Sustained response to brigatinib in a patient with refractory metastatic pheochromocytoma harboring R1192P anaplastic lymphoma kinase mutation: a case report from the Austrian Group Medical Tumor Therapy next-generation sequencing registry and discussion of the literature.

Metastatic pheochromocytoma and paraganglioma (PPGL) are rare diseases with dismal prognosis and standard therapies are lacking. We herein report the first case of a germline anaplastic lymphoma kinase (ALK) mutation in a patient with chemorefractory metastatic pheochromocytoma in the absence of mutations of known PPGL-associated predisposing genes. Therapy with the ALK inhibitor (ALKi) brigatinib led to dramatic and durable disease remission, despite previous disease progression on the ALKi alectinib. This case underscores the potential clinical use of molecular profiling in rare diseases with limited treatment options and suggests that the ALK-R1192P point mutation might predict sensitivity to brigatinib.

Real-world prevalence of programmed death ligand 1 expression in locally advanced or metastatic non-small-cell lung cancer: The global, multicenter EXPRESS study.

OBJECTIVES: Tumor programmed death ligand 1 (PD-L1) expression is associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicenter, retrospective observational study to determine real-world prevalence of tumor PD-L1 expression in patients with NSCLC. MATERIALS AND METHODS: Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumor tissue block (≤5 years old) obtained before treatment were identified in 45 centers across 18 countries. Tumor samples from eligible patients were selected consecutively, when possible. PD-L1 expression was evaluated at each center using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). RESULTS: Of 2617 patients who met inclusion criteria, 2368 (90%) had PD-L1 data; 530 (22%) patients had PD-L1 TPS ≥ 50%, 1232 (52%) had PD-L1 TPS ≥ 1%, and 1136 (48%) had PD-L1 TPS < 1%. The most common reason for not having PD-L1 data (n = 249) was insufficient tumor cells (<100) on the slide (n = 170 [6%]). Percentages of patients with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively were: 22%/52% in Europe; 22%/53% in Asia Pacific; 21%/47% in the Americas, and 24%/55% in other countries. Prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports from metastatic NSCLC studies. Among 1064 patients negative for both EGFR mutation and ALK alteration, the percentage with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively, were 27% and 53%. CONCLUSIONS: This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumor expression using the 22C3 pharmDx kit. Testing failure rate was low with local evaluation of PD-L1 TPS across a large number of centers. Prevalence of PD-L1 TPS ≥ 50% and TPS ≥ 1% among patients with stage IIIB/IV NSCLC was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations.

[Pigmented lesions of the oral mucosa]. / Pigmentierte Veränderungen der Mundschleimhaut.

The oral mucosa contains melanocytes, even though one might not suspect this when examining white subjects. Drug-induced pigmentation is usually irregularly distributed over the oral mucosa; typical causes are contraceptives and tetracyclines. Localized traumatic pigmentation can be due to injuries contaminated by foreign material (dust). Not infrequently an amalgam tattoo can be seen, caused by introduction of amalgam during dental treatment with rotating instruments. Focal melanosis is harmless. Neoplastic pigmentation is rare. Melanotic nevi are small with indistinct borders. Malignant melanoma occurs predominantly on the maxilla or hard palate. Frequently it has already metastasized by the time of diagnosis. Verification by biopsy is essential if a lesion has suddenly appeared, is extensive, elevated, with irregular pigmentation and has no obvious cause.

Cerebral localized marginal zone lymphoma presenting as hypothalamic-pituitary region disorder.

INTRODUCTION: Marginal zone B-cell lymphoma is a rare disease which can be considerably difficult to recognize and diagnose when signs of systemic involvement are absent. CASE PRESENTATION: We report the case of a 57-year-old woman with initial olfactory disturbance, followed by psychosis, diabetes insipidus and hypothalamic eating disorder as an uncommon clinical presentation of marginal zone B-cell lymphoma. CONCLUSION: Marginal zone B-cell lymphoma should be considered as a potential differential diagnosis in patients with hypothalamic disturbances.

Successful bronchoscopic cryorecanalization in a case of endobronchial lipoma.

Endobronchial lipomas are rare benign tumors; less than 150 cases have been reported so far. Bronchial occlusion usually leads to a misdiagnosis of asthma/COPD or malignancy. We report the case of a 67-year-old man with a history of heavy smoking (100 pack years), dyspnea on exertion, cough, and malaise who was treated for pneumonia for three weeks. Due to nonresolving atelectasis of the superior segment of the right lower lobe, a malignant endobronchial tumor was suspected. Rigid bronchoscopy with cryorecanalization led to both the definite histopathological diagnosis of endobronchial lipoma and the reopening of an endoluminal airway obstruction during one procedure.

