Comprehensive genomic profiling of metastatic collecting duct carcinoma, renal medullary carcinoma, and clear cell renal cell carcinoma.

INTRODUCTION AND OBJECTIVE: Unlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy. MATERIAL AND METHODS: DNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations. RESULTS: mCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb. CONCLUSION: Genomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies.

Exceptionality of Distant Metastasis in Node-Negative Hereditary and Sporadic Medullary Thyroid Cancer: Lessons Learned.

CONTEXT: Risk factors of lymph node and distant metastases have rarely been analyzed in hereditary and sporadic medullary thyroid cancer (MTC) using large genetic-clinical data sets. OBJECTIVE: This comprehensive investigation aimed to explore risk factors of lymph node and distant metastases and interdependencies between age at thyroidectomy, primary tumor size, lymph node metastasis, and distant metastasis in patients with hereditary and sporadic MTC. METHODS: We performed comparative analyses of risk factors of metastasis, stratified by hereditary MTC (4 mutational risk categories) and sporadic MTC. RESULTS: There were 1115 patients with hereditary MTC (307 patients) or sporadic MTC (808 patients). Age at thyroidectomy increased proportionately from 12.2, 22.7, 34.3, and 49.8 years for patients with decreasing mutational risk, compared with 52.1 years for patients with sporadic MTC. Metastatic primary tumors overall were 10.7 to 19.4 mm larger in node-positive patients and 15.9 to 19.3 mm larger in distant metastatic patients at thyroidectomy than nonmetastatic tumors. Distant metastases were noted in 13% to 50% of node-positive vs 0% of node-negative hereditary MTC, and in 23.5% of node-positive vs 1.7% of node-negative sporadic MTC. In multivariable logistic regression analysis for sporadic MTC, lymph node metastasis contributed to distant metastasis (odds ratio 12.4) more than primary tumor size (odds ratios of 7.8, 5.5, and 2.4 for tumors measuring >60, 41-60, and 21-40 mm, respectively). CONCLUSION: When thyroidectomy is performed before lymph node metastases have developed, distant metastases are exceptional, both in patients with hereditary MTC (irrespective of mutational risk level) and patients with sporadic MTC.

Predicting Outcomes in Sporadic and Hereditary Medullary Thyroid Carcinoma over Two Decades.

Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease (n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.

Divergent Metastatic Patterns Between Subtypes of Thyroid Carcinoma Results From the Nationwide Dutch Pathology Registry.

BACKGROUND: Metastatic disease is the main cause of cancer-related mortality in thyroid carcinoma (TC) patients. Clinical studies have suggested differences in metastatic patterns between the different subtypes of TC. This study systematically evaluates the metastatic patterns of different subtypes in TC patients. METHODS: A nationwide review of pathological records of all 650 patients diagnosed with a primary malignancy in the thyroid who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). RESULTS: Metastatic disease was present in 228 (35.1%) patients and was found in 38.7%, 17.3%, 75.4%, and 47.8% of patients with follicular, papillary, anaplastic, and medullary types of TC, respectively (P < .0001). The majority of patients had more than 1 metastasis. The most common site of metastatic disease was the lung for papillary (79.7%), follicular (72.9%), and anaplastic (92.1%) carcinoma but not for medullary carcinoma (56.3%), P < .0001. Medullary carcinoma patients most frequently had metastases to the liver (81.3%). The combination of metastases also differed between subtypes. CONCLUSION: There are major differences in metastatic patterns between different subtypes of TC. The patterns and frequencies identified in this autopsy study may reflect the underlying biology of metastatic thyroid cancer and have potential to influence future monitoring and treatment strategies depending on clinical correlations.

Renal Medullary Carcinoma With Metastasis to the Temporal Fossa and Orbit.

A 22-year-old Hispanic man with sickle cell trait presented with blurred vision, double vision, and pain with OD movement. MRI demonstrated an extra-axial mass centered around the temporal bone with extension into the middle cranial fossa and lateral aspect of the extra-conal right orbit, and mass effect on the lateral rectus muscle. Biopsy of the lesion was consistent with renal medullary carcinoma. CT chest/abdomen/pelvis confirmed a primary tumor in the right kidney. No additional metastases were found. Renal medullary carcinoma is a rare, highly aggressive malignancy, which almost exclusively affects young men of African descent with sickle cell trait or sickle cell disease. The authors present the second confirmed case of renal medullary carcinoma metastatic to the orbit, with ocular symptoms prior the typical presenting symptoms of flank pain and hematuria.Renal medullary carcinoma is a highly aggressive malignancy, most commonly seen in African American patients with sickle cell disease. Involvement of the orbit is rare and visual symptoms may precede systemic diagnosis.

