Is the retropharyngeal lymph node the first echelon node for carcinoma tonsil? Prospective evaluation and literature review.

PURPOSE: Tonsil cancer being predominantly treated by non-surgical means, there is a paucity of data on lymph nodal drainage pathways and histo-pathologically confirmed metastatic rates. This study assesses the retropharyngeal lymph node (RPLN) in N0 squamous cell carcinoma tonsil as a possible first echelon node and a site for occult metastasis. METHODS: Prospective study involving treatment naïve N0 carcinoma tonsil treated by primary surgery and adjuvant treatment from June 2017 to March 2019. In-vivo lymph nodal drainage patterns were assessed by sentinel node mapping by preoperative SPECT-CT and intra-operative hand-held Gamma probe. All patients had a subsequent Level I-III/IV sampling neck dissection supplemented with RPLN dissection. Histological evaluation of sentinel nodes and RPLN involved step-serial sectioning and pan-cytokeratin immunohistochemistry. A comprehensive literature review was performed with keywords "retropharyngeal lymph node", "oropharynx", "tonsil", "squamous cell carcinoma" to determine the incidence of RPLN positivity in previously published series. RESULTS: Sentinel node was successfully identified by SPECT-CT in all 17 patients (ipsilateral level 2a-13/17, 2b-1/17, 3-1/17; bilateral 2a-1/17; isolated contralateral retropharyngeal node-1/17). 8/17 had occult neck metastasis. In no patient was an ipsilateral RPLN identified as the sentinel node. Histological sampling did not indicate metastatic tumor in the RPLN in any patient (0/17). A systematic literature review further confirmed that RPLN metastasis in oropharyngeal cancer is noted only in the presence of pN + disease at other neck levels, and isolated RPLN metastasis is extremely rare (1.2%). CONCLUSION: The ipsilateral RPLN is not identified either as the first echelon node or as a site of occult metastatic disease in N0 tonsil cancer. CTRI REGISTRATION: CTRI/2019/06/019551.

Biphenotypic sinonasal sarcoma: A series of six cases with evaluation of role of ß-catenin immunohistochemistry in differential diagnosis.

INTRODUCTION: Biphenotypic sinonasal sarcoma (BSNS) is a recently described mesenchymal tumor exclusive to the sinonasal region. It is a low grade sarcoma, displaying evidence of myogenic and neural differentiation. Role of ß-catenin immunohistochemistry in distinguishing it from its morphological mimics is not well-established. We conducted this study to identify cases of BSNS from our archives, and to examine immunopositivity for ß-catenin in them as well as in its close differential diagnosis. METHODS: All cases of nasal cavity and paranasal sinus mesenchymal neoplasms were identified. Histopathological features were reviewed. Cases showing smooth muscle actin (SMA) and S-100 immunopositivity, and typical morphology were reclassified as BSNS. ß-catenin immunoexpression was assessed. RESULTS: Twenty-one mesenchymal tumors, including 12 sinonasal hemangiopericytoma (SNHPC), five solitary fibrous tumors (SFT), three BSNS, and one synovial sarcoma were identified. Three SNHPC cases were reclassified as BSNS. BSNS patients included one male and five females, with mean age of 51years. Five BSNS cases (83.3%) showed nuclear ß-catenin immunopositivity. SNHPC cases also were ß-catenin positive (60%). CONCLUSION: BSNS is a rare sinonasal neoplasm, frequently misdiagnosed as SNHPC and SFT. ß-catenin immunopositivity is seen in majority of cases, indicating a role in pathogenesis. However, due to positivity in other tumors like SNHPC, it has limited role in differential diagnosis.

