EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation.

High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase in the incidence of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite the favourable prognosis of HPV-HNSCC, the treatment modality, consisting of high dose radiotherapy (RT) in combination with chemotherapy (CT), remains similar to HPV-negative tumours, associated with toxic side effects. Epidermal growth factor receptor (EGFR) is overexpressed in over 80% of HNSCC and correlates with RT resistance. EGFR inhibitor Cetuximab is the only FDA approved targeted therapy for both HNSCC subtypes, however the response varies between HNSCC subtypes. In HPV-negative HNSCC, Cetuximab sensitises HNSCC to RT improving survival rates. To reduce adverse cytotoxicity of CT, Cetuximab has been approved for treatment de-escalation of HPV-positive HNSCC. The results of several recent clinical trials have concluded differing outcome to HPV-negative HNSCC. Here we investigated the role of EGFR in HPV-positive HNSCC response to RT. Remarkably, in HPV-positive HNSCC cell lines and in vivo tumour models, EGFR activation was strongly indicative of increased RT response. In response to RT, EGFR activation induced impairment of DNA damage repair and increased RT response. Furthermore, EGFR was found to downregulate HPV oncoproteinE6 expression and induced p53 activity in response to RT. Collectively, our data uncovers a novel role for EGFR in virally induced HNSCC and highlights the importance of using EGFR-targeted therapies in the context of the genetic makeup of cancer.

Sebaceous carcinoma of upper eyelid.

A middle aged lady was surgically treated repeatedly elsewhere for growth on right upper lid before presentation to this department. On examination she was found to have nodulo-ulcerative non-tender growth, about 40 x 20 mm in size involving the lateral three-fourth of the lid. There was associated mild conjunctivitis and palpable pre-auricular lymph node. Lid growth was excised followed by lid reconstruction. Pre-auricular lymph node was also removed. Histopathology report of the tissue revealed it to be the palpebral sebaceous carcinoma, while lymph node showed reactive hyperplasia.

Histological grading patterns in patients of cutaneous leishmaniasis.

OBJECTIVE: To determine the histological grading patterns in a cohort of hospitalized patients of cutaneous leishmaniasis. DESIGN: Case series. PLACE AND DURATION OF STUDY: The study was conducted at PNS Shifa Hospital, Karachi, from May 2004 to June 2006. PATIENTS AND METHODS: One hundred patients of Cutaneous Leishmaniasis (CL), admitted in dermatology wards at PNS Shifa Hospital, Karachi, were examined. Only admitted patients of all ages and both sexes were included in the study. Patients of CL, who had received or were receiving systemic treatment were excluded. The lesions having marked secondary bacterial infection were also excluded. Initial diagnosis was clinical. History of being to an endemic area supported the diagnosis. The lesions were divided in two groups. Early, with duration less than 03 months and late, with duration between 3 and 12 months. The clinical lesions were noted as nodules, plaques, ulcers, crusted ulcers, lupoid lesions and plaques with scarring. Three types of skin smears (slit skin smear, saline aspirate smear and dab smear) were taken and examined with Giemsa stain. Cultures were performed on Nicolle-Novy-MacNeal (NNN) culture medium from Defense Scientific and Technology Organization (DESTO) Lab., Pakistan. Incisional skin biopsies were done. The biopsy specimens were examined by hemotoxylin and eosin stain (H & E stain). The number of Leishmania Tropica (LT) bodies was graded according to modified Ridley's parasitic index 1983. Clinical features were correlated with the histological patterns. RESULTS: Five histological patterns were identified in current study: 1) diffuse dermal infiltration without necrosis, 2) patchy dermal infiltration, 3) diffuse dermal infiltration with necrosis, 4) early reactive granuloma formation and 5) established epithelioid granuloma formation. LT bodies were identified in 75% of cases. Epidermal features were non-specific. The early lesions presented with diffuse infiltrate and late lesions showed granuloma formation. CONCLUSION: Five distinct types of histological patterns of CL have been recognized in this study. The early lesions presented with diffuse infiltrate and late lesions showed granuloma formation but the mixed patterns were also seen. The yield of LT bodies is much higher with histopathology as compared to skin smears and hence is most diagnostic.

Immunohistochemical pattern of pleomorphic adenoma, polymorphous low grade adenocarcinoma and adenoid cystic carcinoma in minor salivary glands.

OBJECTIVE: To study the immunohistochemical pattern of CD 117, glial fibrillary acidic protein (GFAP), smooth muscle actin (SMA) and CD 43 in pleomorphic adenoma (PA), adenoid cystic carcinoma (AdCC) and polymorphous low grade adenocarcinoma (PLGA) of minor salivary glands. MATERIALS AND METHODS: Twenty cases of PA, 20 cases of AdCC and 10 cases of PLGA were retrieved from record files along with their paraffin blocks at Armed Forces Institute of Pathology, Pakistan. New histological diagnosis was made on freshly prepared H&E sections followed by application and analysis of immunostains. RESULTS: The mean age of the patients was 44 ± 15 (mean SD) (range; 17-86) years. There were 26 male and 24 female patients with a male to female ratio of 1.08:1. Fourteen cases of PA, 14 cases of AdCC and 6 cases of PLGA were positive for CD117. In case of GFAP, only 9 cases of AdCC and 3 cases of PLGA were positive; however, 16 cases of PA were also positive. Twelve cases of AdCC and 7 cases of PA were positive for SMA and half of the PLGA cases were also reactive. Nonetheless, the least expression was seen in case of CD 43, where only five cases of AdCC were positive. Six cases of PA and three cases of PLGA were also positive. CONCLUSION: Our results suggest that the use of GFAP, SMA, CD 117 and CD 43 as an adjunct to histological examination is not helpful in differentiating PA, AdCC and PLGA from one another.

Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population.

BACKGROUND: Nasopharyngeal carcinoma (NPC) accounts for 0.6% of all cancers worldwide with the highest prevalence in South East Asia, Southern China and Northern Africa but the disease is uncommon in Europe with an annual incidence in this region of less than 1 per 100 000. Although the Epstein-Barr virus (EBV) is a well known causative agent in NPC, recent reports have implicated oncogenic Human Papillomavirus (HPV) in a subgroup of these tumours. The recent striking rise of oropharyngeal carcinoma has been attributed to HPV, but little is known about the prevalence and clinical significance of the virus in NPC. The aim of this study was to determine the prevalence of oncogenic HPV in NPC from tissue archives of two head and neck cancer centres in the UK. METHODS: Samples were available for 67 patients with clinically validated NPC. The detection of high-risk HPV was carried out by screening all cases for p16 using immunohistochemistry and HPV DNA by polymerase chain reaction (PCR) using GP5+/6+ primers. All cases with p16 over-expression or positive for HPV by PCR were then examined by high-risk HPV DNA in-situ hybridisation and genotype analysis by PCR. RESULTS: Eleven cases (11/67, 16.4%) showed concurrent over-expression of p16 and evidence of high-risk HPV DNA by in-situ hybridisation; the majority were HPV16 positive. Of these 11 cases, nine occurred in Whites and two in Blacks. Histologically, there were two keratinising squamous cell carcinoma and nine non-keratinising carcinomas (eight differentiated and one undifferentiated). None of the HPV-positive cases showed any co-infection with EBV. There was no statistically significant difference in overall survival outcome between patients with HPV-positive and HPV-negative NPC. CONCLUSION: The results of this study show that oncogenic HPV is associated with a subgroup of NPCs and is more likely to occur in Whites. However, unlike oropharyngeal carcinoma there was no significant difference in overall survival between patients with HPV-positive and HPV-negative NPC.

Diagnostic challenges and role of immunohistochemistry in metastatic liver disease.

OBJECTIVE: To evaluate the role of Immunohistochemistry (IHC) in the diagnosis of metastatic liver disease, with a descriptive, cross-sectional study at the Department of Histopathology, Armed Forces Institute of Pathology (AFIP), Rawalpindi. MATERIAL AND METHODS: A total of 130 cases of metastatic liver disease were retrieved from the tumor registry data. Eosin-haematoxylin stained sections and Immunohistochemistry panels applied to ascertain the site of primary tumor were evaluated. The panels of detailed immunohistochemical markers were applied. Frequency and percentages were calculated for qualitative variables. Mean and standard deviations were calculated for quantitative variables. RESULTS: Males were 87 (67%) and were females 43 (33.07%). The most common site of primary was in GIT (45%), followed by neuroendocrine carcinoma and gall bladder. The other less common sites were lung, breast, ovary and thyroid. CONCLUSION: There is no specific singular panel of immunohistochemistry markers which can be used in all cases of metastatic liver tumors. The best use and selection of IHC markers depend upon morphological features, clinical history and results of other relevant investigations.