Atretic cephalocele and encephalocele: A single-institution clinicopathological study.

BACKGROUND: Encephaloceles are neural tube defects characterized by herniation of meninges, neural tissue and cerebrospinal fluid, while atretic cephaloceles denote a rudimentary connection to the intracranial space with absence of herniated neural tissue and represent an infrequent dermatopathologic diagnosis. Limited reports of these entities confound the challenge in their histopathologic distinction. Accurate classification is important given associated anomalies and neurologic manifestations that impact prognosis. METHODS: We describe the clinicopathological and immunohistochemical [glial fibrillary acidic protein (GFAP), S100, epithelial membrane antigen (EMA), and somatostatin receptor subtype 2A (SSTR2A)] features in a retrospective series encountered at a single institution between 1994 and 2020. RESULTS: We identified 13 cases classified as atretic cephalocele (n = 11) and encephalocele (n = 2). Hamartomatous changes and multinucleated cells were unique to atretic cephaloceles while myxoid areas were unique to encephaloceles. At least focal staining for SSTRA was seen in all atretic cephaloceles with the majority (87.5%) staining for EMA; negative staining for GFAP and S100 confirmed absence of neural tissue. Encephaloceles were GFAP and S100 positive, and negative for SSTR2 and EMA. Atretic cephaloceles had a favorable prognosis compared to encephaloceles, with severe morbidity present in both encephalocele cases. CONCLUSION: Our study raises awareness of atretic cephalocele and encephalocele among dermatopathologists and reveals a mutually exclusive immunophenotype that facilitates their distinction for prognostication and management.

Association between methylation of SHP-1 isoform I and SSTR2A promoter regions with breast and prostate carcinoma development.

Methylation pattern is presented here for first time as a potential molecular marker of changes on SSTR2A and SHP-1(I) gene promoter related to breast and prostate carcinoma. Our results have shown low concordances with SSTR2A and methylated state in prostate cancer and moderate relationship with unmethylated CpG-27 in breast cancer. We found significant concordances for both cancers and SHP-1(I) unmethylation, and increased HER2 expression and SSTR2A methylation in breast cancer. Moreover, we found a correlation between methylation patterns of two genes in normal breast tissue. These data might assist to select subgroups of patients for the administration of alternative therapies.

Clinicopathologic characteristics of pancreatic neuroendocrine tumors and relation of somatostatin receptor type 2A to outcomes.

BACKGROUND: The impact of somatostatin receptor type 2 (SSTR-2a) expression levels on outcomes in patients with pancreatic neuroendocrine tumors (PNETs) has not been evaluated. METHODS: Correlations between clinicopathologic characteristics, including SSTR-2a expression and outcomes, were retrospectively studied in 79 patients with pancreatic neuroendocrine tumors (PNETs). RESULTS: The SSTR-2a score was 0 in 27% of patients, 1 in 24% of patients, 3 in 30% of patients, and 4 in 18% of patients. The overall survival rate was 87% at 1 year, 77% at 3 years, and 71% at 5 years. On univariate analysis, a pancreatic tumor that measured ≥ 20 mm in greatest dimension, stage IV disease, vascular invasion, neuroendocrine carcinoma (NEC), and an SSTR-2a score of 0 were associated significantly with poor outcomes. On multivariate analysis, NEC (P = .000; hazard ratio, 28.8; 95% confidence interval, 7.502-111.240) and an SSTR-2a score of 0 (P = .001; hazard ratio, 3.611; 95% confidence interval, 1.344-9.702) were related independently to poor outcomes. CONCLUSIONS: The current analysis of prognostic factors in patients with PNETs demonstrated that NEC and an SSTR-2a score of 0 both were significant independent predictors of poor outcomes. The results suggest that the assessment of SSTR-2a may facilitate the selection of treatment regimens and the prediction of outcomes. Because a considerable proportion of patients with NEC have SSTR-2a-positive tumors, further analyses of the usefulness of somatostatin analogues are warranted in patients who have SSTR-2a-positive NEC.

