Assessment of HER2 and Ki67 in adenocarcinomas

Biomarkers in tumor tissue can predict cancer behavior or can be targeted with targeted therapy. Two examples of such biomarkers are HER2 and Ki67. These biomarkers are assessed with stains on tissue of patients in clinical pathology. Timco Koopman is a resident in pathology and works at the pathology department of the UMCG. For his thesis he researched the quantitative assessment of HER2 and Ki67 in malignant tumors of glandular tissue (adenocarcinomas). HER2 is a receptor protein that is best known from breast and stomach cancer. Anti-HER2-therapy for HER2-positive tumors of these organs can increase a patient’s chances of curation and survival. Ki67 is a protein that is present in dividing cells. As such, quantification of Ki67 reflects the growth speed and aggressiveness of tumors. The first part of the thesis is about HER2. Koopman explored the prevalence of HER2-positivity in gastric and esophageal cancer and describes how HER2 should be determined in these tumors. Koopman also describes why assessment of HER2 in other tumors than breast, stomach or esophagus can be more problematic. The second part of the thesis is about digital image analysis. Digitizing in modern pathology is on the rise. Digitized images can be analyzed with specific software. Koopman describes why digital image analysis in clinical pathology will benefit the reliability and reproducibility of the assessment of HER2 and Ki67

Assessment of HER2 and Ki67 in adenocarcinomas

Biomarkers in tumor tissue can predict cancer behavior or can be targeted with targeted therapy. Two examples of such biomarkers are HER2 and Ki67. These biomarkers are assessed with stains on tissue of patients in clinical pathology. Timco Koopman is a resident in pathology and works at the pathology department of the UMCG. For his thesis he researched the quantitative assessment of HER2 and Ki67 in malignant tumors of glandular tissue (adenocarcinomas). HER2 is a receptor protein that is best known from breast and stomach cancer. Anti-HER2-therapy for HER2-positive tumors of these organs can increase a patient’s chances of curation and survival. Ki67 is a protein that is present in dividing cells. As such, quantification of Ki67 reflects the growth speed and aggressiveness of tumors. The first part of the thesis is about HER2. Koopman explored the prevalence of HER2-positivity in gastric and esophageal cancer and describes how HER2 should be determined in these tumors. Koopman also describes why assessment of HER2 in other tumors than breast, stomach or esophagus can be more problematic. The second part of the thesis is about digital image analysis. Digitizing in modern pathology is on the rise. Digitized images can be analyzed with specific software. Koopman describes why digital image analysis in clinical pathology will benefit the reliability and reproducibility of the assessment of HER2 and Ki67

A case report of an unusual non-mucinous papillary variant of CPAM type 1 with KRAS mutations

BACKGROUND: congenital pulmonary airway malformation (CPAM) is the most frequent congenital lung disorder. CPAM type 1 is the most common subtype, typically having a cystic radiological and histological appearance. Mucinous clusters in CPAM type 1 have been identified as premalignant precursors for mucinous adenocarcinoma. These mucinous adenocarcinomas and the mucinous clusters in CPAM commonly harbor a specific KRAS mutation. CASE PRESENTATION: we present a case of a 6-weeks-old girl with CPAM type 1 where evaluation after lobectomy revealed a highly unusual complex non-mucinous papillary architecture in all cystic parts, in which both mucinous clusters and non-mucinous papillary areas harbored the known KRAS mutation. CONCLUSIONS: we found that a KRAS mutation thought to be premalignant in mucinous clusters only, was also present in the other cyst lining epithelial cells of this unusual non-mucinous papillary variant of CPAM type 1, warranting clinical follow-up because of uncertain malignant potential

What is the added value of digital image analysis of HER2 immunohistochemistry in breast cancer in clinical practice? A study with multiple platforms

