Most high-grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal-type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal-type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi-lineage differentiation and can form glands with tubal-type epithelium. We used double transgenic Ovgp1-iCreER^T2 ;R26R^LSL-eYFP mice, which express an eYFP reporter protein in OVGP1-positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post-TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM-treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post-TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM-treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre-pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND

The molecular basis underlying the development of thyroid dysgenesis remains largely unknown. The objective of this study was to analyze the PAX8 gene in 32 children with congenital hypothyroidism due to thyroid dysgenesis for mutations, and to characterize the functional consequences of the mutations.

METHODS

The 5'-untranslated region and the entire coding region of the PAX8 gene were analyzed in 32 children. Functional analyses with a reporter gene assay were performed in transfected PCCL3 and TSA cells.

RESULTS

Thirty children did not have any sequence alterations. Two individuals had a previously identified monoallelic cytosine to thymine transition at position -983 in the promoter (-983C>T; mutant P. A of the ATG of the initiator codon is designated as +1), and a novel guanine to cytosine transversion in the non-coding exon 1 (-465G>C; mutant E). Functional analysis revealed that the basal transcriptional activity of the mutants is decreased compared to the wild type. Gel mobility shift assays indicated that mutant P does not interact with a transacting factor whose nature remains to be elucidated. The DNA binding property of mutant E were similar compared to the wild type.

CONCLUSIONS

These results suggest that mutations in PAX8 are most likely a very rare cause of thyroid dysgenesis. The observed sequence alterations result in diminished transcriptional activity and, in conjunction with other genetic and non-genetic modifiers, they may contribute to the pathogenesis of thyroid hypoplasia and hypothyroidism.

OBJECTIVE

To investigate the clinicopathological characteristics and the diagnosis of multilocular cystic renal cell carcinoma (MCRCC).

METHODS

The clinicopathological data of 19 MCRCC cases were collected and immunohistochemical staining assays were carried out. Forty-six cases of other cystic kidney lesions within the same period were collected as controls, including extensively cystic clear cell RCC (12 cases), clear cell tubulopapillary renal cell carcinoma (6 cases), tubulocystic carcinoma (2 cases), simple cortical cysts (22 cases), multilocular cystic nephroma (1 cases) and multicystic kidney (3 cases).

RESULTS

The patients included 14 males and 5 females. The ages ranged from 31 to 66 years (median age = 50 years). Most of the MCRCC cases were detected incidentally in physical examination, occasionally accompanied with hematuria, back pain or other symptoms. The follow-up period of 17 patients ranged from 6 to 170 months. All patients were alive without evidence of tumor recurrence or metastasis. Pathological findings showed that macroscopically, tumor size ranges from 1.5 to 7.0 cm in the maximum diameter, generally a entirely of various sized. The cysts contain serous, hemorrhagic or turbid fluid. Solid areas or substantially discernible mural nodules were absent; histologicallly, single layer of cuboidal and flattened epithelial tumor cells were lined in the cysts, described as clear cytoplasm, small nuclear, no nucleoli and low Fuhrman nuclear grade (I or II). Multilayer tumor cells could be observed in a few cysts, with granular cytoplasm and small intracystic papillae formed. The clear tumor cell clusters, similar as cystic lined tumor cells, were seen within pathological fibrous in almost all cases, and significant myofibroblastic proliferation was found in 14 cases. Immunohistochemically, the cysts lined epithelial cells and the clear tumor cell clusters were positive for epithelium markers, including CKpan(19/19), EMA(16/19) and CK7 (15/19); higher percentage of CAIX (17/19) and PAX8(15/19) than control groups, but lower percentage of CD10 (7/19), RCC (6/19) and AMACR(2/19); and all were negative for 34βE12, CD117 and CD68.

CONCLUSIONS

Multilocular cysts, clear cells clusters of low Fuhrman grade within fibrous septa and capillary vessel proliferation under epithelium are important features of MCRCC. The united using of CAIX, CK7, CD10 and RCC is helpful for differentiating variable cystic renal tumor. MCRCC usually has an excellent prognosis, nephron sparing surgery is first recommended as a therapeutic strategy.

