RATIONALE AND OBJECTIVES:In the care of patients with breast cancer, it is now common for a radiologist to place biopsy markers in suspicious axillary lymph nodes that are biopsied so that the lymph nodes can be identified for later surgical excision. Migration of markers has been reported, but has only been sparingly evaluated. The objective of this study was to evaluate the migration of biopsy markers in a porcine model using longitudinal X-ray computed tomography (CT) imaging MATERIALS AND METHODS: We report the evaluation of migration of a commercial biopsy marker (Tumark Professional Q) and a marker made of polymethyl methacrylate (PMMA) that is being developed for improved ultrasound imaging detection. We tested these markers alone as well as combined with adjacent hernia mesh and injections of ethanol to promote local inflammatory responses to mitigate migration. We imaged animals (N = 3) at monthly time points with CT to evaluate marker-to-lymph node spatial relationships. RESULTS:We observed that migration was the largest with the PMMA marker (< 10 mm) and was mitigated with the mesh and ethanol perturbations. Histomorphometry analysis of the markers revealed that a rind around the markers was formed and increased with the inclusion of mesh and ethanol. CONCLUSION:This pilot study demonstrated that marker migration could be characterized over time and different perturbations modified the amount of migration. Future studies should incorporate randomization of marker placement and larger animal cohorts.

ObjectiveWe have studied the use of polymethyl methacrylate (PMMA) as an alternative biopsy marker that is readily detectable with ultrasound Doppler twinkling in cases of in vitro, ex vivo, or limited duration in vivo settings. This study investigates the long-term safety and ultrasound Doppler twinkling detectability of a PMMA breast biopsy marker following local perturbations and different dwell times in a 6-mo animal experiment.MethodsThis study, which was approved by our Institutional Animal Care and Use Committee, involved three pigs and utilized various markers, including PMMA (Zimmer Biomet), 3D-printed, and Tumark Q markers. Markers were implanted at different times for each pig. Mesh material or ethanol was used to induce a local inflammatory reaction near certain markers. A semiquantitative twinkling score assessed twinkling for actionable localization during monthly ultrasounds. At the primary endpoint, ultrasound-guided localization of lymph nodes with detectable markers was performed. Following surgical resection of the localized nodes, histomorphometric analysis was conducted to evaluate for tissue ingrowth and the formation of a tissue rind around the markers.ResultsNo adverse events occurred. Twinkling scores of all markers for all three pigs decreased gradually over time. The Q marker exhibited the highest mean twinkling score followed by the PMMA marker, PMMA with mesh, and Q with ethanol. The 3D-printed marker with mesh and PMMA with ethanol had the lowest scores. All wire-localized lymph nodes were successfully resected. Despite varying percentages of tissue rind around the markers and a significant reduction in overall twinkling (p < 0.001) over time, mean PMMA twinkling scores remained clinically actionable at 6 and 5 mo using a General Electric C1-6 probe and 9L-probe, respectively.ConclusionsIn this porcine model, the PMMA marker demonstrates an acceptable safety profile. Clinically actionable twinkling aids PMMA marker detection even after 6 mo of dwell time in porcine lymph nodes. The Q marker maintained the greatest twinkling over time compared to all the other markers studied.

center dot Context.-Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. Objective.-To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast spec-imens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. Data Sources.-English-language literature on the sub-ject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. Conclusions.-This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifica-tions for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

Supplementary Figure 2 - PDF file 9846K, Patient Flow Diagram for N9831 MYC IHC Analysis

Supplemental Table 1. Heterogeneity of Cores in Patients with Multiple Cores (N=961) Supplemental Table 2. Clinicopathological Characteristics of Cohort and Non-Cohort Patients. Supplemental Table 3. Patient/Disease Characteristics by {greater than or equal to}2+ IGF1R protein staining >0% (N=1734). Supplemental Table 4. DFS for Patients with Hormone Receptor Positive Patients Breast Tumors by IGF1R Membrane Staining (0,1+ vs 2,3+ ) N=909 (Stratified by nodal status) Supplemental Table 5. DFS for Patients with Hormone Receptor-Negative Breast Tumors by IGF1R Membrane Staining (0,1+ vs 2,3+ ) N=825 (Stratified by nodal status) Supplemental Figure 1. NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy Supplemental Figure 2. Patient Flow Diagram. Supplemental Figure 3. Disease-Free Survival by IGF1R Protein Expression in Patients with Hormone Receptor-Positive Breast Tumors. Supplemental Figure 4. Disease-Free Survival by IGF1R Protein Expression in Patients with Hormone Receptor-Negative Breast Tumors.

