Immunohistochemical and genetic characteristics of HPV-associated endocervical carcinoma with an invasive stratified mucin-producing carcinoma (ISMC) component.

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described entity of human papillomavirus (HPV)-associated endocervical adenocarcinoma with phenotypic plasticity and aggressive clinical behavior. To identify the cell of origin of ISMC, we investigated the immunohistochemical expression of cervical epithelial cell markers (CK7, PAX8, CK5/6, p63, and CK17), stemness markers (ALDH1 and Nanog), and epithelial-mesenchymal transition (EMT) markers (Snail, Twist, and E-cadherin) in 10 pure and mixed type ISMCs with at least 10% of ISMC component in the entire tumor, seven usual type endocervical adenocarcinomas (UEAs), and seven squamous cell carcinomas (SCCs). In addition, targeted sequencing was performed in 10 ISMCs. ISMC was significantly associated with larger tumor size (p = 0.011), more frequent lymphovascular invasion and lymph node metastasis (p < 0.001), higher FIGO stage (p = 0.022), and a tendency for worse clinical outcomes (p = 0.056) compared to other HPV-associated subtypes. ISMC showed negative or borderline positivity for PAX8, CK5/6, and p63, which were distinct from UEA and SCC (p < 0.01). Compared to UEA and SCC, ISMC showed higher expression for ALDH1 (p = 0.119 for UEA and p = 0.009 for SCC), Snail (p = 0.036), and Twist (p = 0.119), and tended to show decreased E-cadherin expression (p = 0.083). In next-generation sequencing analysis, ISMC exhibited frequent STK11, MET, FANCA, and PALB2 mutations compared to conventional cervical carcinomas, and genes related to EMT and stemness were frequently altered. EMT-prone and stemness characteristics and peripheral expression of reserve cell and EMT markers of ISMC suggest its cervical reserve cell origin. We recommend PAX8, CK5/6, and p63 as diagnostic triple biomarkers for ISMC. These findings highlight the distinct biological basis of ISMC.

Cervical carcinomas with serous-like papillary and micropapillary components: illustrating the heterogeneity of primary cervical carcinomas.

Recent changes in the classification of cervical adenocarcinomas have re-categorized serous carcinoma as potentially nonexistent. However, clinical and pathological profiles of cervical adenocarcinomas with serous-like morphological features have not been systematically evaluated using the latest taxonomy and biomarkers. We studied 14 cases of primary cervical carcinomas with serous-like morphologies (papillary and micropapillary patterns). None of these cases exhibited evidence of serous carcinoma involving the upper tracts. Patient ages ranged between 34 and 86 years, most presented with abnormal uterine bleeding. Histologically, ten cases were classified as human papillomavirus (HPV)-associated carcinomas (eight usual-type endocervical adenocarcinomas and two adenosquamous carcinomas), of which six exhibited a papillary pattern and four had a micropapillary pattern. The four remaining cases were HPV-independent gastric-type adenocarcinomas, which displayed a papillary pattern in one case and a micropapillary pattern in three others. All ten HPV-associated carcinomas displayed block positive p16 and wild-type p53 by immunohistochemistry, with nine of them confirmed by HPV testing. Two of the four gastric-type adenocarcinomas had mutation-type p53, one of which also being p16 block positive. HER2 overexpression was demonstrated in 3/14 (21.4%) cases (2 HPV-associated and 1 HPV-independent). PD-L1 expression was identified in 4/10 (40%) cases, all HPV-associated. Targeted next-generation sequencing was performed in two cases with a micropapillary pattern, revealing a missense variant in ATM in an HPV-associated tumor and missense variants in TP53 and SMARCB1 in an HPV-independent tumor. The results demonstrated that primary endocervical adenocarcinomas can mimic the appearance of serous carcinoma, while not representing serous carcinoma. Serous-like papillary and micropapillary patterns may be present in both HPV-associated and HPV-independent cervical carcinomas, but none of the cases studied were unequivocally serous upon detailed analysis. Our findings support the exclusion of "cervical serous carcinoma" from existing classifications of cervical adenocarcinoma.

