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1.  Metachronous, Single Metastasis to the Parotid, from Primary Breast Cancer: A Case Report and Review of the Literature 
Background. The parotid gland is an unusual site for metastatic disease and when metastasis occurs, it commonly originates from head and neck primaries. Spread from distant infraclavicular sites such as the breast, into the parotid, is even more unusual with very few cases reported in the literature. Case Report. We describe the case of a 65-year-old woman presenting for a rapidly enlarging right parotid mass. She had a history of an invasive ductal carcinoma of the right breast and was disease-free in the past 6 years prior to her presentation. She was thereafter diagnosed as having a solitary parotid metastasis from breast origin. A total parotidectomy was done and she was referred for adjuvant radiotherapy. Conclusion. Any parotid metastasis should be investigated, especially in patients with a prior history of cancer where the possibility of metastasis, even if improbable, should be kept in mind. Fine needle aspiration biopsy (FNAB) is the first diagnostic procedure to be done and immunocytochemistry can provide valuable information even if it is not always needed for diagnosis. Superficial parotidectomy when feasible with adjuvant radiotherapy is the preferred approach for solitary metastasis of the parotid. The prognosis, however, remains poor regardless of the treatment modality used.
doi:10.1155/2016/3965283
PMCID: PMC4749787  PMID: 26942028
2.  Salivary duct carcinoma of the parotid gland 
Salivary duct carcinoma of the parotid gland is an uncommon tumor, highly aggressive. About 200 cases have been reported in the English literature. Pathomorphologically, these tumors showed great similarities to ductal carcinoma of the female breast, which is why they described this tumor as “salivary duct carcinoma.” The authors describe a new case of salivary duct carcinoma of the parotid gland. We present the case of a 50-year-old patient with progressive facial paralysis. The MRI examination of the head showed two ill-defined formations. A malignant tumor was strongly suspected, so that a total left parotidectomy with excision of the adjacent facial nerve and left lymph node dissection was performed. Microscopic examination concluded to a salivary duct carcinoma of the left parotid gland negative with Her2/neu antibody with lymph node metastasis. There were no recurrences or metastases within 3 years of follow-up. Salivary duct carcinoma of the parotid gland is a rare tumor with an aggressive behavior. This is due to its propensity to infiltrate distant organs. The diagnosis is based on microscopic examination. Treatment modalities are non-consensual, but some authors advocate the necessity of aggressive approach, especially in tumors negative with Heur2/neu antibody. This is due to the fact that the overexpression of this antigen was reported to be associated with a poor prognosis.
doi:10.4103/0973-029X.92992
PMCID: PMC3303509  PMID: 22434951
Parotid gland; salivary duct carcinoma; treatment
3.  Metastatic hepatocellular carcinoma to the parotid gland: Case report and review of the literature 
INTRODUCTION
Hepatocellular carcinoma, the most frequent primary hepatic tumor, metastasizes in more than 50% of cases. However, parotid gland metastatic HCCs are very uncommon. We report a patient in whom the finding of a left parotid mass revealed metastatic HCC.
PRESENTATION OF CASE
A thirty-six-year-old male presented with a round palpable left neck mass that persisted for 3 months. He had received right hemihepatectomy for hepatocellular carcinoma (HCC). Preoperative evaluation revealed a benign tumor of the parotid gland. We performed superficial parotidectomy. Metastatic hepatocellular carcinoma of the parotid gland was diagnosed.
DISCUSSION
Although HCC metastases to the oral cavity have been reported, to date, only 4 cases HCC metastasis to the parotid gland have been reported. Although clinicians and cytopathologists alike both agree that salivary gland fine needle aspiration biopies (FNABs) are highly useful and safe diagnostic alternatives to biopsies and resections, we believe that in specific clinical situations, awareness of potential diagnostic pitfalls in salivary gland FNAB is a necessary part of the microscopic interpretations of these lesions.
CONCLUSION
Although rare, since HCC can metastasize to the parotid gland, high suspicion should be maintained in a patient presenting with a parotid mass with a history of HCC. In addition, since potential diagnostic pitfalls in salivary gland fine-needle aspiration (FNA) biopsies exist, incisional or excisional biopsy may be necessary for definite diagnosis of metastatic HCC to the parotid gland.
doi:10.1016/j.ijscr.2012.08.018
PMCID: PMC3537927  PMID: 23123420
HCC, hepatocellular carcinoma; FNA, fine-needle aspiration; Metastatic hepatocellular carcinoma; Parotid gland; Fine-needle aspiration
4.  Clinical Outcome of Parotidectomy with Reconstruction: Experience of a Regional Head and Neck Cancer Unit 
Background:
Salivary gland pathologies represent a histologically diverse group of benign and malignant neoplasms. Currently, World Health Organization recognizes 13 benign and 24 malignant variants of all salivary gland neoplasms. Surgery continues to remain the main-stay for treatment of parotid gland neoplasms. The aim of this study was to document our experiences of the patients treated for parotid tumors and find out if any compelling variable predicted the relative clinical outcomes.
Materials and Methods:
This was a retrospective study, from records of parotidectomies performed at the operating theatre by the head and neck cancer division of the study institution between 2010 and 2013. Eligibility for study inclusion included cases with benign or malignant parotid neoplasms requiring surgical management with or without adjunct radiotherapy. The predictors of postoperative complications, overall survival (OS), and disease-free survival (DFS) were analyzed.
Results:
A total of 20 patients underwent parotidectomy. The mean age was 42 years. Tumors were located on the left parotid in 13 cases (65%) and the right parotid in 7 cases (35%). The surgical procedures comprised 16 superficial parotidectomies, 1 total parotidectomy, and 3 radical parotidectomy (inclusive of facial nerve sacrifice) and 2 neck dissections levels II–V. The reconstructive procedures were 2 facial nerve branch cable grafts, 1 end-to-end facial-facial nerve branch anastomoses, and 2 facial re-animation surgeries (temporalis muscle suspensions). A total of five cases (33.3%) had postoperative complications. 2 variables (length of surgery and neck dissection) were found to have an impact on postoperative complications that were statistically significant. Additionally, length of surgery was a significant predictor on the 2 years OS and DFS.
