Pituitary tumours without distinct lineage differentiation express stem cell marker SOX2.

CONTEXT: The recent WHO 2022 Classification of pituitary tumours identified a novel group of 'plurihormonal tumours without distinct lineage differentiation (WDLD)'. By definition, these express multiple combinations of lineage commitment transcription factors, in a monomorphous population of cells. OBJECTIVES: To determine the expression of stem cell markers (SOX2, Nestin, CD133) within tumours WDLD, immature PIT-1 lineage and acidophil stem cell tumours, compared with committed cell lineage tumours. METHODS: Retrospective evaluation of surgically resected pituitary tumours from St Vincent's Hospital, Sydney. Patients were selected to cover a range of tumour types, based on transcription factor and hormone immunohistochemistry. Clinical data was collected from patient files. Radiology reports were reviewed for size and invasion. Samples were analysed by immunohistochemistry and RT-qPCR for SF-1, PIT-1, T-PIT, SOX2, Nestin and CD133. Stem cell markers were compared between tumours WDLD and those with classically "mature" types. RESULTS: On immunohistochemistry, SOX2 was positive in a higher proportion of tumours WDLD compared with those meeting WHO lineage criteria, 7/10 v 10/42 (70 v 23.4%, p = 0.005). CD133 was positive in 2/10 tumours WDLD but 0/41 meeting lineage criteria, P = 0.003. On RT-qPCR, there was no significant difference in relative expression of stem cell markers (SOX2, CD133, Nestin) between tumours with and WDLD. CONCLUSIONS: Our study is the first to biologically characterise pituitary tumours WDLD. We demonstrate that these tumours exhibit a higher expression of the stem cell marker SOX2 compared with other lineage-differentiated tumours, suggesting possible involvement of stem cells in their development.

The evolution in pituitary tumour classification: a clinical perspective.

Objective: Pituitary tumours comprise a pathologically and clinically diverse group of neoplasms. Classification frameworks have changed dramatically in the past two decades, reflecting improving understanding of tumour biology. This narrative review examines the evolution of pituitary tumour classification, from a clinical perspective. Results: In 2004, pituitary tumours were classified as 'typical' or 'atypical', based on the presence of markers of proliferation, Ki67, mitotic count and p53. In 2017, the new WHO marked a major paradigm shift, with a new focus on lineage-based classification, determined by transcription factor and hormonal immunohistochemistry. The terms 'typical' and 'atypical' were omitted, though the importance of proliferative markers Ki67 and mitotic count was acknowledged. The recent WHO 2022 classification incorporates further refinements, specifically recognising some less common types that may represent less well-differentiated tumours. Whilst 'high risk' tumour types have been identified, further work is still required to improve prognostication. Conclusions: Recent WHO classifications have marked significant progress in the diagnostic evaluation of pituitary tumours, though shortcomings and challenges remain for both clinicians and pathologists in managing these tumours.

Pituitary tumours: molecular and genetic aspects.

'Pituitary tumours' is an umbrella term for various tumours originating from different regions of the hypothalamic-pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune-Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial-mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.

Disorders of Salt and Water Balance After Pituitary Surgery.

Transsphenoidal surgery is the first-line treatment for many clinically significant pituitary tumors and sellar lesions. Although complication rates are low when performed at high-volume centers, disorders of salt and water balance are relatively common postoperatively. Both, or either, central diabetes insipidus (recently renamed arginine vasopressin deficiency - AVP-D), caused by a deficiency in production and/or secretion of arginine vasopressin, and hyponatremia, most commonly secondary to the syndrome of inappropriate antidiuresis, may occur. These conditions can extend hospital stay and increase the risk of readmission. This article discusses common presentations of salt and water balance disorders following pituitary surgery, the pathophysiology of these conditions, and their diagnosis and management.

Treatment of Prolactinoma.

Prolactinomas are the commonest form of pituitary neuroendocrine tumor (PitNET), representing approximately half of such tumors. Dopamine agonists (DAs) have traditionally been the primary treatment for the majority of prolactinomas, with surgery considered the second line. The aim of this review is to examine the historical and modern management of prolactinomas, including medical therapy with DAs, transsphenoidal surgery, and multimodality therapy for the treatment of aggressive prolactinomas and metastatic PitNETs, with an emphasis on the efficacy, safety, and future directions of current therapeutic modalities. DAs have been the mainstay of prolactinoma management since the 1970s, initially with bromocriptine and more recently with cabergoline. Cabergoline normalizes prolactin in up to 85% of patients and causes tumor shrinkage in up to 80%. Primary surgical resection of microprolactinomas and enclosed macroprolactinomas performed by experienced pituitary neurosurgeons have similar remission rates to cabergoline. Aggressive prolactinomas and metastatic PitNETS should receive multimodality therapy including high dose cabergoline, surgery, radiation therapy (preferably using stereotactic radiosurgery where suitable), and temozolomide. DAs remain a reliable mode of therapy for most prolactinomas but results from transsphenoidal surgery in expert hands have improved considerably over the last one to two decades. Surgery should be strongly considered as primary therapy, particularly in the setting of microprolactinomas, non-invasive macroprolactinomas, or prior to attempting pregnancy, and has an important role in the management of DA resistant and aggressive prolactinomas.