68Ga-DOTANOC and 18F-FDG PET/CT in metastatic medullary thyroid carcinoma: novel correlations with tumoral biomarkers.

OBJECTIVE: Metastatic disease is common in medullary thyroid carcinoma (MTC) and it is usually detected by raising calcitonin and carcinoembryonic antigen (CEA) levels. Nuclear medicine imaging has an important role in lesion identification/characterisation. We aim to compare 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT performance and to explore the correlations between tumoral markers and functional imaging. METHODS: This a retrospective cross-sectional study including 13 patients with MTC and high calcitonin/CEA levels that underwent both 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT. RESULTS: 68Ga-DOTANOC PET/CT identified MTC metastases in 2twopatients that were 18F-FDG-negative (sensitivity of 69.2% vs. 53.9%, respectively). 68Ga-DOTANOC PET/CT also detected a higher number of lesions than 18F-FDG PET/CT in seven patients, with only one patient showing the opposite pattern. Both differences lacked statistical significance (p = 0.50 and p = 0.86, respectively) but 68Ga-DOTANOC PET/CT better performance allowed changes in patients' management. 68Ga-positive/18F-FDG-negative patients were the ones with the lowest calcitonin doubling time and presented a CEA doubling time >24 months, while the patient with more 18F-FDG-positive lesions was the one with the highest CEA/calcitonin ratio. The number of lesions found in 68Ga-DOTANOC PET/CT were correlated with calcitonin levels (r = 0.73; p < 0.01) but not with CEA ones (r = 0.42; p = 0.15). The number of 18F-FDG hypermetabolic focus were correlated with CEA levels (r = 0.60; p < 0.05) but not with calcitonin (r = 0.48; p = 0.09). CONCLUSIONS: This is the first study to describe a positive correlation between 68Ga-positive lesions and calcitonin levels and between 18F-FDG-positivity and CEA levels. Tumoral markers pattern in metastatic MTC could help clinicians to decide which exam to perform first.

Radioguided hepatic resection with 18F-DOPA in a patient with metastatic medullary thyroid carcinoma. / Resección hepática radioguiada con 18F-DOPA en un paciente con carcinoma medular de tiroides metastásico.

INTRODUCTION: Medullary carcinoma accounts for 1-2% of all thyroid malignancies. 13-20% of patients present with distant metastasis, with 45% of the cases affecting the liver. CLINICAL CASE: A 50-year-old woman, diagnosed with medullary thyroid carcinoma, was treated with total thyroidectomy and a modified neck dissection in 1999. Two lymph node recurrences in the neck were treated with surgical resection; during surveillance, she developed elevated calcitonin levels, the recurrence site was identified with 18F-DOPA PET/CT in the liver. Metabolic activity was not associated with a visible lesion in CT, MRI nor ultrasound. Radioguided surgery with 18F-DOPA allowed an anatomic resection of segments IVb and V. DISCUSSION: In patients with medullary carcinoma and elevated calcitonin during surveillance, 18F-DOPA PET/CT is an option to evaluate the site of recurrence. Radioguided resection was feasible in this patient, whose hepatic recurrence was not visible with any other imaging method. CONCLUSION: Radioguided hepatic resection with 18F-DOPA in metastatic medullary thyroid carcinoma is feasible when the recurrence site is not anatomically identified by any other imaging studies.

Correlation of Cystatin E/M with Clinicopathological Features and Prognosis in Triple-Negative Breast Cancer.

