Ruth S. Prichard

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.

Current and Emerging Therapies for Advanced Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Complete surgical resection offers the only potential for cure; however, even after apparently successful excision, local or metastatic recurrence is frequent. Treatment options for advanced ACC are severely limited. Mitotane is the only recognized adrenolytic therapy available; however, response rates are modest and unpredictable whereas systemic toxicities are significant. Reported responses to conventional cytotoxic chemotherapy have also been disappointing, and the rarity of ACC had hampered the ability to undertake randomized clinical studies until the establishment of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma. This yet-to-be reported study seeks to identify the most effective first- and second-line cytotoxic regimens. The past decade has also seen increasing research into the molecular pathogenesis of ACCs, with particular interest in the insulin-like growth factor signaling pathway. The widespread development of small molecule tyrosine kinase inhibitors in broader oncological practice is now allowing for the rational selection of targeted therapies to study in ACC. In this review, we discuss the currently available therapeutic options for patients with advanced ACC and detail the molecular rationale behind, and clinical evidence for, novel and emerging therapies.

Axillary nodal burden in primary breast cancer patients with positive pre-operative ultrasound guided fine needle aspiration cytology: management in the era of ACOSOG Z011.

INTRODUCTION Recent years have seen a dramatic shift to more conservative management of the axilla in patients with a positive sentinel lymph node biopsy (SLNB). Identification of nodal disease with positive pre-operative ultrasound guided axillary fine needle aspiration cytology (AUS/FNAC) may represent a higher axillary disease burden mandating an axillary clearance and thus an upfront SLNB may be avoided. The aims of this study were to quantify nodal burden in patients with positive pre-operative AUS/FNAC and identify patients who may have been able to avoid an axillary clearance (ALND) based on ACOSOG Z011 criteria. METHODS A retrospective review of a prospectively maintained database identified patients with positive pre-operative AUS/FNAC between 2007 and 2012. Core biopsies were excluded. Demographic and tumour characteristics were analysed. Eligibility for ACOSOG Z011 criteria was assessed and patients who may have avoided ALND were identified. RESULTS 432 patients were identified with positive AUS/FNAC. 85 patients were excluded leaving 347 for analysis. Median age was 56 years (22-87), median tumour size was 25 mm (1.5 mm-150 mm) and median tumour pathology was grade 3 (50%) and invasive ductal carcinoma (82%). Median number of nodes removed at ALND was 23 (1-55) with a median number of positive nodes being 4 (1-47). 134 (39%) patients had ≤2 positive nodes identified on ALND making them eligible for the ACOSOG Z011 study. When other ACOSOG Z011 exclusion factors were applied only 27 (7.8%) patients may have avoided ALND. CONCLUSIONS Nodal positivity on AUS/FNAC is associated with higher axillary disease burden. Few patients would satisfy ACOSOG/Z011 criteria and avoid ALND making an upfront SLNB unnecessary.

Isothermal Diagnostic Assays for monitoring single nucleotide polymorphisms in Necator americanus associated with Benzimidazole drug resistance

Background Soil-transmitted helminths (STHs) are the most prevalent intestinal helminths of humans, and a major cause of morbidity in tropical and subtropical countries. The benzimidazole (BZ) drugs albendazole (ABZ) and mebendazole (MBZ) are used for treatment of human STH infections and this use is increasing dramatically with massive drug donations. Frequent and prolonged use of these drugs could lead to the emergence of anthelmintic resistance as has occurred in nematodes of livestock. Previous molecular assays for putative resistance mutations have been based mainly on PCR amplification and sequencing. However, these techniques are complicated and time consuming and not suitable for resource-constrained situations. A simple, rapid and sensitive genotyping method is required to monitor for possible developing resistance to BZ drugs. Methods To address this problem, single nucleotide polymorphism (SNP) detection assays were developed based on the Smart amplification method (SmartAmp2) to target codons 167, 198, and 200 in the β-tubulin isotype 1 gene for the hookworm Necator americanus. Findings Diagnostic assays were developed and applied to analyze hookworm samples by both SmartAmp2 and conventional sequencing methods and the results showed high concordance. Additionally, fecal samples spiked with N. americanus larvae were assessed and the results showed that the Aac polymerase used has high tolerance to inhibitors in fecal samples. Conclusion The N. americanus SmartAmp2 SNP detection assay is a new genotyping tool that is rapid, sensitive, highly specific and efficient with the potential to be used as a field tool for monitoring SNPs associated with BZ resistance. However, further validation on large numbers of field samples is required.

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.

Mucoepidermoid Carcinoma of the Thyroid: A Report of Three Cases and Postulated Histogenesis

BACKGROUND Primary mucoepidermoid carcinoma (MEC) of the thyroid is a rare clinical and pathological entity that accounts for <0.5% of all thyroid malignancies. Although the histogenesis has been controversial, most investigators now favor it as arising from either metaplasia of thyroid follicular epithelium or heterologous de-differentiation from papillary thyroid carcinoma (PTC). We report three cases of thyroid MEC found in continuity with, and clearly arising from de-differentiation of, well-differentiated thyroid carcinomas (WDTCs). PATIENT FINDINGS AND SUMMARY The cases presented here included two women (aged 22 and 52) and one man (aged 58). One of these cases arose in conjunction with PTC, one with follicular thyroid carcinoma (FTC), and one with Hurthle cell carcinoma (HCC). In all three cases, there was a gradual transition in morphology between the areas of typical WDTC and the areas showing MEC differentiation. In addition, immunohistochemistry demonstrated a gradual loss of thyroid specific markers (thyroid transcription factor-1, thyroglobulin) mirroring the change in morphology. CONCLUSION We conclude that thyroid MEC can arise from metaplastic de-differentiation of WDTC, including FTC or HCC in addition to PTC. Currently, we recommend that after excision, each of the WDTC and MEC components of these tumors be treated with targeted adjuvant therapies, which may involve radioactive-iodine ablation, thyrotropin suppression, and external beam radiotherapy.

