A Rare Perineurioma/Granular Cell Tumor Hybrid Peripheral Nerve Sheath Tumor.

Hybrid peripheral nerve sheath tumors (PNSTs) are rare benign composite neoplasms demonstrating features of multiple endogenous nerve sheath cell types. Hybrid PNSTs with granular cell components are exceedingly rare. Only a handful number of hybrid PNSTs composed of granular cell tumor and perineurioma have been described to date. We present a rare hybrid of perineurioma and granular cell tumor and review the literature.

A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.

PURPOSE: Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. METHODS: We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. RESULTS: We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues. CONCLUSION: The activating NRAS p.Q61R variant is a known "hotspot" variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways. This discovery will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.

Heritable forms of primary hyperparathyroidism: a current perspective.

Primary hyperparathyroidism (PHPT) is one of the most common of all endocrine disorders encountered by the practising histopathologist. The vast majority of lesions are sporadic in nature, approximately 85% of which are parathyroid adenomas, while hyperplasia and carcinoma account for 10-15% and fewer than 1%, of cases, respectively. Heritable forms of PHPT are much less common and present challenges both to clinicians and pathologists, particularly when they are the presenting feature of an endocrine syndrome. In such instances, pathologists play a key role in alerting physicians to the possibility of an underlying heritable endocrine syndrome and the potential for extra-endocrine manifestations. Therefore, a working knowledge of these disorders is essential for providing guidance to treating physicians. The aim of this update is to review the clinicopathological features, genetic bases and current management for patients with PHPT associated with multiple endocrine neoplasia (MEN) types 1, 2A and 4 and hyperparathyroidism-jaw tumour (HPT-JT) syndrome in the context of the 2017 World Health Organization (WHO) Classification of Tumours of the Endocrine Organs. Additionally, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism are discussed.

Diagnosis and Management of Dermatofibrosarcoma Protuberans in a 3-Year-Old Patient.

In this case report, we present a 3-year-old boy with a diagnosis of dermatofibrosarcoma protuberans (DFSP) on the dorsum of his right hand. Although rarely metastatic, DFSP is highly locally invasive and can cause considerable local morbidity. In the hand, DFSP is uncommon in the young pediatric patient. In our patient, the tumor extended down to the second and third metacarpal heads and was treated with a multistaged excision of his tumor to achieve negative margins under slow Mohs micrographic surgery.

Expression of cadherin 17 in well-differentiated neuroendocrine tumours.

AIMS: Cadherin 17 (CDH17) is expressed primarily in normal intestinal epithelium and digestive tract tumours, and has limited expression in other neoplasms. The aims of this study were to examine CDH17 expression in well-differentiated neuroendocrine tumours (WDNETs) from various primary sites, representing the foregut, midgut, and hindgut, and tumours metastasizing to the liver, and to correlate the differences between the expression of CDH17, CDX2, and thyroid transcription factor 1 (TTF1). METHODS AND RESULTS: We investigated CDH17 immunohistochemical expression in 150 primary WDNETs from eight anatomical sites, including 68 from the foregut, 70 from the midgut, and 12 from the hindgut, and 15 metastases. CDH17 immunoreactivity increased significantly from foregut to hindgut WDNETs (P < 0.0001). Pancreatic WDNETs expressed CDH17 at a significantly higher frequency than other foregut tumours. Within the midgut, appendiceal and small-intestinal WDNETs were more frequently positive for CDH17 than for CDX2. All hindgut WDNETs expressed CDH17, in contrast to CDX2 (positive in one rectal case). CDH17 expression in liver metastases was similar to that of the primary tumours. CONCLUSIONS: This study is the first to comprehensively examine CDH17 expression in WDNETs from different sites. CDH17 is a sensitive marker for midgut WDNETs, and the CDH17+/CDX2-/TTF1- phenotype was found to be sensitive (92%) and specific (91%) for hindgut WDNETs.

Claudin expression in high-grade invasive ductal carcinoma of the breast: correlation with the molecular subtype.