BACKGROUND: Among all kinds of breast cancer, triple-negative breast cancer (TNBC) is the most aggressive, with the poorest prognosis and highest mortality rates. Thus, novel biomarkers that personalize the therapeutic regimen and evaluate prognosis for TNBC patients should be determined. METHODS: We analyzed the cystatin E/M (CST6) expression profiles of 161 TNBC tissues and 14 noncancerous tissues through multiple statistical analyses. We also investigated the relationship of CST6 expression with clinical parameters and evaluated the prognostic value of CST6 in 161 TNBC patients. RESULTS: CST6, a member of the cystatin superfamily, was remarkably more up-regulated in TNBC tissues than in adjacent normal breast tissues. High CST6 expression was frequently observed in white people and associated with a high risk of lymph-node metastasis. Cox regression analysis confirmed that the high CST6 expression was an independent predictor of disease-free survival in TNBC. Kaplan-Meier analysis further revealed that high CST6 expression caused a low disease-free survival rate. CONCLUSION: CST6 is involved in the progression of TNBC and may act as a tumor-promoter gene. A systematic literature review shows that our study is the first to explore the relationship between CST6 and TNBC.

Survival in patients with medullary thyroid cancer after less than the recommended initial operation.

BACKGROUND AND OBJECTIVES: We aimed to evaluate the disease specific-survival (DSS) of patients with Medullary Thyroid Cancer (MTC) confined to the central neck based on the extent of the initial operation. METHODS: This retrospective review of patients with MTC from the SEER registry from 2004 to 2012 excluded patients with lateral neck involvement or distant metastases. RESULTS: The cohort (n = 766) included 85(11%) less than total thyroidectomies (TT), 212(28%) TT alone, and 469(61%) TT with lymph node excision. Mean tumor size was similar (2.2cm for

MicroRNA-21 and long non-coding RNA MALAT1 are overexpressed markers in medullary thyroid carcinoma.

BACKGROUND: Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are well-recognized post-transcriptional regulators of gene expression. This study examines the expression of microRNA-21 (miR-21) and lncRNA MALAT1 in medullary thyroid carcinomas (MTCs) and their effects on tumor behavior. METHODS: Tissue microarrays (TMAs) were constructed using normal thyroid (n=39), primary tumors (N=39) and metastatic MTCs (N=18) from a total of 42 MTC cases diagnosed between 1987 and 2016. In situ hybridization with probes for miR-21 and MALAT1 was performed. PCR quantification of expression was performed in a subset of normal thyroid (N=10) and primary MTCs (N=32). An MTC-derived cell line (MZ-CRC-1) was transfected with small interfering RNAs (siRNAs) targeting miR-21 and MALAT1 to determine the effects on cell proliferation and invasion. RESULTS: In situ hybridization (ISH) showed strong (2+ to 3+) expression of miR-21 in 17 (44%) primary MTCs and strong MALAT1 expression in 37 (95%) primary MTCs. Real-time PCR expression of miR-21 (P<0.001) and MALAT1 (P=0.038) in primary MTCs were significantly higher than in normal thyroid, supporting the ISH findings. Experiments with siRNAs showed inhibition of miR-21 and MALAT1 expression in the MTC-derived cell line, leading to significant decreases in cell proliferation (P<0.05) and invasion (P<0.05). CONCLUSION: There is increased expression of miR-21 and MALAT1 in MTCs. This study also showed an in vitro pro-oncogenic effect of MALAT1 and miR-21 in MTCs. The results suggest that overexpression of miR-21 and MALAT1 may regulate MTC progression.

Renal cell carcinoma, unclassified with medullary phenotype: poorly differentiated adenocarcinomas overlapping with renal medullary carcinoma.

Renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma arising in the collecting system and requiring careful correlation with status of sickle cell trait. A panel of international experts has recently proposed provisional diagnostic terminology, renal cell carcinoma, unclassified, with medullary phenotype, based on encountering an extraordinarily rare tumor with RMC morphology and immunophenotype in an individual proven not to have a hemoglobinopathy. Herein, we extend this observation to a cohort of 5 such tumors, morphologically similar to RMC, lacking SMARCB1 expression by immunohistochemistry, but each without evidence of a hemoglobinopathy. The tumors arose in 4 men and 1 woman with a mean age of 44 years, occurring in 3 left and 2 right kidneys. Clinically, aggression was apparent with involvement of perinephric adipose tissue in all 5 cases, nodal metastasis in 4 of 5 cases, and death of disease in 4 of 5 cases within 3-27 months. Histologic sections showed poorly differentiated adenocarcinoma, often with solid and nested growth patterns, as well as infiltrative glandular, tubulopapillary, cribriform, or reticular growth. Rhabdoid and sarcomatoid cytomorphology was seen in a subset. All tumors showed PAX8 nuclear positivity and SMARCB1 loss, with OCT3/4 expression in 4 of 5 cases. In summary, this first series of renal cell carcinoma, unclassified, with medullary phenotype documents tumors with morphologic, immunophenotypic, and prognostic features of RMC occurring in individuals without sickle cell trait. Although greater biologic and molecular understanding is needed, the available evidence points to these cases representing a sporadic counterpart to sickle cell trait-associated RMC.