[Squamous cell carcinoma and potentially malignant disorders of the oral mucosa]. / Plattenepithelkarzinom und potenziell maligne Veränderungen der Mundschleimhaut.

Squamous cell carcinoma is the most frequent malignant tumor of the oral mucosa. Various endogenous and exogenous factors promote its development. Therapy and prognosis depend mainly on tumor stage. Early detection is therefore of utmost importance. In most cases cancer develops from "leukoplakia". Both homogeneous leukoplakias as well as "erythroleukoplakias" should be biopsied. The"brush-biopsy", imaging techniques, molecular biologic or DNA tests are not reliable enough at present, often technically demanding and not applicable in daily practice. In extensive lesions "field cancerization" has to be considered. Further important precursor lesions are proliferative verrucous leukoplakia and erosive lichen planus. The management of oral precancerous lesions should be individually tailored: Low-grade dysplasia can be observed. If indicated, patients at risk should be biopsied in intervals. High-grade dysplasia ("carcinoma in situ") should be surgically removed.

Novel approach of human epidermal growth factor receptor 2 detection in noninvasive and invasive transitional cell carcinoma of the bladder.

PURPOSE: In recent years over expression of HER2 has been identified in malignant tumors of organs other than breast. Studies of bladder carcinoma that analyzed HER2 protein expression and gene amplification with a variety of nonstandardized methods have shown heterogeneous results. The results reported vary from 2% to 74% of protein over expression, to 4% to 59% of gene amplification of HER2, possibly due to differences in study design, material selection or laboratory methodology. MATERIALS AND METHODS: In the present study archival tissue from 87 patients with noninvasive papillary (25) and invasive (62) TCC was analyzed for amplification of the HER2 gene and over expression of its encoded protein. HER2 protein expression was detected by immunohistochemistry using the HercepTest. Routinely processed paraffin embedded tissue was investigated for HER2 gene amplification using CISH and FISH. RESULTS: Of the invasive 37 (58%) and of the noninvasive 19 (76%) transitional cell carcinomas investigated showed over expression of the HER2 protein (3+ and 2+) using a standardized immunohistochemical method. HER2 gene amplification assays performed on positive cases evaluated by immunohistochemistry were obtained in 81% and 43% of 3+ and 2+ HER2 protein over expressing invasive, respectively, and in 21% of noninvasive papillary bladder tumors. HER2 gene amplification detection results using CISH and FISH showed a concordance of 100%. The occurrence of aneusomy of chromosome 17 in association with HER2 gene amplification was investigated. CONCLUSIONS: Validation of the HER2 oncogene in bladder cancer may allow for the potential use of Herceptin(R) antibody therapy. Therefore, the appropriate treatment approach has to be based on reliable and standardized analysis. Our results indicate that CISH could provide an accurate and practical alternative to FISH for the clinical diagnosis of HER2 oncogene amplification in bladder cancer.

Four years experience with teleneuropathology.

Between 2002 and 2005, we made 343 intraoperative frozen section diagnoses with a telepathology system, which connected a neurosurgical department to our department of pathology. An expert neuropathologist performed at least one brief gross examination, and this was followed by a smear preparation and a frozen section slide for each case. Frozen section diagnosis lasted on average 26.1 min, calculated from the beginning of gross examination until the surgeon was given the diagnosis. The majority of cases (283 or 83%) were diagnosed in 15-40 min. The mean time needed for macroscopic examination was 3.0 min, time for staining 4.2 min, smear diagnosis took 5.4 min and time for histological diagnosis 10.7 min. Telemicroscopy of a smear slide took 11 times longer compared with light microscopy, and telemicroscopy of a frozen section slide took 16 times longer than with light microscopy. In 6% of cases, the telepathology software posed technical problems, which delayed the time of diagnosis, but not by more than 4 min. We were able to render a diagnosis in all cases (system reliability 100%). After eliminating sampling errors (i.e. cases with no diagnostic material in the frozen section slides and/or in smear preparations), the diagnostic accuracy for telepathology was 97.9%.

Prostate biopsy outcome using 29 mm cutting length.

OBJECTIVES: The aim of the study was to compare the prostate biopsy outcome by using either standard or extended cutting length of the needles. MATERIAL AND METHODS: A total of 74 consecutive prostates from radical prostatectomy were used. Two sextant biopsies were performed ex vivo. We developed a precise simulation of a transrectal biopsy procedure using ultrasound for guiding the needle. In the first set of biopsies an 18-gauge tru cut needle with 19 mm cutting length, powered by a automatic biopsy gun was used. In the second set a single use gun with an 18-gauge end-cutting needle and 29 mm cutting length was used. RESULTS: In the set of sextant biopsies using 19 mm cutting length 49 (66%) carcinomas were found. In the set of sextant biopsies using 29 mm cutting length 58 (78%) of the tumors were detected. 24 (32%) prostates showed tumor in the transition zones, but there was no transition-zone-only cancer in this study. Nevertheless taking longer cores led to an improvement in prostate cancer detection of 18%. CONCLUSIONS: In this ex vivo setting the use of 29 mm cutting length for prostate biopsy led to an significant improvement in cancer detection. As we found the end-cutting needle not suitable for use in the patient, these results support the idea to develop a longer tru cut needle and corresponding gun for further clinical investigations.

