Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

Nodal positivity in patients with clinically and radiologically node-negative breast cancer treated with neoadjuvant chemotherapy: multicentre collaborative study.

BACKGROUND: The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS: A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS: A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION: The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.

The accuracy of MRI in detecting pathological complete response following neoadjuvant chemotherapy in different breast cancer subtypes.

BACKGROUND: Pathological complete response (pCR) following neo-adjuvant chemotherapy (NACT) for breast cancer is associated with improved disease-free and overall survival in certain breast cancer subtypes. Magnetic Resonance Imaging (MRI) is increasingly used as standard to assess treatment response in patients receiving NACT. The aim of this study was to determine the clinical utility of MRI in accurately predicting pCR post-NACT. METHODS: A single-centre, retrospective study was conducted in breast cancer patients, who received NACT between 2013 and 2020. Patients who had an MRI before and after NACT were included. Pathological and MRI radiological response rates to NACT were analyzed and MRI accuracy assessed in detecting pCR according to breast cancer subtype. RESULTS: One hundred and sixty-seven patients were included in the study. Forty-one of the 167 patients achieved pCR (24.6 %), with the highest proportion in HR- HER2+ subgroup (58.3 %), followed by triple negative breast cancer (TNBC) (35 %). Only 22.2 % and 10.5 % of patients with HR + HER2+ and HR + HER2-respectively achieved pCR. The overall accuracy of MRI in predicting pCR after NACT was 77.3 %. The greatest accuracy was in TNBC (87.5 %) with a specificity and positive predictive value (PPV) of 100 % and the highest number of correctly diagnosed complete responses (14 of 40). MRI was less accurate in predicting response rates in HR + HER2- (PPV 91.2 %) and HR + HER2+ groups (PPV 90.5 %). MRI performed significantly better in predicting complete response in TNBC compared to HR + HER2-subtype (p = 0.0057). CONCLUSION: MRI is a clinically useful adjunct in assessing pCR following NACT and appears to predict pathological response more accurately in TNBC compared to HR + HER2-breast cancer subtypes. This has significant clinical implications in terms of surgical planning, adjuvant treatment options and prognosis.

A systematic review of oncological outcomes after nipple-sparing mastectomy for breast cancer.

Nipple-sparing mastectomy is an alternative to skin-sparing mastectomy in select patients. Increasing evidence supports its use in the setting of breast cancer, however concerns still exist regarding oncological safety. The aim of this systematic review was to evaluate long-term oncological outcomes of patients who underwent nipple-sparing mastectomy for breast cancer. A systematic review of the literature was performed to evaluate oncological outcomes in patients with breast cancer who underwent nipple-sparing mastectomy. Five major databases (PubMed, Embase, Scopus, Web of Science and Cochrane) were searched. The review included all original articles published in English reporting long-term oncological outcomes. 2334 studies were identified. After applying inclusion and exclusion criteria, 17 retrospective studies involving 7107 patients were included. The indication for nipple-sparing mastectomy was invasive carcinoma in 6069 patients (85.4%) and in situ disease in 1038 (14.6%). Median follow up was 48 months (range 25-94). The weighted mean rates of local recurrence and recurrence involving the nipple-areola complex were 5.4% (0.9-11.9) and 1.3% (0-4.9), respectively. The weighted mean distant failure rate was 4.8% (1.5-23.0). Therapeutic nipple-sparing mastectomy is oncologically safe in select patients with breast cancer.

Fertility treatment and breast-cancer incidence: meta-analysis.

BACKGROUND: The significance of exogenous hormone manipulation as part of fertility treatment and its relationship to the development of breast cancer remains uncertain. Several historical reviews have been performed with conflicting results. This study is an updated meta-analysis to determine whether there is a causal relationship between different fertility treatments and breast cancer. METHODS: The study report is based on the guidelines of PRISMA and Meta-Analysis of Observational Studies in Epidemiology. Studies published within the last 20 years were included to reflect up to date in vitro fertilization (IVF) practice. This study was prospectively registered on PROSPERO on 07/04/2021, registration identification CRD42021247706. The primary outcome of the study was to determine whether there is an increased incidence of breast cancer in women treated with hormonal fertility treatment. The secondary outcomes were to determine whether fertility treatments were individually associated with excess breast-cancer risk. RESULTS: Overall, 25 studies, including 617 479 participants, were eligible for inclusion. There was no significant breast-cancer risk association with fertility treatment (compared with general and subfertility reference groups). Summary odds ratio of all included studies was 0.97 (95 per cent c.i. 0.90 to 1.04). Women who received six or more IVF cycles did not have an increased risk of breast cancer. Similarly, there was no excess breast-cancer risk associated with clomiphene, human chorionic gonadotropin, gonadotropin analogues and progesterone when examined individually. Comparably, there was no significant association between fertility treatment and excess breast-cancer risk in patients with more than 10 years' follow-up. Summary odds ratio was 0.97 (95 per cent c.i. 0.85 to 1.12). CONCLUSION: This meta-analysis did not find a significant association between fertility treatments and excess breast-cancer risk. Women considering IVF should be informed that it does not appear to increase breast-cancer risk.

