The Armed Forces Institute of Pathology.

European Organization for Research and Treatment of Cancer

Dedifferentiation is a well recognized, if sometimes controversial, form of tumor progression in certain types of soft tissue and bone sarcoma, and confers a worse prognosis when compared with the low-grade counterpart. To date, dedifferentiation has not been described in solitary fibrous tumor (SFT). Among 948 cases of both intrathoracic and extrathoracic SFTs in our files accessioned between 1988 and 2008, we identified 8 cases of conventional SFT with a discrete anaplastic component, which we believe represents dedifferentiation. These occurred in 3 men and 5 women, 40 to 76 years old (median 60 y), and measured 3.4 to 20.0 cm (median 8.5 cm). Two cases were intrathoracic, 2 were located in the deep soft tissue of thigh, and single cases were located in the omentum, scalp, retroperitoneum, and abdominal wall. In addition to typical features of benign-appearing SFT there was an abrupt transition to nondistinctive high-grade sarcoma in all cases. The latter included epithelioid, round cell, and/or spindle cell components with increased mitotic activity, necrosis, and cystic degeneration. By immunohistochemistry, 7 of 8 cases were CD34 positive in the usual SFT areas, whereas 5 showed loss of CD34 in the poorly differentiated component. Six of 7 cases stained for p53 and p16 showed either negative or scattered positive cells in well-differentiated SFT areas, in contrast to positive or stronger and more diffuse staining in the high-grade component. Follow-up information available in 7 patients ranged from 1 to 58 months (mean 24 mo). Three patients with the largest tumors (9.0, 17.0, and 20.0 cm) died of disease, whereas 3 patients whose tumors measured 8.0 cm or less were treated by surgical excision only, and show no evidence of disease but with only limited follow-up. One patient with an 11.5 cm intrathoracic tumor is alive with disease at 58 months after recurrence and metastasis. We describe, apparently for the first time, what seems, at least in our view, to be dedifferentiation in primary SFT. Our results demonstrate that dedifferentiation in SFT, comparable with that in other low grade/intermediate soft-tissue tumors, poses a higher risk of tumor recurrence and/or metastasis, most notably in large and deep-seated tumors. Similar to other dedifferentiated sarcomas, abrupt transition between low grade and high-grade areas is typically observed with loss of CD34 positivity. The p53 and p16 overexpression in the high-grade component is common as in other dedifferentiated lesions, perhaps pertaining to the underlying molecular mechanism.

Expanding the spectrum of malignant progression in solitary fibrous tumors: a study of 8 cases with a discrete anaplastic component--is this dedifferentiated SFT?

Importance Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. Objective To assess safety and objective response rate of durvalumab combined with tremelimumab. Design, Setting, and Participants The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1–low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. Interventions Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. Main Outcomes and Measures Safety and tolerability and efficacy measured by objective response rate. Results Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. Conclusions and Relevance In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. Trial Registration clinicaltrials.gov Identifier:NCT02319044

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Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.

Purpose Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT. Methods Patients were analyzed from a subset of three previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3 to 4 pharyngeal/laryngeal toxicity (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity scoring system) and/or requirement for a feeding tube ≥ 2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pretreatment and treatment potential factors. Results A total of 230 patients were assessable for this analysis: 99 p...

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Factors Associated with Severe Late Toxicity After Concurrent Chemoradiation for Locally Advanced Head and Neck Cancer: An RTOG Analysis

Dedifferentiation of salivary gland neoplasms is a rare event, unlike bone and soft part sarcomas, which was first described by Stanley et al. in 1988. An additional case of dedifferentiated epithelial-myoepithelial carcinoma (EMC) is reported here. The patient was a 70-year-old Japanese man who requested examination of the rapid growth of a mass in the right parotid region, which he had first noticed 25 years previously. Clinical examination showed an ill-circumscribed, 6.8 x 4.7 x 7.0-cm lesion. Histologically, most parts of the lesion were high-grade carcinoma (HGC) with sheetlike and nestlike growth of markedly atypical cells and comedonecrosis, whereas the minor part consisted of typical EMC. The outer clear cells of EMC were positive for alpha-smooth muscle actin (ASMA), p63, cytokeratin (CK) 14, and vimentin, and the inner ductal cells of EMC were positive for CKs and epithelial membrane antigen. HGC was negative for ASMA, CK14, and vimentin, but diffusely positive for p53 protein and cyclin D1. The Ki-67 labeling index of EMC was 11.5%, whereas that of HGC was 67.1%. These findings and a review of literature indicate that HGC arose from preexisting EMC, and this phenomenon is the dedifferentiation of EMC. Dedifferentiated EMC is extremely rare.

Dedifferentiated epithelial-myoepithelial carcinoma of the parotid gland: a rare case report of immunohistochemical analysis and review of the literature.

Aims
Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and the long-term prognosis is poor. In this study, we examined alterations of AdCC-associated genes, MYB, MYBL1, MYBL2 and NFIB, and their target molecules, including MYC. The results were correlated to clinicopathological profile of the patients.

Methods and results
Using paraffin tumour sections from 33 cases of salivary gland AdCC, we performed a detailed fluorescence in-situ hybridization (FISH) analysis for gene splits and fusions of MYB, MYBL1, MYBL2 and NFIB. We found that 29 of 33 (88%) AdCC cases showed gene splits in either MYB, MYBL1 or NFIB. None of the cases showed an MYBL2 gene alteration. AdCCs were divided genetically into six gene groups, MYB–NFIB (n = 16), MYB–X (n = 4), MYBL1–NFIB (n = 2), MYBL1–X (n = 1), NFIB–X (n = 6) and gene-split-negative (n = 4). AdCC patients showing the MYB or MYBL1 gene splits were associated with microscopically positive surgical margins (P = 0.0148) and overexpression of MYC (P = 0.0164). MYC expression was detected in both ductal and myoepithelial tumour cells, and MYC overexpression was associated with shorter disease-free survival of the patients (P = 0.0268).