Supplementary Tables 1-5 - PDF file 91K, Supplementary Table 1. Patient Characteristics by IHC cMYC Cohort vs Non-Cohort; Supplementary Table 2. Correlation of MYC Nuclear Staining with HER2 FISH - Overall; Supplementary Table 3. Correlation of MYC Nuclear Staining with HER2 FISH - Arm A; Supplementary Data Table 4. Correlation of MYC Nuclear Staining with HER2 FISH - Arm B; Supplementary Table 5. Correlation of MYC Nuclear Staining with HER2 FISH - Arm C

Supplementary Figure 1 - PDF file 5863K, NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy

BACKGROUND:Stromal and immune cell composition alterations in benign breast tissue associate with future cancer risk. Pilot data suggest the innate microbiome of normal breast tissue differs between women with and without breast cancer. Microbiome alterations might explain tissue microenvironment variations associated with disease status.METHODS:Prospectively-collected sterile normal breast tissues from women with benign (n=16) or malignant (n=17) disease underwent 16SrRNA sequencing with Illumina MiSeq and Hybrid-denovo pipeline processing. Breast tissue was scored for fibrosis and fat percentages and immune cell infiltrates (lobulitis) classified as absent/mild/moderate/severe. Alpha and beta diversity were calculated on rarefied OTU data and associations analyzed with multiple linear regression and PERMANOVA.RESULTS:Breast tissue stromal fat% was lower and fibrosis% higher in benign disease versus cancer (median 30% versus 60%, p=0.01, 70% versus 30%, p=0.002, respectively). The microbiome varied with stromal composition. Alpha diversity (Chao1) correlated with fat% (r=0.38, p=0.02) and fibrosis% (r=-0.32, p=0.05) and associated with different microbial populations as indicated by beta diversity metrics (weighted UniFrac, p=0.08, fat%, p=0.07, fibrosis%). Permutation testing with FDR control revealed taxa differences for fat% in Firmicutes, Bacilli, Bacillales, Staphylococcaceae and genus Staphylococcus, and fibrosis% in Firmicutes, Spirochaetes, Bacilli, Bacillales, Spirochaetales, Proteobacteria RF32, Sphingomonadales, Staphylococcaceae, and genera Clostridium, Staphylococcus, Spirochaetes, Actinobacteria Adlercreutzia. Moderate/severe lobulitis was more common in cancer (73%) than benign disease (13%), p=0.003, but no significant microbial associations were seen.CONCLUSION:These data suggest a link between breast tissue stromal alterations and its microbiome, further supporting a connection between the breast tissue microenvironment and breast cancer.

CONTEXT.—:Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. OBJECTIVE.—:To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. DATA SOURCES.—:English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. CONCLUSIONS.—:This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

