Immunohistochemical Hormone Research Articles

Pituitary tumours without distinct lineage differentiation express stem cell marker SOX2

ContextThe recent WHO 2022 Classification of pituitary tumours identified a novel group of ‘plurihormonal tumours without distinct lineage differentiation (WDLD)’. By definition, these express multiple combinations of lineage commitment transcription factors, in a monomorphous population of cells.ObjectivesTo determine the expression of stem cell markers (SOX2, Nestin, CD133) within tumours WDLD, immature PIT-1 lineage and acidophil stem cell tumours, compared with committed cell lineage tumours.MethodsRetrospective evaluation of surgically resected pituitary tumours from St Vincent’s Hospital, Sydney. Patients were selected to cover a range of tumour types, based on transcription factor and hormone immunohistochemistry. Clinical data was collected from patient files. Radiology reports were reviewed for size and invasion. Samples were analysed by immunohistochemistry and RT-qPCR for SF-1, PIT-1, T-PIT, SOX2, Nestin and CD133. Stem cell markers were compared between tumours WDLD and those with classically “mature” types.ResultsOn immunohistochemistry, SOX2 was positive in a higher proportion of tumours WDLD compared with those meeting WHO lineage criteria, 7/10 v 10/42 (70 v 23.4%, p = 0.005). CD133 was positive in 2/10 tumours WDLD but 0/41 meeting lineage criteria, P = 0.003. On RT-qPCR, there was no significant difference in relative expression of stem cell markers (SOX2, CD133, Nestin) between tumours with and WDLD.ConclusionsOur study is the first to biologically characterise pituitary tumours WDLD. We demonstrate that these tumours exhibit a higher expression of the stem cell marker SOX2 compared with other lineage-differentiated tumours, suggesting possible involvement of stem cells in their development.

Delineating the Spectrum of Pituitary Adenoma Based on the WHO 2017 Classification.

The WHO 2017 classification of endocrine tumors incorporates lineage-specific transcription factors (TF) and hormone expression for the classification of pituitary adenoma (PA). There is paucity of reports describing the spectrum of PA based on this classification. The aim of this study was to delineate the spectrum of PA based on WHO 2017 classification of endocrine tumors. PA diagnosed in the year 2018 were studied. H and E and hormonal immunohistochemistry (IHC) for GH, PRL, ACTH, TSH, FSH, LH, CK, T-Pit and MIB-1 were performed and the results were analyzed. The cohort included 88 cases. M: F ratio was 2:1. Clinically, 22 (25%) were functional and 66 (75%) were non-functional adenomas. Amongst the clinically functional adenomas, GH secreting adenomas were the commonest (68%). Majority (83%) of non-functional adenomas were hormone positive with gonadotroph adenomas being the commonest (72.7%). Eleven (12.5%) PA were clinically and hormonally silent. Three of these showed intense nuclear T-Pit positivity, classifying them under silent corticotroph adenoma. Lineage of the remaining eight adenomas remained undetermined, since, IHC for Pit-1 and SF-1 was not performed. The aggressive adenomas identified by IHC included sparsely granulated somatotroph adenoma, Crooke cell adenoma, silent corticotroph adenoma, densely granulated lactotroph adenoma in men and constituted 17% of the PA. Four (4/88) cases were clinically invasive. A large majority of PA including aggressive adenomas can be identified by IHC. Addition of T-Pit helped to identify silent corticotroph adenoma. Pit -1 and SF-1 TF would help identify plurihormonal Pit-1 PA and null cell adenomas.

Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice.

Common variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas]. Following intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μl) in wild-type (WT), heterozygous (R138X+/-), and homozygous (R138X+/+) mutant mice (14-15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS. Our findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X+/- mice, with smaller increases observed in R138X+/+ mice. These data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic β-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion.

The evolution in pituitary tumour classification: a clinical perspective.

Pituitary tumours comprise a pathologically and clinically diverse group of neoplasms. Classification frameworks have changed dramatically in the past two decades, reflecting improving understanding of tumour biology. This narrative review examines the evolution of pituitary tumour classification, from a clinical perspective. In 2004, pituitary tumours were classified as 'typical' or 'atypical', based on the presence of markers of proliferation, Ki67, mitotic count and p53. In 2017, the new WHO marked a major paradigm shift, with a new focus on lineage-based classification, determined by transcription factor and hormonal immunohistochemistry. The terms 'typical' and 'atypical' were omitted, though the importance of proliferative markers Ki67 and mitotic count was acknowledged. The recent WHO 2022 classification incorporates further refinements, specifically recognising some less common types that may represent less well-differentiated tumours. Whilst 'high risk' tumour types have been identified, further work is still required to improve prognostication. Recent WHO classifications have marked significant progress in the diagnostic evaluation of pituitary tumours, though shortcomings and challenges remain for both clinicians and pathologists in managing these tumours.