The correlations between DNA methylation and polymorphisms in the promoter region of the human telomerase reverse transcriptase (hTERT) gene with postoperative recurrence in patients with thyroid carcinoma (TC).

BACKGROUND: This study aims at exploring the correlations between DNA methylation and polymorphisms in the promoter region of the human telomerase reverse transcriptase (hTERT) gene and postoperative recurrence in patients with thyroid carcinoma (TC). METHODS: A total of 312 patients diagnosed with TC were chosen for the study and categorized into recurrence (n = 75) and non-recurrence (n = 237) groups. The hTERT rs2736100 and rs2736098 polymorphisms were detected by performing polymerase chain reaction-restriction fragment length polymorphism. DNA methylation in the promoter region of hTERT gene was evaluated by pyrosequencing. A telephonic and/or outpatient follow-up was conducted for all patients. The correlations of DNA methylation and polymorphisms in the promoter region of hTERT with postoperative recurrence of TC patients underwent analysis. RESULTS: The patient in the recurrence group showed evidently different pathological types and tumor stages in comparison to the non-recurrence group. The GG genotype of hTERT rs2736100 might increase the recurrence risk of TC patients. No correlations between hTERT rs2736098 polymorphisms and recurrence risk were observed. Compared to the TT + TG genotype frequency, the rs2736100 GG genotype frequency increased in patients without multicentricity, patients with extrathyroidal invasion, patients with lymph node metastasis, patients with undifferentiated carcinoma, and patients in the III + IV stage. The recurrence group showed significantly higher DNA methylation level compared to the non-recurrence group. The DNA methylation level was closely associated to tumor stage and lymph node metastasis of TC patients in the recurrence group. CONCLUSIONS: The DNA methylation and rs2736100 polymorphisms in the promoter region of hTERT gene might be in correlation to postoperative recurrence of TC patients.

Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters.

BACKGROUND: Microsatellite instability (MSI) operates as the second major pathway in the colorectal carcinogenesis. Although genetic testing remains the gold standard for the detection of MSI, the College of American Pathologists (CAP) recommends an initial immunohistochemical workup with a four-antibody panel (MLH1, PMS2, MSH2, and MSH6) to screen for a defective mismatch repair system. An increased trend towards young age colorectal carcinoma (CRC) has been noticed in our population over recent years; however, neither screening for MSI by immunohistochemistry (IHC)/genetic testing was done nor were its morphological features studied. We aimed to determine the frequency of mismatch repair deficiency (dMMR) by loss of IHC expression of the aforementioned enzymes in CRC patients and its correlatation with clinicopathologic parameters. METHODS: This was a retrospective study conducted at Liaquat National Hospital, Karachi, between 2012 and 2015. A total of 100 cases of CRC were included in the study that underwent surgical resection. IHC stains using antibodies MLH1, PMS2, MSH2, and MSH6 were performed by DAKO EnVision method on representative tissue blocks. The results were interpreted by senior histopathologists and correlated with clinico-pathological parameters. RESULTS: A total of 100 cases of CRC were studied that included 51 males and 49 females. Thirty-four percent (n = 34) of the patients showed loss of IHC staining for MMR markers. Combined loss of expression for MLH1/PMS2 were observed in 16% (n = 16) of the cases. Loss of MSH2/MSH6 were seen in 6% (n = 6) of the cases. Loss of expression for all markers were noted in 7% (n = 7) of the cases. There were 5% (n = 5) of the cases that showed isolated loss of MLH1 only. The tumors with dMMR status were significantly associated with right-sided location (p = 0.013), exhibited intra-tumoral lymphocytosis (p = 0.007), and lymphovascular invasion (p = 0.043). No significant association was seen with gender, age, tumor stage, grade, or other morphological features. CONCLUSION: The frequency of mismatch repair deficiency in CRC patients was found to be 34% in Pakistani population which warrants further genetic testing to exclude Lynch syndrome. Moreover, right-sided location and intra-tumoral lymphocyte count may be used to identify patients who may need further workup.

