Setting the Stage for 2018: How the Changes in the American Joint Committee on Cancer/Union for International Cancer Control Cancer Staging Manual Eighth Edition Impact Radiologists.

The updated eighth edition of the Cancer Staging Manual of the American Joint Committee on Cancer will be implemented in January 2018. There are multiple changes to the head and neck section of the manual, which will be relevant to radiologists participating in multidisciplinary head and neck tumor boards and reading pretreatment head and neck cancer scans. Human papillomavirus-related/p16(+) oropharyngeal squamous cell carcinoma will now be staged separately; this change reflects the markedly better prognosis of these tumors compared with non-human papillomavirus/p16(-) oropharyngeal squamous cell carcinoma. Nodal staging has dramatically changed so that there are different tables for human papillomavirus/p16(+) oropharyngeal squamous cell carcinoma, Epstein-Barr virus-related nasopharyngeal carcinoma, and all other head and neck squamous cell carcinomas. Extranodal extension of tumor is a new clinical feature for this third staging group. In the oral cavity, the pathologically determined depth of tumor invasion is a new staging criterion, while extrinsic tongue muscle invasion is no longer part of staging. This review serves to educate radiologists on the eighth edition changes and their rationale.

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway.

The limited effectiveness of therapy for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) or recurrent disease is a reflection of an incomplete understanding of the molecular basis of HNSCC pathogenesis. MUC4, a high molecular weight glycoprotein, is differentially overexpressed in many human cancers and implicated in cancer progression and resistance to several chemotherapies. However, its clinical relevance and the molecular mechanisms through which it mediates HNSCC progression are not well understood. This study revealed a significant upregulation of MUC4 in 78% (68/87) of HNSCC tissues compared with 10% positivity (1/10) in benign samples (P=0.006, odds ratio (95% confidence interval)=10.74 (2.0-57.56). MUC4 knockdown (KD) in SCC1 and SCC10B HNSCC cell lines resulted in significant inhibition of growth in vitro and in vivo, increased senescence as indicated by an increase in the number of flat, enlarged and senescence-associated ß-galactosidase (SA-ß-Gal)-positive cells. Decreased cellular proliferation was associated with G0/G1 cell cycle arrest and decrease expression of cell cycle regulatory proteins like cyclin E, cyclin D1 and decrease in BrdU incorporation. Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with histone deacetylase 1/2. This resulted in decreased histone acetylation (H3K9) at cyclin E promoter leading to its downregulation. Orthotopic implantation of MUC4 KD SCC1 cells into the floor of the mouth in nude mice resulted in the formation of significantly smaller tumors (170±18.30 mg) compared to those (375±17.29 mg) formed by control cells (P=0.00007). In conclusion, our findings showed that MUC4 overexpression has a critical role by regulating proliferation and cellular senescence of HNSCC cells. Downregulation of MUC4 may be a promising therapeutic approach for treating HNSCC patients.

Primary cutaneous adenoid cystic carcinoma metastatic to cervical lymph nodes.

BACKGROUND: Adenoid cystic carcinoma (ACC) occurs not only as a neoplasm of salivary glands but also in the skin. Metastasis is rare, and metastasis to lymph nodes has not been reported in the English literature. Case Report A patient with a history of excisions of "cylindroma" of the scalp over the past 20 years was initially seen with 2 recurrent scalp nodules and a firm left neck mass. Both scalp lesions and multiple neck nodes were found to be ACC at resection. The patient underwent postoperative radiation therapy and is clinically free of disease at 4 years. CONCLUSIONS: We believe this represents the first reported case of nodal metastases from primary cutaneous ACC in the English literature.

Recalcitrant oral ulcers caused by calcium channel blockers: diagnosis and treatment considerations.

BACKGROUND: Oral ulcers often pose a dilemma in diagnosis and treatment. Patients seen routinely in dental practices are frequently receiving multiple medications. The authors discuss the pathogenesis, clinical appearance and treatment of drug-induced oral ulcers. CASE DESCRIPTIONS: Two patients with recalcitrant painful oral ulcers caused by calcium channel blockers are described. These ulcers failed to heal despite repeated interventions, including surgery, laser ablation, and topical and systemic steroid therapy. Results of the histopathologic examinations were nonspecific. The patients were in a great deal of pain because of the initial failure to recognize the cause of these ulcers. CLINICAL IMPLICATIONS: A careful medical history, including a detailed list of medications received, is critical in identifying drug-induced oral ulcerations, especially when the ulcer is resistant to treatment and of indeterminate cause. To date, calcium channel blockers have not been reported to cause oral ulcerations.

Microvascular reconstruction of the head and neck after tumor ablation.

Microvascular reconstruction of the head and neck in cancer patients after surgical ablation has significantly improved the quality of life of these patients from both a functional and cosmetic standpoint. Successful management and reconstruction of these patients requires a well-coordinated team approach. Operating room times and hospital stays have significantly decreased with coordination and experience of the team members.

Molecular support for field cancerization in the head and neck.