Causes of peritoneal carcinomatosis (PC) in patients with a history of breast carcinoma include both metastatic breast carcinoma (MBC) and primary peritoneal/ovarian carcinoma (PPOC). The origin of PC is important to determine the appropriate treatment strategy. Cytological examination of the peritoneal fluid (PF), which may be the first diagnostic approach to PC, is of distinct value in confirming the presence of malignant cells and determining the origin of PC. We analyzed the clinicopathological and cytomorphological characteristics of 33 patients with a history of breast carcinoma whose PF cytology contained malignant cells. Cases showing positive immunoreactivity for PAX8 and a lack of GATA3 expression were considered as PPOC. Sixteen patients developed PC caused by PPOC. PPOC patients were characterized by early-stage primary breast carcinoma, absence of non-peritoneal MBC before PC, and normal serum levels of CEA and CA15-3. Fourteen PPOC patients had pathogenic germline BRCA mutations. Cytological examination revealed that most of the PPOC cases had a dominant papillary arrangement of the tumor cells with severe nuclear pleomorphism, occasional bizarre nuclei, and atypical mitotic figures. Patients with PPOC who underwent cytoreductive surgery had a significantly longer survival time compared to those who did not, or MBC patients. In patients with a history of breast carcinoma presenting with PC, the presence of early-stage primary breast carcinoma, no prior non-peritoneal MBC, and a dominant papillary cellular arrangement pattern in the PF cytology were independent predictors of PPOC. Cytoreductive surgery significantly improved survival for patients with PPOC.

OBJECTIVE

Results for the detection of point mutations and rearrangements have thus far been obtained by fresh material of fine needle aspiration cytology (FNAC). After a first retrospective study we report on the diagnostic detection in routinely obtained, consecutive air-dried FNAC smears.

METHODS

RNA and DNA was extracted from 154 consecutive routine air-dried FNAC smears: 80 with microfollicular proliferation (MFP), 45 with follicular neoplasia (FN), 26 with the cytological diagnosis of papillary carcinomas (PTC) and 3 which were suspicious for malignancy. PAX8/PPARG and RET/PTC3 rearrangements were detected by qPCR, while BRAF and RAS point mutations were detected by pyrosequencing.

RESULTS

Only 0.7 % and 5.3 % of the routine air-dried FNAC samples did not allow analysis of a point mutation or rearrangements, respectively. NRAS mutations could be detected in 7 MFP smears, and in one of FN and PTC samples, respectively. HRAS mutations were detected in one MPF and one FN sample. A KRAS mutation was only detected in one FN sample, whereas BRAF mutations were detected in 20 samples with PTC (but in no other sample). PAX8/PPARG was detected in 2 MFP samples, while RET/PTC was detected in only one MFP sample. In total, 13.8 % MFP-FNAC, 6.7 % FN-FNAC, and 80.8 % PTC-FNAC samples harbored a mutation.

CONCLUSIONS

These results demonstrate that rearrangements and point mutations can be detected in routinely obtained air-dried FNAC samples.

We report a hitherto not documented case of primary mucinous cystadenoma arising in the spermatic cord within the right inguinal canal of a78-year-old man. The tumor was painless, hard and mobile. A computed tomography scan on the pelvis revealed an oval shaped, low attenuation mass, measuring 5.0x2.5x2.1 cm, that was present adjacent to the vas deferens. Grossly, the excised mass was multicystic mucinous tumor, filled with thick mucoid materials. Microscopically, the cystic wall was irregularly thickened. The cystic epithelium commonly showed short papillae lined by a single layer of columnar to cuboidal mucinous epithelial cells without significant stratification or cytologic atypia. Goblet cells were also frequently present. Immunohistochemically, the neoplastic cells showed positive reaction to carcinoembryonic antigen, cytokeratin 20, CDX2, epithelial membrane antigen, and CD15. However, they were negative for PAX8 and Wilms' tumor 1 protein. Pathological diagnosis was a papillary mucinous cystadenoma of the spermatic cord. Although mucinous cystadenoma in this area is extremely rare, it is important that these lesions be recognized clinically and pathologically in order to avoid unnecessary radical surgery.

UNASSIGNED

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1720965948762004.

OBJECTIVE

To present six cases of cystic well-differentiated squamous cell carcinoma of the thymus.