Claudin proteins are a major component of the tight junctions. Dysregulation of claudin protein expression has been described in a number of malignancies. Gene expression profiling has stratified breast cancers into distinct molecular subtypes: luminal, HER2 positive (HER2+), and basal-like. Recently, a novel claudin-low molecular subtype has been described. In this study, we correlated the expression patterns of claudins with the molecular subtypes of breast cancer. On the basis of immunohistochemical expression, 226 grade 3 invasive ductal carcinomas were stratified into 65 luminal (estrogen receptor positive (ER+)), 65 HER2+, 86 basal-like, including 14 metaplastic carcinomas (ER-, HER2-, CK5/6, and/or epidermal growth factor receptor positive), and 10 unclassified. Tissue microarrays were analyzed for the expression of claudins 1, 3, 4, 7, and 8 by immunohistochemistry and scored semiquantitatively. High levels of expression were detected in 17% of all cases for claudin 1, 32% claudin 3, 41% claudin 4, 44% claudin 7, and 40% claudin 8. Luminal cancers exhibited increased claudins 7 and 8; basal-like tumors demonstrated increased expression of claudins 1 and 4. Low expression of all five claudins was detected in 30 of 226 cases (13%) and this group was designated 'claudin-low'. The majority of the claudin-low subgroup were basal-like cancers (23 of 30, 77%). In contrast, only 1 of 30 (3%) claudin-low tumors was of the luminal phenotype and 6 of 30 cases (20%) were HER2+ (P<0.001). Within the basal-like subgroup, 64% of the metaplastic and 19% of the non-metaplastic tumors were claudin-low. The claudin-low group was strongly associated with disease recurrence (P=0.0093). In conclusion, this study is the first to examine comprehensively the differential expression of claudins 1, 3, 4, 7, and 8 in the molecular subtypes of high-grade breast cancer. Claudin-low subtype is a frequent phenomenon in metaplastic and basal-like breast cancer and appears to be a strong predictor of disease recurrence.

Expression microarray analysis identifies novel epithelial-derived protein markers in eosinophilic esophagitis.

Gene expression studies in eosinophilic esophagitis support an immune-mediated etiology associated with differential regulation of inflammatory and epithelial-derived genes. We aimed to further characterize epithelial gene expression alterations in eosinophilic esophagitis and to explore the use of immunohistochemistry to identify these alterations. Esophageal biopsies from pediatric patients with eosinophilic esophagitis before and after therapy with topical steroids (N=7) were screened by gene expression microarray and results were validated by RT-PCR. A larger group of eosinophilic esophagitis patients (N=42) was then used to evaluate protein expression by immunohistochemistry compared with reflux patients (N=15) and normal controls (N=17). Microarray and RT-PCR studies identified overexpression of ALOX15 and tumor necrosis factor alpha-induced factor 6 (TNFAIP6) and underexpression of filaggrin (FLG), SLURP1 and cysteine-rich secretory protein 3 (CRISP3) in eosinophilic esophagitis. Immunohistochemistry for ALOX15 was positive in 95% of eosinophilic esophagitis and negative in all controls, all eosinophilic esophagitis after therapy and all reflux biopsies (P<0.001). TNFAIP6 was positive in 88% of eosinophilic esophagitis samples versus 47% of controls, 29% of eosinophilic esophagitis after therapy and 40% of reflux samples (P=0.002). Overexpression of both ALOX15 and TNFAIP6 directly correlated with the degree of eosinophilic infiltration. FLG was positive in 88% of controls and 100% of reflux biopsies, but negative in all eosinophilic esophagitis samples, and its expression was regained in 86% of eosinophilic esophagitis after therapy patients (P<0.001). SLURP1 expression was positive in all controls and reflux samples, but only positive in 5% of eosinophilic esophagitis and was re-expressed to 100% positivity in eosinophilic esophagitis after therapy patients (P<0.001). The majority of controls (89%) and reflux biopsies (100%) were positive for CRISP3 while eosinophilic esophagitis before therapy were positive in 14% of samples (P<0.001) with partial recovery after treatment (43%, P=0.105). This study identified five epithelial-derived markers differentially expressed in eosinophilic esophagitis easily detectable by immunohistochemistry with potential diagnostic utility.

The utility of TLE1 and BCOR as immunohistochemical markers for angiomatoid fibrous histiocytoma.

