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.

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.

HER2 testing in gastric cancer: a practical approach.

Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is approved by the European Medicines Agency for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry 3+ or immunohistochemistry 2+/fluorescence in situ hybridization-positive or immunohistochemistry 2+/silver in situ hybridization-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal junction. Approvals are underway in other countries, with recent approvals granted in the United States and Japan. Experience and data from trastuzumab use in breast cancer have highlighted the importance of quality HER2 testing and scoring to ensure accurate identification of patients eligible for treatment. HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity (focal staining) and incomplete membrane staining. Consequently, gastric cancer-specific HER2 testing protocols have been developed and standardized and it is imperative that these recommendations be adhered to. Given the predictive value of HER2 protein levels with response in the trastuzumab for GAstric cancer study (ToGA), immunohistochemistry should be the initial testing methodology and fluorescence in situ hybridization or silver in situ hybridization should be used to retest immunohistochemistry 2+ samples. Wherever possible, bright-field methodologies should be used as these are considered to be superior to fluorescent methodologies at identifying heterogeneous staining. Specific training is required before embarking on HER2 testing in gastric cancer, irrespective of the experience of HER2 testing in breast cancer. This paper provides the most up-to-date practical guidance on HER2 testing and scoring in patients with gastric and gastro-esophageal junction cancer, as agreed by a panel of expert pathologists with extensive experience of HER2 testing particularly reflecting the European Medicines Agency-approved indication. It is anticipated that these recommendations should ensure accurate and consistent HER2 testing, which will allow appropriate selection of patients eligible for treatment with trastuzumab.

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.

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.

Expression of FOXL2 in human normal pituitaries and pituitary adenomas.

Many transcription factors have important roles in the function and differentiation of the human pituitary adenomas. Forkhead box gene transcription factor L2, Foxl2, is expressed during mouse pituitary development and co-localizes with the expression of α-glycoprotein hormone subunit (αGSU). In addition, Foxl2 regulates expression of the αGSU gene (Cga) in cell culture. To elucidate the functional role of FOXL2 in the human pituitary, we examined the expression and localization of FOXL2 in normal human pituitaries and various types of pituitary adenomas. Human pituitary adenomas were obtained by trans-sphenoidal surgery from 67 patients. Three normal adult pituitaries were obtained from autopsies of non-endocrine cases. The localization of FOXL2 and pituitary hormones in these pituitary patients was examined by immunohistochemical staining and RT-PCR. Quantitative analysis of FOXL2 protein was performed by immunoblotting. FOXL2 was localized in the nuclei of ∼20% of normal pituitary cells that also co-expressed gonadotropins including follicule-stimulating hormone ß (FSHß), luteinizing hormone ß (LHß), and αGSU, whereas it was observed in minor proportion of thyroid-stimulating hormone (TSH)-producing cells, prolactin (PRL)-producing cells, and precursor of adrenocorticotropic hormone (ACTH)-producing cells. FOXL2 immunoreactivity was not detected in growth hormone (GH)-producing cells or S100-positive folliculo-stellate cells. In human pituitary adenomas, FOXL2 was expressed in the nuclei of the adenoma cells. FOXL2 was detected in 13 of 15 gonadotropin-subunit-producing adenoma (Gn-oma) cases and 8 of 11 null cell adenoma cases, but its incidence was reduced or not detected in the other types of adenomas. The results of this study suggest that FOXL2 contributes to the human-specific functional expression and the differentiation of gonadotroph cells and adenomas.

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.

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.

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.

Fine needle aspiration cytology of ductal adenoma of the breast with intracellular mucin: a report of three cases.

BACKGROUND: Ductal adenoma of the breast is a benign lesion that can mimic both the clinical and cytopathologic features of carcinoma. Benign breast lesions with intracellular mucin are extremely rare, and ductal adenoma with intracellular mucin has not previously been reported. Here we present three cases of ductal adenoma of the breast with foci of intracellular mucin. CASES: Three patients were admitted to Tokai University School of Medicine Hospital and underwent fine needle aspiration cytology and histologic examination by excisional biopsy or partial resection. Fine needle aspiration cytology was performed using a 23-gauge needle, and smears were immediately fixed in ethanol and stained as Papanicolaou preparations. Epithelial cells formed cohesive clusters, consisting of biphasic luminal and myoepithelial cells accompanied by apocrine metaplasia with occasional high nuclear atypia. All three cases showed intracellular mucin, in varying amounts, which led to their being overdiagnosed as malignant lesions. CONCLUSION: To avoid overdiagnosis of ductal adenomas as malignant lesions, it is important to recognize that both intracytoplasmic mucin and atypical apocrine features can be usual cytologic findings of this disease.

Hypophysectomy for a dog with coexisting Cushing's disease and diabetes mellitus.

An 11-year-old male mixed breed dog diagnosed with Cushing's disease and diabetes mellitus was treated by hypophysectomy. After surgery, the hypercortisolemia disappeared and the diabetes status improved. The insulin requirement to control hyperglycemia gradually decreased. At 12 weeks after surgery, there was no requirement for insulin and we suspected the diabetes was completely resolved. In the present case, diabetes mellitus seems to be secondary to Cushing's disease. In conclusion, this mixed breed dog with coexisting Cushing's disease and diabetes mellitus is the first case showing the effectiveness of hypophysectomy to treat diabetes mellitus secondary to Cushing's disease in dogs.

Roles of pathologists in molecular targeted cancer therapy.

