needs immunohistochemical staining for final diagnosis. Epithelioid angiomyolipoma is a variant of angiomyolipoma but characterized by the absence of both adipocytes and abnormal blood vessels. We introduce a very rare case with the combination of these two tumours. A Japanese female patient without significant symptom was hospitalized and operated due to multiple uterine leiomyomas. During the operation, the surgeons found another tumour attaching to serosa of sigmoid colon. This tumour was resected and interpreted as solitary fibrous tumour, suspicious of malignancy. After 13 months of treatment, she was hospitalized again due to hematuria. The doctors detected a tumour in her right kidney. After consultation, laparoscopic right nephrectomy was done. The pathological result of this tumour was epithelioid angiomyolipoma. This is the first report on this very rare combination of tumours with extensive immunohistochemical demonstration of both tumours. Hereby, we review clinical information and histopathological findings together with discussion on each tumour.

Transdifferentiation of pituitary thyrotrophs to lactothyrotrophs in primary hypothyroidism: case report.

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.