Transcription factor immunohistochemistry in the diagnosis of pituitary tumours.

OBJECTIVE: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours. METHODS: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent's Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the 'histological cohort'. Patients with at least 12 months of post-surgical follow-up were included in the subgroup 'clinical cohort'. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying 'higher-risk' histological subtypes was assessed. RESULTS: There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher-risk histological subtype tumours. These were associated with tumour invasiveness (P = 0.050), early recurrence (12-24 months, P = 0.013), shorter median time to recurrence (49 (IQR: 22.5-73.0) vs 15 (IQR: 12.0-25.0) months, P = 0.005) and reduced recurrence-free survival (P = 0.031). CONCLUSIONS: Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

Towards precision medicine for clinically non-functioning pituitary tumours.

OBJECTIVE: Clinically non-functioning pituitary tumours (NFPT) are a heterogenous group of neoplasms with diverse outcomes. The purpose of this narrative review was to summarize available data on predictive factors, both in routine practice and research settings. DESIGN: A literature review was conducted for papers published in peer-reviewed journals, investigating clinical, radiological, pathological and genetic predictive factors in NFPT. RESULTS: Several clinical and radiological factors have been associated with NFPT recurrence and/or aggressiveness, including larger size and pre-/post-operative growth rates. Application of transcription factor immunohistochemistry has given rise to improved subtype identification, including 'higher-risk' subtypes, in routine clinical practice. Numerous other pathological and genetic biomarkers have demonstrated promise for prognostication in the research setting. CONCLUSION: NFPT are a heterogenous group of tumours, characterized by diverse presentation, pathogenesis and outcomes. Ongoing refinements in understanding of tumour biology are likely to pave the way to improved integrative prognostication and precision medicine for NFPT.

Pituitary disease: An update.

BACKGROUND: Pituitary lesions are present in >10% of the population. Approximately one in 1000 people has a symptomatic pituitary tumour, which may cause clinical problems from mass effect, hormonal hypersecretion and impairment of normal pituitary function. OBJECTIVE: The aim of this article is to outline the potential causes of a sellar and parasellar mass, with an emphasis on the presenting clinical features and screening investigations that are applicable to doctors working in the primary care setting. DISCUSSION: There is a broad range of causes of a sellar/parasellar mass. Pituitary adenomas and Rathke's cleft cysts are the most frequently encountered. Prolactinomas are the most common functioning tumour and tend to present as macroadenomas in men, while hyperprolactinaemia is associated with 15% of secondary amenorrhoea in women. Acromegaly and Cushing's disease are rare but important diagnoses to detect. Pituitary disease is optimally managed in a specialist centre in the context of an established multidisciplinary team.

The relationship between early post-operative ACTH / cortisol following pituitary surgery and long-term glucocorticoid requirement - Do ultradian rhythms matter?

OBJECTIVE: To determine whether early (4-8h) post-operative ACTH after trans-sphenoidal surgery (TSS) predicts long-term hypothalamic-pituitary-adrenal (HPA) axis function and to investigate early morning day 1 ACTH/cortisol variability using rapid sampling. DESIGN: Prospective observational study. METHODS: Participants undergoing TSS were included; those treated with glucocorticoids pre-operatively received 100 mg intravenous hydrocortisone on anaesthetic induction. ACTH and cortisol were measured post-operatively at + 4h and + 8h after induction and on day 1 every 10 minutes between 0700h and 0900h. PRIMARY OUTCOME: glucocorticoid requirement at 6 months. RESULTS: Nineteen participants (10F, 9M): 6/19 (32%) were treated with replacement glucocorticoids pre-operatively; 4 had ceased by 6 weeks post-operatively. One patient developed new hypopituitarism post-operatively meaning 3/19 (16%) required glucocorticoids at 6 months. Post-operative + 4h ACTH < 14.3 pmol/L (65 ng/L) predicted secondary adrenal insufficiency (SAI) (sensitivity 100%, specificity 75%), whilst no participant with a post-operative + 4h ACTH ≥ 14.3 pmol/L (65 ng/L) required glucocorticoids at 6 months. Day 1 ACTH and cortisol showed a significant circadian fall between 0700h-0900h; ACTH 4.2 pmol/L (IQR 2.9-5.9) to 3.7 pmol/L (IQR 2.9-5.1) P = .006 and cortisol 549 nmol/L (IQR 337-618) to 439 nmol/L (IQR 315-606) P < .001, with clinically insignificant ultradian secretory pulses. CONCLUSIONS: No participant with a post-operative + 4h ACTH ≥ 14.3 pmol/L (65 ng/L) required glucocorticoids at 6 months; however, given only 3/19 participants had the primary outcome of interest, this must be confirmed in a larger cohort. The timing of a day 1 morning cortisol between 0700h and 0900h influences the accuracy of a single cut-off to diagnose SAI after pituitary surgery.