Diagnostic Utility of Somatostatin Receptor 2A Immunohistochemistry for Tumor-induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder caused by excessive fibroblast growth factor 23 (FGF23) secretion. FGF23 immunohistochemistry (IHC) is proposed as a useful adjunctive marker to confirm TIO diagnosis. However, it often stains focally, limiting its diagnostic utility. OBJECTIVE: This work aimed to compare the diagnostic performance between somatostatin receptor 2A (SSTR2A) and FGF23 IHC for TIO. METHODS: We retrospectively reviewed TIO-diagnosed patients in Severance Hospital between July 2006 and May 2020. Histologic evaluation was performed using histoscore (H score) (expression area proportion score [0-2] × intensity score [1-3], [total, 0-6]). FGF23 and SSTR2A IHC were performed using unstained slides from 18 localized TIO patients and 9 and 15 non-TIO controls with bone and soft-tissue tumors, respectively. SSTR2A positivity was defined as cytoplasmic, membranous, or Golgi staining in more than 1% of tumor cells, and negativity as nonspecific nuclear staining. FGF23 positivity was defined as cytoplasmic expression in more than 1% of the tumor area and negativity as nonspecific nuclear staining. RESULTS: Suspicious lesions were successfully detected in 14 of 15 patients who underwent 68Ga-DOTATOC scans. Diffuse cytoplasmic SSTR2A expression was identified in all TIO patients and focal weak nuclear staining in 12 of 15 controls. FGF23 cytoplasmic expression was identified in 11 of 18 TIO patients and diffuse nuclear staining in 9 of 9 controls. The H score was higher in SSTR2A than in FGF23 IHC (median [interquartile range]: 6 [6-6] vs 1 [0-2], P < .001). CONCLUSION: SSTR2A IHC with H-score quantification might be a more sensitive, adjunctive diagnostic tool than FGF23 IHC for TIO diagnosis.

Phosphaturic Mesenchymal Tumors in the Head and Neck Demonstrate a Broad Clinical and Morphologic Spectrum.

Phosphaturic mesenchymal tumour (PMT) is a rare tumour that occurs in bone or soft tissue and is associated with production of fibroblast growth factor 23 (FGF23) leading to tumor-induced osteomalacia. We report three cases of PMT involving the head and neck that highlight the broad spectrum of clinical and histologic features of PMT. One of these lesions from the hard palate demonstrated an admixture of epithelial and mesenchymal elements, a feature that can pose a diagnostic challenge. The diagnostic utility of immunohistochemistry including FGF23, somatostatin receptor 2A, SATB2, ERG and CD56 is discussed. The biochemical pathway in the development of PMT associated tumor induced osteomalacia and its role in investigations and management of PMT is also described.

Sample Preparation for Multicolor STED Microscopy.

Stimulated emission depletion (STED) microscopy is one of the optical superresolution microscopy (SRM) techniques, more recently also referred to as nanoscopy, that have risen to popularity among biologists during the past decade. These techniques keep pushing the physical boundaries of optical resolution toward the molecular scale. Thereby, they enable biologists to image cellular and tissue structures at a level of almost molecular detail that was previously only achievable using electron microscopy. All the while, they retain the advantages of light microscopy, in particular with regards to sample preparation and flexibility of imaging. Commercially available SRM setups have become more and more available and also increasingly sophisticated, both in terms of optical performance and, importantly, ease of use. Institutional microscopy core facilities now offer widespread access to this type of systems. However, the field has grown so rapidly, and keeps growing, that biologists can be easily overwhelmed by the multitude of available techniques and approaches. From this vast array of SRM modalities, STED stands out in one respect: it is essentially an extension to an advanced confocal microscope. Most experienced users of confocal microscopy will find the transition to STED microscopy relatively easy as compared with some other SRM techniques. This also applies to STED sample preparation. Nonetheless, because resolution in STED microscopy does not only depend on the wavelength of the incident light and the numerical aperture of the objective, but crucially also on the square root of the intensity of the depletion laser and, in general, on the photochemical interaction of the fluorophore with the depletion laser, some additional considerations are necessary in STED sample preparation. Here we describe the single color staining of the somatostatin receptor subtype 2A (SSTR2A) and dual color staining of the trans-Golgi-network protein TGN 38 and the t-SNARE syntaxin-6 for STED in the endocrine cell line AtT20 and STED imaging of the samples, providing the protocols in as general a form as possible. The protocols in this chapter are used in this way in an institutional microscopy core facility.