Optimal timing of surgery following breast cancer neoadjuvant chemotherapy: A systematic review and meta-analysis.

BACKGROUND: Administration of chemotherapy before breast surgery has the potential to reduce the risk of distant recurrence by targeting micrometastasis as well as allowing a more minimalistic approach to surgical intervention. We performed a systematic review to determine the optimum timing of surgery post breast cancer neoadjuvant chemotherapy (NACT). METHODS: The primary outcome was to determine whether the timing of surgery post NACT impacted overall survival (OS) and disease-free survival (DFS). We compared patient outcomes between those who had surgery within 8 weeks of completion of NACT to those that had surgery after 8 weeks. An outcome comparison between <4 weeks and 4-8 weeks was also performed. Secondary outcome included complete pathological response (pCR) post NACT. A meta-analysis was performed using the Mantel-Haenszel method. RESULTS: Five studies, including 8794 patients were eligible for inclusion. Patients that had surgery within 8 weeks of completion of NACT had a statistically significant improved OS(OR 0.47, 95% c. i 0.34-0.65) and DFS(OR 0.71 (95% c. i 0.52-0.98, P = 0.04). There were no survival advantages associated with having surgery less than 4 weeks post completion of NACT (OR 0.78, 95% c. i 0.46-1.33, P = 0.37). There was no difference in pCR rate between those that had surgery <4 weeks and 4-8 weeks (OR 1.01, 95% c. i 0.80-1.28, P = 0.93). CONCLUSION: This meta-analysis shows that the optimum timing of surgery post completion of NACT is 4-8 weeks as it is associated with increased OS and DFS.

The Impact of Postoperative Wound Complications on Oncological Outcomes Following Immediate Breast Reconstruction for Breast Cancer: A Meta-analysis.

The association between immediate breast reconstruction (IBR)-related wound complications and breast cancer recurrence (BCR) remains uncertain. This study aimed to investigate the oncological outcomes in patients with wound complications following mastectomy and IBR. A comprehensive search was undertaken for all studies describing complications in patients with breast cancer following IBR. Studies were included if they reported on complications and investigated their relationship with BCR. A meta-analysis was performed using a random-effects model, with data presented as odds ratios and 95% confidence intervals. A total of 1418 patients from five studies were included in the final analysis. The mean age of patients included was 47.2 years. A total of 382 (26.9%) patients had postoperative complications following a majority of implant-based IBR (929/1418). A total of 158 (11.1%) recurrences, which included 63 locoregional and 106 distant recurrences, was noted at a mean follow-up of 66 months. Although there was an increase in recurrence rates in the complication group (n = 66/382; 17.3% vs. n = 92/1036; 8.9%), there was no significant association between complications and BCR (17.3% vs. 8.9%; P = .18) or mortality (3.6% vs. 2.3%; P = .15). Time to adjuvant therapy was significantly increased in patients with complications (mean difference, 8.69 days; range, 1.18-16.21 days; P = .02; I2 = 0.02). This meta-analysis demonstrated a higher incidence of wound complications following IBR and a statistically significant increased time to adjuvant therapy. However, this did not translate into adverse oncological outcomes in patients with breast cancer undergoing IBR.

Fibromatosis of the breast: a 10-year multi-institutional experience and review of the literature.

BACKGROUND: Breast fibromatosis is a rare clinical entity, but poses significant diagnostic and therapeutic challenges. In light of recent changes in management practices, the aim was to review our institutional experience of breast fibromatosis and provide a review of current available literature on such management. METHODS: A search of pathological databases within two tertiary institutions for all patients diagnosed with fibromatosis of the breast over a 10-year period (2007-2016) was performed. Clinicopathological characteristics and modes of treatment were recorded for each patient. Concurrently a comprehensive literature search was performed and studies relating to breast fibromatosis and its management were identified and reviewed. RESULTS: Sixteen patients were identified. Median age at diagnosis was 42 (range 21-70) and all patients were diagnosed with core biopsy. The most useful imaging modality in diagnosis was ultrasonography and magnetic resonance imaging. 13/16 were treated surgically whilst 3/16 were treated using a watch-and-wait approach. 6/13 (46%) required re-excision of margins and 2/13 (15%) had recurrence after surgery. On review of the literature, there is no dedicated guideline in place for the management of breast fibromatosis. Currently a 'watch and wait' approach is favoured over surgical intervention due to high levels of recurrence and associated surgical morbidity. All cases should be discussed at a sarcoma multidisciplinary team meeting and tyrosine kinase inhibitors should be considered in advanced cases. CONCLUSIONS: Breast fibromatosis is rare but affects young patients. Active surveillance is now favoured over surgical resection due to high recurrence rates and extensive morbidity. Dedicated guidelines are required to ensure best outcomes.