Conclusion:
The result of this study showed good clinical outcome, especially in the benign cases. The comprehensive clinical outcome of the malignant cases could not be objectively assessed, as the OS and DFS were 50% at 2-years follow-up. It is our submission that a larger sample size is utilized in subsequent studies and quality of life evaluation is included in the methodology.
doi:10.4103/1117-6806.176396
PMCID: PMC4785688  PMID: 27013855
Facial re-animation; neural anastomosis; parotidectomy
5.  Renal Cell Carcinoma Metastasis to Ipsilateral Parotid and Submandibular Glands: Report of a Case with Sonoelastographic Findings 
Summary
Background
Renal cell carcinoma (RCC) – also known as hypernephroma or grawitz tumor – accounts for 3% of the adulthood malignancies. Approximately 30–40% of the patients have metastasis at the time of the diagnosis and most common sites for metastasis are lung, regional lymph nodes, bone and liver. A total of 8–14% of the patients with RCC has head and neck metastasis. However, metastasis to major salivary glands is rarely seen. In this paper, we aimed to report a RCC case with metastasis to parotid and submandibular glands that has the same sonographic and sonoelastographic findings with the primary tumor.
Case Report
66-year old woman with RCC history was referred to our radiology department for neck ultrasound (US) with painful swelling in the right parotid gland region. A well-defined, 37×21 mm sized hypoechoic heterogeneous solid mass was detected in the superficial-deep lobe of the right parotid gland. The mass was prominently hypervascular in color Doppler ultrasonography scan. Coincidentally, a 13×13 mm hypoechoic lobulated solid mass was detected in the right submandibular gland with similar sonographic findings.
Real-time sonoelastography (SEL) was performed to the masses and both of them were blue-green colored that indicates hard tissue. An US and SEL evaluation was also performed to the renal mass (RCC) of the patient. The primary mass was also similar in sonographic and SEL appearance as salivary gland masses. In the patient history, she revealed chemotherapy-radiotherapy treatment 1.5 years ago due to inoperable mass in the mid-lower pole of the left kidney diagnosed as clear cell RCC with vascular invasion, liver, lung and brain metastasis. Because of known primary tumor, the masses in the salivary glands were suspected to be metastatic and a tru-cut biopsy was performed. Pathological result was reported as clear cell RCC metastasis.
Conclusions
The etiology of RCC is still unknown and metastatic involvement can be seen at unexpected tissue and organs. Metastatic disease should be considered when a salivary gland mass detected in patients with RCC history. SEL examination would be helpful in differentiation of the origin of the metastatic lesion with known SEL features.
doi:10.12659/PJR.895430
PMCID: PMC4721875  PMID: 26834866
Carcinoma, Renal Cell; Elasticity Imaging Techniques; Neoplasm Metastasis; Salivary Glands
6.  Solitary Fibrous Tumor of the Parotid Gland: A Case Report 
Introduction:
Solitary fibrous tumor is a rare, mesenchymal neoplasm that has been reported in numerous sites. Occurrence in the parotid gland is exceedingly rare.
Case Report:
A 53-year-old man with a 2 cm solitary fibrous tumor of the left parotid gland, that was observed clinically and operatively and thought to be a neoplasm arising from Stensen's duct, is described. A pre-operative CT scan demonstrated a well-circumscribed, solid, avidly-enhancing nodule superficial to the masseter muscle, deep to the platysma, and intimately associated with the parotid duct. Multiple fine needle aspirations yielded scant fibrous tissue and lymphocytes. A superficial parotidectomy was performed. The histopathological and immunohistochemical findings were in keeping with solitary fibrous tumor, fibrous variant, with a low mitotic rate and a peripherally-entrapped parotid duct surrounded by abundant periductal collagen and lymphocytes. At a 2-year follow up, there was no evidence of tumor recurrence or metastasis.
Conclusion:
Solitary fibrous tumor should be suspected in the context of a slow-growing, well-circumscribed, solid, avidly-enhancing nodule of the parotid gland. Grossly intimate association with the parotid duct may reflect peripheral entrapment. Fine needle aspirations that predominantly yield collagen without spindle cell clusters should be correlated with clinical and radiological findings, as it is expected in tumor sampling of the fibrous variant. Although solitary fibrous tumor of the parotid gland usually exhibits benign behavior, it is best regarded as potentially malignant. Patient management and follow-up should be tailored to each individual and clinicopathological risk assessment of the recurrent/metastatic potential.
PMCID: PMC4639695  PMID: 26568946
Parotid gland; Parotid diseases; Solitary fibrous tumors
7.  Postoperative Radiation Therapy for Parotid Mucoepidermoid Carcinoma 
Salivary gland cancers are rare and represent approximately 5% of all head and neck cancers and only 0.3% of all malignancies. The majority (75%) of salivary gland tumors occur in the parotid gland, and while benign lesions are more common, mucoepidermoid carcinoma (MEC) makes up 40–50% of malignant parotid gland tumors. No randomized controlled trials exist regarding the role of adjuvant radiation for patients who undergo surgical resection of low-grade MECs. Herein, we report two cases of successful postoperative radiation therapy in low-grade, pT2N0 MEC of the parotid gland. The role of adjuvant radiation therapy for patients with MEC of the parotid gland is based on data from institution reviews and lacks data from randomized controlled trials. Per our review of the literature, the pathological findings of positive surgical margins and/or perineural invasion in two patients with low-grade MEC of the parotid gland warranted adjuvant radiation for improved local control after partial parotidectomy. Both patients tolerated postoperative radiation therapy with only mild side effects and, at last follow-up, five years after completion of therapy, had no clinical or radiographic evidence of either local recurrence or distant metastasis.
doi:10.1155/2014/345128
PMCID: PMC4279126  PMID: 25580323
8.  Metastatic Hepatocellular Carcinoma to Parotid Glands 
Patient: Male, 66
Final Diagnosis: Hepatocellular carcinoma
Symptoms: Abdominal distension • painful right facial swelling • weight loss
Medication: —
Clinical Procedure: —
Specialty: —
Objective:
Rare disease
Background:
Hepatocellular carcinoma is a common cancer, but it rarely metastasizes to the salivary glands. A review of the literature revealed only 5 reported cases of hepatocellular carcinoma metastatic to parotid glands. We here report an additional case of this rare association.