RESULTS

The patients were six men aged between 48 and 75 years (average: 61.5 years) who were symptomatic with chest pain, shortness of breath, and dyspnoea. Diagnostic imaging showed anterior mediastinal masses, and surgical resection was accomplished in all cases. Grossly, the tumours measured 40-90 mm in greatest diameter (average: 65 mm), and were described as ill-defined lesions with a prominent cystic component and focal areas of haemorrhage and necrosis. Histologically, they were characterized predominantly by their cystic architecture. The cyst walls were lined by squamous epithelium showing different degrees of cellular atypia. In focal, more solid areas, the tumours showed evidence of keratinization. By immunohistochemistry, tumour cells were positive for cytokeratin 5/6, p40, and Pax8. All tumours were staged as T1N0M0 according to the Weissferdt-Moran staging system. Clinical follow-up showed that four patients have remained alive and well after a period ranging from 1 to 2 years. Two patients were lost to follow-up.

CONCLUSIONS

The current cases highlight an uncommon growth pattern of well-differentiated squamous cell carcinoma of the thymus that may cause diagnostic difficulty with mediastinoscopic biopsies.

BACKGROUND

The distinction between follicular adenomas (FAs) and well differentiated follicular and papillary carcinomas is often a demanding task and sometimes only intuitive.

OBJECTIVE

We report an histomorphological evaluation of follicular neoplasms [FAs, follicular carcinomas (FCs), and follicular variant of papillary carcinomas (FVPTCs)], supported by a qualitative and quantitative image analysis and by a molecular characterization.

METHODS

Tumor fibrosis and haemorrhage, neoplastic capsule thickness, follicle diameter, number of neoplastic cells, nuclear diameter of neoplastic cells, vessels density, vessels area and intratumoral distribution were evaluated. Ras and BRAF mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements were analyzed. Correlations with clinico-pathological features have been studied.

RESULTS

We found that FAs had a more extensive intratumoral haemorrhage, while malignant neoplasms were characterized by an evident fibrosis, higher cellularity and larger size. FVPTCs had higher nuclear diameter; cells count was higher in the minimally invasive follicular thyroid carcinomas, as well as a thickener neoplastic capsule. The CD34 stain showed a higher microvessel density in the FVPTCs group. A higher peripheral vessels distribution was observed only in malignant neoplasms. We observed overall Ras mutations in 2.4% of adenomas, in 41.5% of FVPTCs, and in 44.8% of FCs. It is outstanding that there is a marked difference in the Ras mutation distribution between the benign and malignant tumors in our series.

CONCLUSIONS

We found that genotyping of Ras gene family together with an accurate analysis of selected morphological features could help in the differential diagnosis of follicular-derived thyroid neoplasms.

Poorly differentiated malignant neoplasia arising within the head and neck region may originate from diverse sources. We report a case of a cytologically undifferentiated malignant neoplasm clinically presenting as masses involving thyroid and parotid. Although PAX8 was immunoreactive and thus worrisome for anaplastic thyroid carcinoma, the tumor was eventually proven to represent PAX5 positive diffuse large B-cell lymphoma expressing cross-reactivity with polyclonal PAX8 antibody. Cross-reactivity between commercially available polyclonal PAX8 and PAX5 immunostains has been described in the literature but is not widely known, and it is a potential pitfall for making a misdiagnosis. This distinction can have importance in selection of subsequent clinical therapy and should be considered in choice of immunohistochemical stains for diagnostic purposes.

UNASSIGNED

Intramucosal gastric adenocarcinoma of the well-moderately differentiated type only exhibits lymph node metastasis in extremely rare cases. We encountered such case and investigated both the lymphangiogenic properties and somatic mutations in the cancer to understand the prometastatic features of early-stage gastric cancer.

UNASSIGNED

We quantitatively measured the density of lymphatic vessels and identified mutations in 412 cancer-associated genes through next-generation target resequencing of DNA extracted from tumor cells in a formalin-fixed and paraffin-embedded tissue. Functional consequence of the identified mutation was examined in vitro by means of gene transfection, immunoblot, and the quantitative real-time polymerase chain reaction assay.