Transcription Factor Immunohistochemistry in the Classification of Pituitary Neuroendocrine Tumor/Adenoma: Proposal in a Limited-Resource Setting.

Pituitary neuroendocrine tumors/adenomas are common intracranial tumors that require accurate subtyping because each tumor differs in its biologic behavior and response to treatment. Pituitary-specific transcription factors allow for improved lineage identification and diagnosis of newly introduced variants. To assess the usefulness of transcription factors and design a limited panel of immunostains for classification of pituitary neuroendocrine tumors/adenoma. A total of 356 tumors were classified as per expression of pituitary hormones and transcription factors T-box family member TBX19 (TPIT), pituitary-specific POU-class homeodomain (PIT1), and steroidogenic factor-1 (SF-1). The resultant classification was correlated with patients' clinical and biochemical features. The performance and relevance of individual immunostains were analyzed. Reclassification of 34.8% (124 of 356) of pituitary neuroendocrine tumors/adenoma was done after application of transcription factors. The highest agreement with final diagnosis was seen using a combination of hormone and transcription factors. SF-1 had higher sensitivity, specificity, and predictive value compared with follicle-stimulating hormone and luteinizing hormone. On the other hand, TPIT and PIT1 had similar performance and Allred scores compared with their respective hormones. SF-1 and PIT1 should be included in the routine panel for guiding the classification. PIT1 positivity needs to be followed by hormone immunohistochemistry, especially in nonfunctional cases. TPIT and adrenocorticotropin can be used interchangeably as per availability of the lab.

Dyspnoea and large‐volume pleural effusion secondary to a cyst involving the cranial mediastinum in a cat

AbstractA 7‐year‐old female spayed domestic shorthair cat presented for dyspnoea and haemoptysis. Point‐of‐care ultrasound revealed pleural effusion. Fluid analysis noted proteinaceous fluid rich in small lymphocytes. A mediastinal mass was present on radiographs. CT revealed a fluid attenuating structure within the left thyroid gland. Right‐sided thyroid tissue was not identified. A fluid attenuating structure with associated amorphous soft tissue was present within the mediastinum. Aspirates were consistent with cystic fluid. A surgical cystectomy was performed. Histopathology of the left thyroid structure revealed a cystic thyroid follicular adenoma. The cystic structure involving the cranial mediastinum was suspected to represent an ectopic parathyroid cyst. Alternative differentials such as a branchial remnant could not be ruled out. Immunohistochemistry of the ectopic endocrine tissue associated with the cyst was negative for thyroglobulin and calcitonin. Parathyroid hormone immunohistochemistry was unavailable for confirmation. Post‐operative hypothyroidism and hypocalcemia were medically managed. Surgical cystectomy resulted in the resolution of pleural effusion.

Serum Inflammation Biomarkers and Micronutrient Levels in Nigerian Breast Cancer Patients with Different Hormonal Immunohistochemistry Status

Background: The importance and relevance of serum inflammation biomarkers and DNA methylation-dependent micronutrients in breast tumorigenesis is gaining wider acceptance. However, the association of serum inflammation biomarkers and micronutrient status with expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2) by the tumor has not been investigated in Nigerian breast cancer patients. The objective of this study was to determine the levels of serum biomarkers of inflammation (Homocysteine, Nitric Oxide (NO), Hydrogen peroxide (H2O2), Myeloperoxidase (MPO), Tumor necrosis factor alpha (TNF-α), Interleukins 6 and 8 (IL-6 and IL-8) and DNA methylation-dependent micronutrients [Zinc (Zn), Folic acid, Vitamin B6 and B12] in breast cancer patients with different hormone receptor levels (ER, PR and HER-2). Methods: One hundred and fifteen women (80 with breast cancer and 35 controls) were randomly recruited for this study. Serum levels of homocysteine, folic acid, vitamins B6, vitamin B12, TNF-α, IL-6 and IL-8) were analyzed using ELISA. The levels of NO, MPO, H2O2 and Zn were analyzed using spectrophotometer. The levels of serum inflammation biomarkers and DNA methylation-dependent micronutrients in patients with breast cancer and control subjects without breast cancer as well as breast cancer patients with ER, PR and HER-2 expression were determined. Results: The results showed that mean serum levels of IL-6 (p=0.002), IL-8 (p=0.018) and H2O2 (p=0.000) were significantly increased while TNF-α (p=0.014) and NO levels (p=0.044) were significantly decreased in breast cancer compared to healthy controls (p<0.05). However, there were no statistically significant differences in the levels of Zn, homocysteine, Vitamin B6, Vitamin B12 and MPO in breast cancer patients and controls (p>0.05). Furthermore, the levels of serum inflammatory biomarkers and methylation-dependent micronutrients were similar in HER-2, ER and PR breast cancer hormone subtypes. Conclusion: Systemic inflammation exists in breast cancer patients but the inflammation biomarkers and methylation-dependent micronutrients did not differ among patients with PR, ER and HER-2 antigen expression.

