Improved concordance of challenging human epidermal growth factor receptor 2 dual in-situ hybridisation cases with the use of a digital image analysis algorithm in breast cancer.

AIMS: Accurate assessment of human epidermal growth factor receptor 2 (HER2) expression by HER2 immunohistochemistry and in-situ hybridisation (ISH) is critical for the management of patients with breast cancer. The revised 2018 ASCO/CAP guidelines define 5 groups based on HER2 expression and copy number. Manual pathologist quantification by light microscopy of equivocal and less common HER2 ISH groups (groups 2-4) can be challenging, and there are no data on interobserver variability in reporting of these cases. We sought to determine whether a digital algorithm could improve interobserver variability in the assessment of difficult HER2 ISH cases. METHODS AND RESULTS: HER2 ISH was evaluated in a cohort enriched for less common HER2 patterns using standard light microscopy versus analysis of whole slide images using the Roche uPath HER2 dual ISH image analysis algorithm. Standard microscopy demonstrated significant interobserver variability with a Fleiss's kappa value of 0.471 (fair-moderate agreement) improving to 0.666 (moderate-good) with the use of the algorithm. For HER2 group designation (groups 1-5), there was poor-moderate reliability between pathologists by microscopy [intraclass correlation coefficient (ICC) = 0.526], improving to moderate-good agreement (ICC = 0.763) with the use of the algorithm. In subgroup analysis, the algorithm improved concordance particularly in groups 2, 4 and 5. Time to enumerate cases was also significantly reduced. CONCLUSION: This work demonstrates the potential of a digital image analysis algorithm to improve the concordance of pathologist HER2 amplification status reporting in less common HER2 groups. This has the potential to improve therapy selection and outcomes for patients with HER2-low and borderline HER2-amplified breast cancers.

Encapsulated papillary carcinoma of the breast: an invasive tumor with excellent prognosis.

UNLABELLED: Papillary carcinoma (PC) of the breast, which accounts for 0.5% to 1% of breast cancer, is a distinct histologic subtype that is characterized by malignant epithelial proliferation supported by fibrovascular stalks. However, the classification of PC (whether they are in situ or invasive), its behavior, and management remain a matter of debate. METHODS: In this study, we reviewed 302 PCs including 247 pure PCs without coexisting conventional non-PCs collected from 3 institutions. This included 208 (84%) intracystic PCs (IPC), 30 (12%) solid PCs (SPC), and 9 (4%) papillary ductal carcinoma in situ (DCISs). In addition, previous studies of PC were reviewed. This included 339 pure PCs of a total of 521 PC patients. Clinical and outcome analyses were carried out to assess nature and behavior of these lesions and to determine their optimal outcome-based management. RESULTS AND CONCLUSIONS: SPC is more frequently associated with coexisting conventional invasive carcinoma than IPC (P<0.05). Although the majority of papillary DCIS and some cases of IPC and SPC (both called encapsulated PC) that are surrounded by an intact layer of myoepithelial cells are considered to be true in situ lesions, PC lacking a peripheral layer of myoepithelial cells can be regarded as a special type of invasive carcinoma associated with low incidence of stromal/skeletal muscle invasion, low frequency of lymph node metastasis (3%), and infrequent development of local or distant recurrence. These lesions are therefore characterized by indolent behavior and extremely favorable prognosis. Encapsulated PC can be treated with adequate local therapy. Routine use of adjuvant therapy, particularly chemotherapy, is clearly not appropriate in view of the very low risk of subsequent events. However, hormonal therapy may be indicated in certain cases such as recurrent PC.

Parotid pleomorphic adenoma with solitary renal metastasis.

We present a rare case of renal metastasis of a recurrent pleomorphic adenoma of the parotid gland in an elderly woman. Metastasising pleomorphic adenoma shows malignant clinical behaviour, and although it appears histologically benign, there may be unknown molecular features that determine its unusual ability to spread.

Haematological toxicity of drugs used in psychiatry.

Almost all classes of psychotropic agents have been reported to cause blood dyscrasias. Mechanisms include direct toxic effects upon the bone marrow, the formation of antibodies against haematopoietic precursors or involve peripheral destruction of cells. Agranulocytosis is probably the most important drug-related blood dyscrasia. The mortality from drug-induced agranulocytosis is 5-10% in Western countries. The manifestations of agranulocytosis are secondary to infection. Aggressive treatment with intravenous broad-spectrum antimicrobials and bone marrow stimulants may be required. Of drugs encountered in psychiatry, antipsychotics including clozapine (risk of agranulocytosis approximately 0.8%, predominantly in the first year of treatment) and phenothiazines (chlorpromazine agranulocytosis risk approximately 0.13%), and antiepileptics (notably carbamazepine, neutropenia risk approximately 0.5%) are the most common causes of drug-related neutropenia/agranulocytosis. Drugs known to cause neutropenia should not be used concomitantly with other drugs known to cause this problem. High temperature and other indicators of possible infection should be looked for routinely during treatment. Clozapine is well known as a drug that can cause blood dyscrasias, but olanzapine and other atypicals may also cause similar problems. In addition to genetic factors, there are likely to be dose-related and immunological components to these phenomena. Important lessons have been learnt from the haematological monitoring that is necessary with clozapine and the monitoring has been very successful in preventing deaths related to clozapine-induced agranulocytosis. Continuing research into the mechanisms of drug-induced neutropenia and agranulocytosis may serve to further enhance the safe use not only of clozapine, but also of other agents.

Rechallenge with clozapine following leucopenia or neutropenia during previous therapy.

BACKGROUND: Further treatment with clozapine is contraindicated in any patient who has previously experienced leucopenia or neutropenia during clozapine therapy. AIMS: To investigate the results of such a rechallenge in 53 patients. METHOD: An analysis was made of the demographic, haematological and outcome data of patients in the UK and Ireland who were rechallenged with clozapine following leucopenia or neutropenia during previous clozapine therapy. RESULTS: Of 53 patients who were rechallenged, 20 (38%) experienced a further blood dyscrasia. In 17 of these 20 patients (85%) the second blood dyscrasia was more severe (P<0.001), in 12 (60%) it lasted longer (P=0.0368) and in 17 (85%) it occurred more quickly on rechallenge (P<0.001). Of the original 53 patients, 55% (29 patients) are still receiving clozapine. CONCLUSIONS: No clear risk factor for repeat blood dyscrasias was identified. Despite this, after risks and benefits have been considered, rechallenge may well be justified in some patients.