Somatostatin Receptor Antagonism Reverses Glucagon Counterregulatory Failure in Recurrently Hypoglycemic Male Rats.

Recent antecedent hypoglycemia is a known source of defective glucose counter-regulation in diabetes; the mechanisms perpetuating the cycle of progressive α-cell failure and recurrent hypoglycemia remain unknown. Somatostatin has been shown to suppress the glucagon response to acute hypoglycemia in rodent models of type 1 diabetes. We hypothesized that somatostatin receptor 2 antagonism (SSTR2a) would restore glucagon counterregulation and delay the onset of insulin-induced hypoglycemia in recurrently hypoglycemic, nondiabetic male rats. Healthy, male, Sprague-Dawley rats (n = 39) received bolus injections of insulin (10 U/kg, 8 U/kg, 5 U/kg) on 3 consecutive days to induce hypoglycemia. On day 4, animals were then treated with SSTR2a (10 mg/kg; n = 17) or vehicle (n = 12) 1 hour prior to the induction of hypoglycemia using insulin (5 U/kg). Plasma glucagon level during hypoglycemia was ~30% lower on day 3 (150 ± 75 pg/mL; P < .01), and 68% lower on day 4 in the vehicle group (70 ± 52 pg/mL; P < .001) compared with day 1 (219 ± 99 pg/mL). On day 4, SSTR2a prolonged euglycemia by 25 ± 5 minutes (P < .05) and restored the plasma glucagon response to hypoglycemia. Hepatic glycogen content of SSTR2a-treated rats was 35% lower than vehicle controls after hypoglycemia induction on day 4 (vehicle: 20 ± 7.0 vs SSTR2a: 13 ± 4.4 µmol/g; P < .01). SSTR2a treatment reverses the cumulative glucagon deficit resulting from 3 days of antecedent hypoglycemia in healthy rats. This reversal is associated with decreased hepatic glycogen content and delayed time to hypoglycemic onset. We conclude that recurrent hypoglycemia produces glucagon counterregulatory deficiency in healthy male rats, which can be improved by SSTR2a.

Expression of potential therapeutic target SSTR2a in primary and metastatic non-keratinizing nasopharyngeal carcinoma.

Somatostatin receptor 2a (SSTR2a) is an important diagnostic and scintigraphic marker in several tumors, as well as a potential therapeutic target. However, the expression and clinicopathologic significance of SSTR2a in nasopharyngeal carcinoma (NPC) remain unknown. The expression of SSTR2a was retrospectively analyzed in a large series of NPC tissue samples (106 primary NPC samples, comprising 99 primary non-keratinizing NPC (NK-NPC) and 7 keratinizing NPC (K-NPC) samples, and 41 metastatic NPC samples) by immunohistochemistry, with 24 cases of normal nasopharyngeal mucosa tissues used as a control group. Normal epithelia in nasopharyngeal mucosa were negative for SSTR2a in all 24 cases. The expression of SSTR2a in primary NPC was correlated to the histological subtype. Most cases of primary NK-NPC showed expression of SSTR2a (93.9%, 93/99 cases). The percentage of SSTR2a-positive tumor cells ranged from 10 to 100%, while the intensity ranged from 2+ to 4+. None of the primary K-NPC samples showed SSTR2a expression (0/7, 100%). All cases of NPC showed negative expression of other neuroendocrine markers, including synaptophysin, chromogranin A, and CD56. Of all 41 cases of metastatic NK-NPC lesions, SSTR2a expression is concordant with that of the primary lesions, which shows statistical significance (p < 0.001). Our observations expand the spectrum of recognized SSTR2a-positive tumors and demonstrate for the first time that SSTR2a is frequently expressed in primary and metastatic NK-NPC, highlighting its potential as a scintigraphic and therapeutic target in this disease.