Transcription factor immunohistochemistry in the diagnosis of pituitary tumours.

The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours. This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent's Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the 'histological cohort'. Patients with at least 12 months of post-surgical follow-up were included in the subgroup 'clinical cohort'. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying 'higher-risk' histological subtypes was assessed. There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher-risk histological subtype tumours. These were associated with tumour invasiveness (P = 0.050), early recurrence (12-24 months, P = 0.013), shorter median time to recurrence (49 (IQR: 22.5-73.0) vs 15 (IQR: 12.0-25.0) months, P = 0.005) and reduced recurrence-free survival (P = 0.031). Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

Transcription Factor Immunohistochemistry in the Diagnosis of Pituitary Tumors

Objective: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumors have not been assessed. This study aimed to (1) To determine the clinical utility of transcription factor analysis for classification of pituitary tumors and (2) To determine the prognostic value of improved lineage-based classification of pituitary tumors. Methods: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumors at a tertiary referral centre between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the “histological cohort”. Patients with at least 12 months of post-surgical follow up were included in the subgroup “clinical cohort”. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying “higher risk” histological subtypes was assessed. Results: There were 172 patient tumor samples analyzed in the histological cohort. Of these, there were 96 patients forming the clinical cohort. Subtype diagnosis was changed in 24/172 (14%) of tumors. Within the clinical cohort, there were 21/96 (22%) patients identified with higher risk histological subtype tumors. These were associated with tumor invasiveness (p=0.032), early recurrence (12-24 months, p=0.016), shorter median time to recurrence (38 [IQR 20-68.5] v 15 [IQR 12-27.25] months, p=0.02) and reduced recurrence-free survival (p=0.023). Conclusions: Application of transcription factor analysis, in addition to hormone IHC, is associated with improved diagnostic information.

Feline Pituitary Adenomas: Correlation of Histologic and Immunohistochemical Characteristics With Clinical Findings and Case Outcome.

Pituitary glands from 141 feline autopsy cases were reviewed histologically. Adenoma and hyperplasia were the most common lesions at 13 cases each. Pituitary adenoma was more likely than hyperplasia to be associated with clinical evidence of endocrinopathy or an intracranial mass (P < .001). A histochemical and immunohistochemical panel was applied to 44 autopsy- or hypophysectomy-derived pituitary adenomas in 43 cats from 2 diagnostic laboratories. Adenomas were differentiated from hyperplasia by the presence of disrupted reticulin fibers. One cat had a double (somatotroph and melanotroph) adenoma. Twenty somatotroph adenomas consisted of periodic acid-Schiff (PAS)-negative acidophils that expressed growth hormone; 16/20 had hypersomatotropism; 17/20 had diabetes mellitus. Eleven melanotroph adenomas consisted of PAS-positive basophils or chromophobes that expressed melanocyte-stimulating and adrenocorticotrophic hormones; 5/11 had hypercortisolism; 6/11 had diabetes mellitus. Eleven gonadotroph adenomas consisted of PAS-negative chromophobes that expressed follicle-stimulating and/or luteinizing hormones. Two thyrotroph adenomas consisted of PAS-negative basophils or chromophobes that expressed thyroid-stimulating hormone. Pituitary-dependent disease was not recognized in cats with gonadotroph or thyrotroph adenomas. The Ki-67 proliferation index in hypophysectomy specimens was lower in somatotroph than in melanotroph adenomas. Fourteen cats with hypophysectomy-treated somatotroph or melanotroph adenoma had an 899-day median survival time versus 173 days in 17 nonsurgical cases. After adjusting for age, adenoma size and type, hypophysectomized cats had an overall better survival time than nonsurgical cases (P = .029). The study results underscore the value of hypophysectomy and trophic hormone immunohistochemistry in the treatment and classification of feline pituitary adenomas.