Aims We aimed to compare digital image analysis (DIA) of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) in breast cancer by two platforms: (i) to validate DIA against standard diagnostics; and (ii) to evaluate the added value of DIA in clinical practice. Methods and results HER2 IHC and in-situ hybridisation (ISH) were performed on 152 consecutive invasive breast carcinomas. IHC scores were determined with DIA using two independent platforms. Manual scoring was performed by two independent observers. HER2 status was considered positive in 3+ and ISH-positive 2+ cases. HER2 status using DIA was compared to HER2 status with standard diagnostics (manual scoring with ISH in 2+ cases). Interplatform agreement of IHC scores was 'moderate' (linear weighted kappa = 0.58), agreement between manual scoring and platform A was 'moderate' (kappa = 0.60) and between manual scoring and platform B 'almost perfect' (kappa = 0.85). Compared to manual scoring, DIA resulted in a reduction of 2+ cases from 17.1 to 1.3% with platform A and from 17.1 to 15.8% with platform B. However, compared to standard diagnostics, there were three false-negative cases with DIA using platform A [81.3% sensitivity, 100% specificity, 100% positive predictive value (PPV), 97.8% negative predictive value (NPV)]. Sensitivity, specificity, PPV and NPV were 100% with DIA using platform B. Conclusions DIA of HER2 IHC is a valid tool in determining HER2 status in breast carcinoma. Algorithms in different platforms can behave differently, and optimal calibration is essential. In clinical practice, DIA offers an objective alternative to manual scoring, but a reduction in 2+ cases could result in loss of sensitivity

Robot-Assisted Laparoscopic Resection of a Todani Type II Choledochal Malformation

Choledochal malformation (CM) comprise various congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. CM is classified into five different types. Our case describes a 58-year-old man presenting with acute abdominal pain. Further examination showed a Todani type II CM. Treatment for type II is complete cyst excision without the need for an extrahepatic bile duct resection. A robot-assisted laparoscopic resection of the CM was performed and the patient recovered without complications. Pathology results showed a Todani type II malformation in which complete squamous metaplasia has occurred. In this paper, we report, to the best of our knowledge, the first description of a robot-assisted laparoscopic resection of a type II CM

Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma

A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental glomerulosclerosis. Surprisingly, the biopsy specimen revealed diffuse glomerular deposition of amyloid that was proved to be derived from the calcitonin hormone (Acal), produced by the medullary thyroid carcinoma. This amyloid was also present in an abdominal fat pad biopsy. Although local ACal deposition is a characteristic feature of medullary thyroid carcinoma, the systemic amyloidosis involving the kidney that is presented in this case report has not to our knowledge been described previously and may be the result of long-term high plasma calcitonin levels. Our case illustrates that systemic calcitonin amyloidosis should be considered in the differential diagnosis of proteinuria in patients with medullary thyroid carcinoma

Digital image analysis of HER2 immunohistochemistry in gastric- and oesophageal adenocarcinoma:a validation study on biopsies and surgical specimens

AimsTo test the validity of diagnostics incorporating digital image analysis (DIA) for human epidermal growth factor 2 (HER2) immunohistochemistry (IHC) in gastro-oesophageal adenocarcinomas, as an alternative to current standard diagnostics using manual scoring. Methods and resultsWe included 319 consecutive gastro-oesophageal adenocarcinomas (232 biopsies and 87 surgical specimens). DIA was applied to determine HER2 IHC classification, using both standard breast cancer (BC) and modified gastro-oesophageal cancer (GEC) cut-offs. Consensus manual scores were established by four independent observers. Chromogenic in-situ hybridization (CISH) was performed on all 2+ cases by manual scoring, DIA or both. HER2 status was considered positive in 3+ and CISH-positive 2+ cases. Overall agreement between DIA and consensus manual scores was 76.5% (weighted = 0.66, BC cut-offs) and 85.6% (weighted = 0.80, GEC cut-offs). Agreement was similar for biopsies and surgical specimens. All disagreement occurred in the manual IHC equivocal cases. DIA resulted in a reduction of 2+ cases: 75.8% with BC cut-offs and 46.5% with GEC cut-offs. HER2 status was positive in 48 cases (15%) with standard diagnostics and DIA using GEC cut-offs, and 46 cases (14.4%) using BC cut-offs (all with CISH in 2+ cases). Considering standard diagnostics as a reference, DIA showed 93.8% sensitivity and 99.6% specificity (BC cut-offs) or 97.9% sensitivity and 99.6% specificity (GEC cut-offs). ConclusionsDIA is a reliable and feasible alternative to manual HER2 IHC scoring in gastro-oesophageal adenocarcinoma, both in biopsies and surgical specimens, leading to a reduction of 2+ cases for which subsequent ISH testing is required