Management of Medullary Thyroid Cancer: Patterns of Recurrence and Outcomes of Reoperative Surgery.

BACKGROUND: There remains uncertainty regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer (MTC). We aim to describe the patterns of disease recurrence and outcomes of the reoperative surgery in a cohort of consecutively treated patients at a specialized tertiary referral center. PATIENTS AND METHODS: A retrospective cohort study of 235 surgically treated patients with MTC at a tertiary referral center was performed using prospectively collected data. RESULTS: In the study period 1986-2022, 235 patients underwent surgery for MTC. Of these, 45 (19%) patients had reoperative surgery for cervical nodal recurrence at a median (range) 2.1 (0.3-16) years following the index procedure. After a median follow-up of 4 years, 38 (84%) patients remain free of structural cervical recurrence, although 15 (33%) underwent 2 or more reoperative procedures. No long-term complications occurred after reoperative surgery. Local cervical recurrence was independently predicted by pathologically involved nodal status (OR 5.10, P = .01) and failure to achieve biochemical cure (OR 5.0, P = .009). Local recurrence did not adversely affect overall survival and was not associated with distant recurrence (HR 0.93, P = .83). Overall survival was independently predicted by high pathological grade (HR 10.0, P = .002) and the presence of metastatic disease at presentation (HR 8.27, P = 0018). CONCLUSION: Loco-regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of the staged approach to the clinically node-negative lateral neck. When recurrent disease is technically resectable, reoperative surgery can be undertaken with minimal morbidity in a specialized center and facilitates structural disease control.

Multimodality Treatment Improves Locoregional Control, Progression-Free and Overall Survival in Patients with Anaplastic Thyroid Cancer: A Retrospective Cohort Study Comparing Oncological Outcomes and Morbidity between Multimodality Treatment and Limited Treatment.

BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC. PATIENTS AND METHODS: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival. RESULTS: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival. CONCLUSION: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk.

Suppurative thyroiditis: Systematic review and clinical guidance.

OBJECTIVE: Acute suppurative thyroiditis (AST) is a rare but potentially fatal condition which can initially be difficult to distinguish from the more common subacute thyroiditis (SAT). We aim to update understanding of this medical emergency. DESIGN: A systematic review over the past 20 years was performed on the epidemiology, clinical features, investigations, management and outcomes of AST. All full-text cases of microscopy or culture- proven AST in the English literature were included. RESULTS: 200 cases of AST have been described in 148 articles from January 2000 - January 2020. Bacterial AST is most common, often presenting with neck pain (89%) and fever (82%). Immunosuppression and pyriform sinus fistula are the most common causes, most often due to gram-positive aerobes. Transient hyperthyroidism is common (42%). Aspiration and antibiotics are becoming a more common treatment. Overall mortality was 7.8%. Tuberculous and fungal AST are less likely to present with fever and neck pain. Fungal AST is more common in immunosuppressed individuals (31%) and has a high overall mortality (33%). Tuberculous AST is more common in TB endemic areas. CONCLUSION: The symptoms and signs of AST commonly overlap with SAT and initially can be hard to diagnose. AST can be rapidly morbid or even fatal. Clinicians need to consider AST when they assess patients with thyroiditis who are systemically unwell, have high fever, high white cell count and c-reactive protein, tender neck and abnormal neck imaging. An investigative and treatment strategy is described based on a systematic review of the literature.

Straddling medical specialties: should we have more comprehensive advanced training?

Over careers spanning 35 years each, we have witnessed great advances in medicine especially in genetics, imaging, immunotherapies and targeted cancer therapies. Our respective specialties of endocrinology and medical oncology have come to overlap significantly necessitating better communication and skills across both specialties. We will highlight common scenarios that straddle endocrinology and medical oncology. The same broad issues apply to other closely related specialties, albeit with different clinical challenges. At present, we see expensive and inefficient cross-referrals to other subspecialists or sometimes no referral at all, leading to significant clinical omissions. Opportunities for dual advanced training, or for more comprehensive single advanced training could more efficiently lead to enhanced patient care and communication.

Clinical guidance for radioiodine refractory differentiated thyroid cancer.

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.

Disease Progression in Papillary Thyroid Cancer with Biochemical Incomplete Response to Initial Therapy.