A young man was found to have desmoid tumors involving multiple sites. This tumor was from the abdominal wall. In addition to multiple desmoid tumors, numerous polyps were identified in the colon, stomach, and duodenum. A mutation in what gene is likely involved in a patient with desmoid tumors and numerous gastric, duodenal, and colon polyps?a.TP53b.RETc.APCd.BRAF Answer: c. APC The APC (adenomatous polyposis coli; OMIM 611731) gene is a tumor suppressor gene on chromosome 5q21-22. It is associated with familial adenomatous polyposis, which is an autosomal dominant condition associated with numerous colorectal and gastrointestinal adenomas and can be associated with prominent extraintestinal manifestations including desmoid tumors, thyroid tumors such as cribriform morular thyroid carcinoma, osteomas of bone, congenital hypertrophy of retinal pigment epithelium, and cutaneous lesions.1Groen E.J. Roos A. Muntinghe F.L. et al.Extra-intestinal manifestations of familial adenomatous polyposis.Ann Surg Oncol. 2008; 15: 2439-2450Crossref PubMed Scopus (174) Google Scholar,2Valanzano R. Cama A. Volpe R. et al.Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Novel criteria of assessment and correlations with constitutional adenomatous polyposis coli gene mutations.Cancer. 1996; 78: 2400-2410Crossref PubMed Scopus (37) Google Scholar Other variants of the disease exist with other tumors (eg, Turcot syndrome and central nervous system tumors). Desmoid tumors occur in approximately 10% to 15% of individuals with familial adenomatous polyposis. Desmoid tumors may occur more frequently after surgery.3Saito Y. Hinoi T. Ueno H. et al.Risk factors for the development of desmoid tumor after colectomy in patients with familial adenomatous polyposis: multicenter retrospective cohort study in Japan.Ann Surg Oncol. 2016; 23: 559-565Crossref PubMed Scopus (20) Google Scholar The adenomas in familial adenomatous polyposis have a histology similar to sporadic tubular adenomas.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Answer: c. Anastomosing hemangiomas have been found to have recurrent GNAQ and GNA14 mutations.Anastomosing hemangioma is a benign vascular tumor that has a predilection for the retroperitoneum and genitourinary tract as well as for the paraspinal region. 1,2These tumors are often incidentally identified.The tumors have a spongy consistency and on histologic evaluation are composed of capillary vessels with an anastomosing and sinusoidal pattern.The tumors lack the markedly infiltrative growth pattern present in angiosarcoma.Anastomosing hemangiomas have been found to have recurrent GNAQ and GNA14 mutations. 3,4

Background Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. Methods Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. Results Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). Conclusion Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

A 5-cm breast mass was excised from an adult female and diagnosed by pathology as a matrix producing metaplastic breast carcinoma. Which of the following statements regarding breast metaplastic carcinoma is correct?a.Metaplastic carcinoma is a common type of breast carcinomab.Metaplastic carcinoma is usually positive for hormonal receptorsc.Metaplastic carcinoma is a heterogeneous group of invasive breast carcinomas with squamous and/or mesenchymal-like morphologyd.Metaplastic carcinoma often occurs in young women Answer: c. Metaplastic carcinoma is a heterogeneous group of invasive breast carcinomas with squamous and/or mesenchymal-like morphology. Metaplastic carcinoma is a heterogeneous group of invasive breast carcinomas with differentiation of the neoplastic epithelium towards squamous cells and/or mesenchymal-like elements, such as spindle, chondroid, and osseous cells. Metaplastic carcinomas account for less than 1% of all invasive breast cancers. Metaplastic carcinoma occurs more common in post-menopausal women and is usually negative for hormonal receptors. A recent SEER study found 3-year overall survival is greatest for women whose metaplastic breast cancers are positive for HER2 compared with those with triple negative or HER2 negative/hormone receptor positive metaplastic breast cancers, a finding more pronounced for stage III disease.1Schroeder M.C. Rastogi P. Geyer Jr., C.E. Miller L.D. Thomas A. Early and locally advanced metaplastic breast cancer: presentation and survival by receptor status in Surveillance, Epidemiology, and End Results (SEER) 2010–2014.Oncologist. 2018; 23: 481-488Crossref PubMed Scopus (32) Google Scholar Matrix-producing metaplastic carcinoma is a type of metaplastic carcinoma with heterologous mesenchymal differentiation, characterized by carcinomatous cells in a chondromyxoid matrix.2Downs-Kelly E. Nayeemuddin K.M. Albarracin C. Wu Y. Hunt K.K. Gilcrease M.Z. Matrix-producing carcinoma of the breast: an aggressive subtype of metaplastic carcinoma.Am J Surg Pathol. 2009; 33: 534-541Crossref PubMed Scopus (50) Google Scholar Generally, matrix-producing metaplastic carcinoma has a worse clinical outcome than conventional invasive ductal breast carcinoma; however, a recent Surveillance Epidemiology and End Results (SEER) study suggests similar survival with HER2-positive metaplastic breast cancer and HER2-positive conventional invasive ductal breast carcinoma.1Schroeder M.C. Rastogi P. Geyer Jr., C.E. Miller L.D. Thomas A. Early and locally advanced metaplastic breast cancer: presentation and survival by receptor status in Surveillance, Epidemiology, and End Results (SEER) 2010–2014.Oncologist. 2018; 23: 481-488Crossref PubMed Scopus (32) Google Scholar