The Impact of Neoadjuvant Chemotherapy on Margin Re-excision in Breast-Conserving Surgery.

BACKGROUND: Neoadjuvant chemotherapy (NAC) can improve cosmesis by reducing resection volume. Breast-conserving surgery (BCS) aims to achieve clear excision margins while optimizing cosmesis. However, the influence of NAC on margin re-excision after BCS is unclear. This study examines the rate and determinants of margin re-excision in patients undergoing BCS following NAC in our institution. METHODS: From 2011-2015, all patients treated with NAC prior to BCS were identified from a prospectively maintained database. Mann-Whitney and Fisher's exact test tests were used to compare variables in patients who did and did not require re-excision. Patients undergoing primary surgical treatment in 2015 comprised an unmatched comparison group. RESULTS: Of 211 patients treated with NAC, 69 initially underwent BCS. The re-excision rate was 32% (n = 22) compared to 17% in the primary operable group (38 of 221, p = 0.02). Re-excision rates were lowest in triple-negative and HER2+ tumors (0% and 10%, respectively). Lobular carcinoma and ER+ tumors had a significantly higher rate of re-excision (100% and 42%, respectively). Of 22 patients undergoing re-excision, 9 had further BCS and 13 had a mastectomy. CONCLUSION: The re-excision rate following NAC is almost twice that of patients who underwent primary operative management. Her2+ and triple-negative tumors have lower re-excision rates and may represent a selected cohort most suitable for BCS. Patients with invasive lobular carcinoma or ER+ disease have significantly higher rates of margin positivity, and these patients should be considered for a cavity shave during primary surgery to reduce the rates of re-excision.

A mimic of breast carcinoma 1-year post vacuum-assisted excision of a benign breast lesion.

A 64-year-old woman underwent vacuum-assisted excision (VAE) for a biopsy-proven radial scar in the right breast detected during screening mammography. A follow-up mammogram was performed at 1 year following multidisciplinary team discussion. This demonstrated a 1 cm mass adjacent to the biopsy clip at the site of the prior VAE. A repeat biopsy of the mass was performed which revealed benign scar tissue. This is the first reported case of post-VAE scar tissue mimicking breast carcinoma on mammography.

Breast screening in symptomatic women over 35 years of age: improvements in service efficiency.

INTRODUCTION: The rationalization of cancer services in Ireland saw all women with symptomatic breast problems referred to one of the eight regional cancer centers. A pilot triaging system was introduced in St Vincent's University Hospital to streamline these services. Women over 35 years who do not meet urgent referral criteria are referred for a mammogram prior to a clinic appointment ("image first"). The aim of this study was to retrospectively determine the recall rates, biopsy rates, and rate of breast cancer identification within this cohort of patients. This was compared to a screening population of patients. METHODS: Patients triaged into the "image first" group within a one-year period were identified. Results of the initial mammogram, further imaging and subsequent biopsies were recorded. Data relating to number of recalls, number of patients biopsied and number of cancers identified within the Merrion Unit of the National Breastcheck Screening Program was obtained for comparison. RESULTS: One thousand six hundred eighty-eight referrals were triaged as "image first" over this period. 185 (11%) of patients required a biopsy of an identified lesion. Breast cancer was diagnosed in 65 patients (3.9%). During the same study period, of the 42,099 women who were screened for breast cancer, 496 (1.8%) underwent biopsy and 267 (0.63%) were diagnosed with breast cancer. CONCLUSION: Image first patients, who represent a cohort of "symptomatic" non-urgent women, have a greater rate of breast cancer detection than an asymptomatic screening population. This may have an impact on the appropriate triaging of symptomatic women in a national cancer center.

Where youth matters-clinicopathologic characteristics and emerging trends in treatment and outcomes in young Irish women with breast cancer.