Case Report:
A 66-year-old male with a background of type 2 diabetes mellitus and post-alcoholic decompensated liver cirrhosis presented with a progressively enlarging painful right facial swelling for 2 months that was eventually found to be due to hepatocellular carcinoma metastatic to the right parotid gland. Fine needle aspiration from the right parotid showed sheets and single malignant cells that were interpreted as carcinoma not otherwise specific. However, biopsy showed metastatic hepatocellular carcinoma into the right parotid gland.
Conclusions:
We report an additional case of the rare metastasis of hepatocellular carcinoma to the parotid glands. It should therefore be considered in a patient with decompensated liver cirrhosis presenting with a parotid swelling. Furthermore, the present case demonstrates the importance of the tissue biopsy for obtaining an accurate final diagnosis.
doi:10.12659/AJCR.890661
PMCID: PMC4144943  PMID: 25129420
Carcinoma, Hepatocellular; Gastrointestinal Neoplasms; Neoplasm Metastasis; Neoplasm Metastasis; Parotid Gland
9.  Primary parotid gland lymphoma: a case report 
Introduction
Mucosa associated lymphoid tissue lymphomas are the most common lymphomas of the salivary glands. The benign lymphoepithelial lesion is also a lymphoproliferative disease that develops in the parotid gland. In the present case report, we describe one case of benign lymphoepithelial lesion with a subsequent low transformation to grade mucosa associated lymphoid tissue lymphoma appearing as a cystic mass in the parotid gland.
Case presentation
A 78-year-old Caucasian female smoker was referred to our clinic with a non-tender left facial swelling that had been present for approximately three years. The patient underwent resection of the left parotid gland with preservation of the left facial nerve through a preauricular incision. The pathology report was consistent with a low-grade marginal-zone B-cell non-Hodgkin lymphoma (mucosa associated lymphoid tissue lymphoma) following benign lymphoepithelial lesion of the gland.
Conclusions
Salivary gland mucosa associated lymphoid tissue lymphoma should be considered in the differential diagnosis of cystic or bilateral salivary gland lesions. Parotidectomy is recommended in order to treat the tumor and to ensure histological diagnosis for further follow-up planning. Radiotherapy and chemotherapy should be considered in association with surgery in disseminated forms or after removal.
doi:10.1186/1752-1947-5-380
PMCID: PMC3170354  PMID: 21843311
10.  Temporal Evolution of Parotid Volume and Parotid Apparent Diffusion Coefficient in Nasopharyngeal Carcinoma Patients Treated by Intensity-Modulated Radiotherapy Investigated by Magnetic Resonance Imaging: A Pilot Study 
PLoS ONE  2015;10(8):e0137073.
Purpose
To concurrently quantify the radiation-induced changes and temporal evolutions of parotid volume and parotid apparent diffusion coefficient (ADC) in nasopharyngeal carcinoma (NPC) patients treated by intensity-modulated radiotherapy by using magnetic resonance imaging (MRI).
Materials and Methods
A total of 11 NPC patients (9 men and 2 women; 48.7 ± 11.7 years, 22 parotid glands) were enrolled. Radiation dose, parotid sparing volume, severity of xerostomia, and radiation-to-MR interval (RMI) was recorded. MRI studies were acquired four times, including one before and three after radiotherapy. The parotid volume and the parotid ADC were measured. Statistical analysis was performed using SPSS and MedCalc. Bonferroni correction was applied for multiple comparisons. A P value less than 0.05 was considered as statistically significant.
Results
The parotid volume was 26.2 ± 8.0 cm3 before radiotherapy. The parotid ADC was 0.8 ± 0.15 × 10−3 mm2/sec before radiotherapy. The parotid glands received a radiation dose of 28.7 ± 4.1 Gy and a PSV of 44.1 ± 12.6%. The parotid volume was significantly smaller at MR stage 1 and stage 2 as compared to pre-RT stage (P < .005). The volume reduction ratio was 31.2 ± 13.0%, 26.1 ± 13.5%, and 17.1 ± 16.6% at stage 1, 2, and 3, respectively. The parotid ADC was significantly higher at all post-RT stages as compared to pre-RT stage reciprocally (P < .005 at stage 1 and 2, P < .05 at stage 3). The ADC increase ratio was 35.7 ± 17.4%, 27.0 ± 12.8%, and 20.2 ± 16.6% at stage 1, 2, and 3, respectively. The parotid ADC was negatively correlated to the parotid volume (R = -0.509; P < .001). The parotid ADC was positively associated with the radiation dose significantly (R2 = 0.212; P = .0001) and was negatively associated with RMI significantly (R2 = 0.203; P = .00096) significantly. Multiple regression analysis further showed that the post-RT parotid ADC was related to the radiation dose and RMI significantly (R2 = 0.3580; P < .0001). At MR stage 3, the parotid volume was negatively associated with the dry mouth grade significantly (R2 = 0.473; P < .0001), while the parotid ADC was positively associated with the dry mouth grade significantly (R2 = 0.288; P = .015).
Conclusion
Our pilot study successfully demonstrates the concurrent changes and temporal evolution of parotid volume and parotid ADC quantitatively in NPC patients treated by IMRT. Our results suggest that the reduction of parotid volume and increase of parotid ADC are dominated by the effect of acinar loss rather than edema at early to intermediate phases and the following recovery of parotid volume and ADC toward the baseline values might reflect the acinar regeneration of parotid glands.
doi:10.1371/journal.pone.0137073
PMCID: PMC4556378  PMID: 26323091
11.  DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer 
PLoS Medicine  2009;6(5):e1000068.
Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker.
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.
Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.
Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
Editors' Summary
Background
Each year, more than one million women discover that they have breast cancer. This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy. These “adjuvant” therapies are designed to kill any remaining cancer cells but can make patients very ill. Generally speaking, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Although breast cancer is usually diagnosed in women in their 50s or 60s, some women develop breast cancer much earlier. In these women, the disease is often very aggressive. Compared to older women, young women with breast cancer have a lower overall survival rate and their cancer is more likely to recur locally or to metastasize. It would be useful to be able to recognize those younger women at the greatest risk of cancer recurrence so that they could be offered intensive surveillance and adjuvant therapy; those women at a lower risk could have gentler treatments. To achieve this type of “stratification,” the genetic changes that underlie breast cancer in young women need to be identified. In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease.
What Did the Researchers Do and Find?