UNASSIGNED

The intramucosal carcinoma was accompanied by abundant lymphatic vessels. The metastatic tumor harbored somatic mutations in NBN, p.P6S, and PAX8, p.R49H. The PAX8R49H showed significantly higher transactivation activity toward E2F1 than the wild-type PAX8 (P< 0.001).

UNASSIGNED

Our data suggest that increased lymphangiogenesis and somatic mutations of NBN and/or PAX8 could facilitate lymph node metastasis from an intramucosal gastric carcinoma. These findings may potentially inform evaluations of the risk of developing lymph node metastasis in patients with intramucosal gastric cancer.

BACKGROUND

An accurate diagnosis of cancer of Müllerian origin is required before the initiation of treatment. An overlap in clinical presentation and cytological, histological, or imaging studies with other nongynecological tumors does occur. Therefore, immunocytochemistry markers are used to determine tumor origin. Human epididymis protein 4 (HE4) is overexpressed in tissue of epithelial ovarian cancer (EOC). It has shown to be a sensitive and specific serum marker for EOC and to be of value for the differentiation between EOC and ovarian metastases of gastrointestinal origin. The objective of the current study was to evaluate HE4 immunocytochemistry in malignant ascites for differentiation between cancer of Müllerian origin, including EOC, and adenocarcinomas of the gastrointestinal tract.

METHODS

Cytological specimens of 115 different adenocarcinomas (45 EOCs, 46 cases of gastric cancer, and 24 cases of colorectal cancer) were stained for HE4, paired box 8 (PAX8), and other specific markers.

RESULTS

91% of the ascites samples from patients with EOC stained for both HE4 and PAX8. The 4 samples without HE4 staining were a clear cell carcinoma, a low-grade serous adenocarcinoma, an undifferentiated adenocarcinoma, and a neuroendocrine carcinoma. All high-grade serous adenocarcinomas (n = 37, 100%) stained with HE4, compared with 94% that stained positively for PAX8. In cases of gastric or colorectal cancer, 25% and 21% of cases, respectively, stained positive for HE4. No PAX8 staining was observed in colorectal or gastric adenocarcinomas.

CONCLUSIONS

HE4 staining in ascites is feasible and appears to have a high sensitivity for high-grade serous ovarian cancer. HE4 is a useful addition to the current panel of immunocytochemistry markers for the diagnosis of EOC and for differentiation with gastrointestinal adenocarcinomas. Cancer Cytopathol 2017;125:197-204. © 2016 American Cancer Society.

Expression of thyroid transcription factor (TTF)-1 corroborates a thyroid origin of neoplasms. Thyroglobulin and calcitonin immunohistochemistry (IHC) can distinguish between a follicular and C-cell origin of thyroid tumours, respectively. Pax8 (expressed by normal canine thyroid follicular cells) and napsin A (expressed mainly by C-cells) labelling was compared with labelling for TTF-1, thyroglobulin and calcitonin in 114 canine proliferative thyroid lesions. All 81 follicular tumours expressed thyroglobulin and were negative for calcitonin; 79/81 (98%) of these tumours expressed TTF-1 and Pax8 and 60/81 (74%) expressed napsin A. All 25 C-cell lesions expressed calcitonin and were negative for expression of thyroglobulin; 22 (88%) were positive for TTF-1, 13 (57%) for Pax8 and 24/24 for napsin A. Six mixed follicular-medullary carcinomas expressed all five markers. Both carcinosarcomas expressed TTF-1 and napsin A, and one each of these tumours expressed thyroglobulin, calcitonin or Pax8. Pax8 expression was also detected in epididymal cells, endometrial cells and vas deferens epithelium, in Sertoli-like ovarian cells, and in some cases of ovarian adenoma, pancreatic carcinoma, renal cell carcinoma and Sertoli cell tumour. Napsin A was also detected in adrenocortical cells, ovarian granulosa cells, epididymal and endometrial cells, as well as in some renal cell carcinomas, pulmonary adenocarcinomas and Sertoli cell tumours. In summary, Pax8 was as sensitive as TTF-1 and slightly less sensitive than thyroglobulin for identification of follicular tumours, but had low sensitivity for C-cell tumours. Napsin A was as sensitive as calcitonin for C-cell neoplasms, but was less sensitive than thyroglobulin for follicular neoplasms. Thus, these markers are sensitive and, except for renal cell carcinoma (for Pax8, napsin A) and pulmonary adenocarcinoma (for napsin A), are specific thyroid tumour markers.

