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Aim: Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC)., Methods: An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis)., Results: Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02)., Conclusion: Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.

The objective of this review study was to encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem. The source of the data was Ovid MEDLINE from 1946 to 2014. Review methods consisted of articles with clinical correlates. The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of pleomorphic adenoma tissue, and satellite pleomorphic beyond the pseudocapsule are also likely linked to recurrent pleomorphic adenoma. Most recurrent pleomorphic adenoma are multinodular. Magnetic resonance imaging is the imaging study of choice for recurrent pleomorphic adenoma. Nerve integrity monitoring may reduce morbidity for recurrent pleomorphic adenoma. Treatment of recurrent pleomorphic adenoma must be individualized. Total parotidectomy, given the multicentricity of recurrent pleomorphic adenoma, is appropriate in many patients, but may be inadequate to control recurrent pleomorphic. There is accumulating evidence from retrospective series that postoperative radiation therapy results in significantly better local control., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Aim: To evaluate the locoregional control and treatment toxicity of patients with pleomorphic adenoma after resection with close or positive margins followed by postoperative radiation therapy (PORT)., Patients and Methods: Between 2002 and 2011, twenty-one patients underwent PORT at the Mount Sinai Beth Israel Medical Center for pleomorphic adenoma of the parotid with close or positive margins. Four out of the 21 patients (19%) had recurrent lesions. The median dose was 57.6 Gy (range 55.8-69.96) delivered at 1.8-2.12 Gy/fraction. Treatment and follow-up data were retrospectively analyzed for locoregional control as well as acute- and late-treatment toxicities. Actuarial survival analysis was also performed., Results: Twelve women and 9 men with a median age of 46 (26-65) at PORT were included in this study. Eighty-one percent of the cohort had positive resection margins while 19% had close margins. At a median follow-up of 92 months, 19/21 patients (90%) had locoregional control. Two patients who failed had primary lesions which recurred locally, and initially had positive margins. The two recurrences occurred at 8 months and 12 months. Acute Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicities were experienced by 11 (52%) and 4 (19%) patients, respectively, while 2 (10%) experienced late RTOG grade 1 toxicities. No patients experienced any grade 2-4 late toxicities. Actuarial survival was 100%., Conclusion: PORT for patients with pleomorphic adenoma of the parotid gland after resection with close or positive margins results in excellent locoregional control and low treatment-related morbidity., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: To evaluate the results of treatment of parotid pleomorphic adenoma, and the risk factors for secondary recurrence., Materials and Methods: Single-centre, retrospective study of 32 patients with pleomorphic adenoma recurrence managed between 1988 and 2008., Results: The mean age at diagnosis of primary pleomorphic adenoma recurrence was 43.4 years. Twenty-eight per cent of patients had secondary recurrence; 32 per cent had undergone two or more surgical resections and external adjuvant radiotherapy. An age of less than 25 years was significantly associated with an earlier primary recurrence (p = 0.008). The most significant histopathological risk factor for secondary recurrence was the presence of a multifocal tumour (p = 0.019). Other histopathological criteria (i.e. cellularity and capsule rupture) were not significant. Radiotherapy was not associated with a decrease in recurrence. Nine per cent of patients progressed to malignancy. The main surgical complication was definitive facial palsy (14 per cent)., Conclusion: Pleomorphic adenoma recurrence requires surgery, with greatly increased risk to the facial nerve. Resection with clear surgical margins is required, especially in young patients with multifocal tumours. Radiotherapy may delay second recurrence in cases of multifocal tumour.

