HPV Status Improves Classification of Head and Neck Gray Zone Cancers.

In epidemiologic studies, patients with head and neck squamous cell carcinoma (HNSCC) are classified mainly by the International Classification of Diseases (ICD) codes. However, some patients are of an unclear subsite, the "gray zone" cases, which could reflect ICD coding error, absence of primary subsite, or extensive primary tumors that cross over multiple subsites of the oral cavity and oropharynx. Patients with gray zone squamous cell carcinomas were compared with patients with oral cavity squamous cell carcinoma (OSCC) or oropharyngeal squamous cell carcinoma (OPSCC) and stratified by human papillomavirus (HPV) status that was determined by p16 immunostaining or HPV serology. Comparisons consisted of clinicodemographic features and prognostic outcomes presented by Kaplan-Meier curves and Cox proportional hazards regression models, reported as hazard ratios. There were 158 consecutive patients with gray zone HNSCC diagnosed at the Princess Margaret Cancer Center between 2006 and 2017: 66 had subsite coding discrepancies against the clinician's documentation ("discrepant" cases; e.g., the diagnosis by the clinician was OSCC, while the classification by ICD coding was OPSCC), while 92 were squamous cell carcinoma of unknown primary of the head and neck (SCCUPHN) after complete diagnostic workup. Comparators included 721 consecutive OSCC and 938 OPSCC adult cases. All HPV-positive cohorts (OPSCC, discrepant, and SCCUPHN) had similar clinicodemographic characteristics and better 3- and 5-y overall survival and disease-free survival than their HPV-negative counterparts. In contrast, HPV-negative discrepant cases had prognostic outcomes most similar to HPV-negative OPSCC cases, while HPV-negative SCCUPHN had survival outcomes most similar to those of patients with OSCC in this study. HPV-positive status can improve the classification of patients with unclear or discrepant oral/oropharyngeal subsite, an improvement over classification systems that are solely clinician defined or conducted through ICD coding. However, due to clinical practice, we could not make definitive reclassification for patients with HPV-negative gray zone HNSCC.

Radiologic-Pathologic Correlation of Tumor Thickness and Its Prognostic Importance in Squamous Cell Carcinoma of the Oral Cavity: Implications for the Eighth Edition Tumor, Node, Metastasis Classification.

BACKGROUND AND PURPOSE: Addressing the performance of an imaging-based parameter compared to a "gold standard" pathologic measurement is essential to achieve accurate clinical T-classification. Our aim was to determine the radiologic-pathologic tumor thickness correlation and its prognostic value in oral squamous cell carcinoma. MATERIALS AND METHODS: All pathologic T1-T3 (seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer) oral squamous cell carcinomas diagnosed between 2010 and 2015 were reviewed. Radiologic tumor thickness was measured on preoperative CT or MR imaging blinded to pathology. The radiologic-pathologic tumor thickness correlation was calculated. The impact of the imaging-to-surgery time interval and imaging technique on the correlation was explored. Intra-/interrater reliability on radiologic tumor thickness was calculated. The correlation of radiologic-versus-pathologic tumor thickness and its performance as the seventh edition T-category modifier was evaluated. Multivariable analysis assessed the prognostic value of the radiologic tumor thickness for overall survival adjusted for age, seventh edition T-category, and performance status. RESULTS: For 354 consecutive patients, the radiologic-pathologic tumor thickness correlation was similar for the image-to-surgery interval of ≤4.0 weeks (ρ = 0.76) versus 4-8 weeks (ρ = 0.80) but lower in those with more than an 8-week interval (ρ = 0.62). CT and MR imaging had similar correlations (0.76 and 0.80). Intrarater and interrater reliability was excellent (0.88 and 0.84). Excluding 19 cases with an imaging-to-surgery interval of >8 weeks, 335 patients were eligible for further analysis. The radiologic-pathologic tumor thickness correlation was 0.78. The accuracy for upstaging the T-classification based on radiologic tumor thickness was 83% for pathologic T1 and 74% for pathologic T2 tumors. Multivariable analysis confirmed the prognostic value of radiologic tumor thickness (hazard ratio = 1.5, P = .02) for overall survival. CONCLUSIONS: This study demonstrates a good radiologic-pathologic tumor thickness correlation. Intrarater and interrater reliability for radiologic tumor thickness was excellent. Radiologically thicker tumor was predictive of inferior survival.