One 10-core prostate biopsy is superior to two sets of sextant prostate biopsies.

OBJECTIVES: To compare the efficiency of different transrectal ultrasonography (TRUS)-guided prostate biopsy techniques for detecting prostate cancer. MATERIALS AND METHODS: In all, 81 prostates from radical prostatectomy were used and two consecutive sets of sextant biopsies and one 10-core biopsy taken in each specimen. The 10-core biopsy consisted of a sextant biopsy and four cores from the far lateral areas of the prostate. To simulate a transrectal biopsy procedure, all biopsies were taken under TRUS guidance. RESULTS: In the first set of sextant biopsies 44 prostate cancers (54%) were detected and in the second set 51 (63%). Combining both sets of sextant biopsies 57 (70%) of the carcinomas were detected. One set of 10-core biopsies detected 66 (82%) of all prostate cancers. Overall, with the 10-core biopsies 16% more prostate tumours were diagnosed than with two consecutive sets of sextant biopsies. To find the same number of prostate cancers as with the 10-core technique, 14% of patients undergoing sextant biopsy would require a second set and 11% at least a third set of biopsies. CONCLUSIONS: The 10-core prostate biopsy technique is superior to the commonly used sextant technique and could spare patients unnecessary repeated biopsy. Even after including a second set of sextant biopsies, the total detection rate with these 12 biopsies was inferior to the 10-core technique.

[Sentinel lymph node biopsy in breast cancer patients--results and experience after 500 sentinel lymph node biopsies]. / Die Sentinellymphknotenbiopsie beim Mammakarzinom. Ergebnisse und Erfahrungen nach 500 Sentinellymphknotenbiopsien.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is a widely used technique for axillary staging in breast cancer patients. The principle to evaluate the axillary status of a breast cancer patient with a less invasive surgery than axillary lymph node dissection (ALND) meets the new minimally invasive concept in breast cancer surgery. Some breast cancer centers proceed to SLNB without ALND in SLN-negative patients. PATIENTS AND METHODS: Between March 1998 and March 2002, 500 SLNBs were performed. After a learning period with SLNB and ALND in 75 patients with a sensitivity of 96.2% and a false-negative rate of 3.8%, SLNB alone without further ALND was performed in a group of patients. In addition, the feasibility of SLNBin patients with locally advanced breast cancer, in patients after neoadjuvant chemotherapy and in patients with multicentricity was evaluated. The combined method with blue dye and technetium-99m-labeled human albumin for identification of SLNs was applied. RESULTS: 500 SLNBs were performed. The identification rate was 86.2%. After exclusion of patients with neoadjuvant chemotherapy and patients with multicentricity, the identification rate was 94.5%. SLNs were positive in 41.3% of patients and negative in 58.7% of patients. DISCUSSION: SLNB is an excellent method for axillary stag-ing and an alternative for ALND in a certain group of breast cancer patients.

Prostate cancer detection with two sets of ten-core compared with two sets of sextant biopsies.

OBJECTIVES: To compare the cancer detection of two consecutive sets of prostate biopsies using either the sextant or the 10-core technique. METHODS: Ninety-one specimens after radical prostatectomy were used and consecutive sets of biopsies were performed ex vivo on each prostate after the operation. The sextant biopsies were taken paramedian and midlobular, three per side. For the 10-core biopsies, two cores per side from the lateral areas of the prostate were added. We developed a realistic simulation of a transrectal sonographic biopsy procedure. RESULTS: In the first set of sextant biopsies, 55 prostate cancers (60.4%) were found; in the second set, 13 additional tumors were detected. Two consecutive sets of sextant biopsies thus found 68 tumors (74.7%). Using one 10-core biopsy led to cancer detection in 71 of the prostates (78%). A second 10-core biopsy revealed 11 additional tumors, for a cumulative cancer detection rate of 90.1%. We found that 9 (9.9%) of all the cancers were not diagnosed by two consecutive sets of this extended biopsy protocol. Eight of these cancers (88.9%) were clinically significant as determined by a tumor volume larger than 0.5 cm(3). CONCLUSIONS: Although the 10-core protocol is far superior to the commonly used sextant protocol, a significant number of prostate cancers can still be found on a second similar set of prostate biopsies. Even after two consecutive sets of 10-core biopsies, approximately 10% of the prostate tumors remained undetected. Most of them were clinically significant.