Purpose: The aim of this study was to update our experience in treating pleomorphic adenoma with radiotherapy (RT)., Materials and Methods: This is a retrospective analysis of 25 patients treated with RT alone (2 patients) or combined with surgery (23 patients), with follow-up ranging from 1.8 to 34.9 years (median, 10.5 years)., Results: Local control was achieved in 13 (75%) of 16 patients with subclinical disease and 5 (56%) of 9 patients with gross disease. Overall local control was achieved in 18 (72%) of 25 patients. The 5-, 10-, and 15-year overall local control rates were 76 %, 76%, and 68%, respectively. Ten patients died of the following causes: recurrent disease, 2; malignant transformation, 2; and intercurrent disease, 6. At last follow-up, 14 patients were alive without evidence of disease, and 1 patient was alive with disease. Dental carries and transient facial nerve deficits were the most common complications. No patients developed severe complications subsequent to RT., Conclusions: In patients at high risk for developing recurrent pleomorphic adenoma after surgery, RT is effective in controlling subclinical disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: This study aims to highlight the current points of view regarding the management of pleomorphic adenomas among oral and maxillofacial surgeons in the United Kingdom., Patients and Methods: A questionnaire was drafted and sent to all the consultant members of the British Society of Oral Maxillofacial Surgery (n=263). The survey evaluated the surgical experience of the surgeon, the preferred surgical treatment of a newly diagnosed 3 cm diameter pleomorphic adenoma in the superficial lobe of the parotid gland in an adult and a child, and the treatment options of pleomorphic salivary adenoma (PSA) with the four following scenarios: (i) PSA with complete excision or incomplete excision; (ii) PSA with carcinoma in situ (atypical pleomorphic adenoma) with complete excision or incomplete excision; (iii) PSA with non-invasive malignant transformation with complete or incomplete excision; and (iv) carcinoma in PSA with complete or incomplete excision. The initial response was low so two reminders were sent to increase the rate of response., Results: The final response rate was 67%. The results showed that there was no significant difference in the opinions of the respondents regarding treatment of pleomorphic adenoma in both adults and children. Seventy-five (56.4%) of 133 surgeons were treated the multinodular recurrence in older patients with surgery combined with radiotherapy. One-hundred and five (78.9%) surgeons were treated older patients with solitary recurrence with surgery alone. There was a consensus on complete excision for the treatment of carcinoma in situ (atypical pleomorphic adenoma) or PSA with non-invasive malignant transformation., Conclusion: This survey shows that superficial parotidectomy is the standard treatment method for primary pleomorphic adenoma in children and adults. Surgery combined with radiotherapy is the preferred option in the case of multinodular recurrence, and surgery alone is recommended in the case of a solitary recurrence.

We discuss the optimal treatment and outcomes for pleomorphic adenoma of the salivary glands by reviewing the pertinent literature. Pleomorphic adenoma is the most common benign salivary gland neoplasm. It is found mostly in the parotid gland in middle-aged women. It progresses slowly and, left untreated, can produce significant morbidity and, rarely, death. The optimal treatment is superficial or total parotidectomy with facial nerve preservation, which results in local control rates of 95% or higher. Radiotherapy (RT) is useful to obtain local control in patients with positive margins, unresectable tumors, and multifocal recurrences after prior resection. Local control rates after RT for microscopic and gross residual tumor are approximately 80% to 85% and 40% to 60%, respectively. The main complication is surgically induced 7th nerve injury. Surgery is the mainstay of treatment and results in a very high cure rate. RT increases the likelihood of local control in the small subset of patients with incompletely resectable tumors and/or multifocal recurrences.

Purpose: To evaluate the impact of postoperative radiation therapy on the clinical course of patients with carcinoma ex pleomorphic adenoma of the parotid gland., Methods and Materials: Between 1960 and 2004, 63 patients were treated with definitive surgery for carcinoma ex pleomorphic adenoma of the parotid gland. Forty patients (63%) received postoperative radiation therapy to a median dose of 60 Gy (range, 45-71 Gy). Adenocarcinoma (29 patients), salivary duct carcinoma (16 patients), and adenoid cystic carcinoma (9 patients) were the most common malignant subtypes. Pathologic T -stage was: 16% T1, 33% T2, 32% T3, and 19% T4. Twenty-one patients (33%) had microscopically positive margins and 39 (62%) had perineural invasion. Median follow-up was 50 months (range, 2-96 months)., Results: The use of postoperative therapy significantly improved 5-year local control from 49% to 75% (p = 0.005) and was associated with an improvement in survival among patients without evidence of cervical lymph node metastasis (p = 0.01). A Cox proportional hazard model identified pathologic involvement of cervical lymph nodes as an independent predictor of overall survival. Overall survival was 16% for patients with pathologic N-positive disease compared with 67% for those whose lymph node status was negative or unknown (p = 0.001)., Conclusion: Surgery followed by postoperative radiation should be considered the standard of care for patients with carcinoma ex pleomorphic adenoma.