A prospective study of heart rate variability in endocrine surgery: surgical training increases consultant's mental strain.

BACKGROUND The aim of this study was to determine whether instructing surgical trainees in technically demanding procedures causes alterations in heart rate variability (HRV) and mental strain in supervising surgeons. METHODS A prospective study of HRV in two consultant surgeons and three endocrine surgical fellows undertaking 50 total thyroidectomy procedures was performed. Fellows and consultant surgeons performed 50 lobectomies as primary operator and 50 as assistants in a cross-over design. HRV was measured during dissection around the recurrent laryngeal nerve. The overall heart rate, time, and frequency domain parameters of HRV, specifically the low frequency/high frequency (LF/HF) ratio, which was used as a measure of cardiac and mental stress, were correlated with the surgical role, particularly teaching surgical fellows at critical points. RESULTS HRV data were collected between October 2009 and March 2010. There was no statistically significant difference in the mean heart rate for either group of participants regardless of role. Energy expenditure was greater for fellows when operating (p = 0.03). Fellows demonstrated a higher LF/HF ratio when acting as the primary operator (p = 0.02). All time domain parameters of HRV increased when attending surgeons were operating, denoting more cardiac relaxation. Similarly, the LF/HF ratio was significantly greater for attending surgeons when teaching (p = 0.05), suggesting an increase in mental strain. CONCLUSIONS The teaching of complex but common endocrine surgical procedures is associated with a measurable increase in mental strain of consultant surgeons, as determined by HRV. Fellows demonstrated increased levels of stress when acting as primary operators.

Postmastectomy radiotherapy: indications and implications.

BACKGROUND Although breast conservation surgery, when combined with radiotherapy, has been shown to provide excellent locoregional control for breast cancer, approximately one third of women with breast cancer require mastectomy. Many of these women are offered immediate reconstruction. Postmastectomy radiotherapy (PMRT) is indicated in some cases, but is associated with side-effects, including its impact on the reconstructed breast. OBJECTIVE To review the pertinent issues surrounding PMRT, including patient selection for radiotherapy and the effect of radiotherapy on reconstructive decisions. METHODS A literature review was performed using the Medline database. CONCLUSIONS PMRT is indicated in patients who are deemed to have a high risk of loco-regional recurrence. Although PMRT is strongly recommended for patients with four or more positive lymphnodes, other indications for PMRT remain controversial. Immediate reconstruction post mastectomy has been shown to have favorable outcomes. However, PMRT may increase the need for revision surgery post immediate reconstruction. There are few randomized trials looking at these key issues, and the evidence is largely derived from observational retrospective studies. Patients should be carefully counseled before a decision is made to proceed with immediate reconstruction, where there is a high chance that PMRT may be indicated.

Pseudoangiomatous stromal hyperplasia of the breast: an unusual pathology necessitating bilateral mastectomy during pregnancy.

A 27-year-old woman underwent endoscopic total thyroidectomy because of the papillary thyroid carcinoma. The I whole-body scan following post-operative radioactive iodine treatment showed no significantly increased accumulation of iodine-131. One year after initial operation, lateral node enlargement was detected during routine ultrasonography. Fine-needle aspiration cytology confirmed metastatic papillary thyroid carcinoma. Computed tomography demonstrated multiple lymphadenopathies in the right internal jugular chain and a suspicious enhancing nodular lesion just beneath the hyoid bone (Fig. 1). A right modified radical neck dissection and regional dissection around the remnant pyramidal lobe were performed in a conventional manner. Operative findings showed multiple enlarged lymph nodes on the right internal jugular chain, which were dissected clearly with no complications, and the 1.5-cm nodular lesion in the remnant pyramidal lobe just beneath the hyoid bone was removed clearly. Post-operative histopathological examination revealed three out of 48 metastatic lymph nodes on the right internal jugular chain, and labelled the remnant pyramidal lobe lesion as papillary thyroid carcinoma. The thyroid pyramidal lobe (also called Lalouette’s lobe) represents the inferior part of the thyroglossal duct and arises from the isthmus of the thyroid gland. Although the pyramidal lobe is considered a common thyroid lobe, it is present in only about half of all individuals. If the pyramidal lobe is present, it is generally excised during thyroid surgery for thyroid carcinoma. Papillary thyroid carcinoma has a relatively good prognosis; however, recurrence ranges from 8.0% to 23.0%. The most common recurrence sites following total thyroidectomy are the central compartment lymph nodes and proper thyroid tissue of the thyroid bed. In the present case, the pyramidal lobe was spared in the initial operation and later hosted an unusual recurrence of malignancy. In conclusion, complete surgical resection of the thyroid, including the pyramidal lobe, is mandatory for treatment of papillary thyroid carcinoma.