BACKGROUND: Young women with breast cancer (YWBC) represent 7-12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved. METHODS: YWBC were identified from pathology databases at two tertiary centers. Patients were divided into two cohorts: those diagnosed from 2000 to 2005 (C1) and from 2006 to 2015 (C2). Data were retrieved from clinical, radiology, and histology databases. Statistical analysis was performed using R® (V3.2.0). RESULTS: We identified 345 patients. Median age was 36 years (23-39 years). Mastectomy was performed in 232 patients (67.2%) and axillary lymph node clearance (ALNC) in 207 patients (60% [C1 82.7 vs. C2: 49.4%, p < 0.001]). One hundred-seventy patients (49%) were ER + HER2-, 88 (25.5%) were HER2+, and 58 (16.8%) were triple negative. Eighty patients (23.2%) received neoadjuvant therapy. Pathological complete response rates were statistically similar between C1 and C2 [C1 1 (0.9%) vs C2 16 (6.8%) p = 0.1]. Distant relapse occurred in 59 (19%) patients. There was a higher relapse rate (RR) in C1 [27 (32.1%) vs. 32 (15.7%), p < 0.002). HER2+ and ER+ HER2- patients in C1 had higher RRs than C2. Median overall survival in patients with metastatic disease was 29 months (range 2-119 months). CONCLUSION: Locally advanced disease was more prevalent in YWBC. Mastectomy and ALNC rates were high and most received multimodal treatment. The extent of axillary surgery declined over time. Outcomes were unchanged in triple negative patients. These remain a priority for research.

The American Joint Commission Cancer 8th Edition Prognostic Stage Including Oncotype DX® Recurrence Score: Impact on Staging of Early Breast Cancer.

BACKGROUND: The American Joint Commission Cancer (AJCC) Cancer Staging Manual 8th edition introduced a breast cancer (BC) Prognostic Stage (PS) that combines tumour grade, oestrogen (ER), progesterone (PgR), and human epidermal growth factor-2 (HER2) receptor status with Anatomic TNM Stage (AS). In a further modification, patients with early BC and an Oncotype DX® Recurrence Score (RS) < 11 are assigned to PS 1A irrespective of grade and size up to 5 cm. This study profiles the impact of these changes on staging in patients with early BC and RS < 11. METHODS: A total of 127 patients, with primary BC and RS < 11, were identified from a consecutive series of 729 patients with ER-positive, HER2-negative, lymph node-negative, primary BC whose tumours were tested using the Oncotype DX® 21 multigene assay. Each patient was assigned AS, PS, and RS-modified PS, and staging categories were compared. RESULTS: Applying AS, 100 patients were stage IA and 27 IIA. Applying PS, 89 were stage IA, 33 IB, 4 IIA, and 1 IIB. All patients were IA according to RS-modified PS. Comparing PS to AS, 26.7% of patients (n = 34) changed stage, 9.4% (n = 12) to a higher and 17.3% (n = 22) to a lower stage. RS-modified PS versus AS resulted in downstaging in 21.3% (n = 27). Comparing PS modified by RS to PS alone, 29.9% (n = 38) were downstaged. CONCLUSION: Application of PS and RS-modified PS results in tumour downstaging in approximately 20% of patients with early BC. Upstaging was observed in 9% of patients when staged according to PS and was primarily due to the impact of high histological grade.

Atypia of Undetermined Significance in Thyroid Fine Needle Aspirates: a 4-Year Audit of Thy3a Reporting.

OBJECTIVE: Thyroid nodules are common within the general population. Cytological analysis of fine needle aspirates (FNAs) of these lesions allows for identification of those that require further surgery. A numerical classification system is in place to streamline reporting. The 3a category is used for lesions that are neither benign nor malignant but show atypia of undetermined significance. We reviewed our use and clinical outcomes of Thy3a over a 4-year period. METHODS: All thyroid FNAs performed at this institute from January 2012 to December 2015 were identified from our laboratory information system using SNOMED codes. Cytology was correlated with histology. RESULTS: Of the 1,259 FNAs reported at this institute, Thy3a constituted only 1.2% (n = 16) of all cases, with a malignancy rate of 7%. Five Thy3a cases had a repeat FNA that was reported as Thy2 (benign), 1 as Thy1c (cyst), 1 as Thy3f (follicular lesion), and 1 as Thy5 (malignant). Six cases without repeat FNA were follicular adenomas at resection. Two cases were lost to follow-up. Within all thyroid cytology categories in this 4-year period, we had a false-positive rate of 1.9% and a false-negative rate of 0.3%. CONCLUSIONS: The Thy3a subclassification has varied diagnostic criteria and lacks reproducibility. Despite the rare use of the Thy3a category at our centre, our diagnostic accuracy remained high. At this time, further Thy3a cohort studies are required to assess the real benefits of this category.