The researchers used “suppression subtractive hybridization” to identify a new gene in a region of human Chromosome 1 where loss of heterozygosity (LOH; a genetic alteration associated with cancer development) frequently occurs. They called the gene DEAR1 (ductal epithelium-associated RING Chromosome 1) to indicate that it is expressed in ductal and glandular epithelial cells and encodes a “RING finger” protein (specifically, a subtype called a TRIM protein; RING finger proteins such as BRCA1 and BRCA2 have been implicated in early cancer development and in a large fraction of inherited breast cancers). DEAR1 expression was reduced or lost in several ductal carcinomas in situ (a local abnormality that can develop into breast cancer) and advanced breast cancers, the researchers report. Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes). To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1. They then examined the growth of these genetically manipulated cells in special three-dimensional cultures. The breast cancer cells without DEAR1 grew rapidly without an organized structure while the breast cancer cells containing the introduced copy of DEAR1 formed structures that resembled normal breast acini (sac-like structures that secrete milk). In normal human mammary epithelial cells, the researchers silenced DEAR1 expression and also showed that without DEAR1, the normal mammary cells lost their ability to form proper acini. Finally, the researchers report that DEAR1 expression (detected “immunohistochemically”) was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome.
What Do These Findings Mean?
These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer. Although laboratory experiments may not necessarily reflect what happens in people, the results from the three-dimensional culture of breast epithelial cells suggest that DEAR1 may regulate the normal acinar structure of the breast. Consequently, loss of DEAR1 expression could be an early event in breast cancer development. Most importantly, the correlation between DEAR1 expression and both local recurrence in early-onset breast cancer and a breast cancer subtype with a poor outcome suggests that it might be possible to use DEAR1 expression to identify women with early-onset breast cancer who have an increased risk of local recurrence so that they get the most appropriate treatment for their cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000068.
This study is further discussed in a PLoS Medicine Perspective by Senthil Muthuswamy
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on genetic alterations in breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; MedlinePlus also provides links to many other breast cancer resources (in English and Spanish)
The UK charities Cancerbackup (now merged with MacMillan Cancer Support) and Cancer Research UK also provide detailed information about breast cancer
doi:10.1371/journal.pmed.1000068
PMCID: PMC2673042  PMID: 19536326
12.  Parotid gland metastasis of lung cancer: a case report 
Background
Parotid gland metastasis in lung cancer is extremely rare, very few cases have been reported.
Case presentation
We report on the case of a 61-year-old Chinese male patient who presented with parotid swelling metastasizing from advanced lung cancer. We therefore performed an operation of partial parotidectomy with preservation of the facial nerve and advised the patient receive chemotherapy, however, the patient died four months later.
Conclusion
Although it is extremely rare, a potential metastasis of lung cancer should not be ignored in the diagnosis of parotid tumor. Preoperative routine examination, such as a chest X-ray and lung computational tomography scan, may play an important role in differential diagnosis. The management of the metastatic tumor to the parotid gland was controversial however, despite combined treatment modalities, long-term survival was not attained.
doi:10.1186/1477-7819-12-119
PMCID: PMC4004509  PMID: 24758587
Parotid gland tumor; Small cell cancer; Lung cancer; Metastasis
13.  Mammary analog secretory carcinoma of the parotid gland: A case report and literature review. 
Highlights
•Mammary analog secretory carcinoma (MASC) is a newly described carcinoma of the salivary glands.•MASC is characterized by morphologic and immunohistochemical features that strongly resemble a secretory carcinoma (SC) of the breast.•MASC and SC of the breast share the presence of translocation t(12;15) (p13;q25), that results in the formation of an oncogenic fusion gene ETV6-NTK3.•The majority of MASC present among men and arise from the parotid gland.•MASC is a low-grade carcinoma with potential for high-grade transformation.
Background
Mammary analog secretory carcinoma (MASC) was first described in 2010 by Skálová et al. This entity shares morphologic and immunohistochemical features with the secretory carcinoma (SC) of the breast. MASC usually presents as an asymptomatic mass in the parotid gland and predominantly affects men. This tumor is considered a low-grade carcinoma but has the potential for high-grade transformation. We report one MASC case and a review of world literature.
Case report
A 66-year-old male patient presented because he noticed a mass of approximately 3 × 3 cm on the right pre-auricular region. Physical examination demonstrated a 3 × 3.5 cm, firm, fixed, non-tender mass in the right pre-auricular region. An MRI of the head and neck showed an ovoid heterogeneous lesion, dependent of the right parotid gland of 27 × 28 mm. We performed a superficial parotidectomy with identification and preservation of the facial nerve. The immunophenotype was positive for epithelial membrane antigen (EMA), CK8/18, vimentin, S-100 protein, and mammoglobin. No further surgical interventions or adjuvant therapies were needed. The patient will have a close follow up.
Conclusion
The presence of t(12;15) (p13;q25) translocation which results in the ETV6-NTRK3 gene fusion or positive immunochemical studies for STAT5, mammoglobin and S100 protein, are necessary to confirm the diagnosis of MASC. MASC treatment should mimic the management of other low-grade malignant salivary gland neoplasms. The inhibition of ETV6-NTRK3 gene fusion could be used as treatment in the future.
doi:10.1016/j.ijscr.2015.09.031
PMCID: PMC4643465  PMID: 26496413
14.  Bilateral synchronous breast carcinomas followed by a metastasis to the gallbladder: a case report 
Background
Breast cancer is usually associated with metastases to lungs, bones and liver. Breast carcinoma metastasizing to the gallbladder is very rare.
Case presentation
A 59-year-old woman presented with bilateral synchronous breast lesions. A palpable, retroareolar solid lesion of diameter equal to 5 cm was present in the right breast, and a newly developed, non-palpable lesion with microcalcifications (diameter equal to 0.7 cm) was present in the upper outer quadrant of the left breast. Modified radical mastectomy was performed on the right breast and lumpectomy after hook-wire localization was performed on the left breast, combined with lymph node dissection in both sides. The pathological examination revealed invasive lobular carcinoma grade II in the right breast and invasive ductal carcinoma grade I in the left breast. Chemotherapy, radiation therapy, trastuzumab and letrozole were appropriately administered. At her 18-month follow-up, the patient was free of symptoms; the imaging tests (chest CT, abdominal U/S, bone scan), biochemical tests, blood cell count and tumor markers were also normal. At the 20th month after surgery however, the patient developed symptoms of cholecystitis and underwent cholecystectomy. The histopathological examination revealed metastasis of the lobular carcinoma to the gallbladder.