Renal medullary carcinoma: A national analysis of 159 patients.

BACKGROUND: Renal medullary carcinoma (RMC) is an aggressive malignancy seen predominantly in young males with sickle cell trait. RMC is poorly understood, with fewer than 220 cases described in the medical literature to date. We used a large national registry to define the typical presentation, treatments, and outcomes of this rare tumor. METHODS: The National Cancer Database was queried for patients under 40 years of age diagnosed with RMC from 1998 to 2011. An analysis of patient and tumor characteristics, treatment details, and overall survival (OS) was undertaken, and factors associated with mortality were identified using multivariable regression analysis. RESULTS: In total, 159 patients with RMC were identified, of whom a majority were male (71%), African American (87%), and had metastatic disease (71%). Median tumor size was 6 cm and median survival was 7.7 months. Most patients underwent surgery (60%) and chemotherapy (65%). Few patients received radiation (12%). Patients with metastatic disease had a significantly worse median survival (4.7 vs. 17.8 months, P < 0.001) and were less likely to receive surgery (42% vs. 91%, P < 0.001). Age and tumor size did not appear to impact OS. CONCLUSION: In the largest cohort to date of patients with RMC, we found a dismal median survival of less than 8 months. Age and tumor size were not associated with OS. Metastatic disease at presentation was the main negative prognostic indicator in RMC and was present in a majority of patients at the time of diagnosis.

Metastatic lymph node ratio can further stratify risk for mortality in medullary thyroid cancer patients: A population-based analysis.

Medullary thyroid cancer (MTC) has a propensity to cervical lymph node metastases (LNM). Recent studies have shown that both the number of involved lymph nodes (LNs) and the metastatic lymph node ratio (MLNR) confer prognostic information. This study was to determine the predictive value of MLNR on cancer-specific survival (CSS) in SEER (Surveillance, Epidemiology and End Results)-registered MTC patients treated with thyroidectomy and lymphadenectomy between 1991 and 2012, investigate the cutoff points for MLNR in stratifying risk of mortality and provide evidence for selection of appropriate treatment strategies. X-tile program determined 0.5 as optimal cut-off value for MLNR in terms of CSS in 890 MTC patients. According to multivariate Cox regression analysis, MLNR (0.50-1.00) is a significant independent prognostic factor for CSS (hazard ratio 2.161, 95% confidence interval 1.327-3.519, p=0.002). MLNR (0.50-1.00) has a greater prognostic impact on CSS in female, non-Hispanic white, T3/4, N1b and M1 patients. The lymph node yield (LNY) influences the effect of MLNR on CSS; LNY ≥9 results in MLNR (0.50-1.00) having a higher HR for CSS than MLNR (0.00-0.49). In conclusion, higher MLNRs predict poorer survival in MTC patients. Eradication of involved nodes ensures accurate staging and maximizes the ability of MLNR to predict prognosis.

Can We Predict the Lateral Compartment Lymph Node Involvement in RET-Negative Patients with Medullary Thyroid Carcinoma?

BACKGROUND: Lateral lymph node dissection (LND) in the absence of macroscopic nodal metastasis remains controversial in sporadic medullary thyroid carcinoma (MTC). OBJECTIVES: The aims of our study were to determine the risk of lateral lymph node (LN) metastases with a focus on lateral contralateral N1, and to define a risk-adapted surgical treatment for these patients. METHODS: All patients who underwent surgery from 1980 to 2012 for previously untreated RET-negative MTC were reviewed. We focused on the lateral compartments of LN metastases and identified three groups: no lateral LN metastases, ipsilateral lateral (ILL)-LN metastases with no contralateral LN involvement, and contralateral lateral (CLL)-LN metastases. RESULTS: Overall, 131 patients underwent surgery for RET-negative MTC. A total thyroidectomy with LND was performed in 112 patients (85 %), including 97 patients who had an ILL-LND and 92 patients who had a CLL-LND. Lateral LN metastases (N1) occurred in 40 patients (37 %): 31 patients (32 %) had ILL-LN metastases with no contralateral LN involvement, and 9 patients (10 %) had CLL-LN metastases. The preoperative cut-offs for LN metastases in the ILL compartment were very low, with a smallest tumor size of 5 mm, and lowest serum calcitonin level of 38 pg/ml. Disease-free survival rates decreased from 92 % for patients with no lateral LN metastases to 41 % for patients with ILL-LN metastases and 0 % for patients with CLL-LN metastases. CONCLUSIONS: ILL-LND should be performed in every patient and only a minority of MTC patients with small micro-MTC, and low serum calcitonin levels should not have a CLL-LND.