Structure, Function, and Morphology in the Classification of Pituitary Neuroendocrine Tumors: the Importance of Routine Analysis of Pituitary Transcription Factors.

The traditional approach to the diagnosis of primary adenohypophyseal cell proliferations uses hormone immunohistochemistry to classify pituitary neuroendocrine tumors (PitNETs). The routine application of immunolocalization of pituitary transcription factors (SF1, PIT1, TPIT, ERα, and recently GATA3) along with adenohypophyseal hormones has taught us critical lessons that are discussed in this communication. We point out that appropriate patient care requires accurate diagnosis and is critical in the era of precision medicine. A misdiagnosis can result in far greater health care costs than the cost of accurate tumor classification and may have other unintended consequences. We provide additional insights about confusing findings in genomic studies, emphasizing that high-quality pathology is essential for strong science and translational research.

Pituitary tumors: Changing paradigms in understanding, nomenclature and the newer basis of classification

The pituitary gland is embryologically divided into two main lobes: adenohypophysis (anterior) and neurohypophysis (posterior). Last five decades have witnessed changes in the tumor classifications – anterior pituitary in 2017 and posterior in 2016, based on hormonal immunohistochemistry, molecular profiles, and pituitary specific transcription factors. Few newer entities/terms have been added and at the same time certain terms have been modified/discarded. In this article, relevant anatomy, development, histology, incidence, and clinical manifestations of pituitary tumors evolution of various classification systems and recommended current classification of pituitary tumors; the genetic alterations and the diagnostic implications for today's pathologist have been reviewed in a comprehensive manner.

Overview of the 2017 WHO Classification of Pituitary Tumors.

This review focuses on discussing the main changes on the upcoming fourth edition of the WHO Classification of Tumors of the Pituitary Gland emphasizing histopathological and molecular genetics aspects of pituitary neuroendocrine (i.e., pituitary adenomas) and some of the non-neuroendocrine tumors involving the pituitary gland. Instead of a formal review, we introduced the highlights of the new WHO classification by answering select questions relevant to practising pathologists. The revised classification of pituitary adenomas, in addition to hormone immunohistochemistry, recognizes the role of other immunohistochemical markers including but not limited to pituitary transcription factors. Recognizing this novel approach, the fourth edition of the WHO classification has abandoned the concept of "a hormone-producing pituitary adenoma" and adopted a pituitary adenohypophyseal cell lineage designation of the adenomas with subsequent categorization of histological variants according to hormone content and specific histological and immunohistochemical features. This new classification does not require a routine ultrastructural examination of these tumors. The new definition of the Null cell adenoma requires the demonstration of immunonegativity for pituitary transcription factors and adenohypophyseal hormones Moreover, the term of atypical pituitary adenoma is no longer recommended. In addition to the accurate tumor subtyping, assessment of the tumor proliferative potential by mitotic count and Ki-67 index, and other clinical parameters such as tumor invasion, is strongly recommended in individual cases for consideration of clinically aggressive adenomas. This classification also recognizes some subtypes of pituitary neuroendocrine tumors as "high-risk pituitary adenomas" due to the clinical aggressive behavior; these include the sparsely granulated somatotroph adenoma, the lactotroph adenoma in men, the Crooke's cell adenoma, the silent corticotroph adenoma, and the newly introduced plurihormonal Pit-1-positive adenoma (previously known as silent subtype III pituitary adenoma). An additional novel aspect of the new WHO classification was also the definition of the spectrum of thyroid transcription factor-1 expressing pituitary tumors of the posterior lobe as representing a morphological spectrum of a single nosological entity. These tumors include the pituicytoma, the spindle cell oncocytoma, the granular cell tumor of the neurohypophysis, and the sellar ependymoma.

Immunohistochemical hormone receptors expression in high grade endometrial cancer

Immunohistochemical hormone receptors expression in high grade endometrial cancer

An association study of established breast cancer reproductive and lifestyle risk factors with tumour subtype defined by the prognostic 70-gene expression signature (MammaPrint®)

