High Molecular Weight Cytokeratin Research Articles

P63 Expressing Adenocarcinoma of The Prostate Gland, A Rare Neoplasm Which Tends to Pose Diagnostic Dilemma Sometimes: Review and Update

It has been documented that prostate cancer is the world's leading cause of cancer and also the second commonest cancer in men which does tend to pose challenges in its diagnosis. It has been iterated that immunohistochemistry studies utilising tumour markers like high molecular weight cytokeratin, p63 aid in the diagnosis of prostate cancer. It has been known for some time that the absence of immunohistochemistry staining of prostate lesion for p63 and high molecular weight cytokeratin and presence of p504s in the biopsies indicate malignant lesions. Nevertheless, it had also been pointed out as well as documented that some rare cases of adenocarcinoma of prostate variants do demonstrate evidence of the tumour cells exhibiting p63 immunohistochemistry staining and this does pose a diagnostic dilemma that may make the unfamiliar pathologist mis-diagnose such a malignant tumour as a benign prostate lesion. p63-positive adenocarcinoma of the prostate gland is a major diagnostic pitfall. There is a danger of interpreting malignant glands as benign and arriving at a false-negative diagnosis. This can be prevented by the understanding of the pattern of immunohistochemistry staining expression related to this variant of prostate cancer. The major points that favour the diagnosis of carcinoma in these cases include: non-basal p63 staining and negative HWMCK and positive p504s staining. The biological behaviour of this particular rare variant of prostatic carcinoma is not certain and requires to be studied further into more detail. Considering the rarity of p63 expressing prostate cancers and the fact that most clinicians including pathologists, urologists, and oncologists would not have encountered a case of p63 expressing prostate cancer before in order to update all clinicians regarding this rare tumour, the ensuing article has been extensively written and divided into two parts: (A) Overview which has discussed general overview aspects of p63 expressing neoplasms and (B) Miscellaneous Narrations and Discussions from Some Case Reports, Case Series, and Studies Related to Primary p63 Expressing Adenocarcinomas of the Prostate Gland. A high-index of suspicion as well as knowledge of the histopathology examination features as well as immunohistochemistry examination features of this rare tumour is required from all clinicians. Knowledge of the treatment options, biological behaviour as well as outcome following treatment of the tumour has been extensively discussed as updating information. The update has clearly pointed out that further studies are required to determine the role of p63 overexpression in prognostication.

The importance of histomorphological features and ERG expression in the diagnosis of malignancy in cases with atypical small acinar proliferation.

Atypical small acinar proliferation (ASAP) cases typically require rebiopsy, which are invasive and associated with increased risk of complications. Our aim in this study was to determine the importance of laboratory and histological findings and E-26 transformation-specific-related gene (ERG) expression in the diagnosis of malignancy. Between March 2016 and March 2022, 84 patients who were diagnosed with ASAP on biopsy or rebiopsy were included in the study. Clinical-laboratory features of age, serum prostate-specific antigen level, and histopathological features were compared and included multifocality, number of suspicious acini, nuclear enlargement, nucleolar prominence, hyperchromasia, cytoplasmic amphophilia, luminal amorphous acellular secretion, crystalloid presence, infiltrative appearance, inflammation, atrophy, α-methyl acyl-CoA racemase, p63, and/or high molecular weight cytokeratin were analyzed. In addition, ERG expression was evaluated immunohistochemically. Statistically significant correlation was found between nucleolar prominence, nuclear hyperchromasia, crystalloid presence, infiltrative pattern, and prostate cancer (p < .001). In 19 of 84 cases (22.6%) ERG was positive in the nucleus. Prostate cancer was diagnosed at rebiopsy in 15 of the 19 ERG-positive cases (78.9%). A statistically significant correlation was found between ERG positivity and prostate cancer (p= .002). Our findings suggest that evaluation of these markers during initial transrectal ultrasound biopsies may decrease and prevent unnecessary prostate rebiopsy.

Evaluation of expression of immunohistochemical markers high molecular weight cytokeratin (HMWCK) and alpha-methylacyl coa racemose (AMACR) in prostatic needle biopsies and transurethral resection of prostate (TURP) specimen – A one year observational study

In view of increasing incidence of Prostate cancer with age, its early detection and management is of utmost importance. Digital rectal examination, clinical picture and USG findings are non-specific. In prostatic lesions having a suspicious morphology, IHC staining (HMWCK and AMACR) is done to distinguish benign from malignant lesions. Absence of myoepithelial layer (HMWCK negative) along with cytoplasmic granular staining in glands (AMACR positive) is consistent with malignant diagnosis.To evaluate the utility of IHC markers HMWCK and AMACR in resolving morphologically suspicious foci on Prostatic needle core biopsies and TURP specimens.Observational StudyA total of 30 cases of prostatic lesions were studied. The specimens were fixed in 10% formalin and routinely processed. Haematoxylin-Eosin (H&amp;E) and IHC staining (HMWCK and AMACR) was done in all 30 cases.Data collected was analyzed using appropriate statistical test.A total of 30 cases including 19 cases prostatic needle core biopsies and 11 cases of TURP specimens were included in our study. Histopathological diagnosis included 1 case each of Adenosis, Atypical adenomatous hyperplasia and Transitional cell metaplasia; 9 cases of BPH with suspicious foci, 4 cases of LGPIN, 3 cases of HGPIN and 11 cases Prostatic adenocarcinoma. In 5 cases including 3 cases of BPH with suspicious foci and 1 case each of adenosis and AAH, the diagnosis was changed to Prostatic Adenocarcinoma after IHC analysis. We conclude that IHC staining should be done in cases where routine H&amp;E sections have an ambiguous morphology. HMWCK along with AMACR is a good marker combination to differentiate Benign from Malignant lesions.

Primary mucinous adenocarcinoma of the urethra: Aclinicopathological analysis of 35 cases.

Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear β-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.

Role of Two Antibodies Panel High Molecular Weight Cytokeratin and Alpha-MethylacylCoA Racemase in Diagnosing Prostatic Lesions: A Cross-sectional Study

Introduction: Prostatic diseases cause significant morbidity and mortality. Although histopathological examination is the gold standard for diagnosing prostatic lesions but diagnosis may be challenging in the presence of benign mimickers or a very small focus of malignancy. Immunohistochemical aid to morphology helps in making a timely and accurate diagnosis. Aim: This study was done to evaluate the role of two antibodies panel High Molecular Weight Cytokeratin (HMWCK) and AlphaMethylacyl-CoA Racemase (AMACR) in improving the diagnostic accuracy of prostatic lesions. Materials and Methods: This was an observational cross-sectional study conducted in the Department of Pathology, Shri Guru Ram Rai Institute of Medical and Health Sciences (SGRRIM and HS), Dehradun, Uttarakhand, India, from May 2019 to October 2020. Haemotoxylin and Eosin (H&amp;E) stained sections of prostatic biopsies were classified into benign and malignant. Amongst malignant lesions, prostatic adenocarcinomas were graded according to Gleason’s grading system and Gleason’s scores were noted. One section from each was subjected to AMACR and HMWCK antibody tests. HMWCK was interpreted as negative/positive and continuous/ discontinuous. For AMACR, both location and intensity of stain was observed. The parameters studied were Gleason’s score, group grade, expression of HMWCK and AMACR. Categorical data was presented in form of frequency and percentage. Independent t-test, Yates Chi-square test were used. Data was entered in Microsoft (MS) Excel sheet and analysis was done using CRAN R 2.1. Results: Total of 80 prostatic biopsies were taken, 24 were malignant and 55 were benign and one was Benign Prostatic Hyperplasia (BPH) with a focus suspicious for malignancy showing atypical small acinar proliferation on histopathological examination. The mean age of non neoplastic cases was 67.68±8.56 years, while that of neoplastic lesions was 75.41±9.34 years. Amongst benign, 56.3% (31/55) cases were BPH, 43.6% (24/55) cases were BPH with associated lesions which included 62.5% (15/24) cases of BPH with non specific prostatitis; 29.2% (7/24) cases of BPH with adenosis and 8.3% (02/24) cases of BPH with basal cell hyperplasia. Of malignant cases, 24 cases were of adenocarcinoma with maximum cases having Gleason’s score 9 (11/24;45.8%) and Group grade V (18/24;75%). The sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV) of HMWCK and AMACR were calculated using histopathology as the gold standard. Conclusion: Although histopathology is the gold standard in prostatic biopsies but immunohistochemistry is additional diagnostic aid in confirmation of diagnosis. Immunohistochemistry not only confirms the histological diagnosis but is of great help in challenging cases. It has markedly increased the diagnostic accuracy

P63-expressing Prostate Adenocarcinoma: A Case Study of a Rare Subtype

Abstract Introduction/Objective Prostate acinar adenocarcinoma (PCa) is a well-researched,and often diagnosed entity. A combination of architectural and cytologic characteristics are used in accurately identifying these carcinomas. However, the diagnosis can be challenging when the foci are minute or the cancer presents with unusual features. Ancillary studies aid in these scenarios. The loss of basal cells in adenocarcinoma makes markers targeting these cells desirable. PIN4 cocktail immunohistochemical stain, which combines alpha-methylacyl-coA racemase (AMACR), that is overexpressed in prostate carcinoma, with basal markers high molecular weight cytokeratin and p63, is a popular ancillary study to assist diagnosing demanding cases. Herein, we present a rare, challenging subtype of prostate carcinoma expressing p63. Methods/Case Report A 66-year-old male, with a past medical history of treated HIV and hyperlipidemia, underwent screening biopsies for a PSA of 7.5 ng/mL. Out of 22 parts, three cores showed modest amounts of atypical infiltrating cells. The architecture comprised of ill-defined glands, individual cells and single files of cells. They possessed high nucleocytoplasmic ratio giving a hint of atrophy, with occasional spindling and prominent nucleoli. To add to the challenge, PIN4 immunostaining showed strong nuclear expression of a basal marker with negative AMACR. Due to unusual morphology and basal marker expression, a consideration of basal cell lesion was entertained. However, subsequent staining revealed negative expression of HMWCK, and positive expressions of NKX3.1 and p40. Overall, with this morphology and immunoprofile we diagnosed our case as prostate carcinoma with aberrant expression of p63. Results (if a Case Study enter NA) N/A Conclusion Grading these lesions is controversial as they are considered to carry a better prognosis over conventional acinar adenocarcinoma of similar grade. A distinct etiopathology is suspected as molecular tests for ERG and PTEN are without alterations. Further discussion and characterization of these lesions is warranted as they are infrequently encountered and prone to being overlooked due to their similarities to benign basal cells.

Metastatic mammary tubulopapillary carcinoma in a captive black jaguar (Panthera onca)

AbstractA 12‐year‐old female captive jaguar (Panthera onca) developed sudden severe respiratory distress and died close to the onset of clinical signs. The animal underwent mastectomy to remove neoplasms in the mammary glands 2 years prior to death. During the post‐mortem examination, multiple nodules were found in the remaining left inguinal mammary glands. Similar lesions were found in other organs. Microscopically, neoplasms were characterised by a tubulopapillary pattern with papillary projections into the central lumen of newly formed tubules (tubulopapillary mammary carcinoma). Immunohistochemistry (IHC) for oestrogen receptor, progesterone receptor and high molecular weight cytokeratin on the mammary tissue site and a metastatic site was performed with positive results. IHC for Ki‐67 was performed in the mammary lesion with positive labelling in 50% of the cells. In captive felids, malignant neoplasms may be aggressive with limited therapeutic options. Thus, attention is needed in anticipating arising tumours to support the use of control therapies and the long‐term preservation of captive jaguars.

Large Cell Neuroendocrine Carcinoma of the Prostate Gland: A Review and Update

It has been documented that the 2016 World Health Organization’s histological classification of prostate cancer has included well-differentiated carcinoid tumours and small- or large-cell poorly differentiated tumours within the category of neuroendocrine tumours. Up to May 2021, only 20 cases of large-cell neuroendocrine tumours of the prostate gland (LCNTPs) had been reported within the literature, among which are nine cases of primary tumours. LCNTPs are a rare histological entity whose evolutive profile and therapeutic potential do differ from those of conventional adenocarcinoma of the prostate gland. Primary neuroendocrine tumours of the prostate gland could be pure or associated with an adenocarcinoma component. Mixed forms of large cell neuroendocrine cancers of the prostate gland (LCNECPs) tend to associated with better prognosis when diagnosed early at a localized stage. Nevertheless, most cases of (LCNTPs) at the time of initial diagnosis could tend to be advanced, locally advanced or metastatic. Even though LCNECPs that are diagnosed initially tend to primary prostate cancers that may be pure primary prostate cancers, few large LCNECPs have been found to be metastatic large cell neuroendocrine carcinomas that had metastasised from other sites of the body for example the lung. Primary LCNECP does tend to manifest similarly to primary adenocarcinoma of prostate gland with lower urinary tract symptoms, haematuria, or signs of obstruction of the upper urinary tract or inability to empty the urinary bladder. Cases of primary LCNECP that manifest tend also to be associated with symptoms related to the sites of the metastases. Serum prostate specific antigen levels tend to be slightly elevated with cases of primary LCNECP, but the levels generally tend not to be as high as most cases of advanced, locally advanced or metastatic primary adenocarcinomas of the prostate gland. Diagnosis of LCNECPs tend to be made pursuant to the undertaking of histopathology and immunohistochemistry staining studies of specimens of the prostate that had been obtained from prostate biopsies, trans-urethral reception of prostate specimens or prostatectomy specimens. The microscopy histopathology examination features of LCNECP the prostate gland have been summarized as follows: (a) Microscopy histopathology examination of LCNECP gland does tend to demonstrate large islands or sheets of tumour cells. (b) Large tumour cells with prominent neuroendocrine features such as salt and pepper chromatin and small nucleoli tend to be visualised upon microscopy examination of specimens of the prostate tumour. (c) High grade features such as lack of glandular formation, frequent mitoses and apoptotic bodies and tumour necrosis tend to be frequent findings upon microscopy examination of specimens of LCNECP. Immunohistochemistry staining features of LCNECP include: (a) At least one of the ensuing neuroendocrine tumour markers should be demonstrated upon immunohistochemistry staining including exhibition of positive immunohistochemistry staining for: chromogranin A, synaptophysin, neuron specific enolase, and CD56 may be positive: It has been stated that immunohistochemistry staining studies may exhibit positive staining in cases of LCNECP with utilization of the following: o TTFI tends to be positive in less than 50% of cases of LCNECP. o Positive AMACR immunohistochemistry staining, but this may be focal or weaker than for adenocarcinoma of the prostate gland. o Positive markers including: PSA, PSMA, NKX3.1 prostein (P501S) tend to be negative in majority of cases of LCNECP, but they could be focally positive in a small subset of the tumours. It has been iterated that in cases of LCNECP, immunohistochemistry staining studies tend to demonstrate negative staining for the ensuing markers: • Urothelial markers such as GATA3, p63, and high molecular weight cytokeratins such as CK5 / 6. • CD99. • Carcinoid tumour of the prostate gland. • PNET/Ewing sarcoma of the prostate gland. • Adenocarcinoma of the prostate gland with focal neuroendocrine differentiation. • Urothelial carcinoma with neuroendocrine differentiation. A high index of suspicion is required in order to diagnose early cases of primary large cell neuroendocrine carcinomas by undertaking early biopsies of prostate glands in all patients who have significant lower urinary tract symptoms if their serum prostate specific antigen (PSA) levels are slightly high or high even if they are commenced on Tamsulosin in an attempt to help improve the symptoms of voiding. There is no consensus opinion on the best management of LCNECP, therefore, there is an urgent need for the establishment of a global multi-centre trial related to various management options for the disease in order to ascertain the best options of management for LCNECP. gland.

Diagnostic significance of combined immunohistochemical panel of p63, High Molecular Weight Cytokeratin (34betaE12) and α‑Methyl Acyl Co A Racemase (AMACR) in resolving suspicious foci in prostatic lesions

Background: The assessment of small foci of atypical glands in prostatic needle biopsy specimens is a key diagnostic challenge in routine histopathology for pathologists. Due to the presence of mimickers of prostate carcinoma, at times making a definitive diagnosis becomes difficult. The use of immunomarkers like α‑Methyl Acyl Co A Racemase (AMACR), p63 and High Molecular Weight Cytokeratin (HMWCK/34betaE12) has made it easier for us to reach the diagnosis in such cases. Material and methods: All the cases which were received in the Department of Pathology, JNMCH, AMU from January 2015 to December 2018 were categorized into four histomorphologic groups on the basis of histopathology, and immunohistochemistry was applied on all the cases which were rendered ‘suspicious’ on histomorphology. Result: One hundred twenty-one prostatic specimens were received. Out of which, 13 biopsies were found to be inadequate for analysis and hence were not included in the study. Out of the rest 108 cases, (1) 52 were benign, (2) 19 were premalignant, (3) 25 were carcinoma and (4) 12 were signed as ‘suspicious’ on histopathology. These 12 suspicious cases were true cut needle biopsies which were considered appropriate for applying immunomarkers along with control cases. Out of 12 suspicious cases, 8 cases (66.7%) were negative and 3 cases (25%) were weakly positive for p63, 1 case showed moderate immunostaining. HMWCK was completely negative in 7 cases (58.33%), 3 cases (25%) showed weak positivity, 1 case showed moderate and 1 case showed strong positivity. While 5 cases (41.67%) were negative and 7 cases (58.33%) were positive for AMACR mostly showing moderate to strong positivity Conclusion: The application of immunomarkers helped us to reach a definite diagnosis in 10 out of 12 cases, which were otherwise difficult to classify. Judicious use of immunomarkers can help in differentiating mimickers of prostate carcinoma from true cancer cases and assist in reaching a definitive diagnosis.

Malignant Glomus Tumor of the Kidney: A Case Report and Review of the Literature

Abstract Introduction/Objective Glomus tumors are rare neoplasms arising from the glomus body which is a specialized arteriovenous anastomosis that has a role in temperature regulation of the skin. They account for less than 2% of soft tissue tumors and typically manifest as painful nodules in the extremities, most commonly in the subungual region of the fingers and dermis of the wrist, forearm, and foot. They rarely arise in visceral organs as they lack glomus bodies. There are rare case reports of benign glomus tumors arising in the kidney, and malignant renal glomus tumors are exceedingly rare. Methods/Case Report We present a case of a 32-year-old man who was found to have a right renal mass incidentally after being involved in a motor vehicle accident. Computed tomography of the abdomen revealed a 5.3 cm enhancing mass in the posterior aspect of the inferior pole of the right kidney. Histological examination revealed a solid neoplasm composed of a pleomorphic population of cells with densely eosinophilic to pale cytoplasm, centrally located round to oval nuclei with fine nuclear chromatin and relatively inconspicuous nucleoli. Prominent lymphovascular invasion and 1 mitotic figure per 10 high power fields were also present. Areas composed of necrosis, sclerosis, hemosiderin deposition and calcification were identified. Immunohistochemical stains revealed the neoplastic cells to be positive for CD34, vimentin, smooth muscle actin, caldesmon, with focal reticulin staining around the tumor cells. Cells were negative for desmin, high and low molecular weight cytokeratins, synaptophysin, chromogranin, PAX8, and GATA3. The morphology and immunoprofile of the mass are consistent with the diagnosis of glomus tumor. Results (if a Case Study enter NA) NA Conclusion Although very rare, the presence of prominent vascular invasion, increased mitotic activity as well as necrosis are consistent with malignant behavior and support the classification as a malignant glomus tumor.

Utility of D2-40, Cytokeratin 5/6, and High-Molecular-weight Cytokeratin (Clone 34βE12) in Distinguishing Intraductal Spread of Urothelial Carcinoma From Prostatic Stromal Invasion.

Intraductal spread of urothelial carcinoma (UC) is not an uncommon finding in bladder cancer that requires appropriate clinical management. The presence of prostatic stromal invasion in non-muscle-invasive bladder cancer upstages the disease, necessitating cisplatin-based neoadjuvant chemotherapy and subsequent cystroprostatectomy. However, the identification of prostatic stromal invasion can be challenging, especially in biopsy and transurethral resection specimens. We assess the utility of D2-40, CK5/6, and high-molecular-weight cytokeratin (HMWCK) immunohistochemistry as an ancillary tool to differentiate prostatic stromal invasion from intraductal UC spread. We reviewed 13 cystoprostatectomies performed for UC with prostatic involvement. The presence of stromal invasion was histologically determined by the presence of circumferential retraction artifact, paradoxical differentiation, complex architecture, and desmoplastic reaction. The areas of interest were subsequently stained with D2-40, CK5/6, and HMWCK (clone 34βE12). Four bladder biopsies were used as a control to assess labeling in the benign urothelium. Nine cases had histologic evidence of prostatic stromal invasion (4 transmurally through bladder wall). D2-40 highlighted basal cells in all benign prostatic ducts and was consistently negative in UC, benign urothelium, prostatic adenocarcinoma, and benign luminal prostatic epithelium. D2-40 and CK5/6 performed similarly for intraductal UC, labeling only the basal cell layer with the exception of 1 case with squamous differentiation where CK5/6 exhibited full thickness staining. HMWCK diffusely stained 9 of 10 intraductal UCs without squamous differentiation and 1 intraductal UC with squamous differentiation. All 8 cases of invasive UC without squamous differentiation were negative for D2-40. Seven of these cases had focal CK5/6 and diffuse HMWCK staining. In 1 case of invasive UC with squamous differentiation, all stains were positive. D2-40 is expressed in prostatic basal cells, but it is not expressed in the benign or neoplastic urothelium. D2-40 and CK5/6 effectively highlight the intraductal spread of UC. While invasive UC is negative for D2-40, CK5/6 is usually patchy and localized to the periphery of the tumor nests. HMWCK often demonstrates diffuse staining in both scenarios. However, these stains do not perform well in cases of UC with squamous differentiation. Thus, D2-40 can be used as an ancillary tool to rule out prostatic stromal invasion.

Role of Claudin-1 on diagnostic cut-off value and multiple tests in patients with papillary thyroid carcinoma

Objective: To explore the diagnostic cut-off value of Claudin-1 (Cla-1) in papillary thyroid carcinoma (PTC) and the efficacy of the multiple test. Methods: Clinical and pathological data were collected from 295 patients with PTC and 137 patients with benign thyroid lesions (BTL) admitted to two hospitals in Pingdingshan City, Henan Province from January 2015 to June 2020. The expression index of Cla-1, the positive expression rate of high molecular weight cytokeratin (HMW-CK) and the negative expression rate of leukocyte differentiation antigen 56 (CD56) were calculated according to the results of immunohistochemistry. Receiver operating characteristic (ROC) curve was used to determine the cut-off value of Cla-1 for diagnosing PTC. Cla-1+HMW-CK, Cla-1+CD56, HMW-CK+CD56 and Cla-1+HMW-CK+CD56 were tested in series, and the diagnostic efficacy was evaluated by sensitivity, specificity and accuracy. Results: The age of PTC patients M (P25, P75) was 48.0 (41.0, 55.0) years old, among which 230 cases were male (78.0%). The age of BTL patients M (P25, P75) was 53.0 (46.0, 61.0) years old, including 34 males (24.8%). Cla-1 detection was conducted in all PTC and BTL patients, whereas only 198 and 97 cases conducted HMW-CK detection, 242 and 136 cases conducted CD56 detection, respectively. The M (P25, P75) of Cla-1 expression index in PTC was 80.0% (45.0%, 90.0%), which was higher than that in BTL [0.0 (0.0, 2.0%)] (P<0.001). The positive expression rate of HMW-CK was 93.9% (186/198) in PTC, and was negative in all BTL. The negative expression rate of D56 was 89.7% (217/242) in PTC, higher than that of BTL [1.5% (2/136)] (P<0.001). When expression index 19.0% was set as the cut-off value of Cla-1 for diagnosing PTC, the area under the ROC curve (AUC) was the maximum [AUC (95%CI): 0.981 (0.969, 0.994)], and the sensitivity, specificity and accuracy were 92.2% (272/295), 98.5% (135/137) and 94.2% (407/432), respectively. In multiple tests for diagnosis of PTC, the sensitivity ranged from 89.3% to 94.7%, specificity were all 100.0% and accuracy ranged from 93.1% to 96.9%. Conclusion: Cla-1 expression index ≥19.0% could be set as a cut-off value for the diagnosis of PTC and serial test of Cla-1 combined with HMW-CK(CD56) improves diagnostic specificity.

Histological and immunohistochemical investigation of canine prostate carcinoma with identification of common intraductal carcinoma component.

A limited number of species, including men and dogs, spontaneously develop prostate cancer (PC). The histological and molecular relevance of canine PC as a model for the disease in men remains controversial. To address this challenge, this study aimed to assess the histomorphology and expression of basal cell, urothelial and neuroendocrine markers [p63, high molecular weight cytokeratin (HMWCK), Uroplakin 3 (UPIII), neuron‐specific enolase (NSE)] in canine PC (n = 41). Based on histomorphology, 10/41 (24%), 21/41 (51%) and 9/41 (22%) were classified as adenocarcinoma (AC), urothelial carcinoma (UC), and mixed carcinoma, respectively. Tumour inflammation was common, frequently severe [20/41 (49%)], and associated with neutering (p < .02) and urothelial differentiation (p < .02). Most (36/40, 90%) cancers contained only rare cells with basal cell marker expression or were negative. The expression of UPIII was absent or weak in the majority (33/38, 87%) of tumours, with moderate to strong staining in the remaining cases. NSE expression in PC was rare and limited to 2/14 (14%) cases. Tumour extension into benign ducts and glands was a common finding with presence in 17/39 (44%) of carcinomas with and without urothelial differentiation. In conclusion, we confirm that canine PC is characterized by absent or weak expression of basal cell and urothelial markers. Although rare, NSE expression, potentially indicating neuroendocrine differentiation, is reported for the first time in canine PCa. Intraductal carcinoma of the prostate with concurrent invasive PCa (IDCP‐inv) is a frequent, not previously described, finding in dogs with PC.

Distal Tubular Hyperplasia: A Proposal for a Unique Form of Renal Tubular Proliferation Distinct From Papillary Adenoma.

We identified an unusual pattern of renal tubular proliferation associated with chronic renal disease, found in 23 patients, diffusely (n=12), or focally (n=11). Incidence was 5% of end-stage renal disease kidneys from one institution (8/177) and 7/23 patients with acquired cystic kidney disease-associated renal cell carcinoma from another. Most (19 patients) had 1 or more neoplasms including papillary (n=9), acquired cystic kidney disease (n=8), clear cell (n=4), or clear cell papillary (n=3) renal cell carcinoma. All (20 men, 3 women) had end-stage renal disease. The predominant pattern (n=18) was the indentation of chronic inflammation into renal tubules forming small polypoid structures; however, 5 had predominantly hyperplastic epithelium with less conspicuous inflammation. In 14 patients both patterns were appreciable, whereas the remainder had only the inflammatory pattern. Immunohistochemistry was positive for cytokeratin 7, high-molecular-weight cytokeratin, PAX8, and GATA3. Staining for alpha-methylacyl-CoA racemase was negative or weak, dramatically less intense than papillary neoplasms or proximal tubules. CD3 and CD20 showed a mixture of B and T lymphocytes in the inflammatory areas. Fluorescence in situ hybridization showed no trisomy 7 or 17 or loss of Y (n=9). We describe a previously uncharacterized form of renal tubular proliferation that differs from papillary adenoma (with weak or negative alpha-methylacyl-CoA racemase, lack of trisomy 7 or 17, and sometimes diffuse distribution). On the basis of consistent staining for high-molecular-weight cytokeratin and GATA3, we propose the name distal tubular hyperplasia for this process. Future studies will be helpful to assess preneoplastic potential and etiology.

Urothelial cancer of the prostate gland. Immunohistochemical analysis of two cases of rare canine cancer.

The study aimed to diagnose urothelial cancer of prostate gland (UCPG) in dogs as the primary focus and in its metastasis based on the expression of specific proteins used in immunohistochemical diagnosis of prostate cancer in men. The study was carried out on specimens collected during a post-mortem examination from macroscopic lesions of the prostate glands from two dogs. The immunoexpression of the following proteins was verified: prostate-specific antigen (PSA), high molecular weight cytokeratins (HMWCK), cytokeratin 7 and 20 (CK-7,-20), E-cadherin, von Willebrand factor, cyclooxygenase-2 (COX-2), microsomal PGE2-1 synthase (mPGES-1) and component of the minichromosome 7 maintenance complex (MCM7). All markers, except for PSA, were expressed both at the primary tumour site and in the metastasis. The immunohistochemical approach was more useful for the diagnosis of UCPG in dog than typical histopathological staining methods because it allowed for precise determination of features, type and grade of the tumour that may affect its early detection and treatment.

Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype.

Simple SummaryTriple Negative breast cancer (TNBC) is an aggressive tumor showing high histological grade, high recurrence, and frequent metastasis, accounting for about 25% of breast cancer-related deaths. Emerging roles and molecular mechanisms by which miRNAs impact pathogenesis and prognosis of basal-phenotype TNBC and their potential clinical utility are analyzed in the present review. Progress achieved in TNBC molecular taxonomy had minimal clinical impact, while miRNAs could act as prognostic/predictive biomarkers for TNBC subtypes. As there are currently no other therapeutic options to treat TNBC apart from chemotherapy, various studies were reviewed to draw the conclusion that ncRNAs might be candidates for drug development and drug resistance. Targeted approaches to epigenetic mechanisms and clarification of the molecular mechanisms of specific miRNAs in TNBC subtypes are fully justified. This review might provide a collection of biomarkers potentially useful in clinical settings and shows that the combination of miRNA-based therapeutic strategies with conventional therapies might synergize anticancer effects improving patient outcome.Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype.

Partial Nephrectomy For a Presumed Single Renal Mass Revealing Multiple Tumor Histologies: A Series of 4 Patients

Abstract Introduction/Objective Renal mass biopsy is known to have a low but unavoidable diagnostic error rate. However, the occurrence of multiple adjacent masses mimicking one mass clinically has been minimally studied. Methods We report a series of four patients who were radiologically presumed to have a single renal mass and treated with partial nephrectomy, yet who were found to have multiple demarcated renal cell carcinoma histologies at pathologic evaluation. Results All were men aged 63–70 years. Grossly, tumors were red brown with scant, bright yellow foci in one of them. Dominant tumors followed by smaller tumors were: patient 1 - clear cell renal cell carcinoma (5.0 cm), clear cell papillary renal cell carcinoma (0.5 cm), and papillary adenoma (0.6 cm); patient 2 - clear cell renal cell carcinoma (1.5 cm) and clear cell papillary renal cell carcinoma (0.5 cm); patient 3 - papillary renal cell carcinoma (5.0 cm) and eosinophilic variant of chromophobe renal cell carcinoma (1.0 cm); patient 4 - chromophobe renal cell carcinoma (4.0 cm) and clear cell papillary renal cell carcinoma (0.6 cm). Immunohistochemical studies for cytokeratin 7, carbonic anhydrase IX, high molecular weight cytokeratin, CD10, and alpha-methyl acyl-CoA racemase (AMACR) confirmed the separate components in all. Conclusion This series adds to the spectrum of causes that may contribute to discordant results of renal mass biopsy and resection specimens. Secondary smaller tumors appear to be predominantly nonaggressive histologies, enriched for clear cell papillary renal cell carcinoma. Pathologists and urologists should be aware of this occurrence when considering the role of renal mass biopsy and interpreting the results.

TAp63 and ΔNp63 (p40) in prostate adenocarcinomas: ΔNp63 associates with a basal-like cancer stem cell population but not with metastasis.

Like other malignancies, prostate tumors are thought to contain cancer stem-like cells (CSCs) that are responsible for growth, metastasis, and therapy resistance. ΔNp63 (also called p40) is a regulator of normal prostate stem/progenitor cell activities and a marker of normal basal epithelial cells. The levels of ΔNp63 are reduced in prostate adenocarcinomas, although there is also evidence that ΔNp63 is involved in CSC regulation and drives metastasis to the bone. We studied metastatic deposits of prostate cancers with isoform-specific ΔNp63 and TAp63 antibodies. We identified p63-positive cells in only 3 of 42 metastatic prostate tumors (7%), including 2/38 (5.3%) "usual-type" adenocarcinomas. ΔNp63 and TAp63 isoforms were present in the nuclei of a small subpopulation (< 1%) of tumor cells in these metastases. ΔNp63-positive cells showed a basal-like cell phenotype (cytokeratin 8- and androgen receptor-negative, high molecular weight cytokeratin- and cytokeratin 19-positive), distinct from the tumor bulk. TAp63-positive cells were similar but were sometimes cytokeratin 8-positive. A subset of ΔNp63-positive tumor cells were CD44-positive, a marker of "basal" CSCs but were not positive for the "epithelial" CSC marker ALDH1. TAp63 was not associated with either of these CSC markers. None of the tumors containing p63-positive cells showed evidence of bone metastasis, compared with 28% of the p63-negative tumors. These data show that both ΔNp63 and TAp63 are present in only a small proportion of prostate adenocarcinomas and do not associate with metastasis. The data suggest heterogeneity of CSCs in prostate cancer, similar to other cancer types.

INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer

Insulinoma associated protein 1 (INSM1) is a relatively new marker of neuroendocrine differentiation. It has been shown to have a high sensitivity for neuroendocrine tumours arising from different organs. This study evaluated INSM1 as a marker for neuroendocrine differentiation in infiltrating breast cancers (IBC). The expression of INSM1, together with other neuroendocrine markers (synaptophysin, chromogranin and CD56) was assessed in a large IBC cohort using tissue microarray by immunohistochemistry. Overall, 13.1%, 4.6%, 7.0% and 6.5% of the cases were positive for synaptophysin, chromogranin, INSM1 and CD56, respectively. INSM1 expression showed similar clinicopathological and biomarker profiles as chromogranin and synaptophysin. They were associated positively with luminal profile (p<0.001) and hormone receptors expression (p≤0.015), but negatively with HER2 (p≤0.044) and high molecular weight cytokeratins (p≤0.047). Using synaptophysin and/or chromogranin to define neuroendocrine differentiation, INSM1 showed a sensitivity of 37.3%, and was more sensitive than chromogranin (33.5%) and CD56 (16.4%) but less than synaptophysin (94.6%). Interestingly, INSM1 expression segregated IBC with neuroendocrine differentiation into different prognostic subgroups, particularly within luminal B subtype. Among the synaptophysin/chromogranin+ luminal B cancers, INSM1 expression was associated with significantly better survival (DFS: χ2=8.009, p=0.004; BCSS: χ2=3.873, p=0.049). Multivariate analysis showed that synaptophysin/chromogranin+ INSM1- status was an independent adverse factor for DFS (HR=2.282, 95%CI=1.196-4.356, p=0.012) in the luminal B subtype. Our data supported the usefulness of INSM1 in detecting neuroendocrine differentiation in IBC. Furthermore, INSM1 expression suggested a favourable prognostic impact; thus, it could be useful for stratifying neuroendocrine tumours with different prognosis.

Best Practice (Efficient) Immunohistologic Panel for Diagnosing Metaplastic Breast Carcinoma.

Immunohistochemistry (IHC) plays a key role in the diagnosis of metaplastic breast carcinomas (MBCs), particularly the spindle cell variant. The most efficient immunopanel has yet to be developed. We studied the immunoprofile of 45 MBCs including 23 matrix-producing MBCs, 11 squamous cell carcinomas, 6 spindle cell carcinomas, and 5 mixed-subtypes (2 cases including spindle cell components). Representative sections from mastectomy or core biopsy specimens were subject to IHC using a list of antibodies including OSCAR, a recently developed antibody against pooled cytokeratins. The staining was interpreted as positive when >1% of tumor cells demonstrated unequivocal staining. As a result, OSCAR showed similar sensitivity to AE1/AE3 and CAM 5.2 (89.1% vs. 89.4% vs. 89.4%) for MBCs, but the former showed more diffuse pattern of staining, particularly in spindle cell carcinomas. High molecular weight cytokeratin CK14, CK5, and CK17 were positive in 91.3%, 87.2%, and 73.3% of MBCs, respectively. CK7 was much less likely to be positive in spindle cell carcinomas (37.5%) than in other variants of MBCs (97.4%). P63 and CK14 were the most useful markers for spindle cell carcinomas, positive in 87.5% and 85.7% of cases, respectively. GATA 3 was positive in 63% MBCs, and nonspecific staining for vimentin and smooth muscle actin were common. Random combination of up to 3 antibodies against keratins including p63 showed sensitivities ranging from 80.9% to 97.9%. Our results suggested the combination of OSCAR, CK14 and p63 is the most efficient panel (sensitivity 97.9%) for diagnosing MBCs.