Conclusion
This extremely rare case confirms on a single patient the results of large series having demonstrated the preferential metastasis of lobular breast cancer to the gallbladder. Symptoms of cholecystitis should not be neglected in such patients, as they might indicate metastasis to the gallbladder.
doi:10.1186/1477-7819-5-101
PMCID: PMC2075501  PMID: 17848197
15.  Extended parotidectomy 
Summary
Malignant tumours of the parotid gland represent a group of relatively rare lesions. The medical records of 363 patients with parotid swelling treated between 1974 and 2003 at the “G. Ferreri” Department of Otorhinolaryngology, “La Sapienza” University in Rome were retrospectively analysed. Clinical presentation, pre-operative investigations, surgical procedure, histopathology report, post-operative complications, and the oncological results of 19 patients who underwent extended radical parotidectomy for malignant neoplasm of the parotid gland are discussed. Extended radical parotidectomy, reserved for neoplasms in an advanced stage, involves the removal of the entire parotid gland, with sacrifice of the facial nerve and the resection en bloc of the adjacent structures affected by neoplastic infiltration, such as the temporal bone, the mandibular bone, the skin, blood vessels and nerves. In addition to this surgical treatment, a cycle of adjuvant radiotherapy is also necessary. The overall rate of survival at 10 years depends mainly on the histological characteristics of the tumour, and, in this series, is reported to be approximately 58%. These data indicate that total extended radical parotidectomy combined with post-operative radiotherapy, represents the best therapeutic approach with regard both to quality of life and life expectancy, in patients with an advanced stage of malignant neoplasm of the parotid gland.
PMCID: PMC2639865  PMID: 16450772
Parotid gland; Malignant tumours; Treatment; Extended parotidectomy
16.  Renal clear cell carcinoma with thyroid and parotid metastases: A case report 
Oncology Letters  2015;10(4):2617-2619.
The present study reports a rare case of a renal clear cell carcinoma with thyroid and parotid metastases. A 56-year-old female, with a painless, right preauricular mass present for 6 months was referred to Renji Hospital (Shanghai, China). Physical examination revealed a mass of 3×3 cm, which was smooth, firm, immobile and non-tender. There was no accompanying facial weakness. Parotid ultrasonography revealed a hypoechoic mass within the right parotid gland, which was potentially a parotid mixed tumor. In July 2011, the patient underwent a superficial parotidectomy with preservation of the facial nerve. Pathology confirmed as right parotid clear cell carcinoma (metastasis). The patient's relevant medical history included a right radical nephrectomy for renal clear cell carcinoma (clinical stage III) in 2004. Additionally, in 2009, the patient underwent a resection of thyroid metastatic renal cell carcinoma. To the best of our knowledge, no similar case has previously been reported in English-language literature. The present study discusses a case report, and investigates the clinical features and treatment strategy.
doi:10.3892/ol.2015.3549
PMCID: PMC4579970  PMID: 26622899
renal clear cell carcinoma; thyroid metastasis; parotid metastasis
17.  Asporin Is a Fibroblast-Derived TGF-β1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer 
PLoS Medicine  2015;12(9):e1001871.
Background
Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving force behind metastatic breast cancer, with promising therapeutic implications.
Methods and Findings
Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78–0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37–0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort.
Conclusions
Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
Andrei Turtoi and colleagues describe a mechanistic role for stroma-derived asporin in breast cancer development.
Editors' Summary
Background
Breast cancer is the most common cancer in women worldwide. Nearly 1.7 million new cases were diagnosed in 2012, and half a million women died from the disease. Breast cancer begins when cells in the breast that normally make milk (epithelial cells) acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). Uncontrolled cell division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). After surgery, women often receive chemotherapy or radiotherapy to kill any remaining cancer cells, and women whose tumors express receptors for the female sex hormones estrogen and progesterone or for HER2, a growth factor receptor, are treated with drugs that block these receptors; estrogen, progesterone, and HER2 all control breast cell growth. Nowadays, the prognosis (outlook) for women living in high-income countries who develop breast cancer is generally good—nearly 90% of such women are still alive five years after diagnosis.
Why Was This Study Done?
The cells surrounding cancer cells—cancer-associated fibroblasts and other components of the stroma—support cancer growth and metastasis and are good targets for new cancer therapies. But, although there is mounting evidence that cancer cells actively adapt the stroma so that it produces various factors the tumor needs to grow and spread, very few molecules produced by the stroma that might serve as targets for drug development have been identified. Here, the researchers investigate whether a molecule called asporin might represent one such target. Asporin, which is highly expressed in the stroma of breast tumors, inhibits a growth factor called TGF-β1. TGF-β1 is involved in maintaining healthy joints, but is also a key molecule in the development of metastatic breast cancer. Most particularly, it modulates an important step in metastasis called the epithelial to mesenchymal transition and it regulates “stemness” in cancer cells. Stem cells are a special type of cell that can multiply indefinitely; tumor cells often look and behave very much like stem cells.
What Did the Researchers Do and Find?
Using a technique called immunohistochemistry, the researchers first showed that asporin is highly expressed in the stroma of most human breast cancers but not in normal breast tissue. Next, they showed that breast fibroblasts secrete asporin when exposed to conditioned medium from some human breast cancer cell lines (breast cancer cells adapted to grow continuously in the laboratory; conditioned medium is the solution in which cells have been grown). Specifically, conditioned medium from hormone receptor positive cells induced strong asporin expression by breast fibroblasts, whereas medium from breast cancer cells not expressing estrogen or progesterone receptors or HER2 receptors (triple-negative breast cancer cells) suppressed asporin expression. Other experiments showed that TGF-β1 secreted by breast cancer cells induces asporin expression in breast fibroblasts, and that asporin, in turn, inhibits TGF-β1-mediated induction of the epithelial to mesenchymal transition and stemness in breast cancer cells. Triple negative breast cancers appear to inhibit stromal expression of asporin at least in part via expression of the soluble signaling protein interleukin-1β. Notably, in mouse models of triple-negative breast cancer, tumors engineered to express asporin grew slower and metastasized less than tumors not expressing asporin. Finally, among women with breast cancer, asporin expression was low in triple-negative and HER2-positive tumors but significantly higher in hormone receptor positive tumors, and low asporin levels in primary breast lesions were associated with a reduced likelihood of survival independent of hormone receptor and HER2 expression.