OBJECTIVES: Diagnosis of angiomatoid fibrous histiocytoma (AFH) can be challenging due to its variable histologic features and a lack of highly sensitive and/or specific immunohistochemical markers. The utility of TLE1 and BCOR as immunohistochemical markers for AFH is not known. METHODS: We examined the spectrum of histologic features of 36 AFHs, and studied the expression of both TLE1 and BCOR in AFH and its mimics by immunohistochemical staining. Positive nuclear expression was scored semiquantitatively. RESULTS: Both typical and unusual histologic features of AFHs were observed in this cohort. TLE1 was moderately to strongly positive in 36/36 AFHs, 4/4 synovial sarcomas, and 2/3 BCOR sarcomas; weakly positive in 4/6 inflammatory myofibroblastic tumors; negative in all dermatofibromas (n = 10), atypical fibrous histiocytomas (n = 5), myofibroma (n = 2) and juvenile xanthogranulomas (n = 5), with an overall sensitivity of 100%, and specificity of 71.4% for AFH. BCOR was moderately to strongly positive in 24/36 AFHs, 4/4 synovial sarcomas, 3/3 BCOR sarcomas, and 1/5 atypical fibrous histiocytomas; weakly positive in 10/36 AFHs; negative in the remaining tumors. The overall sensitivity and specificity of BCOR for AFH were 94.4% and 77.1%, respectively. CONCLUSIONS: TLE1 is a highly sensitive immunohistochemical marker for AFH.

Rectal suction biopsy to exclude the diagnosis of Hirschsprung disease.

OBJECTIVES: Hirschsprung disease (HD) is defined as the absence of ganglion cells in the Meissner and Auerbach plexuses. Diagnosis depends on demonstrating the absence of ganglion cells in rectal biopsy specimens. Rectal suction biopsy is widely employed as the method of choice in obtaining such specimens. Classically, the diagnosis was made until the 1990s by using the Multipurpose Suction Biopsy Kit, or Rubin Tube. This device was replaced by the Model SBT-100 Suction Biopsy Kit as the exclusive device used to procure rectal tissue. Because the suction devices are known to occasionally yield tissue that is insufficient, the present study was undertaken to determine the efficacy of using this technique to make or exclude the diagnosis of HD. METHODS: The last 50 biopsy sessions using the Multipurpose Suction Biopsy Kit and the first 46 sessions using the Model SBT-100 were included for review. RESULTS: Both groups had similar yields (24%) of biopsy sessions with insufficient tissue to allow meaningful interpretation. The predictive value of rectal suction biopsy in excluding HD at the first biopsy session was 65%. CONCLUSIONS: We conclude that HD can be excluded with a single rectal suction biopsy 65% of the time. A second biopsy session will exclude the diagnosis in an additional 11% of patients. Both devices yield biopsies of comparable quality and are equally useful in excluding the diagnoses of HD.

PD-L1 expression in angiomatoid fibrous histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a rare tumor of intermediate malignancy. Treatment options for unresectable and/or metastatic tumors are very limited. Immunotherapy with PD-1/PD-L1 inhibitors may be worth exploring. The aim of this study was to evaluate the expression of PD-L1 in AFHs. PD-L1 expression was assessed on 36 AFHs from 36 pediatric patients by immunohistochemical staining of PD-L1 (clone 22C3). Positivity was defined as membranous expression in ≥ 1% of either tumor or immune cells. The correlations between PD-L1 expression and clinicopathologic features were assessed. Two patients had lymph node metastasis. All patients underwent surgical resection; three of them also had systemic chemotherapy. Three patients had recurrence after initial resection; all patients were alive with a median follow-up of 2.5 years. Overall, twenty-two (61%) tumors were positively stained for PD-L1 and positivity was seen on both tumor and immune cells in eighteen of the 22 tumors. A positive correlation was found between tumor cell PD-L1 expression and CD8+ T-cell infiltration. There were no statistically significant differences between the status of PD-L1 expression and the clinicopathological features assessed. PD-L1 expression was identified in 61% of AFHs with a predominantly adaptive pattern. Our findings provide a rationale for future studies evaluating the potential of checkpoint immunotherapy for patients with unresectable and/or metastatic tumor.

Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for Targeted Therapies.

