Oncocytic/Hürthle cell lesions have the same implied risk of neoplasm/malignancy as their follicular counterparts.

INTRODUCTION: 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. MATERIALS AND 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. CONCLUSION: The predominance of oncocytes does not modify the implied RON, ROM for categories of AUS or FN\ON, even after the adoption of NIFTP.

A Retrospective Study of Clinicopathologic Outcomes of Nodules With Hürthle Cell Cytology and the Thyroid Nodule App (TNAPP) Ultrasound Recommendations.

OBJECTIVES: Hürthle cells are a common finding on thyroid fine-needle aspiration, but when they are the predominant cytology, they represent a difficult diagnostic challenge. The Thyroid Nodule App (TNAPP) is a new, publicly available web application utilizing ultrasound (US) features based on the updated 2016 American Association of Clinical Endocrinologists clinical practice guidelines for thyroid nodule management. This pilot study was performed to assess the TNAPP recommendations and surgical pathology outcomes of Hürthle cell-predominant thyroid nodules. METHODS: A retrospective review of nodules with Bethesda III (atypia of undetermined significance with Hürthle cells) or Bethesda IV (suspicious for Hürthle cell neoplasm) cytology, for which surgery was performed between 2017 and 2021, was conducted. TNAPP US categories 1, 2, and 3 (low, intermediate, and high risk, respectively) were assigned based on nodule characteristics, and clinical management recommendations were recorded. Results were compared with histology-proven diagnoses. RESULTS: Fifty-nine nodules in 57 patients where surgical pathology was available were analyzed with the TNAPP algorithm. Of the 59 nodules, 4 were US category 1 (low risk/suspicion), 40 were US category 2 (intermediate risk/suspicion), and 15 were US category 3 (high risk/suspicion). All US category 1 nodules were benign, while 30% of the US category 2 and 40% of the US category 3 nodules were malignant. Of the patients who had molecular marker testing with ThyroSeq, 22 out of 29 (76%) were positive, indicating either an intermediate or high risk of malignancy, 7 of which were malignant. CONCLUSION: This preliminary study suggests that TNAPP is a useful clinical tool for sonographic assessment of thyroid nodules with Hürthle cell cytology.

Oncocytic nodular hyperplasia of the thyroid.

Nodular hyperplasia of the thyroid is a process whereby the gland experiences growth by nodular expansion of thyroid parenchyma. We have encountered 45 patients in whom the process was caused by the growth of well-defined and sharply circumscribed but unencapsulated nodules composed of oncocytic thyroid follicular cells. The lesions arose in 39 women and 6 men, aged 25-69 years (mean = 50.3 years). The surrounding thyroid parenchyma showed features of chronic lymphocytic thyroiditis. The nodules varied from microscopic to 5 cm and appeared to compress the surrounding thyroid parenchyma. Most of the lesions lacked a well-defined capsule. In 26 tumors, the nodules displayed a predominantly follicular pattern of growth; in 8 cases there were admixtures of follicular and trabecular patterns with focal solid areas devoid of follicles. Clinical follow-up in 39 patients ranging from 7 to 22 years (median = 16 years) showed no evidence of recurrence, metastasis, or malignant transformation. One patient died of unknown causes 15 years after the diagnosis, and another patient died 4 years after diagnosis from metastatic colonic adenocarcinoma. Oncocytic nodular hyperplasia is a benign process associated with chronic lymphocytic thyroiditis that should be distinguished from benign and malignant oncocytic (Hurthle cell) tumors of the thyroid.

Oncocytic intraductal carcinoma of salivary glands: a distinct variant with TRIM33-RET fusions and BRAF V600E mutations.

AIMS: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC. METHODS AND RESULTS: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations. CONCLUSIONS: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics.

Renal cell carcinomas with tubulopapillary architecture and oncocytic cells: Molecular analysis of 39 difficult tumors to classify.