Clinicopathological characteristics and cell cycle proteins as potential prognostic factors in myoepithelial carcinoma of salivary glands.

Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).

Intraosseous mucoepidermoid carcinoma: a review of the diagnostic imaging features of four jaw cases.

The purpose of this case series is to present the common features of intraosseous mucoepidermoid carcinoma (IMC) of the jaws in plain film and CT imaging. Two oral and maxillofacial radiologists reviewed and characterized the common features of four biopsy-proven cases of IMC in the jaws in plain film and CT imaging obtained from the files of the Department of Oral Radiology, Faculty of Dentistry, University of Toronto, Toronto, Canada. The common features are a well-defined sclerotic periphery, the presence of internal amorphous sclerotic bone and numerous small loculations, lack of septae bordering many of the loculations, and expansion and perforation of the outer cortical plate with extension into surrounding soft tissue. Other characteristics include tooth displacement and root resorption. The four cases of IMC reviewed have common imaging characteristics. All cases share some diagnostic imaging features with other multilocular-appearing entities of the jaws. However, the presence of amorphous sclerotic bone and malignant characteristics can be useful in the differential diagnosis.

Sinonasal seromucinous hamartoma: a review of the literature and a case report with focal myoepithelial cells.

Seromucinous hamartoma is a benign lesion of the sinonasal tract. Since its description in 1974, only a small number of additional cases have been reported. It is composed of a proliferation of seromucinous glands and ducts within a variable fibrous stroma. The serous component typically stains positively for S100 (at least focally) and lacks p63 positive abluminal cells. The lack of myoepithelial/basal cells is an important diagnostic feature of seromucinous hamartoma; their absence could lead to an incorrect diagnosis of low-grade sinonasal adenocarcinoma. We report the case of a polypoid mass resected from the posterior nasal cavity and nasopharynx of a 54-year-old woman. The lesion contained a population of small and large glands lined by cuboidal to flattened cells within a hypocellular stroma varying from dense and sclerotic to myxoid. Additionally, there was a superficial focus of ciliated invaginated surface epithelium and glands. Throughout the lesion there were no cytologic or architectural features of malignancy. The histologic features were diagnostic of seromucinous hamartoma. Immunohistochemistry showed focal S100 positivity of the serous glands. However, in contrast to previously reported cases, the glands focally showed an outer basal layer that was calponin, p63 and actin positive. Our case demonstrates two important points. First, complete absence of p63 staining should not necessarily be a required feature in the diagnosis of seromucinous hamartoma. Second, the ciliated larger glands--in keeping with respiratory epithelial adenomatoid hamartoma (REAH)--support the suggestion that seromucinous hamartoma and REAH are a spectrum of lesions, often seen together.

Hamartomas, papillomas and adenocarcinomas of the sinonasal tract and nasopharynx.

Lesions of the sinonasal tract are uncommon, with most of the specimens seen by surgical pathologists consisting primarily of fragments of inflamed sinonasal mucosa or inflammatory polyps from patients with chronic rhinosinusitis, and the occasional squamous cell carcinoma. Other lesions such as hamartomas, various types of Schneiderian papillomas and adenocarcinomas are seen only rarely by most histopathologists; therefore a biopsy or surgical resection specimen from a patient with one of these processes may represent a diagnostic challenge. The aim of this review is to present the pathological features of a group of infrequent epithelial surface and glandular lesions of the sinonasal tract which includes respiratory epithelial adenomatoid hamartoma, glandular (seromucinous) hamartoma, exophytic papilloma, inverted papilloma, cylindrical cell (oncocytic) papilloma, low-grade sinonasal adenocarcinoma and intestinal-type sinonasal adenocarcinoma.

Composite intestinal-type adenocarcinoma and small cell carcinoma of sinonasal tract.