BACKGROUND: Primary adult renal sarcomas (RSs) are rare aggressive neoplasms. Clinical outcomes are extremely poor, and optimal treatment remains challenging. OBJECTIVE: To identify genomic alterations (GAs) in patients with RSs. DESIGN, SETTING, AND PARTICIPANTS: Comprehensive genomic profiling (CGP) was conducted on DNA/RNA extracted from formalin-fixed paraffin-embedded tissue using the FoundationOne Heme/Sarcoma assay in 13 adult, locally advanced or metastatic RSs of various histologic types. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All classes of GAs, including base substitutions, small indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI), were analyzed. RESULTS AND LIMITATIONS: CGP revealed 55 GAs (4.2 per tumor), 29 of which were clinically relevant genomic alterations (CRGAs; 2.2 per tumor). At least one CRGA was detected in nine (69%) cases. High-level amplifications (more than six copies) involving 4q12 amplicon of the KIT and PDGFRA genes were identified in four (31%) cases (two undifferentiated pleomorphic sarcomas [UPSs], one sarcomatoid renal cell carcinoma, and one myxofibrosarcoma). Both UPSs also had KDR gene amplification in addition to KIT and PDGFRA. Additional CRGAs were found in CDKN2A/B (23%), NF1 (23%), and MET (8%). All RSs were MSI stable, the mean TMB was 3.5 mutations/megabase (Mb), and none (0%) featured TMB >10 mutations/Mb. Limitations include the small sample size. CONCLUSIONS: RSs are characterized by diverse histology and genomic profiles including 31% of cases with 4q12 amplification harboring the KIT/PDGFRA/KDR genes. Of the tumors, 69% carry CRGAs, which could lead to potential benefit from targeted therapies; however, a low TMB also suggests that these cases are unlikely to respond to checkpoint inhibitors. PATIENT SUMMARY: This study provides insights into molecular biology of renal sarcoma, a rare aggressive subtype of kidney tumors. We demonstrated that renal sarcomas harbor unique, recurrent, clinically relevant molecular abnormalities that provide new opportunities for targeted therapies.

An unusual clinical presentation of rhabdomyomatous Wilms' tumor.

Wilms' tumor (WT) is the most common primary malignant renal tumor in children and usually presents as an abdominal mass. Rhabdomyomatous nephroblastoma is a rare histologic variant of WT. Herein we report an unusual case of WT with rhabdomyomatous differentiation presenting with hematuria and the passage of tissue via the urethra in a 2-year-old male.

A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.

CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs). Case reports associated with EBV-SMTs are limited. We describe herein a novel homozygous CARMIL2 variant (c.1364_1393del) in two Saudi Arabian male siblings born to consanguineous parents who developed EBV-SMTs. CARMIL2 protein expression was significantly reduced in CD4+ T cells and CD8+ T cells. T cell proliferation on stimulation with soluble (s) anti-CD3 or (s) anti-CD3 plus anti-CD28 antibodies was close to absent in the proband, confirming altered CD28-mediated co-signaling. CD28 expression was substantially reduced in the proband's T cells, and was diminished to a lesser degree in the T cells of the younger sibling, who has a milder clinical phenotype. Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells. FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced. These data confirm the pathogenicity of this novel loss-of-function (LOF) variant in CARMIL2 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.

Free-floating Paratesticular Calcifying Fibrous Pseudotumors in a Pediatric Patient.

Paratesticular masses are a relatively common finding in males. The majority are benign, as opposed to testis masses, which tend to be malignant. Fibrous pseudotumors are rare, but are the third most common paratesticular tumor after adenomatoid and lipoma. The exact cause is unclear but likely from a fibroinflammatory reaction. Because of the non-specific findings on physical exam and scrotal ultrasound, patients may undergo scrotal exploration and occasionally orchiectomy, in spite of the benign nature of this lesion. Here we report the rare case of free-floating paratesticular calcifying fibrous pseudotumors in a prepubertal patient.

INSL3 Expression in Leydig Cell Hyperplasia and Leydig Cell Tumors.

Insulin-like 3 (INSL3) is a hormone produced by Leydig cells (LCs) and leads to physiological testicular descent during embryonic development. We investigated the expression of INSL3 by immunohistochemistry in normal LCs, in Leydig cell tumor (LCT) (n=17 including 15 testes and 2 ovaries) and in Leydig cell hyperplasia (LCH) (n=10). Normally distributed LCs showed strong immunostaining in the cytoplasm in all cases. All 10 cases (100%) of LCH were strongly and diffusely positive in the intertubular areas. Six cases of LCH had nodules raging in size from 0.2 to 0.9 cm with variable INSL3 staining. Fifteen of 17 (88.2%) LCTs showed marked decrease INSL3 staining, 10/17 (58.8%) were completely negative, and 5/17 (29.4%) were only focally positive. Two cases with multifocal LCTs showed strong and diffuse cytoplasmic staining of LCs around seminiferous tubules while the LCTs were negative. Two cases diagnosed as LCT were strongly positive for INSL3. Other sex cord stromal tumors tested were consistently negative including Sertoli-cell tumor (n=4), granulosa cell tumor (n=2), and fibrothecoma (n=1). In conclusion, our results contrast with those of previously published studies, and show that the great majority of LCTs are negative or have decreased expression of INSL3 while its expression is retained in LCH. INSL3 negative nodules within LCH may represent early LCTs. INSL3 immunostaining could be helpful to highlight LCs in cases where it is difficult to identify them (ie, small testicular biopsies performed for infertility workup) and in the differential diagnosis between florid LCH and LCT.