BACKGROUND: Dynamic risk stratification is utilized in the follow-up of patients with papillary thyroid carcinoma (PTC). Analysis of outcomes after biochemical incomplete response (BIR) to initial therapy will allow better individualization of care. METHODS: A total of 494 patients with PTC were followed prospectively. Immunohistochemistry (IHC) for BRAFV600E mutation was completed on all surgical specimens. After exclusion of patients with inadequate data, 353 patients were stratified into four categories of response to initial therapy: excellent, biochemical incomplete, structural incomplete, or indeterminate. Patients with BIR, defined as elevated stimulated thyroglobulin >2 µg/L with negative imaging, were analysed for progression of disease. The primary outcome measure was development of structural recurrence. RESULTS: Forty-nine of 353 (13.9%) patients had BIR. BRAFV600E mutation was present in 32 of 49 (65.3%) with BIR. Progression to structural recurrence occurred in 8 of 49 (16.3%) with BIR, all of whom were positive for the BRAFV600E mutation (p = 0.02). Nine patients (18%) with BIR remitted during follow-up to no evidence of disease (6 had additional RAI therapy). After mean follow-up of 35 months, 12 patients with BIR (24%) remained biochemically abnormal with no structural evidence of disease. CONCLUSIONS: Patients with BIR following initial treatment for PTC have generally favorable outcomes. Positive IHC for BRAFV600E identifies patients at risk of structural disease recurrence.

Is there a role for an ultrasensitive thyroglobulin assay in patients with serum antithyroglobulin antibodies? A large (Australian) cohort study in differentiated thyroid cancer.

OBJECTIVE: Serum thyroglobulin (Tg) is a marker of residual differentiated thyroid cancer (DTC) after total thyroidectomy; however, circulating antithyroglobulin antibodies (TgAb) may interfere with the immunoassay for Tg. Ultrasensitive assays may have a more significant role in detecting circulating Tg in the context of samples containing TgAb. The aim of this study was to evaluate the utility of ultrasensitive thyroglobulin (US-Tg) measurement compared to standard Tg measurement and to assess the influence of serum TgAb positivity on Tg detection in a large tertiary referral centre cohort in Australia. DESIGN: All patients with DTC who had undergone total thyroidectomy were included in this retrospective, observational cohort study. PATIENTS: Patients providing samples for the period of June 2006 until January 2014 were analysed. Three thousand two hundred and eight samples were measured at the same points in time, enabling serum Tg assays to be compared for the same TSH status (stimulated or suppressed). MEASUREMENTS: The standard assay, the Siemens Immulite 2000 Tg assay, was compared to the serum ultrasensitive ELISA RSR™ Tg. TgAb were simultaneously measured using Abbott Architect or Immulite 2000. RESULTS: There were 3019 samples included in the final analysis for comparison of the standard and ultrasensitive assays along with TgAb status. The majority of samples were TgAb negative (87%), with 48% of TgAb-negative samples associated with an undetectable serum Tg, suggestive of disease-free status at the time of sampling. Of note, 26% (n = 104) of the TgAb-positive samples were positive for Tg on the ultrasensitive Tg assay, but negative on the immulite Tg assay, and 62·5% (n = 65) of these samples corresponded to DTC recurrence. CONCLUSION: The US-Tg assay has greater clinical utility than the standard immulite Tg assay specifically in the scenario of antibody positivity, with a significant number of samples corresponding to clinically relevant recurrent or metastatic disease.

TERT promoter mutations are a major indicator of recurrence and death due to papillary thyroid carcinomas.

CONTEXT: TERT promoter mutations have been associated with adverse prognosis in papillary thyroid carcinomas (PTCs). OBJECTIVE: We investigated the association between TERT promoter mutations and survival from PTC. DESIGN: Retrospective observational cohort study. PATIENTS: Eighty consecutive patients with PTC who underwent surgery between 1990 and 2003. MEASUREMENTS: TERT promoter was genotyped in DNA from 80 archival PTCs by Sanger sequencing. Median follow-up was 106 months (range 1-270). Outcomes analysis was stratified according to disease and overall survival status. For each parameter, relative risk (RR) adjusted for age at first surgery and gender was estimated. Both univariate and multivariate analyses were performed using logistic regression, Kaplan-Meier survival analysis and Cox regression models. RESULTS: PTCs from 11 patients (14%) contained either C228T or C250T TERT promoter mutation. TERT mutations were significantly associated with adverse prognostic features such as older age (P = 0·002), male gender (P = 0·01) and Stage IV disease (P = 0·03). Four patients died from PTC during follow-up: 3 patients with TERT mutations (27%) and one without (1·5%). Disease-related mortality rate with or without TERT mutations was 33·7 vs 1·6 per 1000 patient-years respectively, that is 10 (95% CI = 1·0-104·1, P = 0·05) fold higher, after adjustment for age at first surgery and gender. The combination of TERT promoter mutation and BRAF(V) (600E) significantly increased disease-related death risk (P = 0·002). TERT mutations increased expression of a reporter gene in thyroid cells containing BRAF(V) (600E) . CONCLUSIONS: TERT promoter mutations are a major indicator of death due to PTCs. Conversely, absence of TERT mutations portends better survival.