Selective intra-arterial calcium stimulation test for the localization of insulinomas: an Australian hospital experience.

BACKGROUND: Insulinomas are rare tumours of the pancreas and the most common cause of hypoglycaemia in non-diabetic adults. They can be cured by surgery but require precise localization. The aim of this study was to assess the utility of the selective intra-arterial calcium stimulation test (SIACST) in patients with an insulinoma to correctly localize the tumour. METHODS: Medical records of patients with a diagnosis of insulinoma or who underwent an SIACST were retrospectively reviewed. Localization of lesions by SIACST was compared to endoscopic ultrasound and radionuclide imaging studies and verified against findings at surgery. RESULTS: A total of 24 patients (mean age 58 years, 16 females, 20 with insulinoma) underwent SIACST. The SIACST correctly localized the insulinoma in 17 of 20 patients (85%). Localization rate for computed tomography was 55% and 75% for endoscopic ultrasound and glucagon-like peptide-1 receptor scan. CONCLUSION: SIACST provided incremental diagnostic information in patients with insulinoma who had equivocal non-invasive imaging preoperatively. This technique remains an essential diagnostic tool when a lesion is not localized by other methods.

Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia: Prevalence and Risk Factors.

CONTEXT: There are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain. OBJECTIVE: To determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls. DESIGN, SETTING AND PARTICIPANTS: Multicenter cross-sectional analysis of 113 patients and 99 healthy controls. MAIN OUTCOME MEASURES: Participants completed a neuropsychological questionnaire consisting of the Depression Anxiety Stress Scale (DASS21), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP-S), Hypersexual Behavior Inventory (HBI), Hypersexual Behavior Consequences Scale and Social Desirability Response Set Scale. Demographic and clinical data were collated to determine ICD risk factors. Patients testing positive for an ICD were offered a semistructured psychological interview. RESULTS: Patients were more likely than controls to test positive by QUIP-S for any ICD (61.1 vs 42.4%, P = .01), hypersexuality (22.1 vs 8.1%, P = .009), compulsive buying (15.9 vs 6.1%, P = .041) and punding (18.6 vs 6.1%, P = 0.012), and by HBI for hypersexuality (8.0 vs 0.0%, P = 0.004). Independent risk factors were male sex (odds ratio [OR] 13.85), eugonadism (OR 7.85), Hardy's tumor score and psychiatric comorbidity (OR 6.86) for hypersexuality, and age (OR 0.95) for compulsive buying. DASS21 subset scores were higher in patients vs controls and in patients with vs without different ICDs. Only 19/51 (37.3%) interviewed patients were aware of the relationship between DAs and ICDs before the study. CONCLUSIONS: DA therapy poses a high, previously underestimated risk of ICDs, especially in the form of hypersexuality in eugonadal men.

Elevated insulin-like growth factor-1 in Cushing's disease.

