The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5+, androgen-) and luminal (CK5-, androgen+) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases.
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder categorized into 3 phenotypic variants: infantile, juvenile, and adult. Four recent reports have linked NIID to CGG expansions in the NOTCH2NLC gene in adult NIID (aNIID) and several juvenile patients. Infantile NIID (iNIID) is an extremely rare neuropediatric condition. We present a 7-year-old male patient with severe progressive neurodegenerative disease that included cerebellar symptoms with cerebellar atrophy on brain MRI, psychomotor developmental regression, pseudobulbar syndrome, and polyneuropathy. The diagnosis of iNIID was established through a postmortem neuropathology work-up. We performed long-read sequencing of the critical NOTCH2NLC repeat motif and found no expansion in the patient. We also re-evaluated an antemortem skin biopsy that was collected when the patient was 2 years and 8 months old and did not identify the intranuclear inclusions. In our report, we highlight that the 2 methods (skin biopsy and CGG expansion testing in NOTCH2NLC) used to identify aNIID patients may provide negative results in iNIID patients.
- MeSH
- Biopsy MeSH
- Child MeSH
- Intranuclear Inclusion Bodies genetics pathology MeSH
- Infant MeSH
- Skin pathology MeSH
- Humans MeSH
- Spinal Cord pathology MeSH
- Brain pathology MeSH
- Neurodegenerative Diseases diagnosis genetics pathology MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Receptor, Notch2 genetics MeSH
- Trinucleotide Repeats genetics MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in "zymogen granule"-poor examples within the differential diagnostic spectrum of AciCC and MASC.
- MeSH
- Carcinoma, Acinar Cell diagnosis MeSH
- Diagnosis, Differential MeSH
- DNA-Binding Proteins analysis biosynthesis MeSH
- Adult MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Biomarkers, Tumor analysis MeSH
- Salivary Gland Neoplasms diagnosis MeSH
- Receptors, Thyroid Hormone analysis biosynthesis MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sensitivity and Specificity MeSH
- Receptors, Steroid analysis biosynthesis MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
In several solid tumors, an increased stathmin expression is associated with both poor prognosis and resistance to certain chemotherapy types. However, the data regarding melanocytic lesions are very limited. The goals of our study are as follows: the assessment of stathmin expression in benign and malignant melanocytic lesions, and the significance of its expression for the differential diagnostics between benign and malignant lesions; the analysis of the prognostic significance of stathmin expression in melanoma; and the evaluation of stathmin expression in melanoma and melanoma metastases with respect to possible therapeutic targeting. Immunohistochemical analysis of stathmin expression was done in 323 melanocytic lesions, including 205 primary cutaneous melanomas, 60 melanoma metastases, and 58 melanocytic nevi. Stathmin expression was found in all analyzed groups of melanocytic lesions. Using the H-scoring system, the observed intensity of expression was as follows: melanocytic nevi: 146.1 (mean) and 150 (median); melanomas: 116.7 (mean) and 110 (median); and melanoma metastases: 136.8 (mean) and 140 (median). The stathmin expression was significantly lower in the cohort of primary melanomas when compared with metastases and nevi (P=0.001). The stathmin expression showed no prognostic significance. The high stathmin expression in melanoma suggests that stathmin might be a promising marker for therapeutic targeting in ongoing clinical trials. Compared with several other solid tumors, stathmin expression in melanoma showed no prognostic significance. The potential use of stathmin expression in differential diagnostics is limited by its common expression, and despite the statistically significant differences between nevi and melanoma, it may not be used in this setting.
- MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Melanocytes metabolism pathology MeSH
- Melanoma blood pathology MeSH
- Biomarkers, Tumor metabolism MeSH
- Skin Neoplasms blood pathology MeSH
- Prognosis MeSH
- Stathmin metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Heterotopic pancreas is a congenital pathology of the gastrointestinal tract, particularly rare in the esophagus. Both symptomatology and findings during preoperative examinations are non-specific and therefore do not often lead to an accurate diagnosis, which is usually revealed only by histopathological assessment of a resected specimen. We report an unusual case of a patient suffering from severe dysphagia caused by heterotopic pancreas in the distal esophagus with chronic inflammation and foci of premalignant changes. This article also reviews 14 adult cases of heterotopic pancreas in the esophagus previously reported in the literature, with the aim of determining the clinical features of this disease and possible complications including rare premalignant lesions and malignant transformation. Especially with regard to those complications, we suggest that both symptomatic and incidentally found asymptomatic lesions should be resected.
- MeSH
- Biopsy MeSH
- Choristoma diagnosis surgery MeSH
- Adult MeSH
- Esophagectomy MeSH
- Humans MeSH
- Multimodal Imaging methods MeSH
- Esophageal Neoplasms diagnosis surgery MeSH
- Pancreatic Neoplasms * MeSH
- Pancreas MeSH
- Tomography, X-Ray Computed MeSH
- Positron-Emission Tomography MeSH
- Predictive Value of Tests MeSH
- Precancerous Conditions diagnosis surgery MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Review MeSH
