BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology is an effective reporting system for salivary gland fine needle aspirations with well-established risks of malignancy. Salivary gland neoplasm of uncertain malignant potential (SUMP) comprises a heterogenous group of lesions which have features that can be recognized as at least neoplastic but preclude further classification into benign or malignant. In this study, we reviewed the cytomorphologic features of salivary gland fine needle aspirations diagnosed as SUMP at our institution (over the past 6 years) and correlated those with the final diagnosis on surgical follow up.
METHODS: A retrospective search was performed to identify cases classified as SUMP at our institution from January 2018 to February 2024. Cytology slides were reviewed, and cases were subclassified based on key cytomorphologic features into the following categories: (1) basaloid, (2) oncocytic, (3) with clear cell features and (4) mixed features (myoepithelial/oncocytoid/squamoid features). Histologic diagnosis was recorded if available.
RESULTS: A total of 36 cases of SUMP were identified; 31/36 had surgical follow up; final diagnosis included 22 benign lesions (2 non-neoplastic and 20 benign neoplasms), and nine malignant lesions. The overall risk of neoplasm and risk of malignancy were 93.5% and 29% respectively, with the oncocytic sub-category recording the highest ROM (42.8%). Mucoepidermoid carcinoma was the most common malignant diagnosis and pleomorphic adenoma the most common benign diagnoses.
CONCLUSIONS: Our study supports the subclassification of SUMP lesions based on key cytomorphologic features, thereby aiding in refining this ambiguous entity and providing a precise risk assessment.

BACKGROUND: There are conflicting results on whether the presence of oncocytes modifies the risk of neoplasm (RON) or malignancy (ROM) for thyroid fine-needle aspirates (FNAs): Atypia of undetermined significance AUS and Follicular Neoplasm, FN, or Oncocytic Neoplasm, ON. To our knowledge, the effect of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has not yet been studied. We compared RON and ROM between follicular type AUS (AUS-FT) and oncocytic type AUS (AUS-OT) and between FN and ON.
METHODS: We retrospectively analysed all thyroid FNAs with the diagnostic category of AUS-other or Neoplasm (2005-2015). AUS-FT had predominance of microfollicles and AUS-OT had predominance of oncocytes. Histology follow-up was then reviewed and RON, ROM was then calculated and compared (significant at p < 0.05). We repeated the search for 2018 to evaluate for NIFTP effect.
RESULTS: Pre-NIFTP, 859/5063 cases (17%) were AUS-FT, AUS-OT, FN, and ON. Histology follow-up was available for 297 cases (35%). RON was 83/183 (45%) for AUS-FT, 35/76 (46%) for AUS-OT, 15/25 (60%) for FN and 11/13 (85%) for ON. Post-NIFTP, RON was 11/31 (35%) for AUS-FT, 5/8 (63%) for AUS-OT, 1/2 (50%) for FN and 4/5 (80%) for ON. For both periods, RON, ROM of AUS-FT was not significantly different than AUS-OT, and no significant differences were observed comparing FN and ON.
CONCLUSIONS: The predominance of oncocytes does not modify the implied RON, ROM for categories of AUS or FN\\ON, even after the adoption of NIFTP.

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine its most essential features with the systematic review tool. PubMed, Scopus, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathologic, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) The male-to-female ratio was 1.5:1. Pancreatic head was the most common site (131/237; 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1 out of 5 cases (49/237; 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1 or pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and molecular features were as follows. The most commonly expressed mucins were MUC5AC (110/112; 98.2%) and MUC6 (78/84; 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (P < .01). Moreover, fusions involving PRKACA or PRKACB gene were detected in all of the 68 cases examined, with PRKACB::ATP1B1 being the most common (27/68 cases; 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (P < .01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathologic and molecular features. Considering the clinical or prognostic implications, its recognition is essential for pathologists and, ultimately, patients\' management.

Although intraductal oncocytic papillary neoplasm (IOPN) was considered distinct from the intraductal papillary neoplasm of the pancreas, the oncocytic histologic type remained as a subtype of intraductal papillary neoplasms of the bile duct (IPNBs) with gastric, intestinal, and pancreatobiliary types based on the fifth edition of the WHO classification. To test the characteristics of the oncocytic type of IPNBs, the histopathologic, immunohistochemical (Hep Par-1 and CD117), and clinical characteristics of 13 oncocytic type were compared with 114 others (15 gastric, 39 pancreatobiliary, and 60 intestinal) IPNB types. The oncocytic type, which occupied about 9% of IPNBs, was more frequent in females (p < 0.05) and larger (mean, 5.3 vs. 3.6 cm; p < 0.002) than other IPNB types. Immunohistochemically, the oncocytic type had more frequent combined Hep Par-1 and CD117 expression than other IPNB types (all p < 0.05). The recurrence-free survival rate for patients with the oncocytic type (5-year survival, 100%) was significantly higher (p = 0.015) than for those with other histologic types (59.9%). The oncocytic type had distinct histopathologic, immunohistochemical, and survival outcomes from other IPNBs. Therefore, it can be separated from other IPNB types and classified as one independent entity, similar to IOPN of the pancreas.