Dynamics of regulatory T cells (Tregs ) in patients with oral squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: The immune dysfunction in oral squamous cell carcinoma (OSCC) patients is one of the major factors for growth and dissemination of tumor affecting disease-free survival. METHODS: The phenotypic and functional characteristics of Regulatory T (Treg ) CD4+ CD25+ FoxP3+ subsets in OSCC patients were assessed by multicolor flow cytometry and its effector component (TGF-ß) by Western blot and qRT-PCR. RESULTS: An increased (P < 0.05) prevalence of Treg phenotypes (CD4+ CD25+ , CD4+ FoxP3+ , CD8+ FoxP3+ , CD4+ CD25+ FoxP3+ ) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4+ CD8+ CD25+ FoxP3+ , a unique T cell subset, CTLA-4+ , GITR+ , NrP1+ , HLA-DR+ , CD127+ , Tbet+ , TGF-ß+ , and granzyme B+ (GzmB) Tregs also showed a significantly higher prevalence in OSCC patients. Functionally, CD4+ FoxP3+ Tregs showed skewed expression of IL-2, IL-10, and IL-35 in patients as compared with the normal controls. Further, enhanced expression of CCR5 and CCR7 on Tregs with up regulation of their ligands (CCL5, CCL19, and CCL21) in tumor cells indicates efficient recruitment and trafficking of Tregs to the tumor site. CONCLUSION: It seems reasonable to assume that modulation of functional dynamics of selective Treg subsets may be useful in developing immunotherapeutic strategy for OSCC patients.

Gynecological Cancer as a Second Malignancy in Patients With Breast Cancer.

PURPOSE: The aim of this study was to determine the incidence and risk factors for gynecological cancer as second malignancy (SM) after treatment of breast cancer (BC). METHODS AND MATERIALS: Between January 1985 and December 2007, a total of 2756 patients with BC were analyzed for gynecological cancers as an SM. Analysis was carried out for patient-, disease-, and treatment-related characteristics. The Cox proportional hazards regression model was used to estimate the relative risk of gynecologic malignancies. RESULTS: The median age at BC diagnosis was 49 years and median follow-up of 14 years. In total, 25 cases of gynecological cancer were noted with an incidence of 0.9%. We observed 9 ovarian and endometrium (0.3%) as well as 7 uterine cervix (0.25%) cancers. Family history of BC was the most significant risk factor for SM (relative risk, 7.4; 95% confidence interval, 3.03-18.28; P<0.001). Women with a family history of BC had a higher incidence of endometrial (12%) and ovarian (16%) cancer compared with those who have no family history (0.1%, P = 0.003). Statistically significant higher incidence of endometrial cancer was seen in patients undergoing hormonal therapy (0.4%) as compared with those who are not undergoing hormonal therapy (0.1%, P = 0.001). Most of the endometrial (88.9%) and cervical (71%) cancers were detected at an early stage but ovarian cancers (66.6%) in advanced stage. Chemotherapy and radiotherapy did not increase the risk of gynecological SM. CONCLUSIONS: Women with BC are at risk of developing a second primary gynecological malignancy particularly of endometrium and ovary. Family history of BC was a high risk factor for gynecologic SM. These patients should be followed up for its early detection.

Can Diffusion Weighted Imaging Aid in Differentiating Benign from Malignant Sinonasal Masses?: A Useful Adjunct.

BACKGROUND: To evaluate the role of diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) values at 3 Tesla in characterizing sinonasal masses. MATERIAL/METHODS: After ethical clearance, 79 treatment naive patients with head and neck masses underwent magnetic resonance imaging (MRI), including DWI at 3 Tesla using the following b values - 0, 500 and 1000 s/mm2. Thirty-one patients were found to have sinonasal tumours and were subsequently analysed. Image analysis consisted of a morphological evaluation of conventional MR images, qualitative evaluation of DW trace images and quantitative assessment of mean ADC values. Receiver operating characteristic (ROC) curve was drawn to determine a cut-off ADC value for the differentiation between benign and malignant masses. RESULTS: Sinonasal masses showed an overlapping growth pattern on conventional imaging, irrespective of their biological nature. The mean ADC value of benign lesions was 1.948±0.459×10-3 mm2/s, while that of malignant lesions was 1.046±0.711×10-3 mm2/s, and the difference was statistically significant (p=0.004). When a cut-off ADC value of 1.791×10-3 mm2/s was used, sensitivity of 80% and specificity of 83.3% were obtained for characterization of malignant lesions, which was statistically significant. Juvenile nasopharyngeal angiofibroma (JNA) showed distinctly high ADC values, while meningioma was the only benign lesion with restricted diffusion. Atypical entities with unexpected diffusion characteristics included: adenocarcinoma, adenoid cystic carcinoma, meningioma, chondrosarcoma and fibromyxoid sarcoma. CONCLUSIONS: DWI in conjunction with conventional imaging can potentially enhance the diagnostic accuracy in characterizing sinonasal masses as benign or malignant. Some specific entities such as JNA and meningioma showed distinctive diffusion characteristics.