BACKGROUND AND AIMS: Sinonasal intestinal-type adenocarcinomas (ITACs) are rare neoplasms resembling intestinal adenocarcinomas. Although several studies have documented neuroendocrine differentiation in ITACs, the combination of ITAC and small cell carcinoma has not been previously described in detail. The aim of this report is to detail the histopathological and immunohistochemical characteristics of two cases of composite ITAC with small cell carcinoma. METHODS: Two cases of composite ITAC with small cell carcinoma were routinely processed, and representative sections were stained with CAM5.2, AE1:AE3, keratin 7, keratin 20, keratin 19, CDX-2, p63, villin, chromogranin, synaptophysin and CD56. RESULTS: One tumour consisted of a mixed-type ITAC showing colonic-type and poorly differentiated adenocarcinoma with foci of "signet-ring" cells combined with small cell carcinoma. Both components stained positively with CAM5.2, AE1:AE3, CK7, CK20 and CK19, whereas only the small cell carcinoma expressed synaptophysin and CD56. Both components stained negatively with CDX-2, villin, CD99 and p63. The "signet-ring" cells stained positively with chromogranin and synaptophysin. The second tumour showed a papillary-type ITAC combined with a small cell carcinoma. The adenocarcinoma and small cell carcinoma stained positively with CAM5.2, AE1:AE3, CK7, CK19 and CK20. Only the adenocarcinoma was CDX-2 positive, whereas the small cell carcinoma expressed CD56 and synaptophysin. CONCLUSIONS: The two components of the combined ITACs and neuroendocrine small cell carcinoma show significant immunohistochemical overlap, supporting a common origin. The occurrence of a distinct neuroendocrine carcinoma combined with ITACs expands the histopathological spectrum of these tumours.

Mucinous, gland predominant synovial sarcoma of a large peripheral nerve: a rare case closely mimicking metastatic mucinous carcinoma.

Synovial sarcoma is a distinctive soft tissue neoplasm with monophasic and biphasic forms. It is typically a deep-seated soft tissue tumour of the extremities of young adults and occasional cases have been described in large peripheral nerves. A rare example has a predominance of the glandular component and may mimic metastatic carcinoma. Here, a unique synovial sarcoma with <1% spindle cell component involving the posterior tibial nerve is decribed. In addition to having only small bands or islands of stroma, there was also mucin dissection of the surrounding soft tissue. Isolated glands were seen "floating" in pools of mucin. There was abundant intracellular mucin present as well. These latter two findings have not been described in synovial sarcoma thus far, to our knowledge. The diagnosis was confirmed by molecular detection of the t(X;18) by reverse transcription-PCR and confirmed by dual colour break apart fluorescence in situ hybridisation, in a second laboratory. Mucinous, gland predominant synovial sarcoma must be recognised to avoid misdiagnosis of metastatic carcinoma or a glandular malignant peripheral nerve sheath tumour when occurring in a peripheral nerve.

Molecular biology of squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (HNSCC) is a heterogeneous but largely preventable disease with complex molecular abnormalities. It arises from a premalignant progenitor followed by outgrowth of clonal populations associated with cumulative genetic alterations and phenotypic progression to invasive malignancy. These genetic alterations result in inactivation of multiple tumour suppressor genes and activation of proto-oncogenes, including p16(ink4A), p53, cyclin D1, p14(ARF), FHIT, RASSF1A, epidermal growth factor receptor (EGFR), and Rb. Intramucosal migration and clonal expansion of transformed cells with formation of abnormal genetic fields appear to be responsible for local recurrences and development of second primary tumours.

Expression of mismatch repair proteins, beta catenin, and E cadherin in intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Despite their histological resemblance to colorectal adenocarcinomas, there is little information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinomas (ITACs). AIMS: To evaluate the possible role of DNA mismatch repair (MMR) gene defects or disruptions of the E cadherin-beta catenin complex in ITAC by investigating the immunohistochemical expression of the MMR gene products, beta catenin, and E cadherin in a group of sporadic ITACs. METHODS: Ten sporadic cases of ITAC were stained with antibodies against MLH1, MSH2, MSH3, MSH6, beta catenin, and E cadherin. RESULTS: Nine cases showed strong nuclear expression of MLH1, whereas one case showed moderate staining. All 10 cases were strongly positive for MSH2 and MSH3. MSH6 was strong in nine cases, and moderate in one. Membranous beta catenin expression was strong in all 10 cases, and no case showed cytoplasmic or nuclear staining. E cadherin was strong in seven cases, and moderate in three cases. CONCLUSIONS: The preserved nuclear expression of MLH1, MSH2, MSH3, and MSH6 suggests that mutations or promoter methylation of MMR genes do not play a role in the pathogenesis of ITAC. The strong membranous staining for E cadherin and beta catenin and lack of abnormal cytoplasmic or nuclear expression is in keeping with the preservation of E cadherin-beta catenin complexes and beta catenin pathways.