BACKGROUND: Two competing concepts, field cancerization and micrometastatic lesions, have been postulated to account for the high frequency of second primary tumors and multicentric dysplasia in patients with head and neck carcinoma. METHODS: To provide insight into this process, the authors examined histologically normal mucosa and dysplastic tissue adjacent to invasive tumor for loss of heterozygosity (LOH) at three commonly deleted loci. Tissues from 21 patients with carcinoma of the oral cavity and oropharynx were identified and verified by a pathologist to contain histologically normal mucosa, dysplasia, and adjacent invasive squamous cell carcinoma. Each specimen was analyzed for LOH at D9S171 (9p21), D3S1007 (3p21.3-22), and D3S1228 (3p14). RESULTS: Of the 21 patients, 19 had adequate DNA for analysis. Seventeen patients were heterozygous at one or both of the 3p sites and LOH occurred in 6 of 17 invasive tumor specimens, 1 of 17 dysplasia specimens, and in none of the mucosal specimens. LOH at 9p21 occurred in 11 of 13 informative specimens of invasive tumor, 8 of 13 dysplasia specimens, and 6 of 13 normal mucosa specimens. However, one case that did not have 9p deletion in the tumor demonstrated LOH in the mucosa and two cases had LOH in both the tumor and mucosa but with deletion of the opposite allele. CONCLUSIONS: These data suggest that 9p21 but not 3p14 or 3p21 deletions occur in the absence of histologic changes. In two cases preinvasive and invasive lesions that apparently were an example of histologic progression contained disparate genetic events, calling into question the use of adjacent dysplasia as a model for premalignant lesions.

Use of free fibula flap in patients with prior failed mandibular reconstruction.

PURPOSE: The purpose of this study was to assess the efficacy of the free fibula flap in patients who had failed prior attempts at bony reconstruction. PATIENTS AND METHODS: The records of all patients who had undergone free fibula reconstruction for segmental mandibular resections between 1993 and 1995 were retrospectively reviewed. Patients were divided into group I (14 patients who had failed previous bony reconstruction attempts) and group II (50 patients who had no previous reconstruction), and the two groups were compared. RESULTS: No statistical differences were found between group I and group II for mean age, mean hospital stay, mean intensive care unit stay, mean operating room time, mean intraoperative blood loss, mean colloid usage, or mean blood units transfused. Although group I had a statistically higher proportion of both patients with osteoradionecrosis and those receiving hyperbaric oxygen therapy (HBO), the number with a history of radiation therapy was not different in the two groups. Wound complication rates were not statistically different between groups I and II for all patients, or between those group I patients who did or did not receive HBO therapy. CONCLUSION: There was no increase in wound complications in the patients who had failed prior bony reconstructive attempts who underwent free fibula flaps. The free fibula flap is suggested as the reconstructive method of choice in this patient population.

9p21 deletion correlates with recurrence in head and neck cancer.

BACKGROUND: Deletion of 9p21 is a common event in many human tumors, including head and neck squamous cell carcinoma (HNSCC). The gene CDKN2, which encodes the protein p16, a cyclin-dependent kinase-4 inhibitor, maps to 9p21. The role of CDKN2 as the tumor suppressor gene in these neoplasms is unclear. The role of loss of heterozygosity (LOH) as a prognostic tool has not been described in HNSCC. METHODS: We performed deletion mapping using Southern and PCR-based LOH analysis and prospective survival analysis. RESULTS: We demonstrate that LOH of 9p and, specifically, the interferon (IFN) gene cluster correlates with recurrence of HNSCC. We also demonstrate two separate areas of deletion on 9p, one centromeric to IFNbeta and telomeric to CDKN2 and the other centromeric to CDKN2 and telomeric to the polymorphic marker D9S19. All the deletions involve either the markers IFNalpha and/or D9S171 and D9S126 but not necessarily CDKN2. CONCLUSIONS: These results suggest another tumor suppressor gene (TSG) may be involved in HNSCC carcinogenesis and may play a role in aggressive disease as manifest by local, regional, or distant recurrence.

Synovial sarcoma of the head and neck: chromosomal translation (X;18) as a diagnostic aid.

BACKGROUND: Synovial sarcoma, a rare tumor in the head and neck, has been historically diagnosed by its characteristic biphasic histologic pattern. Monophasic variants exist which can be difficult to diagnose. METHODS: Two cases of synovial sarcoma of the head and neck are presented. Both cases, cytogenetic analysis was performed using standard protocols. RESULTS: Both tumors demonstrated a chromosomal translocation, t(X;18)(p11.2;q11.2), which either made or confirmed the diagnosis. CONCLUSIONS: Synovial sarcoma contains a characteristic chromosomal translocation which is a useful diagnostic tool, especially when histologic studies are equivocal.

Conservation surgery for recurrent carcinoma of the glottic larynx.