What Do These Findings Mean?
These findings suggest that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. Importantly, they also provide preliminary evidence that high asporin expression is associated with less aggressive tumors (hormone receptor positive tumors), whereas low asporin expression is associated with more aggressive tumors (triple negative tumors and HER2-positive tumors). Thus, asporin expression might provide a new prognostic marker for breast cancer. However, before asporin can be used as a biomarker to predict outcomes in women with breast cancer and to identify those women in need of more aggressive treatment, these findings need to be confirmed in large prospective clinical studies. If these findings are confirmed, methods for increasing asporin expression in the stromal tissues of triple negative breast cancer could be a promising strategy for targeted therapy for this group of breast cancers, which currently have a poor prognosis.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001871.
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer and an online booklet for patients
Cancer Research UK, a not-for-profit organization, provides information about cancer; its detailed information about breast cancer includes sections on tests for hormone receptors and HER2, on treatments that target hormone receptors and treatments that target HER2, and on triple negative breast cancer
Breastcancer.org is a not-for-profit organization that provides up-to-date information about breast cancer (in English and Spanish), including information on hormone receptor status, HER2 status, and triple negative breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for-profit organization Healthtalk.org also provides personal stories about dealing with breast cancer
doi:10.1371/journal.pmed.1001871
PMCID: PMC4556693  PMID: 26327350
18.  Case report: anti-hormonal therapy in the treatment of ductal carcinoma of the parotid gland 
BMC Cancer  2014;14:701.
Background
Ductal carcinomas of the parotid gland are rare, highly aggressive, have a poor prognosis and are histologically similar to Ductal Breast Cancer. We report what we believe to be the first case in literature of metastatic salivary duct carcinoma (SDC) of the parotid gland with objective response to tamoxifen and aromatase inhibitors, achieving a long-term stability of disease with no associated toxicity.
Case presentation
A 70-year-old female was referred to our institution for treatment of a painless nodular lesion in the scalp, localized in the frontal region of the cranium. A biopsy was taken and tested positive for metastatic ductal carcinoma. On PET CT hypermetabolic nodules were localized in the left parotid gland (11 mm), right parotid gland (10 and 12 mm), submandibular node (11 mm) and left cervical node (10 mm). A salivary ductal carcinoma was considered to be the primary tumor. The patient was subsequently started on tamoxifen, with a complete response from the scalp nodule and left parotid nodule, while the right parotid nodule demonstrated a partial response that maintained stable for 2 years until progression. Anastrazol was chosen as the next line of treatment, achieving 6 more months of stable disease. As a pseudo-adjuvant treatment, surgical resection of the right parotid lesion was performed and helped achieve two years of disease stability.
Conclusions
Estrogen receptor antagonists such as tamoxifen or aromatase inhibitors may represent a target for the establishment of a safe alternative and novel therapy for SDC, however more accurate data obtained from larger studies are required.
doi:10.1186/1471-2407-14-701
PMCID: PMC4190344  PMID: 25249211
Tamoxifen; Salivary gland; Ductal carcinoma; Estrogen receptor antagonist
19.  Carcinoma ex pleomorphic adenoma: Diagnostic dilemma and treatment protocol 
Indian Journal of Dentistry  2014;5(3):157-160.
Carcinoma ex pleomorphic adenoma (CXPA) is a carcinoma arising from a primary or recurrent benign pleomorphic adenoma. It often poses a diagnostic challenge to clinicians and pathologists. The entity is difficult to diagnose preoperatively. Pathological assessment is the gold standard for making the diagnosis. Treatment for CXPA often involves an ablative surgical procedure, which may be followed by radiotherapy. We report a case of a 65-year-old lady with a history of recurrent swelling in the left preauricular region and a history of surgery 10 years back, in the same region. Preoperatively, a diagnosis of pleomorphic adenoma of the parotid gland metastasizing to the cervical lymph node was made, but postoperatively it was reported as CXPA adenoma of the parotid gland. A radical parotidectomy involving en bloc resection of the facial nerve along with deep and superficial lobes of the parotid was performed followed by radiotherapy. The fact that pleomorphic adenomas are classified as benign tumors should not overshadow the wide range of biological behaviors associated with these tumors. On account of the potential for malignant transformation, surgical treatment must be properly performed. Surgery followed by radiotherapy should be considered as the standard care for a patient with carcinoma ex pleomorphic adenoma.
doi:10.4103/0975-962X.140840
PMCID: PMC4213878  PMID: 25565746
Carcinoma ex pleomorphic adenoma; parotidectomy; parotid carcinoma
20.  Multi-atlas-based Segmentation of the Parotid Glands of MR Images in Patients Following Head-and-neck Cancer Radiotherapy 
Xerostomia (dry mouth), resulting from radiation damage to the parotid glands, is one of the most common and distressing side effects of head-and-neck cancer radiotherapy. Recent MRI studies have demonstrated that the volume reduction of parotid glands is an important indicator for radiation damage and xerostomia. In the clinic, parotid-volume evaluation is exclusively based on physicians’ manual contours. However, manual contouring is time-consuming and prone to inter-observer and intra-observer variability. Here, we report a fully automated multi-atlas-based registration method for parotid-gland delineation in 3D head-and-neck MR images. The multi-atlas segmentation utilizes a hybrid deformable image registration to map the target subject to multiple patients’ images, applies the transformation to the corresponding segmented parotid glands, and subsequently uses the multiple patient-specific pairs (head-and-neck MR image and transformed parotid-gland mask) to train support vector machine (SVM) to reach consensus to segment the parotid gland of the target subject. This segmentation algorithm was tested with head-and-neck MRIs of 5 patients following radiotherapy for the nasopharyngeal cancer. The average parotid-gland volume overlapped 85% between the automatic segmentations and the physicians’ manual contours. In conclusion, we have demonstrated the feasibility of an automatic multi-atlas based segmentation algorithm to segment parotid glands in head-and-neck MR images.
doi:10.1117/12.2007783
PMCID: PMC4405673  PMID: 25914491
Image registration; support vector machine; segmentation; MRI; parotid gland; head-and-neck cancer; radiation toxicity; xerostomia
21.  Synchronous Bilateral Warthin Tumors: A Case Report 
Introduction Warthin tumor is described as papillary cystadenoma lymphomatosum and is the second most common tumor of the parotid glands. Bilateral synchronous incidence is rare, occurring in 7 to 10% of the cases. It is more common in males between 60 and 70 years of age and is closely related to smoking. There is slow growth and the condition is a delimited nodule of regular outlines; it has low rates of malignant progression and recurrence.