Expression pattern of CK7, CK20, CDX-2, and villin in intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is an uncommon neoplasm, which resembles adenocarcinoma of the gastrointestinal tract. ITAC occurs sporadically or in association with occupational exposure to hardwood dust and other agents. AIMS: To investigate the phenotype and possible pathogenetic mechanisms of primary sinonasal and nasopharyngeal adenocarcinomas by staining for cytokeratin 7 (CK7), CK20, CDX-2, and villin. METHODS: Twelve sporadic sinonasal and nasopharyngeal adenocarcinomas were stained with monoclonal antibodies to CK7, CK20, CDX-2, and villin. The ITACs were classified as papillary, colonic, solid, mixed, or mucinous types. RESULTS: The diagnosis of ITAC was confirmed in 10 cases: five were colonic type and five were papillary. One was a sinonasal papillary low grade adenocarcinoma, and one a papillary nasopharyngeal adenocarcinoma, and these tumours were CK7 positive, but CK20, CDX-2, and villin negative. All ITACs were positive for CK20, CDX-2, and villin, and six were CK7 positive. One ITAC had a focus of intestinal metaplasia away from the invasive carcinoma. CONCLUSIONS: Sinonasal ITACs have a distinctive phenotype, with all cases expressing CK20, CDX-2, and villin. Most ITACs also express CK7, although a proportion of tumours are CK7 negative. ITAC seems to be preceded by intestinal metaplasia of the respiratory mucosa, which is accompanied by a switch to an intestinal phenotype. Although ITACs are morphologically similar, differences in cytokeratin expression patterns suggest two distinct types. The expression pattern of CK7, CK20, CDX-2, and villin positive may be useful in separating these tumours from other non-ITAC adenocarcinomas of the sinonasal tract and nasopharynx.

Malignant evolution of Schnitzler's syndrome--chronic urticaria and IgM monoclonal gammopathy: report of a new case and review of the literature.

Schnitzler's syndrome, initially described in 1974 is an uncommon condition defined by chronic urticaria and monoclonal IgM gammopathy. Additional features include fever of unknown origin, elevated ESR, bone pain and frequently a benign clinical course. We conducted a literature search of Medline, EMBASE and Cancerlit and found 56 cases of Schnitzler's syndrome reported to date. The absence of lymphoproliferative disease in this condition is typical, but nine patients have progressed to develop lymphoplasmacytic neoplasias, particularly Waldenstrom's macroglobulinemia (WM). Malignant evolution of Schnitzler's syndrome is a rare complication, but emphasizes the importance of long term follow-up and the need for these patients to undergo periodic assessment of the bone marrow and lymph nodes. Treatment of this condition is difficult, with varying response to corticosteroids and largely unsuccessful results with standard chemotherapy used for WM. We describe a case of Schnitzler's syndrome in a 50-year old man with lymphocytic aggregates in the bone marrow after 9 years of chronic urticaria, fever, arthralgias and bone pain. We review the clinical features and treatment, with emphasis on the hematologic aspects of this unusual condition.

Combined large cell neuroendocrine carcinoma and spindle cell carcinoma of the lung.

We report a unique case of a combined pulmonary large-cell neuroendocrine carcinoma and spindle-cell carcinoma. The patient was a 54-year-old female smoker who presented with a 4-month history of increased left-sided chest pain and exertional dyspnea. The left upper lobectomy specimen revealed an 8.0-cm mass with central necrosis. Microscopically, the epithelial areas were composed of well-defined nests of large cells with peripheral palisading expressing low-molecular-weight keratin, synaptophysin, chromogranin, and neuron-specific enolase. The spindle-cell component consisted of pleomorphic cells arranged in fibrosarcoma and malignant fibrous histiocytoma-like patterns. These spindle cells were positive for low-molecular-weight keratin and vimentin with focal expression of CD68 and muscle-specific actin. Electron microscopy in the spindle-cell areas showed cell junctions and numerous tonofilaments, indicative of epithelial differentiation. The tumor behaved aggressively and the patient died with extensive metastases 4 months after surgery. The combination of neuroendocrine malignancies and spindle-cell carcinomas appears to be uncommon in the lung. Previous reports have described this association in single case reports of anaplastic small-cell carcinoma and atypical carcinoid, but not in large-cell neuroendocrine carcinoma.

EBV-associated perianal Hodgkin's disease in an HIV-positive individual.