Carcinoma arising in pleomorphic adenoma is a rare entity. A case of mucoepidermoid carcinoma in pleomorphic adenoma occurring in the soft palate of a 40-year-old woman is reported. An intraoral excision of the tumor was performed. Histopathological examination revealed high-grade mucoepidermoid carcinoma proliferated in pleomorphic adenoma with free surgical margin. The patient received adjuvant neck radiotherapy. She remains free of disease 16 months post-treatment.

We present a case of a 67-year-old female patient having a pleomorphic adenoma of epipharynx with intact fibrous capsula, which despite its benignity recurred and, moreover, responded quite well to irradiation therapy. The patient, at first, refused any therapy. Three years later, when the CT showed tumor enlargement she accepted only irradiation therapy, resulting in significant reduction of tumor size. Five years later the tumor recurred but without malignant transformation. She still refused surgery, but accepted re-irradiation therapy. After a three-year follow-up the patient has no symptoms of the tumor enlargement. This case shows that the irradiation therapy might be quite effective in the treatment of pleomorphic adenoma of epipharynx, but it is clear that much better results could be accomplished in combination with the surgery. In cases when the surgery is rejected or not possible because of the vicinity of the vital structures, we recommend the irradiation therapy as a therapy of the choice.

The purpose of this article was to evaluate the role of radiotherapy (RT) in the treatment of pleomorphic adenoma. This is a retrospective analysis of 17 patients treated with RT alone (2 patients) or combined with surgery (15 patients). Follow up ranged from 1.8 to 27.1 years (median, 9.6 years). Local control was obtained in 8 of 10 patients (80%) with subclinical disease and 3 of 7 patients (43%) with gross disease. Overall local control was obtained in 11 of 17 patients (65%). The 5- and 10-year overall local control rates were 69% and 61%, respectively. One patient died secondary to tumor extension into the central nervous system, 1 patient had recurrence of carcinoma ex-pleomorphic adenoma and died of cancer at the primary site, 5 patients died free of disease, and 10 patients were alive at last follow up. RT is relatively effective at controlling subclinical disease in patients at high risk for developing recurrence after surgery for pleomorphic adenoma. Limited data suggest that RT may also occasionally control gross disease.

Objectives: The aim of this study is to review salivary tumors arising from heterotopic salivary inclusions in the periparotid and cervical lymph nodal tissues over a 25-year span., Methods: A retrospective chart review revealed 24 patients with asymptomatic neck masses treated between 1976 and 2001, whose pathology demonstrated heterotopic salivary tissue or neoplasms arising from heterotopic salivary tissue., Results: Nine cases were benign periparotid lymph nodes with heterotopic salivary inclusions, 3 of which had multimodal involvement. Fifteen cases of heterotopic salivary tumors were identified. The benign tumors were predominantly Warthin's tumor (8) with 1 pleomorphic adenoma. Malignant tumors included mucoepidermoid (3), acinic cell (2), and adenocarcinoma (1). Patients were treated by a superficial parotidectomy, neck dissection, or simple excision depending on site and preoperative workup. Adjuvant radiation therapy was included for high-grade malignancies. Among the 15 tumor patients, follow-up ranged from 1 month to 17 years. Nine patients are alive and disease-free, 5 are deceased, and 1 was lost to follow-up., Conclusions: Heterotopic salivary tissue in periparotid and upper cervical nodes is a more common occurrence than historically recognized. Tumorigenic changes arise from heterotopic nodal inclusions, and although infrequent, should be considered in the differential diagnosis for isolated neck/periparotid masses and parotid Warthin's tumor. Suggested management, after a thorough clinical exam/needle aspiration biopsy, includes an imaging survey of the parotid gland and neck lymphatics with an appropriate resection to include a simple excision, parotidectomy, neck dissection, and/or irradiation as indicated. Isolated low-grade malignant lesions/benign lesions are adequately managed by excision or parotidectomy alone. High-grade malignant lesions require more extended surgery with possible irradiation.

