Dentinogenic Ghost Cell Tumour in Childhood Involving the Temporomandibular Joint: Considerations and Therapy.

Background: Although the uncommon dentinogenic ghost cell tumour (DGCT) is a benign entity, it possesses the ability to cause widespread destruction of the jaws and to recur after bone-preserving therapy. Hence, clear margins should be achieved upon surgery, and reconstruction techniques must often be used to restore osseous defects. However, this can be challenging in cases with involvement of the temporomandibular joint (TMJ), and especially in children. Case report: We present a case of a DGCT in a 12-year-old boy with wide infiltration of the mandible and the TMJ. A two-staged reconstructive approach was performed. Upon primary surgery, tumour-free margins were obtained and mandibular anatomy was restored using an iliac crest graft and an alloplastic condyle implant for temporary TMJ reconstruction. In a second step 5 months later, having received a customized TMJ prosthesis consisting of a fossa and a condyle component, the TMJ was completely replaced for definitive reconstruction. Conclusion: A customized TMJ prosthesis could be a solution for reconstruction of the TMJ in children. However, the further course with respect to growth disturbances must be evaluated upon short-term follow-ups and might require additional corrective interventions.

[Prevention, Diagnosis, Therapy, and Follow-up of Lung Cancer - Interdisciplinary Guideline of the German Respiratory Society and the German Cancer Society - Abridged Version]. / Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms.

The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥ 50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥ 50% stage IIIA and treatment options in PD-L1 ≥ 50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19.

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.

[Detection of BRAF V600E mutation in metastatic colorectal carcinoma : A QuIP round robin test]. / Nachweis der BRAF-V600E-Mutation beim metastasierten kolorektalen Karzinom : Ein QuIP-Ringversuch.

Round robin testing is an important instrument for quality assurance. Increasingly, this also applies to the results of molecular diagnostics in pathology, which directly influence therapy decisions in precision oncology. In metastatic colorectal carcinoma (mCRC), the focus has been on detecting KRAS and NRAS mutations, whose absence allows therapy with EGFR blocking antibodies. Recently, BRAF has been added as another predictive marker, since mCRC patients with BRAF V600E mutation benefit significantly from treatment with encorafenib (a BRAF inhibitor) in combination with cetuximab (anti-EGFR antibody) after systemic therapy. Due to the approval of this treatment in 2020, it is a pre-requisite that BRAF V600E mutation detection in diagnostic pathologies is reliably performed. Therefore, this round robin test with BRAF V600E testing either by immunohistochemistry or molecular methods was performed. The round robin test results demonstrate that molecular BRAF V600E detection is currently clearly superior to immunohistochemical detection.

Expression of Mismatch Repair Proteins in Merkel Cell Carcinoma.

We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients' tumor tissue (n = 56), including neighbored healthy control tissue. In cases with low-level MMR expression (<10th percentile), we performed multiplex PCR in combination with high-resolution capillary electrophoresis in order to confirm microsatellite instability (MSI). Microscopic evaluation revealed a high median expression for all MMR proteins studied (91.6-96.3%). However, six patients (56/10.7%) had low-level MLH1 expression, six (55/10.9%) had low-level MSH2 expression, five (56/8.9%) had low-level MSH6 expression, and six (54/11.1%) had low-level PMS2 expression. Together, we observed nine (56/16.1%) patients who had low-level MMR expression of at least one protein. Of the patients with low-level MMR expression, MSI evaluation was possible in five cases, revealing one case with high-level MSI. In all MMR proteins assessed, low-level expression was significantly (p = 0.0004 to p < 0.0001) associated with a negative Merkel cell polyomavirus (MCPyV) status. However, the expression profiles of the MMR proteins did not correlate with clinical outcome measures such as disease relapse or death (p > 0.05). MCC appears to be a malignancy characterized by low-level MMR rather than completely deficient MMR in a subset of cases, predominantly affecting MCPyV-negative tumors. Future studies will establish whether this subset of MCC patients respond better to immune checkpoint inhibitor therapy.

Melanotic Neuroectodermal Tumour of Infancy: Clinical Courses and Therapeutic Options-A Review of Three Cases.