Neuroblastoma-like schwannoma of the skull base: an enigmatic peripheral nerve sheath tumor variant.

Neuroblastoma-like schwannoma is an extremely rare histological variant of schwannoma, which histologically mimics a malignant small round cell tumor. Only 19 cases have been reported in the literature to date. We report a case of this tumor located at the skull base in a 44-year-old woman who presented with symptoms of right-sided earache and hearing loss. MRI revealed a large, lobulated, extra-axial mass measuring 8.8 cm × 3.6 cm × 4.2 cm in the floor of the middle and posterior cranial fossa. Microscopic examination revealed a perplexing histopathology with peculiar collagenous rosettes. Differential diagnoses included a broad range of benign and malignant tumors. Typical schwannoma seldom poses a difficulty in diagnosis; however, this unusual variant is a diagnostic challenge which requires an extensive clinico-radiological correlation and immunohistochemical work-up. Hence, knowledge of this entity is a must to avoid erroneous diagnosis and inappropriate treatment.

Delivery of affordable and equitable cancer care in India.

The delivery of affordable and equitable cancer care is one of India's greatest public health challenges. Public expenditure on cancer in India remains below US$10 per person (compared with more than US$100 per person in high-income countries), and overall public expenditure on health care is still only slightly above 1% of gross domestic product. Out-of-pocket payments, which account for more than three-quarters of cancer expenditures in India, are one of the greatest threats to patients and families, and a cancer diagnosis is increasingly responsible for catastrophic expenditures that negatively affect not only the patient but also the welfare and education of several generations of their family. We explore the complex nature of cancer care systems across India, from state to government levels, and address the crucial issues of infrastructure, manpower shortages, and the pressing need to develop cross-state solutions to prevention and early detection of cancer, in addition to governance of the largely unregulated private sector and the cost of new technologies and drugs. We discuss the role of public insurance schemes, the need to develop new political mandates and authority to set priorities, the necessity to greatly improve the quality of care, and the drive to understand and deliver cost-effective cancer care programmes.

The growing burden of cancer in India: epidemiology and social context.

Cancer can have profound social and economic consequences for people in India, often leading to family impoverishment and societal inequity. Reported age-adjusted incidence rates for cancer are still quite low in the demographically young country. Slightly more than 1 million new cases of cancer are diagnosed every year in a population of 1.2 billion. In age-adjusted terms this represents a combined male and female incidence of about a quarter of that recorded in western Europe. However, an estimated 600,000-700,000 deaths in India were caused by cancer in 2012. In age-standardised terms this figure is close to the mortality burden seen in high-income countries. Such figures are partly indicative of low rates of early-stage detection and poor treatment outcomes. Many cancer cases in India are associated with tobacco use, infections, and other avoidable causes. Social factors, especially inequalities, are major determinants of India's cancer burden, with poorer people more likely to die from cancer before the age of 70 years than those who are more affluent. In this first of three papers, we examine the complex epidemiology of cancer, the future burden, and the dominant sociopolitical themes relating to cancer in India.

Cancer research in India: national priorities, global results.

Over the past 20 years, cancer research in India has grown in size and impact. Clinicians, scientists, and government and state policy makers in India have championed cancer research, from studies to achieve low-tech, large-scale health outcomes to some of the most advanced areas of fundamental cancer science. In this paper, we frame public policy discussions about cancer with use of an in-depth analysis of research publications from India. Cancer research in India is a complex environment that needs to balance public policy across many competing agendas. We identify major needs across these environments such as those for increased research capacity and training and protected time for clinical researchers; for more support from states and enhanced collaborative funding programmes from government; for development of national infrastructures across a range of domains (ie, clinical trials, tissue banking, registries, etc); and for a streamlined and rational regulatory environment. We also discuss improvements that should be made to translate research into improvements in cancer outcomes and public health.