Therapeutic options in papillary thyroid carcinoma: current guidelines and future perspectives.

The treatment of papillary thyroid cancer is now based on individual patient risk and response to therapies. Molecular techniques are increasingly being used to risk stratify and to guide therapeutic decisions. There have been advances in the treatment of local disease through surgery or radioiodine. Directed techniques can target metastatic disease including bisphosphonates, radiofrequency ablation or radiotherapy. Systemic therapies such as tyrosine kinase inhibitors show great promise although such treatment must be individualized. Future therapies will target treating radioiodine refractory disease.

Pheochromocytomas in Multiple Endocrine Neoplasia Type 2.

Pheochromocytoma (PC) is a neuroendocrine tumor that originates from chromaffin cells of the adrenal medulla. The production of catecholamines, including epinephrine, norepinephrine and dopamine, may lead to haemodynamic instability. Over 30% of PCs are associated with germline mutations, including re-arranged in transfection (RET) mutations seen in multiple endocrine neoplasia type 2 (MEN2) syndromes. Around 40% of individuals with MEN2 develop PC, though it is rarely the presenting feature. Compared to sporadic PC, MEN2-associated PC is more likely to be epinephine secreting and demonstrate bilateral adrenal involvement, and is less likely to be malignant. The diagnosis of PC requires clinical suspicion and biochemical testing, followed by imaging studies. Novel nuclear medicine modalities, including FDG positron emission tomography (PET) and 68Ga DOTATATE PET have added to the conventional techniques of 123I-metaiodobenzylguanindine (MIBG) scintigraphy, computer tomography and magnetic resonance imaging. Treatment of PC is surgical and requires peri-operative alpha and, frequently, beta blockade. Novel surgical techniques, such as adrenal sparing surgery and a laparoscopic approach, have decreased peri-operative morbidity. Surveillance for PC is life long, due to the risk of metastatic disease.

Patterns of structural recurrence in papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) is uncommonly associated with tumor-related mortality, although local recurrence can be a frequent and difficult problem. This study was conducted to clarify the pattern of structural locoregional recurrence in PTC. MATERIAL AND METHOD: A retrospective cohort study of patients undergoing surgical intervention for PTC was undertaken. Data were collected from a comprehensive thyroid cancer database maintained within a single tertiary referral center. The primary outcome measure was cancer recurrence requiring surgical intervention. Secondary outcome measures were site of recurrence, time to recurrence, and risk factors for recurrence. RESULTS: In the period 1980-2013, 1,183 patients with PTC were included in the study. The overall rate of structural recurrence requiring reoperative surgery was 7.9 %. The median time to reoperation was 31 months. Younger age, male gender, large primary tumor diameter, and number of positive lymph nodes at initial presentation were all significantly associated with disease recurrence. The lateral compartments (levels I, II, III, IV, V) were involved almost twice as frequently as the central compartment (level VI) (67 vs 32 %, P < 0.01). The distribution of recurrences was level I (1 %), level II (12 %), level III (18 %), level IV (18 %), level V (17 %), level VI (32 %), level VII (2 %). CONCLUSIONS: In a center with a liberal approach to central compartment lymph node dissection for PTC, the lateral neck compartment is the most common site of structural recurrence requiring reoperative surgery.

A randomized controlled pilot trial comparing the impact of access to clinical endocrinology video demonstrations with access to usual revision resources on medical student performance of clinical endocrinology skills.