Conclusions
The present study suggests that (1) nearly 90% of AdCCs may have gene alterations of either MYB, MYBL1 or NFIB, suggesting the diagnostic utility of the FISH assay, (2) MYB or MYBL1 gene splits may be associated with local aggressiveness of the tumours and overexpression of MYC, which is one of the oncogenic MYB/MYBL1 targets and (3) MYC overexpression may be a risk factor for disease-free survival in AdCC.

MYB, MYBL1, MYBL2 and NFIB gene alterations and MYC overexpression in salivary gland adenoid cystic carcinoma

Objectives: The objective was to compare electrophysiologic investigations of the upper trapezius muscle (UT) after different selective neck dissections (SND) and analyze the differences between types of SND and the preservation and excision of the cervical nerves (the C2–4 rami of the cervical plexus).



Study Design: Retrospective study of 54 patients (average age, 65.1 ± 9.6 yr, 45 males) with 70 SND.



Methods: Patients underwent needle electromyography (EMG) of the UT by 4 months after surgery. The findings were rated according to the 5 point EMG scale system from 1 (total denervation: positive sharp wave or fibrillation potential at rest and electrical silence at voluntary contraction) to 5 (normal pattern).



Results: The average EMG scale was 1.7 ± 1.1, 58.6% for score 1 and only 5.7% for score 5. There was not a significant difference in the EMG scale between the types of SND, whereas the group in which the cervical nerves were excised was significantly lower than in that in which it was preserved. The average EMG scales in the former and latter were 1.5 ± 0.8 and 2.0 ± 1.3, 68.8%.



Conclusions: The study data confirm that complete or incomplete denervation of the UT was caused by axonal injury of the spinal accessory nerve, even though it was spared, because of traction of the nerve during neck dissection. Second, the excision of the C2 to 4 rami of the cervical plexus caused worse damage of the UT. It is suggested that it is important to preserve the cervical nerves to avoid denervation of the UT.

Electromyographic findings after different selective neck dissections

Backgrounds Large cell neuroendocrine carcinoma (LCNEC) is well-known as a lung cancer subtype. This study assessed the prevalence of head and neck mucosal LCNEC (M-LCNEC). Methods M-LCNEC was studied clinically, histologically and immunohistochemically. Results Of 814 surgically resected cases of mucosal head and neck carcinoma, only eight cases (0.98%; all men, mean age 64.6 years) were rediagnosed as M-LCNEC. They occurred in the oropharynx (n¼3), larynx (n¼4) and hypopharynx (n¼1). Seven of the cases had regional lymph node metastases and four resulted in death. Histologically, M-LCNEC had a sheet-like trabacular organoid growth pattern of relatively large basaloid cells in which central necrosis, rosette formation, peripheral palisading and high mitotic figures were evident. M-LCNEC was immunopositive for two or three neuroendocrine markers (CD56, chromogranin-A and synaptophysin). All cases showed high proliferative activity. Conclusion M-LCNEC in the head and neck regions is a distinct histopathological entity whose positivity for neuroendocrine markers makes its diagnosis important. As about half of the patients died of the disease, M-LCNEC has a relatively poor prognosis.

https://jcp.bmj.com/content/jclinpath/65/8/704.full.pdf

Mucosal large cell neuroendocrine carcinoma of the head and neck regions in Japanese patients: a distinct clinicopathological entity.

Objective Depth of invasion (DOI) in oral carcinoma has been integrated into the primary tumor categories in the current tumor-node-metastasis staging (8th edition). However, there is no standard modality to determine DOI preoperatively. The aims of the present study were to evaluate the accuracy of a preoperative measurement of DOI using ultrasonography (US) for superficial oral tongue carcinomas, and to correlate the values obtained with histologically determined DOI measurements. Methods We retrospectively analyzed the records of 56 patients with oral tongue carcinoma who underwent intraoral US preoperatively, followed by curative surgery at the Shizuoka Cancer Center Hospital in Japan. For the measurement of DOI with US, our unique technique (water balloon method) was evaluated. Results The histologically measured tumor size (maximum diameter) showed a distribution of 7.0 to 40.0 mm (mean, 18.6 mm). The correlation between the US-obtained and histologically obtained DOIs was significant (r = 0.867; P 5 mm were 92.3% and 70.6%, respectively. Conclusion Intraoral US provides sufficient accuracy for the measurement of tumor DOI in oral tongue carcinoma and is complementary in assessing superficial lesions. Level of evidence 4. Laryngoscope, 128:2778-2782, 2018.

Yoshiyuki Iida

Papers

Dedifferentiated epithelial-myoepithelial carcinoma of the parotid gland: a rare case report of immunohistochemical analysis and review of the literature.

MYB, MYBL1, MYBL2 and NFIB gene alterations and MYC overexpression in salivary gland adenoid cystic carcinoma

Electromyographic findings after different selective neck dissections

Mucosal large cell neuroendocrine carcinoma of the head and neck regions in Japanese patients: a distinct clinicopathological entity.

Depth of invasion in superficial oral tongue carcinoma quantified using intraoral ultrasonography.