Molecular targeted cancer therapy (MTCT) is the "personalized" or "individualized" approaches toward cancer which targets the particular molecular or genetic changes, i.e. over-expression of molecules, and genetic amplification, mutations and translocations. MTCT is generally composed of two mechanisms, (1) humanized monoclonal antibodies (hMAB) and (2) tyrosine kinase inhibitors (TKI). Somatostatin analogue (SA) is the unique situation for the therapy of neuroendocrine tumors (NETs) which possess somatostatin receptor (SSTR). The cancers which are benefited by MTCT have been increased and will be increased to cover wide varieties of cancers. Good examples are (1) trastuzumab, hMAB against HER2 in breast cancers with HER2 over-expression and amplification, (2) imatinib, TKI, for gastrointestinal stromal tumors (GISTs) with c-kit mutation, (3) gefitinib, TKI, for lung adenocarcinoma with EGFR mutation. The drug effects have been reported to be associated with these molecular and genetic changes. It should be particularly emphasized to treat the patients with corresponding targeted molecular changes. These molecular and genetic analysis should be performed! On the right areas of the cancers, ample amount of viable cancer cells, where the major roles of pathologists are lied. This introductory review of MTCT describes more details of each MTCT.

Selection of buffer pH by the isoelectric point of the antigen for the efficient heat-induced epitope retrieval: re-appraisal for nuclear protein pathobiology.

Epitope retrieval (ER) using heating causes a dramatic improvement in the sensitivity of immunohistochemistry for formalin-fixed paraffin-embedded (FFPE) tissue sections. Here, the relationship between the pH of the retrieval buffer used for heat-induced epitope retrieval (HIER) and the isoelectric points (pI) of the antigen recognized by antibodies against nuclear proteins (mainly human pituitary transcription factors in this study) was investigated using FFPE tissue sections. A universal buffer, with a buffering capacity over a wide pH range from 2.0 to 12.0, was used for HIER. We found that the intensity of staining for most nuclear proteins after HIER depended simply on the pH of the buffer. Importantly, for efficient HIER, antigens with acidic pI required basic pH buffer conditions, while antigens with alkaline pI required acidic conditions. This implies that the electrostatic charge of the antigens contributed significantly to the efficiency of HIER. We conclude that appropriate selection of the pH of the buffer based on the pI of the individual antigens is of great importance for efficient ER. It is concluded that the mechanism of HEIR may, therefore, depend to a large extent on the pI of the antigen under investigation.

Genetics, gene expression and bioinformatics of the pituitary gland.

Genetic cases of congenital pituitary hormone deficiency are common and many are caused by transcription factor defects. Mouse models with orthologous mutations are invaluable for uncovering the molecular mechanisms that lead to problems in organ development and typical patient characteristics. We are using mutant mice defective in the transcription factors PROP1 and POU1F1 for gene expression profiling to identify target genes for these critical transcription factors and candidates for cases of pituitary hormone deficiency of unknown aetiology. These studies reveal critical roles for Wnt signalling pathways, including the TCF/LEF transcription factors and interacting proteins of the groucho family, bone morphogenetic protein antagonists and targets of notch signalling. Current studies are investigating the roles of novel homeobox genes and pathways that regulate the transition from proliferation to differentiation, cell adhesion and cell migration. Pituitary adenomas are a common human health problem, yet most cases are sporadic, necessitating alternative approaches to traditional Mendelian genetic studies. Mouse models of adenoma formation offer the opportunity for gene expression profiling during progressive stages of hyperplasia, adenoma and tumorigenesis. This approach holds promise for the identification of relevant pathways and candidate genes as risk factors for adenoma formation, understanding mechanisms of progression, and identifying drug targets and clinically relevant biomarkers.

Perivascular epithelioid cell tumor (PEComa) of the pancreas: immunoelectron microscopy and review of the literature.

A perivascular epithelioid tumor (PEComa) is a rare tumor probably arising from the perivascular epithelioid cells. Only three cases of pancreatic PEComa have been reported in the English-language literature. The present report describes an extremely rare case of pancreatic PEComa. A 47-year-old Japanese woman complained of lower abdominal pain and a well-demarcated solid tumor was found in the pancreatic head. There was no history of tuberous sclerosis complexes. Pylorus-preserving pancreaticoduodenectomy was thus performed. There was a well-demarcated, solid tumor measuring 17 mm in the pancreatic head. The tumor was composed of a diffuse proliferation of epithelioid tumor cells with many blood vessels but no adipose tissue. The tumor cells expressed HMB45 and alpha-smooth muscle actin. Ultrastructurally, the tumor cells possessed many membrane-bound granules that were positive for HMB45 on immunoelectron microscopy. The results of immunoelectron microscopy show that some PEComas possess not only typical melanosomes or premelanosomes but also aberrant melanosomes.

Coexistence of corticotroph adenoma and thyrotroph hyperplasia in a dog.

Pituitary thyrotroph hyperplasia results from prolonged primary hypothyroidism in humans, mice and rats. In dogs with Cushing's disease, many cases have low serum thyroid hormones concentrations due to euthyroid sick syndrome. A 6-year-old castrated male Beagle diagnosed with Cushing's disease had a high serum thyroid stimulating hormone (TSH) concentration that was treated by hypophysectomy. On histological examination, the resected pituitary gland contained both a corticotroph adenoma and thyrotroph hyperplasia. The TSH-positive cell ratio in this case was greater than that of healthy Beagles. In the present case, the pituitary thyrotroph hyperplasia was probably caused by primary hypothyroidism. In conclusion, this Beagle is the first histological confirmation of the coexistence of a corticotroph adenoma and thyrotroph hyperplasia.

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.