So-called oncocytic papillary renal cell carcinoma (OPRCC) is a poorly defined variant of papillary renal cell carcinoma. Since its first description, several studies were published with conflicting results, and thus precise definition is lacking. A cohort of 39 PRCCs composed of oncocytic cells were analyzed. Cases were divided into 3 groups based on copy number variation (CNV) pattern. The first group consisted of 23 cases with CNV equal to renal oncocytoma. The second group consisted of 7 cases with polysomy of chromosomes 7 and 17 and the last group of 9 cases included those with variable CNV. Epidemiologic, morphologic and immunohistochemical features varied among the groups. There were not any particular histomorphologic features correlating with any of the genetic subgroups. Further, a combination of morphologic, immunohistochemical, and molecular-genetic features did not allow to precisely predict biologic behavior. Owing to variable CNV pattern in OPRCC, strict adherence to morphology and immunohistochemical profile is recommended, particularly in limited samples (i.e., core biopsy). Applying CNV pattern as a part of a diagnostic algorithm can be potentially misleading. OPRCC is a highly variable group of tumors, which might be misdiagnosed as renal oncocytoma. Using the term OPRCC as a distinct diagnostic entity is, thanks to its high heterogeneity, questionable.

Causative role for defective expression of mitochondria-eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors.

Oncocytic cell tumor of the thyroid is composed of large polygonal cells with eosinophilic cytoplasm that is rich in mitochondria. These tumors frequently have the mutations in mitochondrial DNA encoding the mitochondrial electron transport system complex I. However, the mechanism for accumulation of abnormal mitochondria is unknown. A noncanonical mitophagy system has recently been identified, and mitochondria-eating protein (MIEAP) plays a key role in this system. We therefore hypothesized that accumulation of abnormal mitochondria could be attributed to defective MIEAP expression in these tumors. We first show that MIEAP was expressed in all the conventional thyroid follicular adenomas (FAs)/adenomatous goiters (AGs) but not in oncocytic FAs/AGs; its expression was defective not only in oncocytic thyroid cancers but also in the majority of conventional thyroid cancers. Expression of MIEAP was not correlated with methylation status of the 5'-UTR of the gene. Our functional analysis showed that exogenously induced MIEAP, but not PARK2, reduced the amounts of abnormal mitochondria, as indicated by decreased reactive oxygen species levels, mitochondrial DNA / nuclear DNA ratios, and cytoplasmic acidification. Therefore, together with previous studies showing that impaired mitochondrial function triggers compensatory mitochondrial biogenesis that causes an increase in the amounts of mitochondria, we conclude that, in oncocytic cell tumors of the thyroid, increased abnormal mitochondria cannot be efficiently eliminated because of a loss of MIEAP expression, ie impaired MIEAP-mediated noncanonical mitophagy.

DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma.

Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.

Bilateral multiple oncocytic cysts of the parotid gland in type 2 diabetes patients.

AIMS: The hallmarks of type 2 diabetes (T2D) are hyperglycaemia and insulin resistance. These factors, at the cellular level, are associated with mitochondrial dysfunction and increased glucose uptake. Such events are poorly explored in the context of the salivary glands. In this study, we present a series of eight cases of a distinct salivary gland lesion characterised by multiple oncocytic cysts, and we provide new pathological insights regarding its pathogenesis. METHODS AND RESULTS: Seven patients (87.5%) had confirmed T2D, and obesity was identified in five (62.5%) patients. Clinically, the patients showed bilateral parotid gland swelling with recurrent episodes of pain and enlargement. Imaging examination revealed multiple cystic lesions in both parotid glands. Microscopically, the parotid glands showed multiple cysts of different sizes, lined by oncocytic epithelial cells. Intraluminally, strongly eosinophilic glass-like crystalloid material was observed. Immunohistochemical studies were performed, and the most notable finding was glucose transporter 1 (GLUT1) overexpression in the oncocytic cysts which is not observed in any other oncocytic lesion of patients without T2D. In addition, high expressions of mitochondrial antigen, fission 1 protein and mitofusin-2 were observed in the oncocytic epithelium of the cysts. Furthermore, most of the oncocytic cysts showed a pattern of cytokeratin expression consistent with striated ducts. CONCLUSIONS: These results strongly suggest that T2D is associated with alterations in GLUT1 expression in the cells of striated ducts with mitochondrial dysfunction, causing a hyperplastic process characterised by multiple oncocytic cysts. For this lesion, the designation of 'diabetes-associated-bilateral multiple oncocytic cysts of the parotid gland' is proposed.

