Infiltrating stromal immune cells in inflammatory breast cancer are associated with an improved outcome and increased PD-L1 expression.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and rapidly progressive form of invasive breast cancer. The aim of this study was to explore the clinical evolution, stromal tumour-infiltrating lymphocytes (sTIL) infiltration and programmed death-ligand 1 (PD-L1) expression in a large IBC cohort. PATIENTS AND METHODS: Data were collected prospectively from patients with IBC as part of an international collaborative effort since 1996. In total, 143 patients with IBC starting treatment between June 1996 and December 2016 were included. Clinicopathological variables were collected, and sTIL were scored by two pathologists on standard H&E stained sections. PD-L1 expression was assessed using a validated PD-L1 (SP142) assay. A validation cohort of 64 patients with IBC was used to test our findings. RESULTS: Survival outcomes of IBC remained poor with a 5-year overall survival (OS) of 45.6%. OS was significantly better in patients with primary non-metastatic disease who received taxane-containing (neo)adjuvant therapy (P = 0.01), had a hormone receptor-positive tumour (P = 0.001) and had lower cN stage at diagnosis (P = 0.001). PD-L1 positivity on immune cells (42.9%) was higher in IBC than in non-IBC in both our patient samples and the validation cohort. Furthermore, PD-L1 expression predicted pCR (P = 0.002) and correlated with sTIL infiltration (P < 0.001). sTIL infiltration of more than 10% of the stroma was a significant predictor of improved OS (HR 0.47, 95% CI 0.27-0.81, P = 0.006) in a multivariate model. CONCLUSIONS: IBC is characterised by poor survival and high PD-L1 immunoreactivity on sTIL. This suggests a role for PD1/PD-L1 inhibitors in the treatment of IBC. Furthermore, we showed that PD-L1 expression predicts response to neo-adjuvant therapy and that sTIL have prognostic significance in IBC.

The combined presence of CD20 + B cells and PD-L1 + tumor-infiltrating lymphocytes in inflammatory breast cancer is prognostic of improved patient outcome.

PURPOSE: The purpose of the study was to evaluate protein expression of PD-L1 and CD20 as prognostic biomarkers of patient outcome in inflammatory breast cancer (IBC) samples. METHODS: PD-L1 and CD20 protein expression was measured by immunohistochemistry in 221 pretreatment IBC biopsies. PD-L1 was assessed in tumor cells (PD-L1+ tumor cells) and tumor stromal infiltrating lymphocytes (PD-L1+ TILs); CD20 was scored in tumor-infiltrating B cells. Kaplan-Meier curves and Cox proportional hazard models were used for survival analysis. RESULTS: PD-L1+ tumor cells, PD-L1+ TILs, and CD20+ TILs were found in 8%, 66%, and 62% of IBC, respectively. PD-L1+ tumor cells strongly correlated with high TILs, pathological complete response (pCR), CD20+ TILs, but marginally with breast cancer-specific survival (BCSS, P = 0.057). PD-L1+ TILs strongly correlated with high TILs, CD20+ TILs, and longer disease-free survival (DFS) in all IBC and in triple-negative (TN) IBC (P < 0.035). IBC and TN IBC patients with tumors containing both CD20+ TILs and PD-L1+ TILs (CD20+TILs/PD-L1+TILs) showed longer DFS and improved BCSS (P < 0.002) than patients lacking both, or those with either CD20+ TILs or PD-L1+ TILs alone. In multivariate analyses, CD20+TILs/PD-L1+TILs status was an independent prognostic factor for DFS in IBC (hazard ratio (HR): 0.53, 95% CI 0.37-0.77) and TN IBC (HR: 0.39 95% CI 0.17-0.88), and for BCSS in IBC (HR: 0.60 95% CI 0.43-0.85) and TN IBC (HR: 0.38 95% CI 0.17-0.83). CONCLUSION: CD20+TILs/PD-L1+TILs status represents an independent favorable prognostic factor in IBC and TN IBC, suggesting a critical role for B cells in antitumor immune responses. Anti-PD-1/PD-L1 and B cell-activating immunotherapies should be explored in these settings.