Objective Report a case of synchronous bilateral Warthin tumor occurring in an elderly patient, and review incidence and peculiarities of this tumor.
Case Report A 78-year-old man who used to smoke had a history of mild pain in the topography of right parotid three weeks ago. Patient with hypertension, diabetes and a longtime smoker (smoking a pack per day for 32 years) noticed a progressive bulging in the right parotid region for about 2.5 years ago, and noticed another progressive bulging (althought in the left parotid region), for about one year ago. Patient denied fever, redness, skin lesions and pain during this period until last three weeks, when he sought medical attention for a mild pain in the right facial region. The patient underwent cervical magnetic resonance imaging that showed tumor lesions in both parotids. Fine needle aspiration revealed a typical lesion of epithelial oxyphilic cells associated with reactive lymphoid proliferation, suggesting Warthin tumor. The patient underwent two superficial parotidectomies, and the histopathologic result from both tumors of parotid glands showed papillary cystadenoma lymphomatosum.
Conclusion The occurrence of synchronous bilateral Warthin tumor is extremely rare, and anamnesis and physical examination, as well as some complementary examinations, are important means for diagnostic evaluation. Confirmation of the diagnosis can only be obtained through a histopathologic study. A superficial or total parotidectomy is the recommended treatment for the disease.
doi:10.1055/s-0033-1351676
PMCID: PMC4297016  PMID: 25992094
cystadenoma; papillary; salivary glands; neoplasms; multiple primary
22.  Metabolic Imaging Biomarkers of Post-Radiotherapy Xerostomia 
Purpose
Xerostomia is a major complication of head and neck radiotherapy. Available xerostomia measures remain flawed. FDG-PET/CT is routinely used for staging and response assessment of head and neck cancer. We investigated quantitative measurement of parotid gland FDG uptake as a potential biomarker for post-radiotherapy xerostomia.
Methods and Materials
Ninety-eight locally advanced head and neck cancer patients receiving definitive radiotherapy underwent baseline and post-radiotherapy FDG-PET/CT on a prospective imaging trial. A separate validation cohort of 14 patients underwent identical imaging while prospectively enrolled onto a second trial collecting sialometry and patient-reported outcomes. Radiation dose and pre/post-RT SUVs for all voxels contained within parotid gland regions-of-interest were deformably registered.
Results
Average whole gland or voxel-by-voxel models incorporating parotid DMet (defined as the pre-treatment parotid SUV weighted by dose) accurately predicted post-treatment changes in parotid FDG uptake (e.g. fractional parotid SUV). Fractional loss of parotid FDG uptake closely paralleled early parotid toxicity defined by post-treatment salivary output (p < 0.01) and RTOG/EORTC xerostomia scores (p < 0.01).
Conclusions
In this pilot series, loss of parotid FDG uptake strongly associates with acute clinical post-radiotherapy parotid toxicity. DMet may potentially be used to guide function-sparing treatment planning. Prospective validation of FDG-PET/CT as a convenient, quantifiable imaging biomarker of parotid function is warranted and ongoing.
doi:10.1016/j.ijrobp.2011.10.074
PMCID: PMC4271834  PMID: 22658215
Radiotherapy; IMRT; PET/CT; imaging; biomarker; normal tissue toxicity; xerostomia
23.  Association between Cutaneous Nevi and Breast Cancer in the Nurses' Health Study: A Prospective Cohort Study 
PLoS Medicine  2014;11(6):e1001659.
Using data from the Nurses' Health Study, Jiali Han and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk.
Methods and Findings
We followed 74,523 female nurses for 24 y (1986–2010) in the Nurses' Health Study and estimate the relative risk of breast cancer according to the number of cutaneous nevi. We adjusted for the known breast cancer risk factors in the models. During follow-up, a total of 5,483 invasive breast cancer cases were diagnosed. Compared to women with no nevi, women with more cutaneous nevi had higher risks of breast cancer (multivariable-adjusted hazard ratio, 1.04, 95% confidence interval [CI], 0.98–1.10 for 1–5 nevi; 1.15, 95% CI, 1.00–1.31 for 6–14 nevi, and 1.35, 95% CI, 1.04–1.74 for 15 or more nevi; p for continuous trend = 0.003). Over 24 y of follow-up, the absolute risk of developing breast cancer increased from 8.48% for women without cutaneous nevi to 8.82% (95% CI, 8.31%–9.33%) for women with 1–5 nevi, 9.75% (95% CI, 8.48%–11.11%) for women with 6–14 nevi, and 11.4% (95% CI, 8.82%–14.76%) for women with 15 or more nevi. The number of cutaneous nevi was associated with increased risk of breast cancer only among estrogen receptor (ER)–positive tumors (multivariable-adjusted hazard ratio per five nevi, 1.09, 95% CI, 1.02–1.16 for ER+/progesterone receptor [PR]–positive tumors; 1.08, 95% CI, 0.94–1.24 for ER+/PR− tumors; and 0.99, 95% CI, 0.86–1.15 for ER−/PR− tumors). Additionally, we tested plasma hormone levels according to the number of cutaneous nevi among a subgroup of postmenopausal women without postmenopausal hormone use (n = 611). Postmenopausal women with six or more nevi had a 45.5% higher level of free estradiol and a 47.4% higher level of free testosterone compared to those with no nevi (p for trend = 0.001 for both). Among a subgroup of 362 breast cancer cases and 611 matched controls with plasma hormone measurements, the multivariable-adjusted odds ratio for every five nevi attenuated from 1.25 (95% CI, 0.89–1.74) to 1.16 (95% CI, 0.83–1.64) after adjusting for plasma hormone levels. Key limitations in this study are that cutaneous nevi were self-counted in our cohort and that the study was conducted in white individuals, and thus the findings do not necessarily apply to other populations.