OBJECTIVE: To determine if patients with untreated Cushing's disease have higher serum insulin-like growth factor-1 (IGF-1) compared to matched controls, and if IGF-1 decreases following remission of Cushing's disease. DESIGN: Retrospective case-control study matching Cushing's disease cases to control patients for adenoma size, age, sex, diabetic and gonadal status, body mass index and serum IGF-1 measured within one year. Paired analysis of pre-operative (untreated) and >3 months post-operative (remission) serum IGF-1 for cases. PATIENTS AND MEASUREMENTS: All patients were investigated at the Princess Alexandra Hospital Endocrine Unit between 2005 and 2017. Serum IGF-1 was measured in 25 cases and 49 controls, 23 case-control pairs and 13 cases pre- and post-operatively. RESULTS: Mean serum IGF-1 in cases was significantly higher compared to controls-32 ± 12 nmol/L compared to 25 ± 8 nmol/L, (P = 0.005). The proportion of cases with elevated serum IGF-1 above an age-adjusted reference range was higher compared to 1:1 matched controls (8/23 (35%) vs 1/23 (4%), P = 0.02). In 13 cases in remission post-operatively, serum IGF-1 decreased significantly from 31 (IQR 29-40.5) nmol/L to 23 (IQR 15-28.5) nmol/L, (P < 0.001), despite no difference in the prevalence of pre- vs post-operative pituitary hormone dysfunction (P = 0.47). CONCLUSION: Patients with untreated Cushing's disease may have elevated IGF-1, which decreases following remission. Mildly elevated IGF-1 in Cushing's disease does not imply pathological growth hormone (GH) excess.

Radioiodine treatment for graves' disease: a 10-year Australian cohort study.

BACKGROUND: Radioactive iodine (I131) is a common definitive treatment for Graves' Disease. Potential complications include worsening, or new development of Graves' eye disease and development of a radiation thyroiditis. The purpose of the present study was to assess outcomes of patients treated with I131 in an Australian tertiary centre over 10 years. METHODS: Data from 101 consecutive patients treated with I131 for a diagnosis of Graves' disease between 2005 to 2015 was collected and reviewed retrospectively. Baseline TSH receptor antibody titre, pre-treatment free thyroxine (FT4), technetium scan uptake, initial treatment, duration of treatment, reason for definitive therapy, complications, and time to remission (defined as euthyroidism or hypothyroidism after 12 months) were recorded. RESULTS: Of the 92 patients with adequate outcome data, 73 (79.3%) patients achieved remission with a single dose of I131. Of the remaining 19 patients, 12 had a second dose and became hypothyroid. TSH receptor antibody titre at diagnosis was significantly lower in the group that achieved remission with the first dose compared with those who did not (P = 0.0071). There was no difference in technetium uptake, I131 dose, duration of therapy or pre-treatment free thyroxine (FT4). I131 was complicated by development of eye disease in 3 patients and 1 (of 11 with pre-existing eye disease) had worsening eye disease. A clinically apparent flare of hyperthyroidism following I131 was evident in 8 patients (8.6%). CONCLUSION: Radioiodine is an effective therapy for Graves' Disease with few complications. The majority of patients achieve remission with a single dose. Those who require a second dose are more likely to have higher TSH receptor antibody titres at diagnosis. To the best of our knowledge, this is the first study to report outcomes from radioiodine treatment for Graves' disease in an Australian population.

Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain.

Objective To evaluate pituitary function, sexual function and quality of life (QoL) in patients on oral or transdermal opioids. Design and methods Cross-sectional study comparing pituitary function, QoL and sexual function in people on long-term opioid therapy (n = 40) vs an age- and sex-matched control group (n = 25). Baseline pituitary function was assessed on blood samples collected prior to 0900 h. Further testing with corticotropin (250 µg IV) and metyrapone (30 mg/kg) stimulation tests was undertaken on participants with serum cortisol <250 nmol/L. Validated questionnaires completed to assess QoL, fatigue and sexual function. Results Secondary adrenal insufficiency (SAI) was identified on the basis of a failed stimulation test in 22.5% of opioid users vs no controls (P = 0.01). Opioid users with SAI had a higher median morphine-equivalent daily dose (MEDD), P = 0.037 - 50% with MEDD >200 mg and 0% with MEDD <60 mg had SAI. Among male participants, testosterone was inversely associated with BMI (P = 0.001) but not opioid use. A non-significant trend to low testosterone <8 nmol/L in male opioid users (11/24 opioid users vs 2/14 control, P = 0.08) suggests a small subgroup with opioid-induced androgen deficiency. Opioid users had greater fatigue, reduced quality of life in all subsections of the SF-36 and impaired sexual function in both males and females (all scores P < 0.001 compared to controls). Conclusion Long-term opioid therapy was associated with dose-related SAI in over 20% of chronic pain patients and is associated with poor quality of life, fatigue and sexual dysfunction. Obesity confounds the interpretation of opioid-induced male androgen deficiency.

The Third Case of Cabergoline-Associated Valvulopathy: The Value of Routine Cardiovascular Examination for Screening.