A case of tumor-to-tumor metastasis of cutaneous malignant melanoma.

We report a case of tumor-to-tumor metastasis of a cutaneous malignant melanoma to a synchronous thyroid Hurthle cell carcinoma. A 42-year-old male underwent a biopsy of right inguinal lymphadenopathy which showed metastatic melanoma. The primary lesion was identified on his right posterior leg, and staging workup discovered a synchronous left thyroid lobe nodule concerning for a follicular neoplasm. He underwent excision of the primary melanoma, right inguinal lymphadenectomy, and total thyroidectomy. The resected thyroid contained a 6.6-cm, well-encapsulated left-sided nodule, red-brown in color and homogenous in consistency, with areas of focal hemorrhage and no grossly identifiable calcification. Microscopically, large tumor cells with distinct cell borders were present, with deeply eosinophilic and granular cytoplasm, large nuclei with prominent nucleoli, and loss of polarity consistent with oncocytes. A microscopic single focus of vascular invasion was identified, and a diagnosis of angioinvasive Hurthle cell carcinoma was made. Within the Hurthle cell carcinoma, multiple deposits of metastatic melanoma were seen. These findings were indicative of tumor-to-tumor metastasis of the cutaneous melanoma to the angioinvasive Hurthle cell carcinoma. Our findings show the ability of melanoma to metastasize to a pre-existing neoplasm.

CD117 Is a Specific Marker of Intraductal Papillary Mucinous Neoplasms (IPMN) of the Pancreas, Oncocytic Subtype.

The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring PRKACA/B fusion genes as their genetic hallmark. Although IOPNs are associated with an infiltrative adenocarcinoma in up to 30% of cases, the survival rate after surgical resection approaches 100%. This highlights the importance of the correct IOPN diagnosis, above all in cases with an associated invasive component. In this study, the immunohistochemical expression of CD117 was investigated in 111 IPMNs, including 17 oncocytic, 45 gastric, 20 pancreatico-biliary, and 29 intestinal IPMNs. We also tested the expression of MUC5AC, MUC6, and Hep Par-1 in the IOPN cohort. CD117 positivity was significantly more frequent in IOPNs compared to the other IPMN subtypes (p < 0.0001). Furthermore, within IOPN, a lower or absent CD117, MUC5AC, MUC6, and Hep Par-1 expression tended to be associated with the presence of an infiltrative component. Our findings shed light into the biology of these complex lesions, which are confirmed to be a distinctive IPMN subtype; notably, CD117 emerged as a potential, additional tool in the differential diagnosis of IPMNs.

Parotid gland oncocytic carcinoma: A rare entity in head and neck region.

Oncocytic carcinoma of the salivary gland is an uncommon tumour in the head and neck region. Owing to its rarity, identifying the histopathological features of a malignant tumour can be difficult and challenging. We report a case of a 70-year-old man who presented with a left facial weakness for six months in a background history of left parotid swelling over the past 10 years. Clinical examination revealed a 3x3cm left parotid mass and grade 4 facial nerve palsy. Fine needle aspiration of the mass showed scattered cohesive, monolayered sheets of uniform oncocytic cells. Subsequently, a left total parotidectomy and selective neck dissection were performed. Histological examination showed sheets of small oncocytes with minimal nuclear atypia. Evidence of nerve entrapment, capsular invasion and perivascular permeation were identified in focal areas. Thus, a final diagnosis of oncocytic carcinoma was rendered.

Thyroid nodules with Hürthle cells: the malignancy risk in relation to the FNA outcome category.