Evaluation of the tracing effect of carbon nanoparticle and carbon nanoparticle-epirubicin suspension in axillary lymph node dissection for breast cancer treatment.

BACKGROUND: Carbon nanoparticle suspension, using smooth carbon particles at a diameter of 21 nm added with suspending agents, is a stable suspension of carbon pellets of 150 nm in diameter. It is obviously inclined to the lymphatic system. There were some studies reporting that carbon nanoparticles are considered as superior tracers for sentinel lymph nodes because of their stability and operational feasibility. However, there were few study concerns about the potential treatment effect including tracing and local chemotherapeutic effect of carbon nanoparticle-epirubicin suspension on breast cancer with axillary metastasis. METHODS: In the current study, a randomized controlled analysis was performed to investigate the potential treatment effect of carbon nanoparticle-epirubicin suspension on breast cancer with axillary metastasis. A total of 90 breast cancer patients were randomly divided into three equal groups: control, tracer, and drug-load groups. The control group patients did not receive any lymphatic tracers, the tracer group patients were subcutaneously injected with 1 ml carbon nanoparticle suspension, and the drug-load group patients were injected with 3 ml carbon nanoparticle-epirubicin suspension at four separate sites around the areola 24 h before surgery. Modified radical mastectomy, endoscopic subcutaneous mammary resection plus axillary lymph node dissection, and immediate reconstruction with implants or breast-conserving surgery were performed. RESULTS: The mean number of the dissected lymph nodes per patient was significantly higher in the tracer (21.3 ± 6.1) and drug-load (19.5 ± 3.7) groups than in the control group (16.7 ± 3.4) (P < 0.05). Most lymph nodes in the former two groups were stained black (75.7 and 73.3 %, respectively), but with no significant difference between the groups. Most metastatic lymph nodes were also stained black in the tracer group (68.6 %) and drug-load group (78.1 %) and with no significant difference between the groups (P = 0.198). Microscopic examination revealed that the carbon nanoparticles were localized around or among the cancer cell masses and residues of necrotized cancer cells surrounded by fibroblastic proliferation could be found within the stained lymph nodes in the drug-load group. CONCLUSIONS: The majority of axillary lymph nodes were stained black by the suspension of carbon nanoparticles, which helped identify the lymph nodes from the surrounding tissues and avoided aggressive axillary treatment. Thus, a combination therapy of carbon nanoparticles with epirubicin could play an important role in lymphatic chemotherapy without affecting tracing. TRIAL REGISTRATION: ChiCTRTRC13003419.

Medullary carcinoma in the colorectum: a systematic review and meta-analysis.

Medullary carcinoma (MC) is a very rare variant of colorectal carcinoma (CRC). Its clinicopathologic findings are not fully elucidated. The aim of this study was to investigate the clinicopathological characteristics of MC in the colorectum through a systematic review and meta-analysis. The meta-analysis examined the incidence, age, sex, site, mismatch repair deficiency (MMRd), MMR protein expression, ARID1A expression, BRAF(V600E) mutation, KRAS mutation, and survival rate of MC. The 21469 CRCs included 462 MCs in 16 eligible studies, representing an estimated incidence of MC of 0.027 (95% confidence interval [CI] 26 0.016-0.045). MC frequently occurred in female patients and in the right colon. Lymph node metastasis of MC was significantly lower than that of poorly differentiated adenocarcinoma/undifferentiated adenocarcinoma (PDA/UDA). In addition, MC had a higher MMRd rate (0.892, 95% CI 0.758-0.956), higher BRAF(V600E) mutation rate (0.652, 95% CI 0.143-0.954) and lower KRAS mutation rate (0.171, 95% CI 0.065-0.378) than PDA/UDA and conventional adenocarcinoma. Patients with MC had significantly better overall survival rate compared to patients with PDA/UDA (hazard ratio 0.441, 95% CI 0.262-0.742). However, there was no significant difference of overall survival rate between MC and conventional adenocarcinoma patients. MC predominantly occurred in females and in the right colon, and had different molecular characteristics and behaviors compared to PDA/UDA and conventional adenocarcinoma.