Do Canine Pancreatic Neuroendocrine Neoplasms Resemble Human Pancreatic Neuroendocrine Tumours? A Comparative Morphological and Immunohistochemical Investigation.

Although canine pancreatic neuroendocrine neoplasms (PanNENs) have been proposed as a model for the counterpart human neoplasms, the type or grade of human PanNEN that they resemble is unclear. PanNENs in animals are classified as adenoma or carcinoma, whereas in humans they are classified as pancreatic neuroendocrine tumour (PanNET) if well-differentiated, or as pancreatic neuroendocrine carcinoma (PanNEC) if poorly differentiated. We evaluated 16 canine primary PanNENs and two metastases histologically and immunohistochemically, and graded them using the animal and human grading systems. All neoplasms had local or vascular invasion and were classified as pancreatic islet cell carcinomas according to the current WHO classification. The Ki-67 index was low in all cases (0.01-1.50%). All had cytoplasmic expression of synaptophysin and insulin but were immunonegative for glucagon, confirming a functional diagnosis of canine insulinoma. Membranous expression of SSTR2A and nuclear expression of ATRX, but no p53 expression, was found in all neoplasms. One primary tumour was diagnosed as a mixed neuroendocrine-non-neuroendocrine neoplasm, which is the first report of this neoplasm in dogs. The other 15 primary tumours and both metastatic tumours were graded as PanNET G1, according to the human WHO classification. We conclude that canine PanNENs share well-differentiated histomorphology, SSTR2A expression and absence of nuclear p53 immunolabelling with human PanNETs G1. However, they differ in ATRX gene expression and functionality, and seem to have a worse prognosis than human PanNETs G1, although their generally low Ki-67 index precludes more precise assessment of prognosis. Membranous SSTR2A expression renders canine PanNENs potentially amenable to treatment with somatostatin analogues or SSTR targeted in-vivo imaging methods.

Constant expression of somatostatin receptor 2a in minute pulmonary meningothelial-like nodules.

AIMS: Although ultrastructural studies showed that minute pulmonary meningothelial-like nodules (MPMNs) cells closely resembled meningothelial cells, their immunophenotype has not been well characterised, partly due to their rarity. METHODS: Somatostatin receptor 2a (SSTR2a) and other markers of meningioma, including epithelial membrane antigen (EMA), progesterone receptor (PR) and S100, were analysed retrospectively in 19 MPMN cases from two institutions in China. RESULTS: The median age of patients with MPMNs was 62.5 years (32-73 years), with a male-to-female ratio of 1:8.5. Most (15/19) patients with MPMNs had coexisting diseases, including adenocarcinomas (12 cases), bronchiectasis (1 case) and tuberculosis (2 cases). Just over half of the cases (10/19) were multifocal lesions (2-5 lesions). An additional 53 cases with 123 lesions from the literature were reviewed with reported immunophenotype information. In total, 162 lesions were included in the analysis. The size of nodules was 1-4 mm. All MPMN lesions (39/39) in the 19 cases showed strong and diffuse cytoplasmic expression of SSTR2a. The expression rate of SSTR2a was higher than that of conventional markers of meningioma, including EMA (86/138), PR (32/68) and S100 (1/125). CONCLUSIONS: Our observations expand the spectrum of recognised SSTR2a-positive lesions and once again demonstrated that MPMNs show immunohistochemical characteristics similar to meningothelial cells.

Prognostic Characterization of Higher-Grade Meningiomas: A Histopathological Score to Predict Progression and Outcome.