Pelvic nodal CTV from L4-L5 or aortic bifurcation? An audit of the patterns of regional failures in cervical cancer patients treated with pelvic radiotherapy.

OBJECTIVE: To assess the patterns of recurrence in cervical cancer patients treated with pelvic nodal clinical target volume at L4-L5 junction instead of aortic bifurcation. METHODS: Records of patients with locally advanced cervical cancer treated with chemo-radiation were reviewed. Patients treated with standard pelvic fields (superior border of the field at L4/L5 junction), without any radiological evidence of regional lymphadenopathy (<10 mm) were included in the study. The level of aortic bifurcation was retrospectively documented on computed tomography. Patterns of recurrences were correlated to the aortic bifurcation and the superior border of the radiation fields (L4/L5). RESULTS: Aortic bifurcation was above the radiation fields (above L4/5) in 82 of 116 (70.7%) patients. Of the nine patients that recurred above the radiation field, 5 (55%) were above L4/5 failures, i.e. between aortic bifurcation and L4/5, and 4 (45%) had para-aortic failures. On retrospective analysis, 16 patients were found to have subcentimeter lymph nodes and higher nodal failures (7/16) were observed in patients with subcentimeter regional lymph nodes at diagnosis. CONCLUSIONS: Superior border of nodal clinical target volume should ideally include the aortic bifurcation instead of L4-L5 inter space in patients with locally advanced cervical cancer. Radiotherapy fields need to be defined cautiously in patients with subcentimeter pelvic lymph nodes.

Primitive neuroectodermal tumor of the uterine cervix diagnosed during pregnancy: a rare case with review of literature.

Primitive neuroectodermal tumors of the cervix are very rare. A 28-year-old pregnant woman presented with a cervical mass. The tumor was staged as IB2. The biopsy from tumor was suggestive of malignant small round cell tumor. She then underwent termination of pregnancy followed by radical hysterectomy. Based on morphologic and immunohistochemical profile, a diagnosis of peripheral primitive neuroectodermal tumor of the cervix was made. The patient received adjuvant chemotherapy and radiotherapy. The patient is alive and disease-free 33 months post-surgery. The present case highlights the importance of keeping primitive neuroectodermal tumors in the differential diagnosis of small cell neoplasms of the uterine cervix. Pregnancy should not be a barrier to early detection and treatment of this potentially aggressive tumor. The optimal treatment methods have not yet been established because of the rarity of the tumor.

Potential importance of Maackia amurensis agglutinin in non-small cell lung cancer.

Maackia amurensis agglutinin is a NeuNAcα (2-3) Galß (1-4) GlcNAc/Glc-specific lectin, which was shown to have diagnostic potential in cancers of different origin. In a previous report, we demonstrated that GM3 specific IgG from bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients interacted with ∼66kDa membrane glycoprotein band of NSCLC cell lines, which was also recognised by this lectin. This observation prompted us to assess the potential of Maackia amurensis agglutinin in NSCLC. Accordingly, we examined the reactivity of this lectin with NSCLC cell lines as well as the tissue biopsies and cells obtained from fine needle aspirations of NSCLC patients. Maackia amurensis agglutinin showed strong reactivity, specifically with cells and biopsy samples of NSCLC origin. Furthermore, this lectin was found to induce apoptosis in NSCLC cells. The mechanism of this lectin-induced apoptosis involved downregulation of Bcl-XL, upregulation of Bax, release of cytochrome c and activation of procaspase-3. Collectively our results have suggested that Maackia amurensis agglutinin may have the potential to serve as a unique probe for detection of NSCLC and also as a specific apoptosis-inducing agent in NSCLC cells.