Changes in Swallowing-related Quality of Life After Endoscopic Treatment For Zenker's Diverticulum Using SWAL-QOL Questionnaire.

Dysphagia affects the most cardinal of human functions: the ability to eat and drink. The aim of this prospective study was to evaluate swallowing dysfunction in patients diagnosed with Zenker's diverticulum using the Swallowing Quality of Life (SWAL-QOL) questionnaire preoperatively. In addition, SWAL-QOL was used to assess changes in the outcome of swallowing function after endoscopic treatment of Zenker's diverticulum compared to baseline. Pre- and postoperative SWAL-QOL data were analyzed in 25 patients who underwent endoscopic treatment of Zenker's diverticulum between January 2011 and December 2013. Patients were treated by different endoscopic techniques, depending on the size of the diverticulum: CO2 laser technique or stapler technique, or the combination of both techniques used in larger diverticula. Their mean age was 69 years, and 28% of patients were female. The mean interval between endoscopic surgery and completion of the postoperative SWAL-QOL was 85 days. The median (min-max) preoperative total SWAL-QOL score was 621 (226-925) out of 1100, indicating the perception of oropharyngeal dysphagia and diminished quality of life. Following endoscopic treatment of Zenker's diverticulum, significant improvement was demonstrated in the postoperative total SWAL-QOL score of 865 (406-1072) out of 1100 (p < 0.001). On the majority of subscales of SWAL-QOL there was significant improvement between pre- and postoperative scores. To the authors' knowledge, this is the first report in the literature on the changes in pre- and postoperative SWAL-QOL scores for patients with Zenker's diverticulum before and after treatment. The results of this study indicate that endoscopic treatment of Zenker's diverticulum leads to significant symptom relief as documented by significant changes in the majority of the SWAL-QOL domains.

Intracranial complications of acute otitis media and Gradenigo's syndrome.

We describe the case of a 12-year-old girl with acute otitis media complicated by acute mastoiditis, epidural empyema, thrombosis of the sigmoid sinus and paralysis of the abducens nerve. The patient underwent a mastoidectomy on the left side combined with drainage of the epidural empyema through an extended burr holl and received intravenous antibiotics for 6 weeks and anticoagulation for 12 weeks. This report discusses the intracranial complications of acute otitis media, which were a common problem before the advent of adequate antibiotic drugs but have become rare since their introduction.

A high neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are associated with a worse outcome in inflammatory breast cancer.

INTRODUCTION: Inflammatory breast cancer (IBC) is an uncommon, but aggressive form of breast cancer that accounts for a disproportionally high fraction of breast cancer related mortality. The aim of this study was to explore the peripheral immune response and the prognostic value of blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), in a large IBC cohort. PATIENTS & METHODS: We retrospectively identified 127 IBC patients and collected lab results from in-hospital medical records. The differential count of leukocytes was determined at the moment of diagnosis, before any therapeutic intervention. A cohort of early stage (n = 108), locally advanced (n = 74) and metastatic breast cancer patients (n = 41) served as a control population. RESULTS: The NLR was significantly higher in IBC compared to an early stage breast cancer cohort, but no difference between IBC patients and locally advanced breast cancer patients was noted. In the metastatic setting, there was also no significant difference between IBC and nIBC. However, a high NLR (>4.0) remained a significant predictor of worse outcome in IBC patients (HR: 0.49; 95% CI: 0.24-1.00; P = .05) and a lower platelet-lymphocyte ratio (PLR) (≤210) correlated with a better disease-free survival (DFS) (HR: 0.51; 95% CI: 0.28-0.93; P = .03). CONCLUSION: Patients with a high NLR (>4.0) have a worse overall prognosis in IBC, while the PLR correlated with relapse free survival (RFS). Since NLR and PLR were not specifically associated with IBC disease, they can be seen as markers of more extensive disease.

Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype.

Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter occurs in about 40% of breast tumours and has been correlated with reduced APC protein levels. To what extent epigenetic alterations of the APC gene may differ according to specific breast cancer phenotypes, remains to be elucidated. Our aim was to explore the role of APC methylation in the inflammatory breast cancer (IBC) phenotype. The status of APC gene promoter hypermethylation was investigated in DNA from normal breast tissues, IBC and non-IBC by both conventional and real-time quantitative methylation-specific PCR (MSP). APC methylation levels were compared with APC mRNA and protein levels. Hypermethylation of the APC gene promoter was present in 71% of IBC samples (n=21) and 43% of non-IBC samples (n=30) by conventional MSP (P=0.047). The APC gene also showed an increased frequency of high methylation levels in IBC (in 74% of cases, n=19) vs non-IBC (in 46% of cases, n=35) using a qMSP assay (P=0.048). We observed no significant association between APC methylation levels by qMSP and APC mRNA or protein expression levels. In conclusion, for the first time, we report the association of aberrant methylation of the APC gene promoter with the IBC phenotype, which might be of biological and clinical importance.

MR mammography is useful in the preoperative locoregional staging of breast carcinomas with extensive intraductal component.

PURPOSE: To determine the role of magnetic resonance (MR) mammography in detection and assessment of extent of tumors with extensive intraductal component (EIC+). MATERIAL AND METHODS: In a prospective study, 233 consecutive women with a suspicious lesion underwent preoperative MR mammography and 209 invasive ductal carcinomas were detected. We studied the prediction of intraductal spread on mammography (MX), ultrasound (US) and MR. We compared the size of the total lesion on MX, US and MR and correlated it with histopathology. Enhancement patterns on MR were described. RESULTS: Of 209 invasive ductal carcinomas, 50 were EIC+ (24%). MX predicted intraductal spread in EIC+ carcinomas in 48.5%, US in 34.2% and MR in 68%. Compared to MX and US, MR was best in assessment of total tumor size. On MR, ductal spread in EIC+ tumors presented as ductal or linear enhancement, long spicules, a regional enhancing area or nodules adjacent to a mass. CONCLUSION: MR had the highest sensitivity to predict intraductal spread and was superior in assessing total tumor size.

Quality of pathology reporting is crucial for cancer care and registration: a baseline assessment for breast cancers diagnosed in Belgium in 2008.

OBJECTIVES: Given the crucial role of pathology reporting in the management of breast cancers, we aimed to investigate the quality and variability of breast cancer pathology reporting in Belgium. MATERIALS AND METHODS: Detailed information on non-molecular and molecular parameters was retrieved from the pathology protocols available at the Belgian Cancer Registry for 10,007 breast cancers diagnosed in Belgium in 2008. RESULTS: Substantial underreporting was shown for several clinically relevant non-molecular parameters, such as lymphovascular invasion. High-volume laboratories performed only slightly better than others, and analyses at the individual laboratory level showed clear inter-laboratory variability in reporting for all volume categories. Information on ER/PR and HER2 IHC was mentioned in respectively 91.7% and 90.8% of evaluative cases. HER2 ISH data were available for 78.5% of the cases judged to be 2+ for HER2 IHC. For cases with different specimens analysed, discordance between these specimens was highest for HER2, followed by PR. For HER2, results obtained from different laboratories were even less concordant. In addition, inter-laboratory differences were noted in the used ER/PR scoring systems, the proportion of ER-/PR+ cases, and the relation between histological grade and ER/PR positivity. Data on Ki67 were only available for 43.8% of the investigated cases, and showed inconsistent use of cut-off values. CONCLUSION: Breast pathology reporting in Belgium in 2008 was suboptimal and showed considerable inter-laboratory variability. Synoptic reporting has been proposed as a facilitator towards increased reporting quality and harmonization, but the lack of aligned informatics remains a major hurdle in its concrete implementation.

Atypical or worrisome features in cellular neurothekeoma: a study of 10 cases.