Sertoli cell (SC) and sertoliform tumors of the testis are very uncommon; for this reason their differential diagnosis and classification can be challenging. We applied an extensive immunophenotypic panel that included androgenic hormones, enzymes and receptors, neuroendocrine, lineage and genitourinary markers to a series of these lesions to determine if and which immunostains can aid in their diagnostic workup. Study cases included: 2 androgen insensitivity syndrome-associated SC adenomas, 3 SC tumors (SCT) not otherwise specified (SCT-NOS), 3 sclerosing SCT, 2 large cell calcifying SCT, 1 SCT with heterologous sarcomatous elements, 1 malignant SCT, and 1 sertoliform rete testis adenoma (sertoliform RTA). We found that SCT-NOS and variants with sclerosis showed a phenotype akin to atrophic seminiferous tubules characterized by gain of expression of pankeratin, calretinin, CD56, which are negative in normal SC. Distinctive phenotypes were identified in: sclerosing SCT: androgen receptors (AR) + (strong)/PAX2/PAX8+ (subset)/S100+/inhibin-; large cell calcifying SCT: calretinin+ (strong)/S100+/AR-; sertoliform RTA: PAX2/PAX8+/pankeratin+/inhibin-. Androgenic hormones and enzymes did not show diagnostic utility. A panel of calretinin, inhibin, pankeratin, S100, PAX2/PAX8, and AR consistently allowed distinction between variants of Sertoli and sertoliform tumors.

BACKGROUND

Thymic epithelial tumors (TET) are rare neoplasms with inconsistent treatment strategies. When researching for molecular pathways to find new therapies, the correlation between specific molecular markers and outcome has only rarely been investigated. The aim of this study was to investigate the correlation between survival, metastatic potential and invasiveness of aggressive subtypes of TET and immunohistochemical markers.

METHODS

Overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and metastasis-free survival (MFS) of patients with WHO type B2/B3 mixed type thymoma (MT), thymoma type B3 (B3) and thymic carcinoma (TC), undergoing surgery [1998-2013] were determined. Tumor specimens were stained using a tissue microarray (TMA) (CD117, CD5, p63, p40, p21, p27, p53, Bcl-2, Ki67, podoplanin, synaptophysin, PTEN and Pax8). Invasive behavior of primary tumors and the presence of extrathoracic metastases were assessed.

RESULTS

We found in 23 patients included into this study (four MT, ten B3, nine TC) that (I) p21 expression in the cytoplasm significantly correlated with a decrease of OS (P=0.016), PFS (P=0.034) and MFS (P=0.005); (II) MFS was significantly shorter when the combination of p21-low p27-low p53-high was present (P=0.029); and (III) nuclear p27 (P=0.042), Ki-67 (P=0.024) and podoplanin (P=0.05) expression correlated with the presence of extrathoracic metastases.

CONCLUSIONS

The main finding of this study is that cytoplasmic p21 expression negatively influences the outcome of malignant TETs and correlates with metastatic activity. Additionally, selected immunohistochemical markers correlate with the distant metastatic potential of TETs. These results may contribute to the stratification of diagnosis and improvement of treatment strategies for thymic malignancies.

We investigated the role of fluorescence in situ hybridization (FISH) in the diagnosis of primary renal neoplasms and lesions suspicious for metastatic renal cell carcinoma. Consecutive fine-needle aspiration biopsies (FNAB) of 39 renal masses and 41 metastatic tumours suspicious for renal cell origin were assessed with an immunohistochemical panel for CK7, RCC antigen, CD10, AMACR, PAX8, vimentin, and CD117. In addition, FISH was performed using probes for chromosomes 1p, 3p, 7, 17, X, and Y. A total of 31 of 39 primary renal masses and 33 of 41 metastatic tumors suspicious for renal origin demonstrated typical cytological and immunohistochemical (IHC) features of subtypes of renal neoplasms (40 clear cell renal cell carcinoma (RCC), 20 papillary RCC, and 4 renal oncocytomas). FISH analysis of 15 randomly selected cases each of primary and metastatic lesions revealed chromosomal abnormalities consistent with the diagnosis in 73% of these cases. Of 8 primary renal masses demonstrating atypical microscopic features and noncontributory IHC profiles, FISH was helpful in subtyping 5 (62%) of these lesions (2 clear cell RCC, 1 solid variant of oncocytic papillary RCC, 1 mixed clear cell and papillary RCC, and 1 chromophobe RCC with papillary architecture). Of 8 metastatic tumors clinically suspicious for renal cell origin and supportive, but nondiagnostic IHC, FISH revealed supportive chromosomal changes in 6 (75%) cases. In conclusion FISH analysis on FNAB material, even with limited tissue, may be contributory to the diagnosis and subtyping of RCC in diagnostically challenging biopsies.