Solitary cystic metastatic lymph node of occult human papillomavirus-related oropharyngeal cancer mimicking second branchial cleft cyst: A case report.

RATIONALE: Human papillomavirus (HPV)-related oropharyngeal cancer is becoming more common, the primary cancer AQ4 usually occult and appearing only as cystic cervical lymph node (LN) metastasis. Distinguishing between a benign cystic lesion and cystic LN metastasis is challenging given their similar radiologic and histologic appearances. PATIENT CONCERNS: A 54-year-old man presented with a bulging cystic mass measuring 6.4cm on the right side of neck. DIAGNOSES: Postexcision diagnosis was second branchial cleft cyst. After 2 years, the cystic mass recurred, and HPV-related tonsillar squamous cell carcinoma with cystic metastatic LNs was confirmed after wide tonsillectomy and neck dissection. The previous cystic lesion proved to be a cystic metastatic LN from the same malignancy with additional p16 immunostain. INTERVENTIONS: The patient was treated with adjuvant concurrent chemoradiation therapy. OUTCOMES: The patient was followed up in the outpatient department with no evidence of recurrence after 1 year. LESSONS: When an adult has a cystic mass in the upper neck, we must rigorously exclude it as a cystic metastatic LN of occult HPV-related oropharyngeal cancer. Additional p16 staining might be helpful.

Human cytomegalovirus in high grade serous ovarian cancer possible implications for patients survival.

Patients diagnosed with high grade serous ovarian adenocarcinoma have a poor prognosis. Recently human cytomegalovirus (HCMV) has been detected in several tumors. Here, we evaluated HCMV in ovarian cancer tissue specimens obtained at pre- and postchemotherapy tumor resection.Available paraffin embedded ovarian cancer tissues from matched pre- and postchemotherapy tumor resection specimens (i.e., diagnostic excisional biopsy prechemotherapy; DEBPC) and neoadjuvant chemotherapy followed by interval debulking surgery (NACT + IDS) from 10 patients with stage IIIC-IV high grade serous ovarian carcinoma (HGS) diagnosed between years 2007 and 2008 at Karolinska University Hospital were examined for HCMV immediate-early protein (HCMV-IE), tegument protein pp65, and nucleic acid (ß2.7) by immunohistochemistry and in situ hybridization.HCMV-IE and pp65 were detected in 8/10 (80%), 4/9 (44%) and in 4/10 (40%), 5/8 in ovarian cancer tissue specimens from DEBPC and NACT + IDS, respectively. HCMV-ß2.7 was detected in all available tissue sections obtained from DEBPC and NACT + IDS. Patients with HCMV-IE or pp65 positive cells in their ovarian tumors at IDS after NACT had a median overall survival of 23.4 and 18.2 months, respectively, compared to 29.6 and 54 months, respectively, in those who did not express HCMV proteins in their tumors.In conclusion, HCMV proteins and nucleic acids are frequently detected at different levels in HGS ovarian carcinoma. Despite the limitation of our study, shorter median overall survival of patients with HCMV-IE and pp65 in their tumor highlights the need to further investigate the role of HCMV in ovarian cancer patients.

Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings.

Stratified mucin-producing intraepithelial lesion (SMILE) is considered to be a variant of adenocarcinoma in situ (defined as intraepithelial malignant glandular epithelium without invasion) or adenosquamous carcinoma in situ of the uterine cervix. However, recent study suggested that SMILE is more similar to high-grade squamous epithelial lesion by their immunohistochemical findings. An invasive form of SMILE "invasive stratified mucin-producing carcinoma (ISMC)" has been also proposed, but immunohistochemical features are not well documented. Therefore, this study aimed to clarify the immunohistochemical characteristics of SMILE and ISMC. Twelve cases of SMILE were found among 445 patients (2.7%) with high-grade intraepithelial lesions or invasive carcinomas, 3 of whom had solely intraepithelial disease with SMILE component (mean age, 37 years; range, 30-48 years) and 9 with invasive carcinomas (mean age, 47 years; range, 37-66 years; including ISMC). Immunohistochemically, SMILE and ISMC were diffusely positive for p16 and CAM5.2, focally for IMP3, and almost negative or only focally positive for p63. Nuclear signals in SMILE and invasive carcinomas were detected by human papillomavirus (HPV) in situ hybridization; 5 cases showed HPV16 and/or HPV18 polymerase chain reaction products. The ultrastructural study of 1 case showed surface microvilli and small vacuolar structure in SMILE; ISMC had mucous-like vacuoles, many mitochondria and intracytoplasmic lumen but lacked tonofilament. These findings were more similar to adenocarcinoma in situ or adenocarcinoma than squamous intraepithelial lesion or squamous cell carcinoma. We suggest that SMILE is an intraepithelial neoplasm and ISMC is an invasive form of SMILE.

Penile Analogue of Stratified Mucin-Producing Intraepithelial Lesion of the Cervix: The First Described Case. A Diagnostic Pitfall.

The authors report a case where undifferentiated (classic) penile intraepithelial neoplasia was associated with the presence of goblet cells throughout the full epithelial thickness and which later progressed into an invasive carcinoma. The lesion evolved in three consecutive biopsies from only surface epithelium occupying numerous goblet cells in the first to variably sized solid nodules in the dermis composed of atypical squamous and/or basaloid cells intermixed with numerous goblet cells in the third biopsy. Both cellular components expressed CK7 and p16 protein. Human Papillomavirus (HPV) genotyping revealed high risk HPV type 16. To the best of our knowledge, this is the first description of such a lesion occurring on the penis, which can be considered the penile analogue of cervical stratified mucin-producing intraepithelial lesion (SMILE). The correct diagnosis was rendered retrospectively, after recognition of the existence of a vulvar lesion resembling cervical SMILE. The initial biopsy was misinterpreted as extramammary Paget disease, which also constitutes the main pitfall in the differential diagnosis. Another important differential diagnosis is penile/vulvar mucinous metaplasia. The finding of atypical squamous epithelial cells positive for p16 associated with mucinous cells present throughout the full epithelial thickness is a clue to the diagnosis of penile SMILE.

Immunophenotype and human papillomavirus status of serous adenocarcinoma of the uterine cervix.

Serous adenocarcinoma of the cervix (SACC) is a very rare tumor. Our study aimed to characterize the immune profile and human papillomavirus (HPV) status of SACC, in comparison with other serous adenocarcinomas arising in the female genital tract. The pathological specimens obtained from 81 patients with serous carcinoma of the uterine cervix (n = 12), 29 endometrium, 20 ovary and 20 patients with mucinous carcinoma of the uterine cervix were reviewed. We assessed the expression of WT-1, p53, p16, HER2, CEA, and CA125 by immunohistochemistry and HPV DNA by PCR in 12 SACC samples. Their immune profile was compared with that of uterine papillary serous carcinoma (UPSC), ovarian serous adenocarcinoma (OSA), and mucinous endocervical adenocarcinoma (MEA). WT-1 and HER2 were expressed in very few SACC samples (0 and 0%, respectively), but p16, CA125, CEA and p53 were present in 100, 92, 58 and 50%, respectively. The difference in WT-1 expression between SACC and UPSC, MEA is not significant, but SACC differ significantly from OSA (p < 0.01). HPV DNA (type 16 or 18) was detected in 4 of the 12 SACC. The immunophenotype of SACC was similar to UPSC, whereas the frequency of expression of WT-1 was significantly lower in SACC than OSA. It appeared that p53 expression was associated with worse clinical outcome in patients with SACC, and that HPV infection was related to its occurrence.