BACKGROUND: Oncocytoid salivary tumors include several entities such as oncocytoma, Warthin tumor, secretory carcinoma (SC), salivary duct carcinoma (SDC), acinic cell carcinoma (AciCC), oncocytic mucoepidermoid carcinoma (OMEC), intraductal carcinoma, and epithelial myoepithelial carcinoma (EMC). This review investigates the differential diagnosis of oncocytoid salivary tumors and explore the role of newly described immunostains as valuable tools for their diagnosing and potentially guiding treatment options.
METHODS: We assess the utility of incorporating new immunohistochemical markers in routine practice to aid in diagnosing oncocytoid salivary tumors and potentially provide treatment options.
RESULTS: In SDC, AR and Her2 immunostains are utilized as diagnostic tools and biomarkers for selecting patients who might benefit from Androgen-deprivation therapy (ADT) and HER2-targeted therapy. Furthermore, nuclear Pan-Trk immunostaining can aid in diagnosing SC. Additionally, NR4A3 immunostaining has been shown high sensitivity and specificity in identifying AciCC in both surgical and cytologic specimens. Similarly, RAS Q61R mutant-specific immunostaining, detected in EMC, may offer a cost-effective diagnostic marker for this tumor. Although further studies are required to evaluate the role of BSND, this marker has been reported to be positive in Warthin tumor and oncocytoma, aiding in differentiating them from other oncocytoid tumors, particularly OMEC. In addition, BRAFV600E mutant-specific immunostaining can serve as a diagnostic and potentially therapeutic marker for oncocytic intraductal carcinoma in mutation positive cases.
CONCLUSIONS: Oncocytoid salivary tumors may have overlapping morphologies, posing diagnostic challenges for pathologists. Recently described immunohistochemical markers may offer valuable tools for diagnosing and potentially guiding treatment options for these tumors.

In the spectrum of oncocytic renal neoplasms, a subset of tumors with high-grade-appearing histologic features harboring pathogenic mutations in mammalian target of rapamycin (mTOR) and hitherto clinical indolent behavior has been described. Three cases (2F,1 M) with histologically documented metastases (lymph node, skull, and liver) were retrieved and extensively investigated by immunohistochemistry, FISH, and next-generation sequencing. Tumors were composed of eosinophilic cells with prominent nucleoli (G3 by ISUP/WHO) arranged in solid to nested architecture. Additionally, there were larger cells with perinuclear cytoplasmic shrinkage and sparse basophilic Nissl-like granules, superficially resembling the so-called spider cells of cardiac rhabdomyomas. The renal tumors, including the skull and liver metastases, showed immunoexpression PAX8, CK8-18, and cathepsin-K, and negativity for vimentin. NGS identified mTOR genetic alterations in the three cases, including the skull and liver metastases. One patient was then treated with Everolimus (mTOR inhibitors) with clinical response (metastatic tumor shrinkage). We present a distinct renal tumor characterized by high-grade eosinophilic cells, cathepsin-K immunohistochemical expression, and harboring mTOR gene mutations demonstrating a malignant potential and showing responsiveness to mTOR inhibitors.

A 67-year-old female with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presented with right sided otalgia and a 2-3 cm firm, tender right posterior parotid mass. Fine needle aspiration biopsy (FNAB) established a diagnosis of acinic cell carcinoma (AciCC). Further workup demonstrated lung nodules which were confirmed by FNAB to represent metastatic AciCC. A right radical parotidectomy with sacrifice of the facial nerve, segmental mandibulectomy, and selective neck dissection (levels II-IV) was performed. Microscopically, the tumor displayed an infiltrative border with a solid multinodular growth pattern and fibrosclerotic septation. The tumor was composed mainly of uniform cells with abundant eosinophilic granular cytoplasm with round nuclei with prominent nucleoli. Nuclei were fairly monomorphic, mitotic counts were 3-4 per 2mm2 and there was no necrosis despite the aggressive growth pattern. An anti-mitochondrial immunohistochemical stain showed strong reactivity in the tumor cells, with an internal positive control of adjacent striated ducts. An immunohistochemical stain for NR4A3 demonstrated strong nuclear reactivity in the tumor cells. Electron microscopy highlighted the tumor cells with numerous mitochondria and distinctive electron dense intramitochondrial inclusions. Concurrent CLL/SLL was identified on histologic examination of the lymph nodes, but they were free of AciCC. After eight weeks of follow-up, she tolerated the surgery well and is currently receiving radiation therapy to the parotid and neck. In this illustrative case, we justify the oncocytic designation of AciCC by morphology, immunohistochemistry, and electron microscopy.