Pax8, napsin A, and CD10 are useful immunohistochemical markers of human renal cell carcinoma (RCC); however, their diagnostic utility in canine RCC is unclear. Forty formalin-fixed paraffin-embedded renal cell carcinomas from dogs (15 papillary, 12 solid, and 13 tubular) and 10 metastases were evaluated for expression of Pax8, napsin A, and CD10. Thirty-nine (98%), 24 (60%), and 19 (50%) tumors expressed Pax8 (nuclear labeling), napsin A (cytoplasmic labeling), and CD10 (cytoplasmic and membranous labeling), respectively. Pax8 was expressed in 92% of solid, 100% of papillary, and 100% of tubular tumors. Napsin A was expressed in 58% of solid, 60% of papillary, and 62% of tubular RCC. CD10 was expressed in 33% of solid, 47% of papillary, and 62% of tubular RCC. Pax8 was expressed in 80% of the metastatic tumors, napsin A in 60%, and CD10 in 50%. Additionally, Pax8 immunoreactivity was stronger overall than that of napsin A or CD10. In summary, Pax8 is a more sensitive marker than napsin A or CD10 for primary and metastatic canine RCC; its nuclear and more intense reactivity also makes it easier to interpret. Tubular and papillary RCCs were more likely than solid RCC to express all 3 markers. These findings highlight the utility of Pax8 as an immunohistochemical marker in diagnosing all major subtypes of canine primary and metastatic renal cell carcinoma.

Renal cell carcinoma (RCC), the most common type of kidney cancer in adult, rarely metastasizes to the ovary or fallopian tube, and most cases published in the literature were case reports. Herein, we describe the clinicopathological features of 9 cases of RCC metastatic to the ovary (n = 8) or the fallopian tube (n = 1). The patients' age at the onset of primary renal tumor was available in 8 patients, ranging from 37 to 73 years (mean, 51 years; median, 50 years). Ovarian metastasis was detected prior to or concurrently with the primary renal tumors in 3 patients, and after the diagnosis of renal tumors in 6 patients. The histotypes of the RCCs were clear cell (n = 7), chromophobe (n = 1), and unclassified (n = 1). Immunohistochemical stainings were performed on the sections containing metastatic tumors in 4 cases. Interestingly, pagetoid intraepithelial spread in the tubal mucosa was observed in the case of RCC metastatic to the fallopian tube. Among the 8 patients with follow-up data, 5 died of disease and 3 were alive with disease, with a follow-up period ranging from 3.7 months to 17 years (mean, 77 months; median, 53 months) after the diagnosis of primary kidney tumors. Diagnostically, metastatic RCC may mimic primary ovarian tumors clinically, morphologically, or immunophenotypically. Pathologists should also keep in mind that both ovarian and kidney tumors express PAX8 and PAX2, the markers commonly used to diagnose metastatic RCC. In addition, chromophobe RCC only rarely metastasizes, but it can be a diagnostic challenge when it metastasizes to the ovary.

