Hanan Farghaly

Human papillomavirus in metastatic squamous carcinoma from unknown primaries in the head and neck: A retrospective 7 year study

GOAL Human Papillomavirus (HPV) is found to be increasingly implicated in head and neck cancers. The objective of this study was to determine the primary site of origin of HPV positive squamous carcinomas metastatic to lymph nodes of the neck. METHODS Surgical pathology records from January 1, 2000 to July 31, 2007 were used to identify surgically removed neck lymph nodes with the diagnosis of metastatic squamous carcinoma. Specimens in formalin-fixed, paraffin-embedded blocks were examined for HPV (+) by analyzing sequencing data generated by PCR and immunostaining for the expression of the p16INK biomarker, which is overexpressed if Rb is not present. H & E stained slides were also reviewed for histological classification. The available retrospective demographics were extracted from the charts to determine trends of confounding factors. RESULTS Of the 43 patient samples, 41 contained adequate DNA to test for HPV. The mean age of the 41 patients was 62 years. All of the patients smoked and 39/41 patients consumed alcohol. The overall HPV (+) incident rate was 27% (11/41) by PCR with strongly diffuse or strong focal p16 staining. 9 of the 34 males and 2 of the 7 females had HPV (+) carcinomas. The average age of the 2 HPV (+) females was 44, compared to the HPV (-) females who averaged 70. The average age of the HPV (+) males was 56 compared with the average age 55 of the HPV (-) males. HPV (+) carcinomas appeared to arise from multiple sites in the oropharynx, particularly the tonsils and tongues, including unknown primaries. By histological exam, most metastatic HPV(+) squamous carcinomas were poorly differentiated (basaloid) microscopically and grossly cystic. CONCLUSION The 27% HPV (+) squamous cancers metastatic to neck lymph node originated from multiple sites in the oropharynx. The HPV (+) female population, although a total of only 2, tended to be much younger than the HPV (-) ones, whereas the HPV (+) male population was similar in age to the HPV (-) male population.

HPV: A factor in organ preservation for locally advanced larynx and hypopharynx cancer?

PURPOSE/OBJECTIVE To assess the interaction of HPV/p16 status and therapy rendered in patients with locally advanced squamous cell carcinoma of the larynx and hypopharynx. MATERIALS AND METHODS Forty-seven consecutive patients receiving definitive treatment between 2009 and 2011 for locally advanced larynx or hypopharynx cancer with high-risk HPV and/or p16 testing performed were identified and retrospectively investigated. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival (LRFS) were assessed. RESULTS Of 47 evaluable patients, there were 38 (81%) with laryngeal and 9 (19%) with hypopharyngeal tumors, 13 (28%) of which were found to be either HPV or p16 positive. At a median follow-up of 24 months, comparing HPV/p16+ versus HPV/p16- patients, there was no difference in OS, DFS, or LRFS. There was an improvement in 2-year DFS (60% vs 100%, P=.03) and LRFS (80% vs 100%, P=.08), in HPV/p16+ patients treated with chemo/RT versus surgery. There was an improvement in 2-year DFS (100% vs 68%, P=.04) and LRFS (100% vs 72%, P=.05) in HPV/p16+ versus HPV/p16- patients who received chemo/RT. CONCLUSIONS Patients with HPV/p16+ tumors fared more favorably with chemo/RT than up-front surgery, with improvements in DFS and LRFS. In patients treated with the intent of organ preservation therapy, HPV/p16+ patients had no observed treatment failures. HPV/p16 status should be taken into account when considering organ preservation for locally advanced larynx and hypopharynx cancers.

Comparison of Sentinel Lymph Node Micrometastatic Tumor Burden Measurements in Melanoma

BACKGROUND Multiple methods have been proposed to classify the micrometastatic tumor burden in sentinel lymph nodes (SLN) for melanoma. The purpose of this study was to determine the classification scheme that best predicts nonsentinel node (NSN) metastasis, disease-free survival (DFS), and overall survival (OS). STUDY DESIGN A single reviewer reanalyzed tumor-positive SLN from a multicenter, prospective clinical trial of patients with melanoma ≥ 1.0 mm Breslow thickness who underwent SLN biopsy. The following micrometastatic disease burden measurements were recorded: Starz classification, Dewar classification (microanatomic location), maximum diameter of the largest focus of metastasis, maximum tumor area, and sum of all diameters. Univariate and multivariate models and Kaplan-Meier analysis were used to evaluate each classification system. RESULTS We reviewed 204 tumor-positive SLNs from 157 patients. On univariate analysis, all criteria except Starz classification were statistically significant risk factors for NSN metastasis. On multivariate analysis, including Breslow thickness, ulceration, age, sex, and NSN status, maximum diameter (using a cut-off of 3 mm) was the only classification system that was an independent risk factor predicting DFS (hazard ratio 2.31, p = 0.0181) and OS (hazard ratio 3.53, p = 0.0005). By Kaplan-Meier analysis, DFS and OS were significantly different among groups using maximum diameter cut-offs of 1 and 3 mm. CONCLUSIONS Maximum tumor diameter outperformed other measurements of metastatic tumor burden, including microanatomic tumor location (Dewar classification), Starz classification, maximum tumor area, and sum of all diameters for prediction of survival. Maximum tumor diameter is a simple method of assessing micrometastatic tumor burden that should be reported routinely.

Mucin poor mucinous tubular and spindle cell carcinoma of the kidney, with nonclassic morphologic variant of spindle cell predominance and psammomatous calcification

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor that has only been recently described. The classic MTSCCs are polymorphic renal neoplasms characterized by small, elongated tubules lined by cuboidal cells and/or cords of spindled cells separated by pale mucinous stroma. Nonclassic morphologic variants and features of MTSC have not been well studied and rarely been reported. We report a challenging case of mucin-poor MTSCC with marked spindle cell predominance and focal psammomatous calcification in a 39-year-old man and describe its histologic and immunohistochemical features. Pathologists must be aware of the histologic spectrum of MTSCCs to ensure their accurate diagnosis.

Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/−) transgenic mice

BackgroundPituitary tumor-transforming gene (PTTG) is an oncogene that is overexpressed in variety of tumors and exhibits characteristics of a transforming gene. Previous transgenic mouse models to access the tumorigenic potential in the pituitary and ovary have resulted in dysplasia without formation of visible tumors, possibly due to the insufficient expression of PTTG. PTTG expression level is critical for ovarian tumorigenesis in a xenograft model. Therefore, the tumorigenic function of PTTG in vivo remains unclear. We generated a transgenic mouse that overexpresses PTTG driven by the CMV promoter to determine whether PTTG functions as a transforming oncogene that is capable of initiating tumorigenesis.MethodsTransgenic animals were generated by microinjection of PTTG transgene into the male pronucleus of FVB 0.5 day old embryos. Expression levels of PTTG in tissues of transgenic animals were analyzed using an immunohistochemical analysis. H&E staining and immunohistostaining were performed to examine the type of tumor in transgenic and PTTG transgenic/p53+/- animals.ResultsPTTG transgenic offspring (TgPTTG) were monitored for tumor development at various ages. H&E analysis was performed to identify the presence of cancer and hyperplastic conditions verified with the proliferation marker PCNA and the microvessel marker CD31. Immunohistochemistry was performed to determine transgene expression, revealing localization to the epithelium of the fallopian tube, with more generalized expression in the liver, lung, kidney, and spleen. At eight months of age, 2 out of 15 TgPTTG developed ovarian cancer, 2 out of 15 developed benign tumors, 2 out of 15 developed cervical dysplasia, and 3 out of 15 developed adenomyosis of the uterus. At ten months of age, 2 out of 10 TgPTTG developed adenocarcinoma of the ovary, 1 out of 10 developed a papillary serous adenocarcinoma, and 2 out of 10 presented with atypia of ovarian epithelial cells. Tumorigenesis is a multi-step process, often requiring multiple oncogenes and/or inactivation of tumor suppressor genes. Therefore, to understand the contribution of p53 to PTTG induced tumorigenesis, we crossbred TgPTTG to p53+/− mice and maintained those 8 to 10 months. TgPTTG/p53+/− animals developed sarcomas faster than p53+/− alone as well as different tumor types in addition to cervical carcinomas in situ in 10 out of 17 females.ConclusionsWe conclude that while PTTG is a functional transforming oncogene, it requires an additional partner to effectively promote tumorigenesis through the loss of p53 include or between function or modulation.

Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth

BackgroundConstitutive activation of Ras in immortalized bronchial epithelial cells increases electron transport chain activity, oxygen consumption and tricarboxylic acid cycling through unknown mechanisms. We hypothesized that members of the Ras family may stimulate respiration by enhancing the expression of the Vb regulatory subunit of cytochrome c oxidase (COX).ResultsWe found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells increased eIF4E-dependent COX Vb protein expression simultaneously with an increase in COX activity and oxygen consumption. In support of the regulation of COX Vb expression by the Ras family, we also found that selective siRNA-mediated inhibition of K-Ras expression in A549 lung adenocarcinoma cells reduced COX Vb protein expression, COX activity, oxygen consumption and the steady-state concentration of ATP. We postulated that COX Vb-mediated activation of COX activity may be required for the anchorage-independent growth of A549 cells as soft agar colonies or as lung xenografts. We transfected the A549 cells with COX Vb small interfering or shRNA and observed a significant reduction of their COX activity, oxygen consumption, ATP and ability to grow in soft agar and as poorly differentiated tumors in athymic mice.ConclusionTaken together, our findings indicate that the activation of Ras increases COX activity and mitochondrial respiration in part via up-regulation of COX Vb and that this regulatory subunit of COX may have utility as a Ras effector target for the development of anti-neoplastic agents.

Cytology of a sarcomatoid renal cell carcinoma with unusual coexpression of S-100 protein: A case report, review of the literature and cytologic–histologic correlation

Sarcomatoid renal cell carcinoma (SRCC) is an aggressive variant of renal cell carcinoma; it is an uncommon, malignant neoplasm, and its diagnosis is usually based on the histologic evaluation of a nephrectomy specimen. Patients are treated with systemic therapy and, generally, a nephrectomy is not performed. Therefore, arriving at an accurate diagnosis is critical for planning further management. Cytomorphological findings of SRCC have rarely been reported. This article reports the cytological findings in a case of SRCC composed predominantly of spindle cells and discusses its differential diagnosis in a 50‐year‐old female who presented with sharp right groin pain. A CT scan showed an enlargement of the right kidney. Cytology smears showed a malignant neoplasm composed predominantly of spindle cells. A panel of immunohistochemical stains performed on a core biopsy confirmed the epithelial nature of the spindle cells. A diffuse positive staining of the neoplastic cells for S‐100 protein was also observed. It has been reported in the medical literature that almost all SRCC cases demonstrate negative staining for S‐100 protein, with only a single case having been reported as focally positive. The cytologic differential diagnosis of spindle cell neoplasm with expression of S‐100 protein should be broadened to include SRCC. Furthermore, the S‐100 protein expression in SRCC that was observed in this case merits further investigation. Diagn. Cytopathol. 2009.

Erratum: MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway (Oncogene (2015) 34:2814 DOI:10.1038/onc.2015.116)

Correction to: Oncogene (2015) 34, 1698–1708; doi:10.1038/onc.2014.102; published online 21 April 2014 The authors wish to add H Farghaly, originally included in the Acknowledgements, to the authorship of this article, published online 21 April 2014. Dr Farghaly was omitted from the byline at final submission due to communication impediments outside the authors’ control during the manuscript review period which were shortly thereafter resolved.

Castleman's disease and primary effusion lymphoma in a HIV-positive patient.

We present a case of primary effusion lymphoma (PEL) occurring simultaneously with Castleman’s disease in the same patient. Castleman’s disease is distinct from PEL, although both are associated with HHV-8. Other cases have debated whether the coexistence of PEL and Castleman’s disease is a recurrence of an original PEL tumour in an extracavitary site, or a secondary HHV-8-associated lymphoma distinct from primary PEL. Our case, along with those described previously, show that co-occurrence of PEL and Castleman’s disease is possible and plausible. PEL needs to be included in the differential diagnosis in any HIV-positive patient who presents with a pleural effusion, and diagnosis requires only a simple thoracentesis and appropriate immunohistochemistry.

Metastatic endometrial endometrioid carcinoma with clear cell changes to the breast: a case report

Metastasis to breast from extramammary tissue is rare, and endometrial cancer has rarely been reported to metastasize to the breast. An extensive search in the medical literature reveals only 2 cases. They can be easily mistaken for primary breast carcinoma both clinically and radiologically, even with known history of endometrial carcinoma. This report presents a case of a 64-year-old woman who had endometrial carcinoma treated with total hysterectomy and adjuvant radiation and chemotherapy. Three years after the diagnosis, she had evidence of a solitary breast metastasis. To our knowledge, this is the third described case of endometrial cancer metastatic to the breast and the first in which the endometrial carcinoma demonstrates significant clear cell changes. This report is a reminder that although rare, endometrial carcinoma has the potential to metastasize to breast and illustrates how metastatic lesions in the breast can masquerade clinically as a primary carcinoma. Furthermore, essential guidelines necessary to distinguish primary from metastatic lesions in the breast are presented.