OBJECTIVES We investigated the impact of our laboratory's reflex testing process for resolving ERBB2 (HER2) status on breast cancer samples that require additional workup after fluorescence in situ hybridization (FISH), per guideline recommendations published in 2018 by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). METHODS In total, 500 breast cancer specimens with ERBB2 FISH results in groups 2 through 4 (all reported as immunohistochemistry [IHC] equivocal [2+] at external laboratories) were resubmitted for IHC testing in our laboratory. Per the ASCO/CAP guideline, FISH was rescored when internal IHC was also equivocal (2+), targeted to tumor areas demonstrating more intense IHC staining, if observed. RESULTS Reflex IHC/FISH testing changed the final reported ERBB2 status in 185 of 500 (37.0%) samples. Result changes included discordant IHC (n = 4 score 0, n = 132 score 1+, and n = 16 score 3+) and discordant FISH (n = 33). Numerical differences in FISH scores were comparable for targeted vs nontargeted FISH rescoring (P = .086 for ERBB2 copy number; P = .49 for ERBB2 ratio). Two cases showed larger differences in FISH scores, suggesting heterogeneity. CONCLUSIONS Retesting of breast cancer samples with equivocal IHC frequently changes IHC results, but targeted reanalysis of borderline FISH results rarely identifies significant differences in ERBB2 copy number or ratio.

Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

Context.-Guidelines for HER2 testing in breast cancer have changed over time, from the US Food and Drug Administration guideline to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines published in 2007, 2013, and 2018. Objective.-To investigate the change in assignment of HER2 status in breast cancers with equivocal (2+) immunohistochemistry (IHC) results by fluorescence in situ hybridization (FISH) following implementation of the ASCO/CAP 2018 guideline. Design.-The study included 3556 invasive breast cancers that were HER2 equivocal (2+) by IHC and were submitted to our FISH laboratory after July 2018. Reflex testing (with repeat IHC staining) was performed on certain categories of FISH results known as groups 2, 3, and 4. Concomitant review of IHC and FISH was performed on these reflex cases per 2018 guideline recommendations. The FISH data were analyzed to compare US Food and Drug Administration and ASCO/ CAP 2007, 2013, and 2018 interpretations. Results.-Of 3548 invasive breast cancers with complete data available, the percentage agreement for FISH according to different guidelines was highest for ASCO/ CAP 2018 versus US Food and Drug Administration (96.5%), followed by ASCO/ CAP 2018 versus 2007 (93.8%), and lowest with ASCO/CAP 2018 versus 2013 (83.7%). Per the 2018 guideline, reflex IHC testing was performed on 633 breast cancers (17.8%); the majority of reflex testing results were negative (541 of 633; 85.5%). The overall distribution of HER2 FISH results (per the 2018 guideline) was 88.5% negative and 11.5% positive. Conclusions.-By eliminating the equivocal FISH category, the 2018 ASCO/CAP guideline significantly reduced the HER2 FISH-positive rate in tumors with equivocal (2+) IHC results.

A palpable breast mass was excised and diagnosed as juvenile papillomatosis in a young woman. Which of the following statements regarding juvenile papillomatosis is incorrect?a.Juvenile papillomatosis is a localized benign proliferative lesion and usually occurs in women younger than 30 years of ageb.Juvenile papillomatosis typically presents as a solitary, discrete, unilateral massc.Juvenile papillomatosis is a common lesion and can be easily diagnosed by core biopsyd.Surgical excision is usually the treatment of choice for juvenile papillomatosis Answer: c Juvenile papillomatosis is a rare mass-like benign proliferative lesion in young women.1Rosen P.P. Kimmel M. Juvenile papillomatosis of the breast: a follow-up study of 41 patients having biopsies before 1979.Am J Clin Pathol. 1990; 93: 599-603Crossref PubMed Scopus (53) Google Scholar Histologic examination reveals a constellation of proliferative changes and large cysts; thus, is rarely diagnosed as juvenile papillomatosis on core biopsy. Patients with bilateral, multicentric juvenile papillomatosis or family history of breast cancer have a higher risk of developing breast cancer. Recently, juvenile papillomatosis of the breast has been found to have frequent associations with PIK3CA and/or AKT1 mutations.2Guillet C. Rechsteiner M. Bellini E. et al.Juvenile papillomatosis of the breast (Swiss cheese disease) has frequent associations with PIK3CA and/or AKT1 mutations.Hum Pathol. 2020; 98: 64-73Crossref PubMed Scopus (3) Google Scholar Another recent study identified clonal somatic PIK3CA hotspot mutations in 2 of 3 cases of juvenile papillomatosis, including 1 with an associated ductal carcinoma in situ and invasive ductal carcinoma.3D'Alfonso T.M. Pareja F. Da Cruz Paula A. et al.Whole-exome sequencing analysis of juvenile papillomatosis and coexisting breast carcinoma.J Pathol Clin Res. 2021; 7: 113-120Crossref PubMed Scopus (1) Google Scholar Interestingly, the in situ and invasive carcinomas and the juvenile papillomatosis had a somatic clonal PIK3CA E542K hotspot mutation.3D'Alfonso T.M. Pareja F. Da Cruz Paula A. et al.Whole-exome sequencing analysis of juvenile papillomatosis and coexisting breast carcinoma.J Pathol Clin Res. 2021; 7: 113-120Crossref PubMed Scopus (1) Google Scholar