PURPOSE: The aim was to find whether the presence of Hürthle cells (HC) in a smear influences the categorization of FNA results or the risk of malignancy (RoM) of particular categories of cytological diagnosis. METHODS: 25,220 FNA performed in a single center in years 2005-2017 were analyzed. Almost all the examined patients were exposed to moderate iodine deficiency for most of their lives. The distribution of FNA outcome categories was compared between two groups: with or without HC (HC and non-HC). The RoM was evaluated on the basis of postoperative histopathological examination (3082 patients). RESULTS: HC were found in 7.5% of diagnostic FNA. HC nodules were classified into categories II (78.2% vs. 91.9%, p < 0.0000) and VI (0.4% vs. 1.2%, p = 0.0017) less often than non-HC nodules, but more frequently to categories III (14.4% vs. 5.8%, p < 0.0000), IV (11.2% vs. 0.9%, p < 0.0000) and V (1.5% vs. 0.8%, p = 0.0013). There were no significant differences in RoM between HC and non-HC nodules. The RoM in HC and non-HC nodules of particular categories of the Bethesda system was as follows: II: 1.8% vs. 0.8%, III: 9.7% vs. 3.8% when only the last FNA was considered and 10.8% vs. 6.4% when the category III in any performed FNA was considered; IV: 12.7% vs. 10.9%; V: 41.7% vs. 58.2%; and VI: 100% vs. 96.9%. CONCLUSIONS: HC nodules are classified into categories of equivocal cytological outcomes more often than nodules without HC. Nevertheless, the presence of HC in a smear does not significantly affect the RoM of FNA categories.

Both Ultrasound Features and Nuclear Atypia are Associated with Malignancy in Thyroid Nodules with Atypia of Undetermined Significance.

BACKGROUND: The optimal management of thyroid nodules that undergo fine-needle aspiration (FNA) with findings of atypia of undetermined significance (AUS) is unclear. Categorizing nodules by AUS subtype and ultrasound characteristics may improve risk stratification. Therefore, the purpose of this study is to evaluate the association between AUS subtype and ultrasound features on risk of malignancy (ROM). METHODS: We performed a review of all patients with a thyroid nodule who underwent an FNA at our institution between January 2010 and November 2015. Patients with AUS were divided into groups with (1) nuclear atypia, (2) architectural atypia, or (3) Hurthle cell atypia. Their ultrasound features were assessed using the American Thyroid Association (ATA) thyroid nodule sonographic patterns. We conducted a univariate and multivariable analysis to determine the association between AUS subtype and other variables of interest with ROM. RESULTS: Of the 3428 thyroid nodules that underwent FNA, 237 (6.9%) had AUS. Of the 97 surgically resected nodules, 67 (69%) were benign and 30 (31%) were malignant. On univariate analysis nuclear atypia (p < 0.01) was associated with a thyroid malignancy. On multivariable analysis, both ATA high-risk ultrasound features (p = 0.04, odds ratio [OR] 3.68) and nuclear atypia (p < 0.01, OR 11.8) were independently associated with a final diagnosis of thyroid carcinoma. CONCLUSIONS: Nuclear atypia and ATA high-risk ultrasound features are useful in identifying patients with AUS that are at a higher risk of thyroid malignancy. Surgeons should take these factors into consideration when evaluating patients with AUS.

Low-grade intraductal carcinoma of the salivary gland with prominent oncocytic change: a newly described variant.