The Value of Isosulfan Blue Dye in Addition to Isotope Scanning in the Identification of the Sentinel Lymph Node in Breast Cancer Patients With a Positive Lymphoscintigraphy: A Randomized Controlled Trial (ISRCTN98849733).

BACKGROUND: Sentinel lymph node biopsy (SLNB) has become the gold standard for axillary staging. Debate remains as to the optimal method of SLN detection. OBJECTIVES: Determine whether patients undergoing an SLNB required the addition of isosulfan blue dye to radioisotope when an SLN was identified on a preoperative lymphoscintigram. METHODS: A prospective randomized controlled trial comparing the combination of radioisotope and blue dye versus radioisotope alone was performed between March 2010 and September 2012. The trial protocol was registered with Current Controlled Trials. Women with clinically and radiologically node-negative breast cancer with a positive preoperative lymphoscintigram were eligible for inclusion. RESULTS: A total of 667 patients were included in the analysis with 342 patients receiving the combination (blue dye and radioisotope) and 325 patients receiving radioisotope alone. The groups were evenly matched both demographically and pathologically. The mean age was 48 years (48.3 vs 47.7 years; P = 0.47), the mean tumour size was 24.2 mm (24.3 mm vs 24.1 mm; P = 0.7) and there was no statistically significant difference in the grade of the tumors between the 2 groups (P = 0.58). There was no difference in the identification rate, nor was that in the number of nodes retrieved between the 2 groups (P = 0.30). There was no difference in the number of positive lymph nodes that were identified between the 2 groups (23.8% vs 22.1%; P = 0.64). CONCLUSIONS: This study failed to demonstrate an advantage with the addition of isosulfan blue dye to radioisotope in the identification of the SLN in the presence of a positive preoperative lymphoscintigram.

Thyroid lymphoma: recent advances in diagnosis and optimal management strategies.

Primary thyroid lymphoma is rare, composing approximately 5% of all thyroid malignancies and less than 3% of all extranodal lymphomas. It typically presents as a rapidly enlarging goiter with associated compressive symptoms. Thyroid ultrasound and fine needle aspiration cytology, using flow cytometry and immunohistochemistry, remain the main modalities used to confirm the presence of lymphoma. The increasing use of an ultrasound-guided core biopsy to achieve an accurate diagnosis has further limited the role of surgery. An open surgical biopsy may still be required not only for definitive diagnosis but also to confirm the subtype of lymphoma. There are limited numbers of randomized or prospective trials to guide management, and controversy remains over optimal treatment. Treatment and prognosis of this disease can be dichotomized into two separate groups: pure mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) or mixed subtypes. Early stage (stage IE) intrathyroidal MALT lymphomas typically have an indolent course and may be treated with single-modality surgery, radiotherapy, or a combination of both. DLBCLs are more aggressive, and survival outcomes are highest with multimodal therapy incorporating monoclonal antibodies, chemotherapy, and radiotherapy. The prognosis is generally excellent but can be varied because of the heterogeneous nature of thyroid lymphomas. The aim of this paper is to discuss the changes in diagnostic modalities and to focus on the recent alterations in the management of this rare disease, including targeted therapies as well as the more limited role of the endocrine surgeon.

Molecular and therapeutic advances in the diagnosis and management of malignant pheochromocytomas and paragangliomas.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-secreting tumors derived from chromaffin cells originating in the neural crest. These tumors represent a significant diagnostic and therapeutic challenge because the diagnosis of malignancy is frequently made in retrospect by the development of metastatic or recurrent disease. Complete surgical resection offers the only potential for cure; however, recurrence can occur even after apparently successful resection of the primary tumor. The prognosis for malignant disease is poor because traditional treatment modalities have been limited. The last decade has witnessed exciting discoveries in the study of PCCs and PGLs; advances in molecular genetics have uncovered hereditary and germline mutations of at least 10 genes that contribute to the development of these tumors, and increasing knowledge of genotype-phenotype interactions has facilitated more accurate determination of malignant potential. Elucidating the molecular mechanisms responsible for malignant transformation in these tumors has opened avenues of investigation into targeted therapeutics that show promising results. There have also been significant advances in functional and radiological imaging and in the surgical approach to adrenalectomy, which remains the mainstay of treatment for PCC. In this review, we discuss the currently available diagnostic and therapeutic options for patients with malignant PCCs and PGLs and detail the molecular rationale and clinical evidence for novel and emerging diagnostic and therapeutic strategies.