The differential diagnosis for oncocytic renal tumors spans the spectrum from benign entities to more aggressive renal cell carcinomas (RCC). Recent work has characterized a provisional renal oncocytic neoplasm, namely the low-grade oncocytic tumor (LOT), which demonstrates overlapping morphologic features with oncocytoma and chromophobe RCC, but also has a unique immunoprofile (ie, diffusely positive for KRT7, negative for KIT) and a high rate (80% to 100%) of mTOR pathway gene alterations. Given the diagnostic overlap among oncocytic tumors, we looked for concordance between mTOR pathway mutations and LOT. Thirty low-grade renal oncocytic neoplasms underwent histologic review and immunohistochemistry for KRT7 and KIT. Tumors were classified as \"determinate\" (eg, LOT) for tumors with solid, nested or vaguely tubular growth and diffuse KRT7 staining and negative KIT, or \"indeterminate\" if the morphology and/or immunostains did not fully support a definitive LOT diagnosis. Next-generation sequencing was performed without any knowledge of the diagnoses, and identified mTOR pathway mutations in 80% (12/15) of the determinate tumors, compared with 7% (1/15) in the indeterminate group. One determinate tumor was reclassified as papillary RCC (MTOR mutation negative) and 6 indeterminate tumors were confirmed to be oncocytoma (N = 4), clear cell RCC or papillary RCC with reverse polarity, respectively. Overall, integration of morphology, immunohistochemistry, and molecular data enabled a final definitive diagnosis for 70% of tumors (21 of the total 30), with a high concordance (93%) for LOT specifically in the determinate group; the remaining 9 tumors (30%) were classified as renal oncocytic neoplasm, not otherwise specified.

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a distinct entity from intraductal papillary mucinous neoplasms (IPMNs) and is considered one of the precursor lesions of pancreatic cancer. Through immunohistochemistry (IHC) and an artificial intelligence (AI)-based approach, this study aims at characterizing its immune microenvironment. Whole-slide IHC was performed on a cohort of 15 IOPNs, 2 of which harboring an associated adenocarcinoma. The following markers were tested: CD3, CD4, CD8, CD20, CD68, CD163, PD-1, PD-L1, MLH1, PMS2, MSH2, and MSH6. The main findings can be summarized as follows: (i) CD8+ T lymphocytes were the predominant immune cells (p < 0.01); (ii) the vast majority of macrophages were concurrently CD68+ and CD163+; (iii) all tumors showed an activated PD-1/PD-L1 axis, but none had mismatch repair deficiency; (iv) AI-based analysis revealed the presence of 2 distinct regions in each case, namely, Re1, localized at the center of the tumor, and Re2, located at tumor periphery; (v) the infiltrating component of the 2 invasive IOPNs showed a smaller extent of Re1 and a reduced rate of CD4+ cells, as well as a larger extent of Re2 and increased rate of CD8+ cells. IOPNs are lesions enriched in immune cells, with a predominance of CD8+ T lymphocytes and class 2 macrophages. Differently from IPMN-oncogenesis, the progression towards invasive carcinoma is accompanied by an increased rate of CD8+ lymphocytes. This finding may suggest the presence of an active self-immune surveillance in invasive IOPNs, potentially explaining, at least in part, the excellent survival rate of IOPN patients.

BACKGROUND: Oncocytes are a component of many metaplastic and neoplastic lesions throughout the head and neck area, primarily originating in salivary/seromucinous glands and the thyroid gland. In addition, other lesions can contain cells that mimic oncocytes (pseudo-oncocytes); these can be of epithelial or non-epithelial origin.
METHODS: Review article.
RESULTS: Oncocytic metaplasia is common in seromucinous glands throughout the upper aerodigestive tract, most notable in the oral cavity, nasopharynx and larynx. The main oncocytic salivary gland neoplasms are Warthin tumor and oncocytoma. Infarction of Warthin tumor may lead to recognition difficulties. Oncocytic subtypes of mucoepidermoid carcinoma and intraductal carcinoma have morphologic and immunohistochemical features that allow distinction from major oncocytic entities. Oncocytic thyroid tumors include adenoma, carcinoma (follicular, papillary and medullary), along with poorly differentiated tumors. Oncocytic papillary sinonasal and middle ear tumors must be distinguished from low grade adenocarcinomas. Pseudo-oncocytic entities include paraganglioma, Langerhans cell histiocytosis, giant cell tumor, rhabdomyoma, and metastatic tumors.
CONCLUSIONS: Correct diagnosis of oncocytic head and neck lesions requires a knowledge of the spectrum of possible entities, their characteristic sites of occurrence, architecture, histomorphology, and immunohistochemistry. Oncocytic subtypes of several newly described entities are now recognized. Both epithelial and non-epithelial mimics of oncocytes exist. The molecular features of oncocytic tumors can be helpful in their diagnosis and understanding their pathogenesis.