Cellular neurothekeoma is a recently characterized benign cutaneous neoplasm arising usually on the upper trunk or head and neck of children or young adults. Typical histology is that of a lobulated dermal tumor composed of spindle and epithelioid cells, arranged in fascicles and nests, lacking immunoreactivity for S-100 protein, but usually being NK1/C3 positive. We present 10 new cases of cellular neurothekeoma with atypical histologic features that have not been described previously and that suggested the possibility of malignancy. The age range of affected patients was 1 to 44 years (median, 20.5 years); sites included the head and neck (three cases), the upper limbs (two cases), the lower limbs (two cases), and the trunk (two cases). Atypical findings in individual cases included large size (up to 6 cm), deep penetration (extending into skeletal muscle or subcutaneous fat, or both), diffusely infiltrative borders, vascular invasion, high mitotic rate, and marked cytologic pleomorphism. Clinical follow-up was available in 7 of 10 cases. Although the atypical features raised concern about the biologic potential of these lesions, preliminary follow-up (1-5 years) has shown no recurrence and suggests that complete surgical excision of these lesions is curative. These new data expand the morphologic spectrum of cellular neurothekeoma.

Fryns syndrome without diaphragmatic hernia?

We report on a child with Fryns syndrome including lung hypoplasia, characteristic facial appearance, cleft palate, cardiac anomaly, distal limb abnormalities, absent nipples, bicornuate uterus and early death. In contrast to most patients with Fryns syndrome, diaphragmatic hernia was absent in our patient. However, the diaphragm was reduced to a fibrous web with reduced muscular component.

Multiple pterygium syndrome with body asymmetry.

We report on a fetus with multiple pterygia in the popliteal, antecubital, intercrural, axillary, and nuchal region, arthrogryposis, camptodactyly, anal atresia, hypospadias, ambiguous genitalia, and neonatal death. Arthrogryposis was much more pronounced at the left than at the right side. Moreover, there was gross body asymmetry with hypoplasia of the left arm, leg, pelvis, and kidney. As this spectrum of anomalies does not fit any of the known multiple pterygium syndromes, this patient adds another clinical entity to the already wide spectrum of multiple pterygium syndromes.

Acute superior vena cava obstruction after rupture of a bronchial artery aneurysm.

A patient was referred to our hospital with a superior vena cava syndrome after the rupture of a bronchial artery aneurysm. To our knowledge, this complication has not been reported before. An urgent thoracotomy was performed after embolization had failed.

Spontaneous dissection of three major coronary arteries subsequent to cystic medial necrosis.

This case report describes the devastating consequences of spontaneous coronary dissection in a 36-year-old female patient. Surgical revascularization was attempted, but diffuse myocardial infarction developed. The patient was bridged to heart transplantation but died secondary to multiple organ failure. To our knowledge, this is the only reported case of spontaneous dissection of the three main coronary arteries due to severe cystic medial necrosis.

Biphasic sarcomatoid carcinoma (carcinosarcoma) of the renal pelvis with heterologous chondrogenic differentiation.

A case of a man with biphasic sarcomatoid carcinoma of the right kidney with chondrosarcomatous foci and with invasion of the pelvic mucosa and submucosa into the peripelvic adipose tissue is presented. In situ carcinoma of the urothelium of the right renal pelvis and proximal ureter was also noted. Comments on the nomenclature of malignant tumours with apparently mixed carcinomatous and sarcomatous phenotypes and a hypothesis on the histogenesis of these tumours are presented. Cytokeratin and p53 protein expression patterns, and the results of angiogenesis quantification are consistent with an epithelial-to-mesenchymal conversion induced by the stroma.

Biventricular assist for severe acute rheumatic pancarditis.

Severe heart failure in acute rheumatic myocarditis is rare. It may be rapidly reversible with treatment, so maximal medical treatment and, if necessary, mechanical support should be given before heart transplantation is considered.

Malignant melanoma of soft parts. Further cytogenetic characterization.

We report the cytogenetic findings in a case of malignant melanoma of soft parts. Overrepresentation of 1q together with a del(1)(q42), extra copies of chromosomes 7 and 8, and t(12;22)(q13;q13) were found. These findings allow further delineation of the chromosomal pattern found in this uncommon neoplasm.

Leiomyoma of the right common iliac vein presenting as a duodenal tumour.

A case of vascular leiomyoma originating from the wall of the right common iliac vein is presented. Clinical and radiological features suggested a well circumscribed tumour arising from the duodenal wall. Laparotomy revealed a tumour without connection to the duodenum, but attached to the right iliac vein. The tumour was totally resected, including partial resection of the common iliac vein. Pathology showed a smooth muscle tumour with histological features of benignity. Six months after surgery the patient is asymptomatic.