Higher-grade meningiomas (WHO grade II and III) represent a diagnostic and prognostic challenge. We assessed the pathological and molecular characteristics of 94 higher-grade meningiomas (85 grade II, 9 grade III) to identify novel prognostic parameters. Higher mitotic count (p = 0.018), diffuse (≥50%) prominent nucleoli (p < 0.001), and sheeting (p < 0.001) were associated with recurrence. Lower SSTR2a-positive cells median rate (p = 0.048) and TERT promoter mutations (p = 0.014) were associated with recurrence and patient death, respectively; further analyses did not identify other outcome associations. Presence of Ki67 hot spots was associated with a shorter progression-free survival (PFS), independently of WHO grade at multivariate analysis (HR = 3.35, p = 0.008). Necrosis was related to a poorer overall survival (OS) at univariate (focal: HR = 4.55, p = 0.041 and diffuse: HR = 7.38, p = 0.020) and Kaplan-Meier analyses. A prognostic score was designed based on previous results: Presence of diffuse (≥50%) prominent nucleoli (0/1 point), diffuse (≥50%) sheeting (0/1 point), focal (<50%) or diffuse (≥50%) necrosis (0/1/2 points), and Ki67 hot spots (0/1 point). A total score ≥4 predicted poorer PFS and OS by Kaplan-Meier (PFS: 1.7 vs 6.4 years, p < 0.001 and OS: 5.2 vs 10.8 years, p = 0.001) and multivariate (PFS: HR = 5.98, p < 0.001 and OS: HR = 2.99, p = 0.048) analyses. These results were confirmed in an independent series of 58 grade II meningiomas (PFS: HR = 7.22, p = 0.002 and OS: HR = 9.69, p = 0.003). These associations and the integrated score could complement WHO grading.

Value of SSTR2A and Claudin - 1 in Differentiating Meningioma from Schwannoma and Hemangiopericytoma.

BACKGROUND: The distinction between meningioma, schwannoma and solitary fibrous tumour/ hemangiopericytoma can be challenging in some cases. This study evaluates the expression of Somatostatin receptor 2A (SSTR2A) and Claudin-1 in these different tumours. MATERIAL AND METHODS: Thirty-five cases of meningioma, 10 cases of intracranial schwannoma and 10 cases of hemangiopericytoma were assessed. The immunohistochemical expression of SSTR2A and Claudin-1 was evaluated and scored according to the percentage of immunostained tumour cells (0: 1+, 2+ and 3). The intensity of staining was classified as weak, moderate and strong. RESULTS: Positivity for SSTR2A and Claudin-1 was encountered in 89% and 49% of meningiomas respectively. None of the schwannomas or hemangiopericytomas was positive for any of both markers. All grade I and II meningiomas were positive for SSTR2A, and only 20% of grade III showed positive staining (p < 0.05). Claudin-1 positivity was detected in 50%, 43% and 60% of grade I, II and III meningioma respectively, with significantly higher intensity in grade III (p < 0.05). CONCLUSION: SSTR2A is highly sensitive and specific for meningioma. Claudin-1 is highly specific for meningioma, with low sensitivity. The adjunctive use of both markers can be very helpful in the diagnosis of meningioma and its distinction from schwannoma and hemangiopericytoma.

Real-Time Signaling Assays Demonstrate Somatostatin Agonist Bias for Ion Channel Regulation in Somatotroph Tumor Cells.

Acromegaly is a neuroendocrine disorder caused by excess secretion of GH by somatotroph tumor cells. It is often treated with somatostatin receptor (SSTR) 2 agonists, which suppress GH secretion. SOM230 is a somatostatin analogue that targets multiple SSTRs and was recently approved for patients with treatment-resistant acromegaly. Previous reports indicate that SOM230 may function as a biased agonist, suggesting that its ability to selectively activate SSTR-dependent signaling events may contribute to its therapeutic efficacy. To better understand how SOM230 modulates Sstr2A function, which is the most commonly expressed SSTR in somatotrophs, we used real-time assays to study SOM230-dependent signaling in rat pituitary tumor cells. We observed that SOM230 suppressed cAMP production in a Gαi-dependent manner, similar to conventional Sstr2A agonists. However, it did not cause receptor internalization as would be expected for an Sstr2A agonist. Surprisingly, SOM230 did not cause membrane hyperpolarization, which is an important mechanism by which Sstr2a activation suppresses intracellular calcium (Ca2+) accumulation and GH secretion. In fact, SOM230 inhibited the ability of conventional somatostatin analogues to control membrane potential. However, SOM230 still inhibited intracellular Ca2+ accumulation in a novel, Gßγ-dependent manner. These studies show that SOM230 exhibits strong agonist bias in regulating signaling pathways downstream of Sstr2A that control GH secretion.

Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature.

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.

Somatostatin receptor 2A protein expression characterizes anaplastic oligodendrogliomas with favorable outcome.

Diffuse gliomas are classified according to the 2016 WHO Classification of Tumors of the Central Nervous System, which now defines entities by both histology and molecular features. Somatostatin receptor subtype 2A (SSTR2A) expression has been reported in various solid tumors as associated with favorable outcomes. Its expression has been reported in gliomas with uncertain results regarding its prognostic value. The objective of this study was to assess the prognostic impact of SSTR2A protein expression in a large cohort of grade III and IV gliomas classified according to the updated 2016 WHO classification. We further validated our result with an independent cohort of low grade glioma using dataset generated by The Cancer Genome Atlas (TCGA) Research Network.We analyzed clinical and molecular data from 575 patients. SSTR2A protein expression was evaluated using immunohistochemistry on tissue microarrays. High expression of SSTR2A protein associated with the anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted subgroup (p < 0.001). Among these tumors, SSTR2A protein expression was significantly associated with a lower proliferative index, the absence of microvascular proliferation and the absence of necrosis (p < 0.001). Furthermore SSTR2A protein expression associated with better overall survival (p = 0.007) and progression-free survival (p = 0.01) in both univariate and multivariate analysis when adjusted by the age, the presence of necrosis and the mitotic index. Similar results were obtained regarding SSTR2 mRNA expression in the TCGA low grade glioma, subtype IDH-mutant and 1p/19q-codeleted, dataset.SSTR2A might represent an attractive biomarker and therapeutic target in anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted specific subgroup. Understanding the implicated molecular pathways may represent a step forward to improve therapeutic approaches.

In liver metastases from small intestinal neuroendocrine tumors, SSTR2A expression is heterogeneous.

We examined somatostatin receptor type 2A (SSTR2A) expression in primary and metastatic small intestinal neuroendocrine tumors (SI-NETs). We retrieved 156 liver metastases from 26 patients (10 males, 16 females) who had two or more liver lesions resected. A representative formalin-fixed paraffin-embedded section of tumor tissue from each liver metastasis and from the primary tumor, when available, were immunohistochemically stained for SSTR2A. SSTR2A expression was evaluated by the Her2/neu-scoring system and the scoring system proposed by Volante et al. Based on the Her2/neu-scoring system, moderate to strong SSTR2A expression was observed in 121 of 156 (78%) liver metastases. In 15 (58%) subjects, all liver metastases showed moderate to strong SSTR2A expression, whereas in 11 (42%) one or more liver tumors had weak or no expression. Of the 16 stained primaries, 11 (69%) showed heterogeneous SSTR2A expression. The corresponding liver metastases showed only weak to no expression in one, moderate to strong in five, and both weak to no and moderate to strong expression in five of the 11 cases. Using the Volante scoring system, no tumor was scored 0 (0%), two were scored 1 (1%), 38 were scored 2 (24%), and 116 were scored 3 (74%). No statistically significant association was observed between SSTR2A expression and Ki67 index (p = 0.56). Fifteen of 18 (83%) metastatic tumors with a Ki67 index >20% showed moderate to strong SSTR2A. Most liver tumors with weak SSTR2A expression or an IHC score of 2 were detected by OctreoScan. SSTR2A expression in liver metastases of SI-NETs can be variable, even between lesions in the same patient. Expression in metastatic lesions is not always similar to that in the primary tumor. SSTR2A expression is not associated with the Ki67 index.

Immunohistochemical Approach to the Differential Diagnosis of Meningiomas and Their Mimics.