The pathogenesis of thyroid lymphoepithelial cysts is controversial, and two hypotheses have been proposed, namely derivation from branchial-derived remnants or from squamous metaplasia of the follicular cells. The aim of this study was to clarify the pathogenesis of thyroid lymphoepithelial cysts. We performed pathological and immunohistochemical examination of 21 thyroid lymphoepithelial cysts, 13 non-neoplastic squamous metaplasia samples without thyroid carcinoma, 13 solid cell nests, and 14 lateral cervical cysts. On ultrasound, half of thyroid lymphoepithelial cysts were interpreted as calcified nodules regardless of no calcification. Thyroid lymphoepithelial cysts and squamous metaplasia tended to be located in the central and lower portions of the thyroid, while solid cell nests were located in the upper and central portions (p < 0.05). In 95.2% of patients with thyroid lymphoepithelial cysts and all patients with squamous metaplasia, lesions were histologically associated with chronic thyroiditis forming lymph follicles. Hashimoto's disease was serologically confirmed in 18 patients with lymphoepithelial cysts (85.7%) and 10 patients with squamous metaplasia (76.9%). Immunohistochemically, lymphoepithelial cysts showed nuclear positivity for PAX8, thyroid transcription factor 1, and p63. One lateral cervical cyst (7.1%) showed positive staining for PAX8, while solid cell nests were PAX8-negative. In three (14.3%) cases of thyroid lymphoepithelial cysts, squamous cells located on the superficial layer were focally and weakly positive for CEA. We concluded that thyroid lymphoepithelial cysts originate from follicular cells and are unrelated to solid cell nests and lateral cervical cysts arising from branchial-derived remnants.

Objective: To investigate the clinicopathologic characteristics, diagnostic features and prognosis of primary renal neuroendocrine carcinoma (NEC). Methods: The clinicopathologic data of eight cases of renal NEC was collected from January 2008 to December 2017 from Affiliated Hospital of Qingdao University. Immunohistochemical staining was performed, and follow-up information was analyzed, and the relevant literature reviewed. Results: The patients' mean age at diagnosis was 45 years (range, 27-66 years); five were women, and three were men. The tumors located on the left side in five patients, and on the right side in three. Five cases were detected incidentally, and three patients presented with loin pain. Microscopically, these cases included five well-differentiated NECs (three carcinoids, two atypical carcinoids), two small cell NECs, and one large cell NEC according to the World Health Organization classification of 2016. The tumors infiltrated the renal capsule in six cases. Necrosis was found in five cases. Vascular invasion with tumor emboli was seen in three cases. Lymph node metastasis was identified in one case. Immunohistochemically, the expression rates of neuroendocrine markers CD56, chromogranin A (CgA) and synaptophysin (Syn) were 6/8, 4/8, and 8/8 respectively. Some of the NECs were positive for epithelial markers CKpan (6/8, with three cases showing focal positivity) and CAM5.2 (4/8) of variable degrees. The Ki-67 proliferation index was≤3% in the carcinoids; ≥50% in the small cell carcinoma and large cell carcinoma; and 5% and 8% for the two cases of atypical carcinoid, respectively. All cases were negative for EMA, CK7, CA9, CD10, CD117, PAX2, PAX8, WT1, p63, S-100 and TTF1. Three patients (two with small cell carcinoma and one with large cell carcinoma) died of extensive metastases at 3 months, 4 months and 9 months after operation, while five patients were well, without recurrence or distant metastasis for follow-up period of one to nine years. Conclusions: Primary renal NEC is rare. Carcinoid is the most common histological type. The pathomorphological features and neuroendocrine markers (CD56, CgA, Syn), epithelial markers (CKpan, CAM5.2) and nephrogenic markers (PAX2, PAX8) are important for the diagnosis. Renal carcinoid tumors are indolent and prone to early metastasis, but are associated with prolonged survival. The small cell renal cell carcinoma and large cell carcinoma are highly malignant renal tumors with poor prognosis and short survival.

OBJECTIVE

Neuroendocrine middle ear adenoma (MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours.

RESULTS

We investigated six cases of neuroendocrine MEA, and stained them, for the first time, for the transcription factors CDX2, TTF1, PAX8, and ISL1 (islet-1). The patients were four men and two women (mean age, 39 years; range, 27-53 years). Two of four patients with extended follow-up (4.5-22 years) experienced recurrence at 92 months, and at 9 and 22 years, respectively. One case extending into the external ear coexisted with cholesteatoma. Histological examination showed trabecular, solid, acinar, glandular, cribriform, organoid, nested, diffuse non-cohesive plasmacytoid and pseudoalveolar patterns in varying combinations. Immunohistochemistry showed consistent expression of vimentin (4/4), pancytokeratin (6/6), synaptophysin (6/6), CD56 (4/4), and ISL1 (6/6). A CK7 antibody stained scattered cells in two of five cases. The myoepithelial markers and transcription factors TTF1, CDX2 or PAX8 were not expressed in any of the cases.