Extensive cytogenetic investigations of pleomorphic adenomas of the salivary glands have unequivocally demonstrated that they are cytogenetically monoclonal and are characterized by a high frequency of tumor specific chromosome abnormalities involving in particular chromosome bands 3p21, 8q12 and 12q14-15. Here we show that two radiation-associated and cytogenetically polyclonal adenomas without gross rearrangements of these breakpoints show simultaneous overexpression of the PLAG1 and HMGIC genes, i.e. the target genes of the 8q12 and 12q14-15 rearrangements in sporadic adenomas. In addition, one of the tumors expressed a cryptic CTNNB1-PLAG1 fusion transcript. Our findings strongly suggest that identical or very similar molecular mechanisms are operating during adenoma tumorigenesis irrespective of whether the tumors are cytogenetically polyclonal or whether they have non-random, tumor specific abnormalities. Cytogenetically polyclonal adenomas are thus most likely also of monoclonal origin.

Introduction: Pleomorphic adenoma is the most common neoplasm arising in the salivary glands. Surgical management is the primary therapeutic modality. With the use of modern surgical techniques, recurrence is infrequent, and facial nerve sparing is the norm. However, for patients with recurrent disease, the risk of further relapses is increased with surgical resection alone, particularly for those patients in whom multiple recurrences have already occurred. The role of adjuvant radiotherapy in this setting remains uncertain. Although neutron radiotherapy is superior to conventional radiotherapy for malignant salivary gland tumors, its role in the treatment of pleomorphic adenomas is less well defined. We report our experience using this modality for high-risk, recurrent pleomorphic adenomas., Methods: Sixteen patients were treated with neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands from 1986 through 1993. The median age at diagnosis was 33 years (range, 11-77 years); median age at the time of neutron radiotherapy was 52 years (range, 22-77 years); median number of prior surgical procedures was 3 (range, 1-6); median duration from initial diagnosis to radiotherapy was 14.5 years (range, 3 months-30 years); median follow-up was 83 months (range, 9-144 months). The median period at risk for survivors was 96 months (defined as the interval from completion of neutron radiotherapy to last follow-up). Ten patients had evidence of gross residual disease at the time of treatment as determined by imaging studies, with nine patients having multinodular disease., Results: The 10-year actuarial survival was 79%. One patient died from lung metastases 9 months after treatment; one patient died from a liver tumor of uncertain origin, but the histology could not rule out a metastasis from the previous pleomorphic adenoma; and one patient died from recurrent disease at the base of skull. The 15-year actuarial locoregional control rate was 85%. One of the two patients with locoregional recurrence had a malignant transformation into an adenocarcinoma. No statistical difference in 15-year actuarial survival (75% vs 83%, p =.82) was found comparing patients with gross residual disease vs microscopic residual disease. The actuarial 15-year locoregional control was 76% for patients with gross residual disease vs 100% for those with microscopic disease. The 15-year actuarial risk of RTOG/ESTRO nonaudiologic grade III/IV complications was 21%. No facial nerve injuries were observed as a direct consequence of neutron radiotherapy., Conclusions: Neutron radiotherapy offers both excellent local control rates and survival rates in patients with multiply recurrent pleomorphic adenomas that are not candidates for surgical resection, even in the presence of gross residual disease. The treatment-related morbidity is acceptable. Malignant transformations and metastases, although uncommon, may be observed in this tumor., (Copyright 2001 John Wiley & Sons, Inc.)

Background: Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive, poorly understood salivary gland malignancy. Misdiagnosis is common, because the residual mixed tumor component may be small, and various carcinoma subtypes are possible., Methods: We retrospectively reviewed the medical records of 73 patients with major salivary gland CXPA treated at our institution from 1960 to 1994. Of the 73 patients, 66 had primary tumors and 7 had recurrent tumors; 47 were men, and 26 were women; the mean age was 61 years., Results: Adenocarcinoma (31 cases) and salivary duct carcinoma (24 cases) were the most common malignant subtypes. All patients were treated surgically, and 32 also had radiation therapy. Of 66 patients with primary tumors, 23% had local recurrence. Metastasis (either initial or delayed) occurred regionally in 56% and distantly in 44%. Thirty-six patients (55%) died of the disease. At 3 years, overall survival was 39% and at 5 years, 30%., Conclusions: Important prognostic factors include tumor size, grade, and clinical and pathologic stage. Patients with minimally invasive tumors (<5 mm) should do well with appropriate surgical treatment., (Copyright 2001 John Wiley & Sons, Inc.)