BackgroundReproductive and lifestyle factors influence both breast cancer risk and prognosis; this might be through breast cancer subtype. Subtypes defined by immunohistochemical hormone receptor markers and gene expression signatures are used to predict prognosis of breast cancer patients based on their tumour biology. We investigated the association between established breast cancer risk factors and the 70-gene prognostication signature in breast cancer patients. Patients and methodsStandardised questionnaires were used to obtain information on established risk factors of breast cancer from the Dutch patients of the MINDACT trial. Clinical-pathological and genomic information were obtained from the trial database. Logistic regression analyses were used to estimate the associations between lifestyle risk factors and tumour prognostic subtypes, measured by the 70-gene MammaPrint® signature (i.e. low-risk or high-risk tumours). ResultsOf the 1555 breast cancer patients included, 910 had low-risk and 645 had high-risk tumours. Current body mass index (BMI), age at menarche, age at first birth, age at menopause, hormonal contraceptive use and hormone replacement therapy use were not associated with MammaPrint®. In parous women, higher parity was associated with a lower risk (OR: 0.75, [95% confidence interval {CI}: 0.59–0.95] P = 0.018) and longer breastfeeding duration with a higher risk (OR: 1.03, [95% CI: 1.01–1.05] P = 0.005) of developing high-risk tumours; risk estimates were similar within oestrogen receptor–positive disease. After stratifying by menopausal status, the associations remained present in post-menopausal women. ConclusionUsing prognostic gene expression profiles, we have indications that specific reproductive factors may be associated with prognostic tumour subtypes beyond hormone receptor status.

The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas.

Clinically nonfunctioning pituitary adenomas (NFAs) may be hormonally inactive tumors of differentiated cells, mainly not only gonadotroph adenomas (GAs) but also silent corticotroph adenomas (SCAs) and other differentiated silent adenomas. Recently, the use of transcription factors has been recommended to confirm cytodiffererentiation of these neoplasms. Our objective was to assess the clinical significance of the new classification system using transcription factors. Five hundred sixteen consecutive NFAs were studied retrospectively. They were initially classified based on hormone immunohistochemistry as follows: 119 hormone-negative adenomas (23.1 %), 300 GAs (58.1 %), 51 SCAs (9.9 %), and 46 other silent adenomas. The 119 hormone-negative adenomas were further evaluated for expression of transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-α (ERα), pituitary-specific transcription factor 1 (Pit-1), and t-box transcription factor (Tpit). One hundred thirteen of 119 (95 %) hormone-negative adenomas showed mutually exclusive lineage-specific differentiation as gonadotrophs (SF-1 positive), corticotrophs (Tpit positive), or somatotrophs/mammosomatotrophs/lactotrophs/thyrotrophs (Pit-1 positive) in 79 cases (66.4 %), 32 cases (26.9 %), and 2 cases, respectively. The 32 ACTH-negative and Tpit-positive adenomas had higher pro-opiomelanocortin mRNA expression levels compared with GAs (P = 0.0001) on quantitative real-time PCR. They showed a female preponderance (P < 0.0001) and were more frequently giant adenomas (P = 0.0028) associated with marked cavernous sinus invasion (P < 0.0001) compared with GAs. These clinical features were identical to those of the 51 ACTH-positive SCAs. Our results justify the complementary role of transcription factors in the precise classification of NFAs that can more accurately characterize biological behavior. Our data suggest that more than one quarter of hormone-negative adenomas are SCAs that share distinct clinicopathological features with ACTH-expressing SCAs.

New aspects of tumor pathology of the pituitary

Pituitary adenomas have to be studied in detail for structural characteristics, especially regarding the degree of granulation and immunohistochemical hormone expression, such as growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and proliferation markers (e.g. Ki-67 and p53) for correlation to clinical data and assessment of the prognosis. If histological and immunostaining data do not correlate to the patient data, explanations for the discrepancies must be found. All active adenoma types can also be present as inactive, so-called silent adenomas showing the same features. An increased Ki-67 index (> 3%), significant nuclear expression of protein p53 and mitoses are characteristic of atypical adenomas. Up to now the biological relevance of these atypical adenomas, especially their role as preneoplasms for pituitary carcinomas has not been fully elucidated. The only proof of a pituitary carcinoma is the existence of metastases. Extensive local invasion and a greatly increased Ki-67 index are not sufficient for this diagnosis. Craniopharyngiomas have to be classified into adamantinomatous types (intrasellar and suprasellar) and papillary types (only suprasellar). Regressive changes are found in adamantinomatous types only. Strong regression may lead to difficulties in the differential diagnosis of Rathke's cleft cysts with squamous metaplasia. Demonstration of nuclear expression of beta-catenin in these cases enables the diagnosis of craniopharyngioma. Papillary craniopharyngiomas are characterized by BRAF mutations that may be helpful in the differential diagnosis. All pituicytomas of the neurohypophysis, all spindle cell oncocytomas of the anterior pituitary and all granular cell tumors of the posterior pituitary express thyroid transcription factor 1 (TTF-1) and are thought to be variants of a common uniform spindle cell tumor of the pituitary.