Contrast-enhanced MR imaging of breast lesions and effect on treatment.

PURPOSE: To assess the value of local staging with preoperative magnetic resonance imaging (MRI) in patients with suspect breast lesions and the effect on therapeutic approach. MATERIALS AND METHODS: Two hundred and four consecutive women with suspect breast lesions on clinical examination (CE) and/or mammography (MX) and/or ultrasound (US) underwent preoperative contrast-enhanced MRI. Detection of multifocal, multicentric and bilateral breast cancer by all three imaging modalities was evaluated. Results of preoperative breast MRI were discussed with the treating surgeons. The type of therapeutic change after preoperative MRI was marked on a questionnaire (none, additional fine needle aspiration, core biopsy, open biopsy, wider excision, mastectomy) and considered 'necessary' or 'unnecessary' using final histopathological results as gold standard. RESULTS: In 170 patients, breast cancer was diagnosed. MRI detected 96% of multifocal disease and 95% of multicentric disease, whereas MX depicted 37 and 18%, and US 41 and 9% of them, respectively. All bilateral breast cancers were seen on MRI; both MX and US detected 56%. Findings of more extensive disease and unsuspected multiple breast cancer foci identified on MRI only, changed the therapeutic approach correctly in 30.6% of breast cancer patients. Nine unnecessary wider excisions and three unnecessary FNA/core biopsies were performed because MRI overestimated the number or size of malignant lesions. CONCLUSION: Preoperative breast MRI is an important adjunct to conventional imaging in the loco-regional staging of breast cancer and a useful tool in treatment planning.

The prevalence of hairy leukoplakia in HIV seropositive and HIV seronegative immunocompromised patients.

The prevalence of hairy leukoplakia was determined among 176 symptomatic HIV seropositive patients seen at the outpatient department of the Institute of Tropical Medicine in Antwerp, Belgium. Moreover, systematic tongue biopsies were performed during postmortem examination of 21 patients with AIDS, 100 HIV seronegative immunocompromised patients with haematologic or other malignancies and 100 HIV seronegative non-immunocompromised patients who died at the University Hospital Antwerp. Hairy leukoplakia was observed in 52 (29.5%) of the outpatients, but only in one (5%) of the AIDS patients in the postmortem study (P = 0.03). An explanation for this difference may be that significantly more AIDS patients who died had received either acyclovir or ganciclovir during the 3 months prior to the postmortem examination than the HIV seropositive outpatients during the 3 months prior to examination. Hairy leukoplakia occurred more often in Caucasian homosexual men with HIV infection (38%) than among heterosexual Africans with HIV infection (17%) (P = 0.06). Hairy leukoplakia was observed in none of the HIV seronegative patients.

Limb-body wall complex: 4 new cases illustrating the importance of examining placenta and umbilical cord.

Limb-body wall complex (LBWC) is a rare, sporadic, congenital defect defined as a combination of at least two of three characteristics: 1. limb defects, 2. anterior body wall defects, and 3. exencephaly or encephalocoele with/without facial clefts. Three pathogenic mechanisms have been proposed: early amnion rupture, vascular disruption and embryonic dysgenesis. In this study we carried out the pathological evaluation of four fetuses with LBWC and their placentas. None of the cases had craniofacial defects. Three fetuses showed an abdominal wall defect with eventration of abdominal organs, cloacal exstrophy, absent external genitalia, abnormal internal genitalia, scoliosis and lower limb defects. One fetus showed failure of closure of both thoracic and abdominal walls with ectopia cordis, evisceration of left lung and abdominal organs, severe reduction defect of left arm, but normal colon, anus, bladder, genitalia and lower limbs. All cases had a short, malformed umbilical cord, incompletely covered by amnion. The umbilical vessels were embedded in an amniotic sheet which connected the skin margin of the anterior body wall defect to the placenta. These anomalies suggest an abnormal body stalk development as a pathogenic mechanism for LBWC. Prenatally, the abnormal fetoplacental attachment can be detected ultrasonographically by the end of the first gestational trimester. Postnatally, the examination of placenta, umbilical cord and membranes is crucial in confirming the diagnosis of LBWC.