Proximity to the Diaphragm Predicts the Presence of Rhabdomyomatous Dysplasia in Congenital Pulmonary Airway Malformations.

INTRODUCTION: Rhabdomyomatous dysplasia (RD) is a pathologic finding in CPAMs that was incorrectly attributed to their malignant potential. The increasing recognition of extrathoracic (intradiaphragmatic and intraabdominal) congenital pulmonary airway malformations (CPAMs) offers a clue to the origin of RD. We hypothesize that the presence of RD is related to the CPAM's anatomic location. MATERIALS AND METHODS: Retrospective review was performed of all children who underwent resection of a CPAM during a 10-year period. The age at the time of operation, location of the CPAM, and pathologic findings were collected. Peridiaphragmatic location was defined as within the inferior pulmonary ligament, deep to the diaphragmatic portion of the parietal pleura ("intradiaphragmatic") or adjacent to the abdominal side of the diaphragm. Statistical analysis was performed using Fisher's exact test for 2 × 2 tables. RESULTS: Twenty-six patients with CPAM were identified. Preoperative imaging was performed by computed tomography (CT) scan (16/26), ultrasound (5/26), magnetic resonance imaging (MRI) (1/26), and chest radiograph (4/26). The median age at resection was 15 months. Of these, 16 were pure cystic adenomatoid malformations, 4 were extralobar sequestrations, 4 were intralobar sequestrations, and 2 were bronchogenic cysts. Nine lesions were peridiaphragmatic with four being intradiaphragmatic (44%). Eight of the nine resected peridiaphragmatic lesions contained histologic evidence of rhabdomyomatous changes (89%, confidence interval [CI] 52-99%). None of the other lesions contained RD (CI 0-19%, p < 0.001). CONCLUSION: RD was seen exclusively, and in virtually all peridiaphragmatic CPAMs. While the exact significance of RD remains unclear, it may represent incorporation of striated muscle tissue associated with the developing diaphragm.

Metanephric Adenoma-Epithelial Wilms Tumor Overlap Lesions: An Analysis of BRAF Status.

Metanephric adenoma (MA) has historically been considered to represent a differentiated form of epithelial Wilms tumor (WT), based in part upon cases that morphologically overlap these 2 neoplasms. More recently, BRAF V600E mutations have been demonstrated in the majority of MAs but not in unselected or even epithelial-predominant WTs, suggesting 2 genetically distinct entities. However, no prior study has examined BRAF status in neoplasms with overlapping histologic features of epithelial WT and MA. We studied a cohort of 11 such overlapping lesions, 2 of which we considered morphologically to be otherwise typical MAs with unusually prominent mitotic activity and 9 of which we classified as epithelial WTs with areas resembling MA. Both mitotically active MAs demonstrated the BRAF V600E mutation. While the majority (5/9) of epithelial WTs with areas resembling MA were negative for BRAF V600E mutation, 4 such cases were positive. Two BRAF V600E mutation-positive WTs occurred in children. One case in a 6-year-old male was morphologically similar to the BRAF V600E mutation-positive adult cases and subsequently metastasized to the lungs; remarkably, the metastases then completely resolved on Braf targeted therapy. A second occurred in a 3-year-old girl whose posttherapy nephrectomy specimen's tumor was encapsulated and mitotically active like a typical WT, but also had more differentiated areas resembling MA. Immunohistochemistry for Braf V600E paralleled the molecular findings, demonstrating immunoreactivity in both the WT and MA-like areas of all 4 of these neoplasms. In summary, we demonstrate that BRAF V600E mutations are not entirely restricted to typical MA, as they may be seen in MAs showing mitotic activity along with a subset of epithelial-predominant WTs in adults and children that have foci which overlap morphologically with MA.

Thoracoscopic resection of a giant thymolipoma in a 4-year-old girl.

Thymolipoma is a very rare, benign mediastinal tumor. In this paper, we report on the thoracoscopic resection of such a lesion in a 4-year-old girl.