AIMS: Low-grade intraductal carcinoma (LG-IDC) is a clinically indolent malignant tumour of the salivary glands. Because of its rarity, the histological variants of LG-IDC have not been well characterised. Herein, we describe five LG-IDC cases with prominent oncocytic change in the major salivary glands. METHODS AND RESULTS: We examined five cases, three males and two females (mean age = 63 years), of LG-IDC with oncocytic change. The sites affected by LG-IDC were the parotid and submandibular glands. The lesions were macroscopically unilocular or multilocular cysts with a solid tumour arising from the cyst wall. Smaller tumour cell nests were also observed. As with classic LG-IDC, the cyst wall was surrounded by myoepithelial cells with no invasive component. The tumour cells had abundant oncocytic cytoplasm and proliferated in a low-papillary, tubular or cribriform pattern. Immunohistochemically, the tumour cells were diffusely positive for pan-cytokeratin, S100, mammaglobin and antimitochondria antibody, and were negative for androgen receptor and gross cystic disease fluid protein-15. Unlike classic LG-IDC, some of these cases demonstrated focal invagination of myoepithelial cells in the intraductal tumour. CONCLUSION: Oncocytic LG-IDC should be recognised as a histologically unique variant of LG-IDC. Awareness of this entity is important to avoid erroneous diagnosis and inappropriate treatment for histological mimics.

Oncocytic Metaplasia in Melanocytic Tumors.

Oncocytic metaplasia represents a histopathologic feature that can be observed in normal tissue such as salivary and lacrimal glands but may also constitute a degenerative metaplastic process as a result of repeated oxidative damage during cellular aging. Although cutaneous oncocytic metaplasia has been considered rare, the finding was seen in over one-third of melanocytic nevi prospectively evaluated, in one study. This case series reports on a small series of oncocytic melanocytic tumors, with the aim of describing this phenomenon in varied contexts and also describing the use of a mitochondrial antigen immunostain, which has not been previously reported.

A rare case of cutaneous oncocytic hidradenoma.

Oncocytes are epithelial cells characterized by their abundant eosinophilic and finely granular cytoplasm. Their histologic appearance is due to excessive amounts of cytoplasmic mitochondria. Oncocytes generally occur in the setting of benign neoplasms. Oncocytomas, or tumors composed primarily of oncocytes, are typically found in the kidneys. Other common sites include the salivary, thyroid, and parathyroid glands. Oncocytic metaplasia has only been rarely reported in various cutaneous neoplasms. We report a case of an elderly male presenting with a 5 mm erythematous papule on his left scalp, who underwent a shave biopsy showing a nodular, dermal-based adnexal tumor with prominent ductal differentiation, composed of multiple small, well-formed lumina surrounded by enlarged and bland-appearing epithelioid cells. Cytokeratin 7 (CK7), epithelial membrane antigen (EMA) and monoclonal carcinoembryonic antigen (mCEA) immunohistochemical stains were positive, consistent with adnexal differentiation. Phosphotungstic acid-hematoxylin (PTAH) and Luxol fast blue (LFB) stains highlighted the cytoplasmic granules, consistent with mitochondria. The overall findings were consistent with an oncocytic nodular hidradenoma. Oncocytic hidradenoma is a very rare entity, with only 1 previously reported case in the literature.

The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes.

In 2010, the World Health Organization reclassified the entity originally described as intraductal oncocytic papillary neoplasm as the 'oncocytic subtype' of intraductal papillary mucinous neoplasm. Although several key molecular alterations of other intraductal papillary mucinous neoplasm subtypes have been discovered, including common mutations in KRAS, GNAS, and RNF3, those of oncocytic subtype have not been well characterized. We analyzed 11 pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms. Nine pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms uniformly exhibited typical entity-defining morphology of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent, nucleoli, and intraepithelial lumina. The remaining two were atypical. One lacked the arborizing papilla and had flat oncocytic epithelium only; the other one had focal oncocytic epithelium in a background of predominantly intestinal subtype intraductal papillary mucinous neoplasm. Different components of this case were analyzed separately. Formalin-fixed, paraffin-embedded specimens of all cases were microdissected and subjected to high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes in a platform that enabled the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Fresh frozen specimens of two cases were also subjected to whole-genome sequencing. For the nine typical pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms, the number of mutations per case, identified by next-generation sequencing, ranged from 1 to 10 (median=4). None of these cases had KRAS or GNAS mutations and only one had both RNF43 and PIK3R1 mutations. ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were somatically altered in more than one of these typical 'oncocytic subtype' of intraductal papillary mucinous neoplasms but not in the other two atypical ones. In the neoplasm with flat oncocytic epithelium, the only mutated gene was KRAS. All components of the intestinal subtype intraductal papillary mucinous neoplasms with focal oncocytic epithelium manifested TP53, GNAS, and RNF43 mutations. In conclusion, this study elucidates that 'oncocytic subtype' of intraductal papillary mucinous neoplasm is not only morphologically distinct but also genetically distinct from other intraductal papillary mucinous neoplasm subtypes. Considering that now its biologic behavior is also being found to be different than other intraductal papillary mucinous neoplasm subtypes, 'oncocytic subtype' of intraductal papillary mucinous neoplasm warrants being recognized separately.