BACKGROUND: Demonstrating competence in clinical skills is key to course completion for medical students. Methods of providing clinical instruction that foster immediate learning and potentially serve as longer-term repositories for on-demand revision, such as online videos demonstrating competent performance of clinical skills, are increasingly being used. However, their impact on learning has been little studied. The aim of this study was to determine the value of adjunctive on-demand video-based training for clinical skills acquisition by medical students in endocrinology. METHODS: Following an endocrinology clinical tutorial program, 2nd year medical students in the pre-assessment revision period were recruited and randomized to either a set of bespoke on-line clinical skills training videos (TV), or to revision as usual (RAU). The skills demonstrated on video were history taking in diabetes mellitus (DMH), examination for diabetes lower limb complications (LLE), and examination for signs of thyroid disease (TE). Students were assessed on these clinical skills in an observed structured clinical examination two weeks after randomization. Assessors were blinded to student randomization status. RESULTS: For both diabetes related clinical skills assessment tasks, students in the TV group performed significantly better than those in the RAU group. There were no between group differences in thyroid examination performance. For the LLE, 91.7% (n = 11/12) of students randomized to the video were rated globally as competent at the skill compared with 40% (n = 4/10) of students not randomized to the video (p = 0.024). For the DMH, 83.3% (n = 10/12) of students randomized to the video were rated globally as competent at the skill compared with 20% (n = 2/10) of students not randomized to the video (p = 0.007). CONCLUSION: Exposure to high quality videos demonstrating clinical skills can significantly improve medical student skill performance in an observed structured clinical examination of these skills, when used as an adjunct to clinical skills face-to-face tutorials and deliberate practice of skills in a blended learning format. Video demonstrations can provide an enduring, on-demand, portable resource for revision, which can even be used at the bedside by learners. Such resources are cost-effectively scalable for large numbers of learners.

Lobectomy and completion thyroidectomy rates increase after the 2015 American Thyroid Association Differentiated Thyroid Cancer Guidelines update.

Background: The 2015 American Thyroid Association (ATA) Guidelines permit thyroid lobectomy (TL) or total thyroidectomy in the management of low-risk papillary thyroid cancer (PTC). As definitive risk-stratification is only possible post-operatively, some patients may require completion thyroidectomy (CT) after final histopathological analysis. Methods: A retrospective cohort study of patients undergoing surgery for low-risk PTC in a tertiary referral centre was undertaken. Consecutive adult patients treated from January 2013 to March 2021 were divided into two groups (pre- and post-publication of ATA Guidelines on 01/01/2016). Only those eligible for lobectomy under rule 35(B) of the ATA Guidelines were included: Bethesda V/VI cytology, 1-4 cm post-operative size and without pre-operative evidence of extrathyroidal extension or nodal metastases. We examined rates of TL, CT, local recurrence and surgical complications. Results: There were 1488 primary surgical procedures performed for PTC on consecutive adult patients during the study period, of which 461 were eligible for TL. Mean tumour size (P = 0.20) and mean age (P = 0.78) were similar between time periods. The TL rate increased significantly from 4.5 to 18% in the post-publication period (P < 0.001). The proportion of TL patients requiring CT (43 vs 38%) was similar between groups (P = 1.0). There was no significant change in complications (P = 0.55) or local recurrence rates (P = 0.24). Conclusion: The introduction of the 2015 ATA Guidelines resulted in a modest but significant increase in the rate of lobectomy for eligible PTC patients. In the post-publication period, 38% of patients who underwent TL ultimately required CT after complete pathological analysis.

A Retrospective Cohort Study with Validation of Predictors of Differentiated Thyroid Cancer Outcomes.