Incomplete excision of a pleomorphic adenoma exposes to a high risk of recurrence and tumor spread, making secondary surgery more difficult or a malignant transformation with a poor vital prognosis likely. Three histological types of pleomorphic adenomas can be observed when the tumor undergoes a transformation, namely the carcinoma ex-pleomorphic adenoma, the true malignant mixed tumor and the benign metastasizing mixed tumour.

Background: It has been suggested that metastasizing pleomorphic adenomas may represent unrecognized malignancy., Methods: The cytologic and clinical characteristics of two metastasizing pleomorphic adenomas diagnosed by fine-needle sampling are reported., Results: Both showed malignant evolution: the primary tumors arose from the palate and the parotid salivary glands, respectively. Metastases occurred simultaneously with local recurrence in the first patient and after a second local recurrence in the second patient. Both patients were treated by surgery and radiotherapy but died of disseminated disease 8 and 4 years after initial diagnosis. No histologic evidence of malignancy was observed on cytology smears or histology sections in either case., Conclusion: Clinically, our cases support the hypothesis that metastasizing pleomorphic adenomas represent unrecognized malignancy, because the biologic course of two tumors led to unequivocally lethal outcome.

Between 1947 and 1992, 1403 patients with 1432 salivary gland tumours were treated at the Christie Hospital, Manchester. There were 1194 epithelial neoplasms: parotid, 1082 (91 per cent); submandibular, 47 (4 per cent); minor glands, 65 (5 per cent). The commonest histological diagnoses were pleomorphic adenoma (n = 776) and adenolymphoma (n = 159). A total of 244 carcinomas were seen (adenoid cystic carcinoma, n = 75). Treatment was primarily surgical, conservative where possible, and determined by tumour extent and not histology. Adjuvant radiation therapy was used in over half the definitively treated malignancies. The recurrence rate following the treatment of 551 new parotid pleomorphic adenomas was 1.6 per cent at median follow-up 12.5 (range 1-34) years, increasing to 15 per cent in the secondarily referred group (n = 170). For patients with definitively treated primary salivary carcinomas (n = 148), the disease-free survival rate at 5, 10 and 15 years was 58, 47 and 45 per cent respectively. Using multivariate analysis, clinical stage was the most important predictor of survival; the 10-year survival rate for stages I-IV was 96, 70, 47 and 19 per cent respectively.

Longterm results in 92 patients after primary or postoperative irradiation for carcinoma of the major or minor salivary glands of the head are analyzed. Target volume included the region of the primary tumor; ipsilateral cervical lymph nodes were included in patients with metastases of the lymph nodes. Target doses were 25 to 35 X 2.0 Gy or in some cases 16 to 18 X 3.30 Gy. Local control was 93% in tumors of limited extension (I), 84% in extensive but macroscopically complete resected tumors (II) and 26% in biopsied or partially resected tumors (III). There were no major complications. Recurrence in the lymph nodes were observed in less than 5% of the group I + II NO and could be controlled permanently by secondary surgery plus irradiation. According to the own and published results the following target volumes are adequate: region of the primary tumor in adenoid-cystic carcinoma NO plus the ipsilateral cervical-supraclavicular region in patients with other high grade cancers or evidence for metastases. Target doses between 5940 and 7020 cGy are recommended.

A series of mixed parotid tumours treated by simple enucleation and radiotherapy between 1962 and 1968 is discussed. There were 73 primary and 8 recurrent cases. Only 2 small recurrences occurred in the 73 primary cases, although 4 other patients were lost to follow-up after 7 years or more. In the 8 recurrent cases, 7 had been treated elsewhere by enucleation alone, thus confirming the opinion that this operation is frequently unsuccessful. Treatment was by further local excision and radiotherapy and no recurrences have occurred. The view is therefore expressed that simple enucleation and radiotherapy is the treatment of choice in all primary mixed parotid tumours.