Conclusions
Our results suggest that the number of cutaneous nevi may reflect plasma hormone levels and predict breast cancer risk independently of previously known factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
One woman in eight will develop breast cancer during her lifetime. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably (which leads to the formation of a lump in the breast) and to move around the body (metastasize). The treatment of breast cancer, which is diagnosed using mammography (a breast X-ray) or manual breast examination and biopsy, usually involves surgery to remove the lump, or the whole breast (mastectomy) if the cancer has started to metastasize. After surgery, women often receive chemotherapy or radiotherapy to kill any remaining cancer cells and may also be given drugs that block the action of estrogen and progesterone, female sex hormones that stimulate the growth of some breast cancer cells. Globally, half a million women die from breast cancer each year. However, in developed countries, nearly 90% of women affected by breast cancer are still alive five years after diagnosis.
Why Was This Study Done?
Several sex hormone–related factors affect breast cancer risk, including at what age a woman has her first child (pregnancy alters sex hormone levels) and her age at menopause, when estrogen levels normally drop. Moreover, postmenopausal women with high circulating levels of estrogen and testosterone (a male sex hormone) have an increased breast cancer risk. Interestingly, moles (nevi)—dark skin blemishes that are a risk factor for the development of melanoma, a type of skin cancer—often darken or enlarge during pregnancy. Might the number of nevi be a marker of hormone levels, and could nevi counts therefore be used to predict an individual's risk of breast cancer? In this prospective cohort study, the researchers look for an association between number of nevi and breast cancer risk among participants in the US Nurses' Health Study (NHS). A prospective cohort study enrolls a group of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of certain diseases. The NHS, which enrolled 121,700 female nurses aged 30–55 years in 1976, is studying risk factors for cancer and other chronic diseases in women.
What Did the Researchers Do and Find?
In 1986, nearly 75,000 NHS participants (all of whom were white) reported how many nevi they had on their left arm. Over the next 24 years, 5,483 invasive breast cancers were diagnosed in these women. Compared to women with no nevi, women with increasing numbers of nevi had a higher risk of breast cancer after adjustment for known breast cancer risk factors. Specifically, among women with 1–5 nevi, the hazard ratio (HR) for breast cancer was 1.04, whereas among women with 15 or more nevi the HR was 1.35. An HR compares how often a particular event occurs in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event. Over 24 years of follow-up, the absolute risk of developing breast cancer was 8.48% in women with no nevi but 11.4% for women with 15 or more nevi. Notably, postmenopausal women with six or more nevi had higher blood levels of estrogen and testosterone than women with no nevi. Finally, in a subgroup analysis, the association between number of nevi and breast cancer risk disappeared after adjustment for hormone levels.
What Do These Findings Mean?
These findings support the hypothesis that the number of nevi reflects sex hormone levels in women and may predict breast cancer risk. Notably, they show that the association between breast cancer risk and nevus number was independent of known risk factors for breast cancer, and that the risk of breast cancer increased with the number of nevi in a dose-dependent manner. These findings also suggest that a hormonal mechanism underlies the association between nevus number and breast cancer risk. Because this study involved only white participants, these findings may not apply to non-white women. Moreover, the use of self-reported data on nevus numbers may affect the accuracy of these findings. Finally, because this study is observational, these findings are insufficient to support any changes in clinical recommendations for breast cancer screening or diagnosis. Nevertheless, these data and those in an independent PLOS Medicine Research Article by Kvaskoff et al. support the need for further investigation of the association between nevi and breast cancer risk and of the mechanisms underlying this relationship.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001659.
An independent PLOS Medicine Research Article by Kvaskoff et al. also investigates the relationship between nevi and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the Nurses' Health Study is available
doi:10.1371/journal.pmed.1001659
PMCID: PMC4051600  PMID: 24915186
24.  Adenoid cystic carcinoma of the parotid metastasizing to liver: case report 
BMC Cancer  2004;4:41.
Background
Adenoid cystic carcinoma is a rare malignant parotid tumor. Metastasis can occur even a decade or more after initial treatment of the primary.
Case presentation
We report a 60 year old female patient who presented with adenoid cystic carcinoma of the parotid gland. She underwent a total conservative parotidectomy followed by adjuvant radiotherapy. While on follow up, patient developed multiple liver metastases which manifested three years later. Patient lived for another two years before she died of her disease.
Conclusions
Although distant metastases of adenoid cystic carcinoma develop frequently, isolated metastasis to liver is unusual. Even after manifestation of distant metastasis, patients can be expected to live for a number of years. Palliative chemotherapy can be considered in symptomatic cases while the usefulness of metastatectomy is controversial.
doi:10.1186/1471-2407-4-41
PMCID: PMC509249  PMID: 15285782
25.  An unusual case of spleen metastasis from carcinoma ex pleomorphic adenoma of the parotid gland 
Carcinoma ex pleomorphic adenoma is a rare tumor arising from the salivary glands that spreads through direct extension, through the lymphatic vessels, and, rarely, hematogenously. When distant metastases have been found, they have been reported mainly in the lung. We present an unusual case of carcinoma ex pleomorphic adenoma of the parotid gland with splenic metastases. The patient presented with a primary carcinoma ex pleomorphic adenoma of the parotid gland and he underwent a total parotidectomy with laterocervical lymphadenectomy ipsilateral and adjuvant radiation therapy to the right parotid area. One year later, the patient showed an ipsilateral supraclavicular lymph node recurrence, treated with surgery and radiation therapy. Two more years later, the patient developed lung and splenic lesions, detected through CT and PET. He underwent splenectomy and pathologic assessment of the specimen showed metastatic carcinoma ex pleomorphic adenoma. To our knowledge, there is no reported case of a carcinoma ex pleomorphic adenoma metastasizing to the spleen. Patients treated for carcinoma ex pleomorphic adenoma should be investigated for distant metastases with a long-term follow-up examination for local and distant metastases and new splenic lesions in these patients should be investigated.
doi:10.1186/1477-7819-12-18
PMCID: PMC3905163  PMID: 24456816
Carcinoma ex pleomorphic adenoma; Parotid tumours; Pleomorphic adenoma; Splenic metastases

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