This thyroid tumor was identified incidentally with choline PET-CT which was being performed in follow-up of prostate cancer. The thyroid tumor was diagnosed as thyroid carcinoma on fine needle aspiration. A left lobectomy with isthmusectomy (hemithyroidectomy) was performed, and a 1.3 cm papillary thyroid carcinoma, classic/conventioinal type, was identified. What statement is most accurate regarding papillary thyroid carcinoma?a.The most common genetic alteration in papillary thyroid carcinoma involves RASb.Although papillary thyroid carcinomas may be classified into different variants (classic/conventional, tall cell, hobnail, solid cell, follicular variant, etc...), the behavior and prognosis are similar regardless of variantc.Papillary thyroid carcinoma is less common than other types of thyroid carcinomad.The most relevant genetic alterations in papillary thyroid carcinoma involve BRAF, RET, and RAS, are generally mutually exclusive, and are associated with activation of the MAPK pathway Answer: d. The most relevant genetic alterations in papillary thyroid carcinoma involve BRAF, RET, and RAS, are generally mutually exclusive, and are associated with activation of the MAPK pathway Papillary thyroid carcinoma is a predominant form of thyroid cancer. Different variants of papillary thyroid carcinoma can have prognostic significance as some variants such as the tall cell variant in the hobnail variant may be associated with more aggressive disease.1Nath M.C. Erickson L.A. Aggressive variants of papillary thyroid carcinoma: Hobnail, tall cell, columnar, and solid.Adv Anat Pathol. 2018; 25: 172-179Crossref PubMed Scopus (40) Google Scholar Some variants are significant due to their possible association with other diseases such as the cribriform morular variant of papillary thyroid carcinoma and familial adenomatous polyposis.2Erickson L.A. Unique clinical significance of the cribriform-morular variant of papillary thyroid carcinoma.Mayo Clin Proc. 2020; 95: 831-833Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The most relevant genetic alterations in papillary thyroid carcinoma involve BRAF, RET, and RAS.3Lloyd R.V. Osamura R.Y. Kloppel G. Posai J. Editors (2017). WHO Classification of Tumours of Endocrine Organs.4th edition. IARC, Lyon, France2017Google Scholar BRAF mutations are very common in papillary thyroid carcinoma, particularly classic/conventional and tall cell variants. However, the follicular variant of papillary thyroid carcinoma is more often associated with RAS alterations. These alterations are generally mutually exclusive. Point mutations such as that of BRAF V600E are particularly common, but gene fusions and copy number variations can also be identified in some papillary thyroid carcinomas.3Lloyd R.V. Osamura R.Y. Kloppel G. Posai J. Editors (2017). WHO Classification of Tumours of Endocrine Organs.4th edition. IARC, Lyon, France2017Google Scholar The papillary thyroid carcinoma in this case was conventional/classic type and associated with BRAF mutation – the most common driver mutation in papillary thyroid carcinoma. The following photomicrograph demonstrates the histologic features of the tumor with an inset showing positivity with BRAF immunostain.

To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52–1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. ClinicalTrials.gov Identifier: NCT00684983