A decade after the alarming association of cabergoline-associated valvulopathy (CAV) in Parkinson disease, only two confirmed cases have occurred in patients with prolactinoma. Routine screening for CAV by echocardiography has not proved to be of diagnostic utility, has several limitations, and is not widely practiced. We have previously highlighted the value of annual cardiovascular examination as a screening tool for CAV in patients with prolactinoma. We present a case, now the third confirmed case of CAV, to highlight the value of the cardiovascular examination. A 52-year-old woman with a 25-year history of macroprolactinoma had received multimodal treatment, including surgery, radiosurgery, and medical therapy. Her medical therapy initially consisted of bromocriptine, followed by cabergoline. The cabergoline dose was 6 mg weekly. In 2009, the cumulative dose was 3272 mg when an echocardiogram showed no evidence of valvular disease. A routine cardiovascular examination in the clinic detected a new murmur in 2016. The echocardiogram demonstrated new-onset mild to moderate aortic regurgitation, with a thickened and restricted valve consistent with CAV. The cumulative dose of cabergoline at that point was 4192 mg. Follow-up echocardiography at 6-month intervals showed progression to moderate to severe aortic regurgitation, which has since stabilized. Cabergoline therapy was weaned and stopped completely in April 2017. An annual cardiovascular examination is the best screening test for CAV and can change the course of a patient's treatment. Echocardiograms should be reserved for patients with a new-onset cardiac murmur or a high cumulative dose of cabergoline.

Predictors for secondary therapy after surgical resection of nonfunctioning pituitary adenomas.

OBJECTIVE: Factors determining recurrence of nonfunctioning pituitary adenomas (NFAs) that require further therapy are unclear as are postoperative follow-up imaging guidelines. We aimed to identify predictors for secondary therapy after surgical resection of NFAs and use this knowledge to inform postoperative management. DESIGN AND PATIENTS: A single-centre retrospective study of surgically resected NFAs in 108 patients followed for up to 15 years. Serial tumour images were analysed for size, location and growth rate (GR) and tissue analysed for hormone cell type and proliferation indices with secondary treatment as outcome measure. RESULTS: Twenty-four of 66 (36%) patients harbouring a postoperative remnant required secondary treatment, all occurring within 10 years. No secondary treatment was required in any of 42 patients with complete tumour resection. Age, gender, remnant volume and tumour histology were not different between patients requiring and not requiring secondary therapy. Remnant GRs in those requiring secondary therapy were more than 10-fold higher (P<.01). Tumours with a GR ≥80 mm3 /y (Hazard Ratio[HR]: 8.1, Confidence Interval [CI]: 2.4-27.3,P<.01) and those located in the suprasellar region (HR: 6.1, CI: 1.1-32, P=.03) had a higher risk for secondary therapy. Tumour GR in the first three postoperative years correlated significantly (r2 =.6, P<.01) with GR during the period of follow-up. CONCLUSION: In surgically resected NFAs further treatment is dependent on the presence of residual tumour, growth rate and location but not tumour histology. Postoperative growth rate of NFAs in the first 3 years of imaging can be used to tailor long-term follow-up to optimize use of health resources.

Younger age is a risk factor for regrowth and recurrence of nonfunctioning pituitary macroadenomas: Results from a single Australian centre.

OBJECTIVE: The natural history of nonfunctioning pituitary macroadenomas (NFPMA) after surgical resection is variable, with guidelines unable to define the duration of radiological follow-up. In this first Australian series, we identify risk factors for regrowth/recurrence of NFPMA to assist with guiding recommendations for long-term follow-up. DESIGN: Retrospective analysis of all radiotherapy-naïve cases with NFPMA resected between 1995 and 2013. PATIENTS: One hundred and twenty-three cases had both ≥2 postoperative scans and ≥12-month follow-up. MEASUREMENTS: Regrowth was defined as any sustained increase in diameter of residual adenoma or recurrence as any new adenoma occurring post complete resection on serial pituitary MRI. RESULTS: Median follow-up time was 48 months (interquartile range [IQR]: 31-86). Overall regrowth/recurrence occurred in 29% (36/123). Regrowth occurred in 40% (30/76) at a median time of 44.5 months (IQR 22-80) compared to recurrence of 12.5% (6/48; P=.003), occurring at a median time of 48 months (IQR 12-96; P=.7). Further treatment was required in 66.7% and 56.7%, respectively (=1.0). Risk factors for regrowth/recurrence by multivariate analysis were presence of residual disease and younger age at presentation. The longest time for regrowth was 168 months (14 years) and recurrence 156 months (13 years). CONCLUSIONS: Presence of postoperative residual adenoma and younger age at presentation are the main predictors of regrowth/recurrence in NFPMA. Long-term serial imaging is required to detect regrowth and recurrence in younger patients and those with residual disease. Most regrowth/recurrences will occur within 10 years of follow-up.