Implications of oncocytic change in papillary thyroid cancer.

OBJECTIVE: Although the presence of oncocytic change in less than 75% of a tumour is not considered to indicate oncocytic variants of papillary thyroid carcinoma (PTC), we frequently observe partial oncocytic change, especially in obese PTC patients. Thus, we sought to investigate the relationship between the presence of oncocytic change of PTC and its prognosis. DESIGN, SETTING AND PARTICIPANTS: We retrospectively studied 142 patients with PTC who had undergone surgery between 2000 and 2005, and re-evaluated their PTC slides to record the proportion of oncocytic change in 10% increments from 0% to 100%. MAJOR OUTCOME MEASURE: We analysed the relationship between the proportion of oncocytic change and clinicopathological prognostic factors. RESULTS: Oncocytic change was found in 45·8% (65/142) of PTC patients. The proportion of patients with oncocytic change was higher in obese patients than in lean patients and showed a significant correlation with the BMI (r = 0·195, P = 0·020). The PTC patients with oncocytic change showed a higher recurrence rate than PTC patients without oncocytic change (30·8% vs 11·7%, respectively; P = 0·005). The presence of oncocytic change in PTC patients was associated with a shorter disease-free survival in a Kaplan-Meier analysis after a mean follow-up of 8·9 years. CONCLUSION: The patients with PTC with oncocytic change presented with a higher recurrence rate and were more likely to be obese. These findings suggest that presence of oncocytic change is a poor prognostic factor in PTC patients, even if the oncocytic change involves less than 75% of a tumour.

Hidradenoma Papilliferum With Oncocytic Metaplasia: A Histopathological and Immunohistochemical Study.

Hidradenoma papilliferum is a benign cutaneous adnexal neoplasm, commonly occurring in the vulva and perianal region of adult women. It has characteristic histopathological features composed of anastomosing and branching tubules, lined by columnar cells, and a basal layer of myoepithelial cells. A 39-year-old woman was evaluated for 2 asymptomatic labial masses. The histopathological examination revealed a Bartholin's cyst and a hidradenoma papilliferum. The latter contains a distinct area of oncocytic/oxyphilic metaplasia. Immunohistochemical stains revealed positive staining for gross cystic disease fluid protein (GCDFP)-15 and androgen receptor. GATA-3, a protein expressed in sweat glands, highlights a similar positive staining pattern with weaker staining in areas of oncocytic metaplasia. P63 highlighted the myoepithelial differentiation. In situ hybridization for Human Papilloma Virus 6, 11, 16, and 18 was negative. P53 was negative and Ki-67 was low, confirming its benign nature. Oncocytes are enlarged epithelial cells with voluminous eosinophilic granular cytoplasm resulting from staining of nonribosomal cytoplasmic components. Few reports documented it in hidradenoma papilliferum. Our case demonstrated a florid distinct appearance of this metaplasia. The immunoprofiles of this oncocytic metaplasia such as p53 negativity and positivity for androgen receptor and GCDFP-15 demonstrates similarity to apocrine metaplasia in the breast. The authors' case demonstrates the benign nature of oncocytic metaplasia and supports the common origin of oncocytic cells and columnar cells in hidradenoma papilliferum.