Hodgkin's disease (HD) has a higher incidence in HIV-positive individuals. It tends to occur at extranodal sites, frequently exhibits an unfavorable histological type with large numbers of neoplastic cells, and almost invariably harbors Epstein-Barr Virus (EBV). We describe a case of a 33-year-old HIV-positive man who presented with anal pain from a 4-cm mass in the anorectal canal. He had no B symptoms or peripheral lymphadenopathy. A chest X-ray was within normal limits. A biopsy showed an ulcerated mass composed of a mixed infiltrate of lymphocytes, plasma cells, eosinophils, and Reed-Sternberg (RS) cells positive for CD15 and strongly positive for CD30. They were negative for CD45 and CD20. Numerous RS cells and lymphocytes were positive for EBV RNA using the EBER-1 probe. This highly unusual presentation of HD may reflect the greater incidence of anorectal lymphoma and of extranodal HD in the HIV-positive population.

Epithelioid hemangioendothelioma of the spine presenting as cervical myelopathy: case report.

OBJECTIVE AND IMPORTANCE: We report the first case in the literature of cervical myelopathy caused by progressive cord compression as a result of epithelioid hemangioendothelioma of the cervical vertebra. CLINICAL PRESENTATION: A 58-year-old man presented with progressive cervical myelopathy. Imaging revealed a vascular, expansile lesion of contiguous cervical vertebrae causing cord compression. The surgical pathology revealed epithelioid hemangioendothelioma, a rare tumor not previously reported to present in such a fashion. INTERVENTION: Preoperative embolization and a two-stage anterior and posterior surgical decompression and fusion procedure were performed. The high vascularity of this lesion makes surgery a formidable surgical challenge. Adjuvant radiotherapy was administered to the residual tumor because of its potential for low-grade malignancy. CONCLUSION: The diagnosis relied on accurate histopathological assessment. The general principles of achieving cord decompression and tumor control are important. The literature on epithelioid hemangioendothelioma involving the spine is reviewed, and the tumor biology and the role of adjuvant therapy are discussed.

Primary spinal epidural mantle cell lymphoma: case report.

OBJECTIVE AND IMPORTANCE: Mantle cell lymphoma is a distinct clinicopathological type of non-Hodgkin's lymphoma that often presents at an advanced stage, with systemic spread. Spinal involvement is uncommon and generally occurs as part of advanced disease or generalized relapses. Primary spinal epidural lymphoma is a rare initial manifestation of non-Hodgkin's lymphoma, and mantle cell lymphoma with initial presentation in the spinal epidural space is extremely rare, having been previously reported in only two cases. CLINICAL PRESENTATION: We report a case of a 71-year-old man who presented with increasing weakness and numbness of the legs. Magnetic resonance imaging revealed a spinal epidural mass in the lumbosacral region. INTERVENTION: The patient underwent a partial L4 and L5-S1 laminectomy, with incomplete resection of the mass for spinal decompression and tissue diagnosis. Mantle cell lymphoma was diagnosed in the pathological examination. CONCLUSION: After radiotherapy, the disease recurred with a soft-tissue mass in the anterior maxillary area of the face. The patient underwent restaging and was treated with chemotherapy, with only a partial response. Mantle cell lymphoma with primary spinal epidural presentation is rare. This diagnosis can be established and other causes of spinal cord compression can be ruled out by obtaining tissue for proper histopathological examinations. Because of its aggressive behavior and poor prognosis, mantle cell lymphoma should be treated using a combined-modality approach.

Primary cutaneous B cell lymphoma during methotrexate therapy for rheumatoid arthritis.

A patient with rheumatoid arthritis developed a reversible, primary cutaneous, large B cell lymphoma during prolonged methotrexate (MTX) treatment. Regression of the skin lesions after discontinuation of the drug suggested a close relationship to MTX. Increased clinical awareness, discontinuation of MTX, and close observation are important in the initial management of this rare lymphoproliferative disorder.

Mesothelial lesions of the paratesticular region.

Mesothelial lesions involving the paratesticular region include mesothelial cysts, reactive mesothelial hyperplasia, adenomatoid tumors, benign cystic mesothelioma, well-differentiated papillary mesothelioma, and malignant mesothelioma. The diagnosis and management of these lesions are often difficult for surgical pathologists, surgeons, and oncologists alike. Mesothelial lesions are relatively uncommon and most benign and malignant tumors present as testicular tumors with no specific findings. A preoperative diagnosis of malignancy is rarely made, and there is no established effective therapy for malignant mesothelioma. This article reviews the clinicopathologic features of paratesticular mesothelial lesions with emphasis in their differential diagnosis and prognosis.