Abstract P6-06-24: Intact p53 can predict more hormonal therapy benefit in invasive breast cancer: Evaluation of interactions between immunohistochemical p53 status and adjuvant therapy

Abstract Background: To confirm the prognostic and predictive values of p53 accumulation, particularly in invasive breast cancer patients sorted according to subgroup based on immunohistochemical hormone receptor (HR) and HER2 status. Methods: A total of 15,598 immunohistochemical data for p53, ER, PgR, and HER2 were retrospectively retrieved from the web-based database of the Korean Breast Cancer Society. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated and compared with the Kaplan-Meier method with log-rank test. Multivariate analyses were performed using a stratified Cox proportional hazard regression model. A model evaluating interactions between p53 and both hormonal therapy and chemotherapy was used to determine the treatment benefit from both modalities. Results: Prognostic value of p53 was most significant in the HR+/HER2- subgroup for OS and BCSS, with hazard ratios of 1.44 (95% CI, 1.08-1.93) and of 1.47 (95% CI, 1.09-1.99). The hazard ratios for p53 overexpression had borderline significance in the HR+/HER2+, and were invalid in the HR-/HER2+ and HR-/HER2- subgroups. The model with interaction terms revealed that hormonal therapy significantly interacts with p53 status (p = .002 and .007 for OS and BCSS), resulting in an insignificant prognostic value of p53 status (p = .268 and .296 for OS and BCSS). An interaction between chemotherapy and p53 status was not found in this model. Conclusion: p53 overexpression has independent prognostic value, particularly in the HR+/HER2- invasive breast cancer, which is most likely caused by differential treatment benefits from hormonal therapy depending on p53 status. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-24.

Silent Corticotroph Adenoma with Adrenal Cortical Choristoma: a Rare but Distinct Morphological Entity

This report describes a case of pituitary adenoma with interspersed adrenal cortical cells. The pituitary cells were confirmed to be corticotrophs with Tpit and adrenocorticotropic hormone immunohistochemistry, whereas the adrenal cortical cells were verified to be such with steroidogenic factor-1 (SF-1), inhibin, calretinin, and Melan A staining. The presence of normal adrenal cortical cells in the heterotopic location of the sella fulfills the definition of choristoma. The origin of adrenal cortical cells within a pituitary adenoma remains unexplained. The important role of SF-1 in both pituitary and adrenal cortex may explain a relationship that supports the possibility of an abnormal proliferation and differentiation of uncommitted mesenchymal stem cells within the sella. However, it remains possible that misplaced adrenal cortical cells derived during embryogenesis give rise to this rare but distinct morphological entity that can pose a difficult diagnostic dilemma. The approach to differential diagnosis is discussed.

Effect Modification of Hormonal Therapy by p53 Status in Invasive Breast Cancer

PurposeWe aimed to confirm the prognostic and predictive value of p53 expression, particularly in invasive breast cancer patients, according to immunohistochemical hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status.MethodsImmunohistochemical data for p53, estrogen receptor, progesterone receptor, and HER2 expression from a total of 15,598 patients were retrospectively retrieved from the web-based database of the Korean Breast Cancer Society. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated and compared using the Kaplan-Meier method and log-rank test, respectively. Multivariate analyses were performed using a stratified Cox proportional hazard regression model. A model evaluating interactions between p53 expression and both hormonal therapy and chemotherapy was used to determine the treatment benefit from both modalities.ResultsThe prognostic value of p53 for OS and BCSS was most significant in the HR+/HER2- subgroup, with hazard ratios of 1.44 (95% confidence interval [CI], 1.08-1.93) and 1.47 (95% CI, 1.09-1.99), respectively. The p53 overexpression hazard ratios were of borderline significance for the HR+/HER2+ subgroup and were not significant for the HR-/HER2+ and HR-/HER2- subgroups. The model with interaction terms revealed that hormonal therapy significantly interacts with p53 status (p=0.002 and p=0.007 for OS and BCSS, respectively), suggesting an insignificant prognostic value for p53 status (p=0.268 and p=0.296 for OS and BCSS, respectively). An interaction between chemotherapy and p53 status was not found in this model.Conclusionp53 overexpression has independent prognostic value, particularly in cases of HR+/HER2- invasive breast cancer, which may be due to effect modification of hormonal therapy dependent on p53 status.