Background: The goal of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is to treat metastasis and reduce recurrence risk. International guidelines provide broad risk stratification to aid treatment decisions, but a more nuanced approach to individualize care is warranted. We developed a predictive risk model for DTC. Methods: We performed a retrospective multivariable analysis of 899 patients who received RAI after thyroidectomy at a quaternary center in Australia between 2008 and 2016. Collected data included age, gender, histology, stimulated thyroglobulin (sTg), and 8th American Joint Committee Cancer (AJCC) staging. The ATA Modified Initial Risk (ATA) was calculated retrospectively. Recurrence was defined as clinically significant progression requiring either surgical intervention or administration of a second activity of RAI. Synchronous metastasis was defined as distant metastasis (i.e., outside of the neck) that was present at the time of diagnosis on structural imaging or initial post-iodine treatment scan. The features significantly associated with synchronous metastasis or recurrence were employed in the generation of a predictive risk model. A separate cohort of 393 patients who received RAI in 2017-2021 was used for validation. Results: On multivariate analysis, sTg ≥10 µg/L, extrathyroidal extension (ETE) and lymph node involvement predicted recurrence. Independent of ATA, patients with sTg ≥10 µg/L had a shorter disease-free survival (DFS) than those with sTg <10 µg/L (p < 0.001). The ETE stratified by four histological categories was significantly associated with worse DFS (p < 0.001). In a subset of patients, the presence of thyroglobulin antibody (TgAb) did not influence recurrence in patients with sTg <10 µg/L. On multivariate analysis, widespread ETE, sTg ≥10 µg/L, multifocal papillary thyroid cancer and follicular thyroid cancer were positively associated with synchronous metastasis. A predictive risk model was developed to estimate synchronous metastasis/recurrence risk and validated successfully in the second cohort. Conclusions: Our novel predictive risk model modifies and extends ATA stratification by including sTg and ETE, which we found to be independent predictors of both recurrence and synchronous metastasis in DTC.

Medullary thyroid carcinoma: long-term outcomes of surgical treatment.

BACKGROUND: Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths. METHODS: We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009. RESULTS: We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort. CONCLUSIONS: A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.

Parathyroid carcinoma encountered after minimally invasive focused parathyroidectomy may not require further radical surgery.

BACKGROUND: Parathyroid carcinoma accounts for <1% of tumors in primary hyperparathyroidism (PHPT). Distinguishing parathyroid malignancy from benign disease is difficult both before and after initial surgery. Despite the improved specificity of a malignant diagnosis with immunohistochemistry for parafibromin and PGP9.5, proven metastatic behavior remains the gold standard of diagnosis. Minimally invasive focused parathyroidectomy (MIP) is widely performed in patients with PHPT and positive localization studies; thus, it is inevitable that some parathyroid carcinomas will be encountered at MIP. We present our experience of this rare entity. METHODS: The present study represents a surgical case series of patients with parathyroid carcinoma encountered after MIP. The clinicopathological features of benign and malignant parathyroid tumors were compared. Multiple regression analysis was undertaken to compare indicators of malignancy. RESULTS: Between May 1999 and April 2010, a total of 1,292 patients underwent MIP at the University of Sydney Endocrine Surgical Unit, and a histopathological diagnosis of parathyroid carcinoma was made in seven patients (0.5%). Staining for parafibromin and/or PGP9.5 was abnormal in five carcinomas (71%). Despite subsequent unilateral thyroid lobectomy and lymphadenectomy in six patients, no further malignancy was identified in any specimens. Compared to controls, preoperative calcium (p = 0.04) and parathyroid hormone (p = 0.01) were significantly higher in patients with malignancy. The positive predictive value of these parameters for carcinoma was 56 and 75%, respectively. CONCLUSIONS: In patients diagnosed with parathyroid carcinoma after MIP where preoperative imaging had already demonstrated localized disease, revision en bloc surgery did not reveal any residual disease. The benefits of further radical surgery for parathyroid carcinoma after MIP remain controversial.

Complexities surrounding the diagnosis and management of hypercalcaemia in pregnancy.

SUMMARY: Hypercalcaemia in pregnancy is uncommon, with associated adverse obstetric and perinatal outcomes for both the mother and the fetus. Determination of causality is central to its management. Diagnostic imaging techniques are limited during pregnancy and the diagnosis is made more complex by physiological changes in calcium and vitamin D homeostasis in pregnancy. Further, therapeutic options are limited due to safety considerations for the pregnant woman and the developing foetus. Three cases of hypercalcaemia in pregnancy will be presented, highlighting the distinct aetiologies and management strategies for hypercalcaemia in pregnancy and the importance of early measurement of serum calcium in pregnancy screening. LEARNING POINTS: There are complex physiological changes in calcium balance in pregnancy, including increased calcium intestinal absorption and renal excretion. Hypercalcaemia in pregnancy is uncommon but has important potential maternal and foetal complications, making a compelling argument for routine antenatal, calcium screening. Identifying the cause of hypercalcaemia in pregnancy can be challenging due to the complex placental interplay in biochemical test interpretation and due to safety constraints restricting imaging and surgery. Acute medical management of hypercalcaemia must be considered in the context of both maternal and foetal well-being, along with gestational age and specific consideration for the safety of the developing fetus in late gestation.