Aberrant promoter hypermethylation of p21 (WAF1/CIP1) gene and its impact on expression and role of polymorphism in the risk of breast cancer.

p21 (Waf-1) is a cyclin-dependent kinase inhibitor that plays essential roles in cell growth arrest, terminal differentiation, and apoptosis. Statistically significant difference in the level of methylation of p21/CIP1 (p < 0. 05) between the patients with breast cancer and the healthy controls was observed. Risk of breast cancer was increased in patients with hypermethylated p21/CIP1 promoter by 2.31-fold (OR = 2.31, 95 % CI 1.95-2.74). The downregulation of p21/CIP1 mRNA expression was statistically significant in patients with methylated promoter (p < 0.00) in comparison to patients with unmethylated genes. Downregulation of mRNA expression of p21/CIP1 was up to 79% due to promoter hypermethylation. We examined several p21/CIP1 genotypes in the patients with breast cancer and found that there is no significant association of these p21/CIP1 genotypes with the risk of developing breast cancer. However, a significant 2.21-fold increase in the chance of developing breast cancer was observed in the candidates carrying at least one allele Arg mutant in p21/CIP1 genotype (i.e., Ser/Arg + Arg/Arg) with age >50 (OR = 2.21; 95 % CI 1.03-4.79).

Promoter hypermethylation of tumour suppressor genes (p14/ARF and p16/INK4a): case-control study in North Indian population.

The epigenetic modifications have been reported to be key factors in breast carcinogenesis. In the current study, it has been tried to determine the methylation status of two tumour suppressor genes p14/ARF and p16/INK4a in 150 breast cancer patients as well as 150 controls by using MSP-PCR. There was, highly significant difference in methylation of p14/ARF and p16/INK4a (P=0.000) between patients and controls. Methylation of both the genes together significantly increased the risk of breast cancer by 12.31 folds. The present study concludes that hypermethylation of p14/ARF and p16/INK4a promoters demonstrate significant association with the risk of breast cancer, hence indicating these as important tumour suppressor genes involved in the pathogenesis of breast cancer in North Indian population (i.e. Punjab, Haryana, Uttar Pradesh, Himachal Pradesh as well as Union Territory of Chandigarh).

Dosimetric comparison of doses to organs at risk using 3-D conformal radiotherapy versus intensity modulated radiotherapy in postoperative radiotherapy of periampullary cancers: implications for radiation dose escalation.

CONTEXT: Postoperative periampullary cancers with high risk features are managed with adjuvant chemo radiotherapy. Doses of 40-50 Gy have generally been used in conventional radiotherapy. Dose escalation with conventional radiotherapy has been restricted due to surrounding critical organs. OBJECTIVE: The objective of this dosimetric analysis was to evaluate the dose of radiation received by organs at risk using 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT). METHODS: Ten postoperative patients of periampullary cancers were selected for this dosimetric analysis. Planning CT scans films were taken with slice thickness of 2.5 mm and transferred to Eclipse treatment planning system. The clinical target volume (CTV) included the postoperative tumor bed and draining lymph nodal areas. A 1 cm margin was taken around the CTV to generate the planning target volume (PTV). Critical structures contoured for evaluation included bowel bag, bilateral kidneys, liver, stomach and spinal cord. IMRT plans were generated using seven field coplanar beams and 3DCRT planning was done using one anterior and two lateral fields. A dose of 45 Gy in 25 fractions was prescribed to the PTV. RESULTS: V45 for bowel bag was 212.3 ± 159.0 cc (mean volume ± standard deviation) versus 80.9 ± 57.4 cc in 3DCRT versus IMRT (P=0.033). The V28 dose analysis for bilateral kidneys showed a value of 32.7±23.5 cc (mean volume ± standard deviation) versus 7.9 ± 7.4 cc for 3DCRT versus IMRT, respectively (P=0.013). The D60 for liver using 3DCRT and IMRT was 28.4 ± 8.6 Gy (mean dose ± standard deviation) and 19.9 ± 3.2 Gy, respectively (P=0.020). CONCLUSIONS: Doses to bowel bag, liver and kidneys was significantly reduced using IMRT leaving ample scope for dose escalation.

Uterine sarcoma-current management and experience from a regional cancer centre in North India.