The differential diagnosis between meningioma and others tumors can be challenging. This study aimed to evaluate different immunohistochemical markers for the differential diagnosis between meningioma and their morphological mimics. Immunohistochemistry was performed on tissue microarray with antiepithelial membrane antigen (EMA), progesterone receptor, somatostatin receptor 2A (SSTR2A), CD34, STAT6, S100, SOX10, HMB45, MelanA, GFAP, inhibin, and BCL2 antibodies. One hundred and twenty-seven meningiomas, 26 solitary fibrous tumor/hemangiopericytomas (SFT/HPC), 39 schwannomas, 17 hemangioblastomas, 21 melanomas, 9 gliosarcomas, 5 neurofibromas, 9 peripheral primitive neuroectodermal tumors, 7 synovial sarcomas, and 5 malignant peripheral nerve sheath tumors were included in the microarray. SSTR2A was the most sensitive (95.2%) and specific (92%) marker of meningiomas. In combination, SSTR2A and/or EMA positivity reached maximal sensitivity (100%). Coexpression of SSTR2A and EMA was the most specific (94.8%) for the diagnosis of meningioma, regardless of the grade or subtype, with the exception of the differential diagnosis with synovial sarcoma. All synovial sarcomas were EMA-positive and 6/7 SSTR2A-positive. STAT6 showed optimum sensitivity and specificity (100%) for SFT/HPC. SOX10 was the most sensitive (94.3%) and specific (100%) marker to discriminate meningiomas from schwannomas. In conclusion, SSTR2A, STAT6, and SOX10 were the most sensitive and specific markers to distinguish meningiomas from their morphological mimics.

Expression of Somatostatin Receptor Type 2A and PTEN in Neuroendocrine Neoplasms Is Associated with Tumor Grade but Not with Site of Origin.

Neuroendocrine neoplasms (NENs) are derived from endocrine cells in various organs and share common morphological features. This study aimed to clarify whether NENs of different organs are comparable at the molecular pathologic level. We retrospectively collected 99 cases of NENs from gastro-entero-pancreatic, lung, and other organs and reclassified these according to identical criteria. Grade, site, and molecular expression profile including NE markers, Ki-67, p53, somatostatin receptor type 2A (SSTR2A), and phosphatase and tensin homolog (PTEN) were compared. PTEN immunoreactivity was also compared with genomic copy number by fluorescence in situ hybridization (FISH) and droplet digital polymerase chain reaction (ddPCR). No significant differences were observed in the immunoreactivities of NE markers, p53, SSTR2A, or PTEN expression in NENs between the different organ sites. PTEN and p53 functional inactivation along with the loss of membranous SSTR2A expression appeared to be commonly involved in high-grade NEN. FISH results were significantly correlated with the level of PTEN immunoreactivity and with the findings of ddPCR analyses. The demonstration that these tumors are comparable at the molecular level will likely contribute to the broadening of therapeutic options such as the use of somatostatin analogues and mTOR inhibitors against NENs regardless of the affected organ, whereas molecular characterization of tumor grade will be useful for determining treatment strategy.

CD56 may be a more useful immunohistochemical marker than somatostatin receptor 2A for the diagnosis of phosphaturic mesenchymal tumors.

Phosphaturic mesenchymal tumors (PMTs) are the most typical cause of tumor-induced osteomalacia (TIO) associated with mesenchymal neoplasms. Specifically, TIO is attributed to the production of phosphatonins, such as fibroblast growth factor 23 (FGF23), participating in the homeostasis of phosphate. Although immunohistochemistry (IHC) for FGF23 showed characteristic positive staining in PMTs, FGF23 antibodies that can be used for the reliable diagnosis of PMTs are hard to obtain in common pathology laboratories. Somatostatin receptor 2A (SSTR2A) has been previously proposed as an alternatively useful marker for the diagnosis of PMTs. However, SSTR2A is not commonly utilized in pathological laboratories. The CD56 marker is a useful alternative that is comparable to SSTR2A and is similar considering the sensitivity. Even in cases of PMTs originating in the bones, ethylenediaminetetraacetic acid-based decalcification for tissue processing does not seem to affect the IHC of CD56. As CD56 immunopositivity in mesenchymal tumors is limited, it also has some degree of specificity for PMTs. Thus, when PMTs are suspected, the use of CD56 is recommended.

Phosphaturic mesenchymal tumors show positive staining for somatostatin receptor 2A (SSTR2A).

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis.