Expression of high molecular weight cytokeratin-A novel feature of aggressive and innate hormone-refractory prostatic adenocarcinoma.

BACKGROUND: Castration-resistance is common in advanced prostatic adenocarcinomas (PACs) treated with androgen deprivation therapy (ADT) and usually occurs after 2 years following treatment. A minority of PACs confer innate ADT resistance without prior hormonal treatment. The expression of HMWCK in PAC cells has not been studied. This study aimed to investigate the clinicopathologic and genomic features of HMWCK-expressing PACs and the relationship to ADT resistance. METHODS: A total of 469 PACs were studied for HMWCK expression (39 postradiotherapy, 57 post-ADT, 373 treatment-naïve PACs). Clinicopathologic correlations of the HMWCK expression with tumor grade groups, specific tumor morphologies, tumor stages and disease recurrence/persistence/progression were performed. Five HMWCK+ PACs were also sequenced for genetic alterations. RESULTS: Thirty one of the 469 cases (6.6%) showed variable HMWCK+ PAC. The HMWCK+ PAC often focally presented in the tumor and vast majority were associated with high Gleason scores and unfavorable growth patterns (cribriform, comedo-necrosis, and intraductal carcinoma) as well as high tumor stages. A small percentage of the HMWCK+ PCA (2/31, 6.5%) presented with frank squamous histomorphology. Vast majority (22/31, 87%) had no history of prior ADT. The HMWCK+ PAC all displayed diminished to lost expression of AR/NKX3.1. Most of the cases progressed within 12 months of ADT or disease persisted despite ADT. Of the 5 HMWCK+ PACs subjected to gene sequencing, 4 presented with PTEN/PI3K/MAPK pathway alterations. CONCLUSION: The study demonstrated HMWCK+ PAC to be a novel type of innate ADT-resistant PAC. Overexpression of HMWCK in PAC can be potentially used as a surrogate biomarker for aggressive and innate hormone-refractory PACs. The genetic alterations imply potential therapeutic implications of PI3K/MAPK inhibitors in the treatment of these deadly diseases.

Comparison of Immunohistochemistry Expression of CK7, HMWK and PSA in High-Grade Prostatic Adenocarcinoma and Bladder Transitional Cell Carcinoma.

BACKGROUND & OBJECTIVE: Prostate adenocarcinoma is the most common malignancy in males, and the urothelial bladder carcinoma is also prevalent. The histological characteristic of these two tumors is very similar in high-grade cases, and their differentiation is difficult. This study was performed to compare the immunohistochemistry panel of high-grade prostate adenocarcinomas and high-grade urothelial bladder carcinomas. METHODS: In this cross-sectional study, 36 cases of prostate adenocarcinoma and 36 urothelial bladder carcinoma samples were collected from the pathology department of Shahid Beheshti Hospital in Hamedan. For each sample, expression of Cytokeratin 7, high-molecular-weight cytokeratin and Prostate-specific antigen markers was evaluated by immunohistochemistry. Comparison of expression of these markers in high-grade bladder tumors and prostate tumors was made by SPSS 25 using Chi-square test. RESULTS: In this study, the Cytokeratin 7 positivity was seen in 88.9% of bladder cancer versus 27.8% of prostate cancer samples. High-molecular-weight cytokeratin positive immunoreactivity was noted in 55.6% of bladder cancer and 5.6% of prostate cancer samples. Prostate-specific antigen marker showed positive results in 94.4% of prostate cancer samples, but no positivity was evident in those of bladder cancer. CONCLUSION: A panel of immunohistochemical stains can be used to differentiate high-grade prostate adenocarcinoma from urothelial bladder carcinoma in those cases which are challenging to diagnose.

Double cocktail immunostains with high molecular weight cytokeratin and GATA-3: useful stain to discriminate in situ involvement of prostatic ducts or acini from stromal invasion by urothelial carcinoma in the prostate.

BACKGROUND: Distinguishing prostatic stromal invasion (PSI) by urothelial carcinoma (UC) from in situ UC involving prostatic ducts or acini with no stromal invasion (in situ involvement) may be challenging on hematoxylin and eosin stained sections. However, the distinction between them is important because cases with PSI show worse prognosis. This study was performed to assess the utility of double cocktail immunostains with high molecular weight cytokeratin (HMWCK) and GATA-3 to discriminate PSI by UC from in situ UC involvement of prostatic ducts or acini in the prostate. METHODS: Among 117 radical cystoprostatectomy specimens for bladder UCs, 25 cases showed secondary involvement of bladder UC in prostatic ducts/acini only or associated stromal invasion and of these 25 cases, seven cases revealed equivocal PSI. In these seven cases with equivocal PSI, HMWCK, and GATA-3 double immunohistochemical stains were performed to identify whether this cocktail stain is useful to identify the stromal invasion. RESULTS: In all cases, basal cells of prostate glands showed strong cytoplasmic staining for HMWCK and UC cells showed strong nuclear staining for GATA-3. In cases with stromal invasion of UC, GATA-3-positive tumor cells in the prostatic stroma without surrounding HMWCK-positive basal cells were highlighted and easily recognized. Among seven equivocal cases, two cases showed PSI and five in situ UC in the prostate. In two cases, the original diagnoses were revised. CONCLUSIONS: Our study suggested that HMWCK and GATA-3 double stains could be utilized as an adjunct method in the distinction between PSI by UC from in situ UC involving prostatic ducts or acini.

Diagnostic utility of triple antibody (AMACR, HMWCK and P63) stain in prostate neoplasm.

AIMS AND OBJECTIVE: In recent period, basal cell markers high molecular weight cytokeratin (HMWCK), P63 and prostate biomarker AMACR have been used as adjuvant to morphology in diagnostically challenging cases with a very high sensitivity and specificity. MATERIALS AND METHODS: In this prospective study, total of 80 cases including 40 cases of malignant lesions and 40 cases of benign lesions of the prostate were taken. Tumor grade was determined according to Gleason's grading system. AMACR, HMWCK, P63 expressions were determined by immunohistochemical staining. RESULTS: This study showed AMACR had a sensitivity of 90%, specificity of 100%. AMACR was not expressed in any of the 40 cases of benign lesions of the prostate while in malignant lesions of prostate it was expressed in 36 of 40 (90%) cases; 15 of 16 (93%) of well-differentiated carcinoma were positive for AMACR expression; 17 of 19 (89.47%) moderately differentiated and 4 of 5 (80%) cases of poorly differentiated tumors were positive for AMACR. There was statistically significant difference in expression of AMACR between benign and malignant lesions of the prostate (P = 0.001). In benign lesions, HMWCK and P63 were expressed in all the 40 (100%) cases, while in malignant lesions of prostate it was not expressed in any of the (0%) case. AMACR expression was not seen in any of the benign lesion. Out of 40 malignant cases, 4 cases were negative for AMACR, HMWCK and P63, 36 cases were positive only for AMACR, but no case was positive for HMWCK and P63. CONCLUSIONS: As an adjunct to biopsy, AMACR, HMWCK and P63 have potential for combating diagnostically challenging cases.

Use of immunohistochemical analysis of CK5/6, CK14, and CK34betaE12 in the differential diagnosis of solid papillary carcinoma in situ from intraductal papilloma with usual ductal hyperplasia of the breast.

OBJECTIVES: The aim of this study was to use immunohistochemistry to differentiate solid papillary carcinoma in situ from intraductal papilloma with usual ductal hyperplasia (IPUDH). Three types of high-molecular-weight cytokeratins (CKs) - CK5/6, CK14, and CK34betaE12 - were targeted. METHODS: We studied 17 patients with solid papillary carcinoma in situ and 18 patients with IPUDH diagnosed by at least two pathologists. Immunohistochemical analyses used antibodies to CK5/6, CK14, and CK34betaE12 to make the differential diagnosis of solid papillary carcinoma in situ versus IPUDH. Immunohistochemical staining was scored as 0-5 using Allred score. RESULTS: Immunohistochemistry with CK5/6 and CK14 antibodies produced scores of 0-3 in all patients with solid papillary carcinoma in situ and 2-5 in all patients with IPUDH. Immunohistochemical staining with CK34betaE12 antibody produced scores of 1-3 in all patients with solid papillary carcinoma and 3-5 in all patients with IPUDH. In tissues from patients with IPUDH, significantly more cells were stained with CK34betaE12 than CK5/6 (p < 0.05) or CK14 (p < 0.05). CONCLUSION: The immunoreactivity of CK5/6, CK14, and CK34betaE12 antibodies was useful to differentiate solid papillary carcinoma in situ from IPUDH. CK34betaE12 is especially useful for distinguishing solid papillary carcinoma from IPUDH.

A case of intracystic apocrine papillary tumor: diagnostic pitfalls for malignancy.

Intraductal/intracystic papillary carcinoma (IPC) of the breast is defined as a malignant non-invasive papillary tumor arising from the ductal-lobular system. Based on the presence of myoepithelial cells in the cystic wall, IPC is distinguished from encapsulated papillary carcinoma (EPC). Here, we report a case of an intracystic apocrine papillary tumor in the breast of a 49-year-old woman. Histopathologic examination revealed that the entire papillary structures and cyst wall were comprised of apocrine cells, some of which showed nuclear atypia with macronucleoli. Immunohistochemical examination revealed a lack of myoepithelial cells in the papillary fronds and cyst wall. Although the dense proliferation of apocrine cells mimicked a cribriform pattern, detailed examination identified a delicately intermingled interstitium in the cribriform-like growth area in the present case. We judged the current case to be benign apocrine papilloma. Only a few apocrine variants of IPC or EPC have been reported to be malignant or potentially malignant. Since even benign apocrine lesions are known to lack myoepithelial cells, histopathologic evaluation regarding malignant potential requires caution in apocrine variants. The detection of clearly benign areas and knowledge of the "pseudo-cribriform" pattern should provide clues to distinguish between benign and malignant apocrine papillary tumors.

V-ets erythroblastosis virus E26 oncogene homolog (avian)/Trefoil factor 3/high-molecular-weight cytokeratin triple immunostain: a novel tissue-based biomarker in prostate cancer with potential clinical application.

Trefoil factor 3 (TFF3) is associated with various cancers and overexpressed in a subset of prostate cancers. Functional studies suggest that v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) down-regulates TFF3 expression in hormone-naïve prostate cancer. To characterize this inverse relationship, we developed a triple immunostain encompassing ERG, TFF3, and high-molecular-weight cytokeratin. Triple stain was performed on 96 tumors and 52 benign cases represented in tissue microarrays. Distinct ERG and TFF3 protein was expressed in 45% (43/96) and 36% (35/96) of prostate cancers, respectively. Coexpression was observed in 5% (5/96) of tumor cases, and 24% (23/96) did not express ERG or TFF3. The inverse expression of ERG and TFF3 was significant (P < .0001), with 57% (30/53) of ERG-negative tumors demonstrating TFF3 expression. Sensitivity and specificity of combined ERG and TFF3 expression in detecting prostate cancer were 76% and 96%, respectively. The feasibility of triple immunostain protocol was validated in a set of 76 needle biopsies. The application of this multiplex in situ biomarker for molecular characterization of prostate cancer and as a supplemental diagnostic and prognostic tool in prostate needle biopsies should be further explored.

CD56 and High Molecular Weight Cytokeratin as Diagnostic Markers of Papillary Thyroid Carcinoma

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has been increasing recently and a precise diagnosis is essential for optimal treatment. Ancillary immunohistochemical stains are important for diagnosing some difficult cases. METHODS: The dignostic value of CD56, high molecular weight cytokeratin (HMCK), galectin-3 (GAL3), and cytokeratin 19 (CK19) were evaluated to distinguish PTC from other benign thyroid lesions (BTL). We studied 23 cases of papillary thyroid overt carcinomas, 57 papillary thyroid microcarcinomas, five follicular adenomas, five cases of Hashimoto's thyroiditis, and 12 nodular hyperplasias. RESULTS: The statistical analysis showed significantly different expressions of CD56, HMCK, GAL3, and CK19 in PTC vs other BTL. The diagnostic specificity of HMCK and CD56 (90.9% and 72.7%, respectively) was higher than that of GAL3 and CK19 (50.0% and 36.4%, respectively). However, the sensitivity of HMCK and CD56 detection (92.5% and 95.0%, respectively) was lower than that of GAL3 and CK19 (98.8% and 100.0%, respectively). The combined use of CD56, HMCK, GAL3, and CK19 showed 87.5% sensitivity, 100.0% specificity, and 100.0% positive predictive value in differentiating PTC from other BTL. CONCLUSIONS: Although the differential diagnosis of thyroid follicular lesions are based on histological and cytomorphological criteria, CD56 and HMCK might be useful markers for diagnosing PTC.

The Utility of HMW-CK and CK5/6 Immunohistochemical Stains for Differentiating Ductal Proliferative Lesions and Ducal Carcinoma of the Breast

BACKGROUND: Basal-type cytokeratins may help to distinguish benign from malignant intraductal proliferative lesions. The basal-type cytokeratins expression is markedly decreased or absent in atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDC). However, the expression patterns vary according to the antibodies that are used for staining. METHODS: HMW-CK (clone 34 E12) was applied to 175 lesions, and CK5/6 (clone D5/16B4) was applied to 145 lesions. The specimens were IDC (n=165), DCIS (n=35), ADH (n=37), florid ductal hyperplasia (FDH) (n=38) and columnar cell lesion (CCL) (n=45). The expression patterns of HMW-CK and CK5/6 were categorized as negative, focal positive and positive. RESULTS: Loss of the HMW-CK expression was noted in 76% (66/87) of the IDC, 78% (21/27) of the DCIS, 78% (21/28) of the ADH, and 55% (10/18) of the FDH. Loss of the CK5/6 expression was found in 96% (75/78) of the IDC, in all the DCIS (n=8) and ADH (n=9), and in none of the FDH (n=20). Loss of the CK5/6 expression is more reliable than that of the HMW-CK expression for differentiating FDH, ADH and malignant intraductal proliferatve lesions. Eleven (73%) of 15 CCLs revealed the loss of the HMW-CK expression, but all the CCLs (n=30) were negative for CK5/6 (p=0.0161). CONCLUSION: CK5/6 antibody is more reliable than HMW-CK antibody for differentiating FDH from ADH or DCIS, and for discriminating CCL.

A Case of Trichilemmal Carcinoma

Trichilemmal carcinoma is a rare tumor that is located predominantly on sun-exposed skin of the elderly. It is thought to be related to the external root sheath of the hair follicle and the malignant counterpart of a trichilemmoma. We report a case of trichilemmal carcinoma in a 88-year-old woman who had a 10 year history of a single, dark brown tumor on the right preauricular region. In her past medical history, it had been excised twice at a private clinic without a histopathological evaluation and recurred 2 years later. Histopathological findings showed atypical clear cells resembling those of the outer root sheath. Tumor cells showed PAS-positive cytoplasm. Immunohistochemistry revealed positive high molecular weight cytokeratin expression. To our knowledge, this is the second case of trichilemmal carcinoma in the Korean literature. (Ann Dermatol 100) 175178, 1998).