PURPOSE: We intended to assess the clinicopathological features and treatment outcome in patients of uterine sarcoma. METHOD: A retrospective review of medical records of patients of uterine sarcoma (2002-2007) was conducted. Overall survival (OS) was analyzed by Kaplan-Meier method. RESULTS: Forty-two patients met the study criterion [15 carcinosarcoma, 12 endometrial stromal sarcoma, 11 leiomyosarcoma, 3 undifferentiated endometrial sarcoma (UES), and 1 mixed sarcoma]. Median age and performance status were 52 years and ECOG 0, respectively. All patients underwent primary surgery out of which 66.7 % was total abdominal hysterectomy and bilateral salpingo-oophorectomy. FIGO (2009) stage was I, II, III, IV and unknown in 66.7, 7.1, 14.3, 9.5, and 2.4 % of the patients. Eight patients were kept on follow-up only. Adjuvant radiation, chemoradiation, and chemotherapy were offered in 8, 9, and 3 patients, respectively. Pelvic radiation: 46 Gray/23 fractions/4.5 weeks and vincristine, adriamycin, cyclophosphamide (VAC) regimen were most commonly used. Overall clinical complete response (CR), stable disease (SD), and progressive disease (PD) were, respectively, 59.5, 2.4, and 26.2 % (response not evaluable in 12 %). In the evaluable patients (N = 33), median OS was noted to be 7.67 months (mean 30.19 months). 1- and 2-year actuarial survival were 45.45 and 36.36 %. Stratified by histology, median survival in patients with carcinosarcoma, endometrial stromal sarcoma, leiomyosarcoma, and UES were, respectively, 6.57, 18.7, 6.8, and 9.38 months. On univariate analysis, response to therapy (p = 0.0003), disease stage (p = 0.00001), tumor size (p = 0.02), and performance status (p = 0.03) were significant predictors of OS. Disease stage (p = 0.005) and response to therapy (p = 0.01) retained significance on multivariate analysis. CONCLUSIONS: Median OS of only 6.57, 6.8, and 9.38 months, respectively, in patients with carcinosarcoma, leiomyosarcoma, and UES in our series reflect the aggressive clinical course and poor prognosis of these rare neoplasms, which mandate intensive multimodality therapy. Even in low-grade endometrial stromal sarcoma, median survival of 18.7 months in our series is far from satisfying. However, small series, poor treatment compliance and socio-economic constraints in the Indian scenario are limiting factors in the result analysis.

Clival giant cell tumor presenting with isolated trigeminal nerve involvement.

Giant cell tumour (GCT) constitutes about 5 % of all skeletal tumors. They rarely occur in the skull. When involved, they preferentially involve the sphenoid or temporal bones. Skull-base GCTs generally present with multiple cranial nerves involvement, most commonly sixth followed by the third cranial nerve. We describe a case of clival GCT presenting with an isolated trigeminal nerve involvement in a 19-year-old man which was managed by surgery and adjuvant radiation. At 18 months of follow-up, the patient is clinically asymptomatic. Clival GCT should also be considered in the differential diagnosis of any isolated trigeminal nerve palsy. Adjuvant radiation has an important role to play in managing this tumour.

Over Expression of Cancer Stem Cell Marker CD44 and Its Clinical Significance in Patients with Oral Squamous Cell Carcinoma.

Cancer stem cell marker CD44 is a cell-surface glycoprotein which is involved in various cellular functions such as cell-cell interactions, cell adhesion, haematopoiesis and tumour metastasis. The CD44 gene transcription is partly activated by beta-catenin and Wnt signalling pathway, the later pathway being linked to tumour development. However, the role of CD44 in oral squamous cell carcinoma (OSCC) is not well understood. We investigated the expression of CD44 in peripheral circulation, tumour tissues of oral cancer patients and oral squamous cell carcinoma cell lines by ELISA and quantitative (q)-RTPCR. Relative CD44s mRNA expression was significantly higher in peripheral circulation (p = 0.04), tumour tissues (p = 0.049) and in oral cancer cell lines (SCC4, SCC25 p = 0.02, SCC9 p = 0.03). Circulating CD44total protein levels were also significantly (p < 0.001) higher in OSCC patients that positively correlated with increasing tumour load and loco-regional spread of the tumour. The circulating tumour stem cell marker CD44 appears to be a potent indicator of tumour progression and may be useful for developing suitable therapeutics strategies for patients with oral squamous cell carcinoma.