CONCLUSIONS

Middle ear adenoma is an indolent, locally recurring, but generally non-metastasizing neoplasm with uniform expression of synaptophysin and ISL1, indicating true neuroendocrine differentiation. Because of its highly varied cellular and architectural appearance, MEA should be distinguished from tympanic paraganglioma and a variety of rare benign and malignant lesions at this site.

At the present time, the differentiation between follicular thyroid carcinoma (FTC) and adenoma can be made only postoperatively and is based on the presence of capsular or vascular invasion. The ability to differentiate preoperatively between the malignant and benign forms of follicular thyroid tumors assumes greater importance in any clinical setting. The PAX8-PPARG translocation has been reported to occur in the majority of FTC. In this study, a group of 60 follicular thyroid neoplasms [18 FTC, 1 Hurthle cell carcinoma (HCC), 24 follicular thyroid adenomas (FTA), 5 Hurthle cell adenomas (HCA), and 12 follicular variants of papillary thyroid carcinomas (FV-PTC)] were analyzed to determine the prevalence of the PAX8-PPARG translocation by fluorescence in situ hybridization. The PAX8-PPARG translocation was detected in 2/18 FTC (11.1%). In addition, 2/18 (11.1%) FTC and 1/5 (20%) HCA showed 3p25 aneusomy only. The frequency of the translocation detected in the study was lower compared to the earlier studies conducted in Western countries. This might be attributed to the ethnic background and geographic location. Detection of either the PAX8-PPARG translocation or the 3p25 aneusomy in FTC indicates that these are independent genetic events. It is hereby concluded that 3p25 aneusomy or PAX8-PPARG translocation may play an important role in the molecular pathogenesis of follicular thyroid tumors.

Nephroblastomas are uncommon embryonal tumors in dogs. We report herein a blastema-predominant nephroblastoma with gingival metastasis in an 8-y-old Miniature Pinscher dog. Histologically, the mass was composed mainly of blastemal elements with minor epithelial and mesenchymal differentiation. Metastatic masses in the gingiva had histologic and immunohistochemical features similar to those of the primary renal nephroblastoma. Neoplastic cells were extensively positive for both vimentin and PAX8, and scattered positive for cytokeratin. Using the clinical staging of human Wilms tumor, we staged our case as stage IV with <4 mo of survival time. We summarized previous studies of canine renal and spinal nephroblastomas, and analyzed the correlations among clinical staging, histologic classification, and mean survival time of dogs with renal nephroblastomas. Clinical staging was significantly correlated with survival time, as shown in humans. In dogs, however, additional factors can potentially influence the outcome of treatment and disease development.

The distinction between follicular thyroid carcinomas (FTCs) and follicular-patterned benign lesions is almost impossible on fine-needle aspiration cytology. Furthermore, minimally invasive FTCs (MI-FTCs) with less than 4 vascular invasion foci generally have an excellent prognosis, but there are exceptions and, so far, no molecular marker appears able to identify them reliably. We aimed to distinguish benign lesions from low- and high-risk FTCs by a small-scale combination of genes. The expression analysis of 75 selected genes was performed on 18 follicular adenomas (FAs), 14 MI-FTCs and 6 widely invasive FTC (WI-FTCs). The mutational status of the RAS genes, TERT promoter and PAX8-PPARG rearrangements was also investigated. Seven samples were mutated, namely 3 MI-FTCs and 4 WI-FTCs. Twenty-five genes were differentially expressed (FDR <0.05) between FAs and WI-FTCs. Six of these (ECM1, RXRG, SDPR, SLC26A4, TIFF3, TIMP1) were also differently expressed among MI-FTCs and FAs or WI-FTCs and were considered to build a classification model, which was tested to classify samples according to their histological class. Hence, 31 out of 38 were correctly classified, and accuracy remained high after cross-validation (27/38). The 2 MI-FTCs incorrectly classified as WI-FTCs harbored both RAS and TERT promoter mutations. The capability of these six genes to stratify benign, low- and high-risk lesions appears to be promising in supporting the diagnosis of indeterminate thyroid nodules.