BACKGROUND: Partial laryngectomy following previous irradiation is an oncologically sound procedure with excellent local control and survival rates. Several reports suggest an increased complication rate in previously irradiated patients. METHODS: To analyze whether previous irradiation affected complications, disease control, or survival we performed a retrospective analysis of all patients who underwent vertical partial laryngectomy (VPL) for squamous cell carcinoma of the glottic larynx between January 1984 and August 1993. RESULTS: Sixty-eight patients had adequate followup. The overall 5-year survival rates were 79% for previously treated patients and 95% for primary VPL patients (P = NS). The local control rates with surgical salvage were 93% and 98%, respectively. No increase in wound complications, time to decannulation, length of hospitalization, or ability to swallow were found. CONCLUSIONS: VPL can be performed safely in selected patients following previous radiotherapy without a significant increase in complications or cost.

Posterior pharyngeal carcinoma resection with larynx preservation and radial forearm free flap reconstruction: a preliminary report.

BACKGROUND: Surgical management of selected posterior pharyngeal wall lesions can be performed with pharyngectomy, allowing for larynx preservation, with radial forearm free flap (RFFF) reconstruction. METHODS: Retrospective review of our experience using RFFF reconstruction in 9 patients. RESULTS: All 9 patients had a posterior pharyngectomy with larynx preservation, neck dissection (3 bilateral, 6 unilateral), and RFFF reconstruction. Six patients experienced 8 postoperative complications including one postoperative death. Only 3 patients were able to obtain all nutrition orally. Tracheotomy decannulation occurred in 4 patients and voice was maintained in all patients. American Society of Anesthesiologists score (ASA) was an accurate predictor of postoperative medical complications. CONCLUSIONS: Posterior pharyngeal resections with larynx preservation and RFFF reconstruction can be accomplished with acceptable morbidity in healthy patients with carefully selected lesions of the posterior pharyngeal wall. However, in patients with significant co-morbidities as reflected by an ASA of 3 or more, larynx preservation and RFFF reconstruction was fraught with significant morbidity and is not recommended.

Cyclin D1 abnormalities and tobacco exposure in head and neck squamous cell carcinoma.

BACKGROUND: Amplification of the cyclin D1 (CCND1) gene, which encodes a cell cycle regulating protein, has been described in several solid tumors including head and neck squamous cell carcinoma (HNSCC). While correlations between CCND1 amplification and tumor behavior have been suggested, no investigation has focused on risk factor exposure as a potential cause of CCND1 alteration. METHODS: Southern blotting was used to identify CCND1 amplification in 57 previously untreated HNSCC tumor specimens Tissue from 27 cases was analyzed for CCND1 mRNA expression by Northern biot analysis. RESULTS: In 13/57 (23%) cases, a 2-5 fold amplification of CCND1 was found. CCND1 mRNA expression was higher in amplified than in non-amplified tumors and supported an association between CCND1 amplification and increased expression of CCND1 mRNA. No correlation was found between CCND1 amplification or CCND1 expression and clinical or pathological parameters. However, analysis of risk factor exposure revealed that patients with greater tobacco exposure were more likely to have tumors with CCND1 amplification (p = .037). Also, tobacco exposure was correlated with CCND1 expression in tumors. CONCLUSION: Tobacco exposure is a well-known risk factor for HNSCC. CCND1 amplification and alterations in expression may be causally related to tobacco carcinogen exposure and lead to a loss of cell cycle regulation.

Biological staging of head and neck cancer and its role in developing effective treatment strategies.

The purpose of a cancer staging system is to encompass all attributes of a tumor that define its life history. We propose a biological staging system which incorporates all of the phases of the natural history of head and neck cancer beginning with the earliest cellular changes extending through the early phase of invasion to the occurrence of metastasis and, finally, culminating in therapeutically refractory disease. This temporally structured system recognizes the importance of constitutional predisposition, and the impact of environmental factors. The intent is to augment the AJCC/UICC staging system and use this system to provide a framework which will easily incorporate current and future advances in basic science, prevention, therapy and palliation which will improve the quality and quantity of life for patients.

Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors.

Deletion of 9p21-22 is a common genetic alteration in dysplastic, in situ, and invasive head and neck squamous cell carcinoma (HNSCC). However, a candidate tumor suppressor gene (TSG) at this site has thus far not been identified in HNSCC. We report homozygous deletion of the recently identified multiple tumor suppressor I (MTSI)/cyclin-dependent kinase-4-inhibitor (CDKN2) gene mapped to 9p21, which encodes the p16 protein, a regulator of cyclin-dependent kinase 4, in six of 16 HNSCC cell lines. We also show absence of the CDKN2 mRNA in all cell lines with CDKN2 deletion as well as in an additional two cell lines without deletion. Overall, we have identified 9p abnormalities in 12 of 16 (75%) cell lines, at least nine of which involved CDKN2. We further demonstrate that the CDKN2 deletion in HNSCC is located within a previously described region of allelic loss between D9S171 and IFNW, which spans a 4 cM region of 9p. However, examination of 36 primary tumors revealed genetic alterations in only seven of 36 (19%) tumors. These results suggest that genetic alterations at CDKN2 are frequent in HNSCC cell lines, but the role of this gene in primary tumors is less compelling. CDKN2 does not appear to be the only TSG on 9p21 in HNSCC, and our results suggest that another region of deletion exists proximal to the IFNW locus.