BACKGROUND: Melanotic neuroectodermal tumour of infancy (MNTI) is a rare benign neoplasm. MNTI appears most often during the first year of life, arises predominantly in the maxilla and tends to recur. We discuss possible therapeutic options given in the literature and within our experience in three cases. PATIENTS: In our recent case, we used an intraoral approach to perform resection of the right-sided maxilla. Despite tumour-positive margins, there was no recurrence over the course of one year. In a previous case of MNTI, two recurrences occurred and 6 months after last resection patient received a rib graft for maxillary reconstruction. However, at the age of 7 years, the infant displayed severe maxillary hypoplasia. In a third case of MNTI, the patient was followed up after initial therapy for two decades and underwent multiple reconstruction procedures to achieve successful rehabilitation. CONCLUSION: Surgical treatment of MNTI should respect vital anatomic structures to avoid gross mutilation. The need for extended and repetitive tumour resection in early childhood can lead to growth disturbances and to further multiple reconstruction procedures in adulthood. Because of the rarity of MNTI, an international database is warranted to evaluate therapies and clinical courses over decades.

Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy.

Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge. Patients and Methods: Formalin-fixed paraffin embedded (FFPE) tissue specimens from cRCC (n=71) and rO (n=64) were analyzed by MSI. Data were classified by linear discriminant analysis (LDA), classification and regression trees (CART), k-nearest neighbors (KNN), support vector machine (SVM), and random forest (RF) algorithm with internal cross validation and visualized by t-distributed stochastic neighbor embedding (t-SNE). Most important variables for classification were identified and the classification algorithm was optimized. Results: Applying different machine learning algorithms on all m/z peaks, classification accuracy between cRCC and rO was 85%, 82%, 84%, 77% and 64% for RF, SVM, KNN, CART and LDA. Under the assumption that a reduction of m/z peaks would lead to improved classification accuracy, m/z peaks were ranked based on their variable importance. Reduction to six most important m/z peaks resulted in improved accuracy of 89%, 85%, 85% and 85% for RF, SVM, KNN, and LDA and remained at the level of 77% for CART. t-SNE showed clear separation of cRCC and rO after algorithm improvement. Conclusion: In summary, we acquired MSI data on FFPE tissue specimens of cRCC and rO, performed classification and detected most relevant biomarkers for the differential diagnosis of both diseases. MSI data might be a useful adjunct method in the differential diagnosis of cRCC and rO.

Graded expression of microRNA-371a-3p in tumor tissues, contralateral testes, and in serum of patients with testicular germ cell tumor.

Background: Serum levels of microRNA-371a-3p represent a specific tumor marker of testicular germ cell tumors (GCTs) but the origin of circulating miR-371a-3p is not finally resolved. The correlation between miR-levels in tissue and serum is unclear. Results: MiR-levels in GCT tissue are 399-fold higher than in contralateral testicular tissue and 5843-fold higher than in non-testicular tissue. MiR tissue levels correlate with corresponding serum levels (r 2 = 0.181). ISH detected miR-371a-3p intracellularly in GCT cells except teratoma. A low expression was also detected in normal testicular germ cells. Conclusions: Circulating miR-371a-3p is specifically derived from GCT tissue. The miR is present in GCT cells except teratoma. A low expression is also found in normal testicular tissue but not in non-testicular tissue. MiR-371a-3p levels in tissue and serum correlate significantly. This study underscores the usefulness of serum miR-371a-3p as tumor marker of GCT. Patients and methods: Expression levels of miR-371a-3p were concurrently measured in tissues of GCT, contralateral testes ( n = 38), and in serum ( n = 36) with real time PCR. For control, 5 healthy testicles and 4 non-testicular tissue samples were examined. MiR-levels were compared using descriptive statistical methods. We also performed in situ hybridization (ISH) of GCT tissue with a probe specific for miR-371a-3p.

Osteonecrosis of the maxilla related to long-standing methamphetamine abuse: a possible new aspect in the etiology of osteonecrosis of the jaw.

BACKGROUND: Osteonecrosis of the jaw (ONJ) related to toxic effects of illicit drugs such as cocaine is not very common and might be overshadowed today by the incidence of bisphosphonate-related osteonecrosis of the jaw. However, we present a case which suggests a close relationship between abuse of the illicit drug methamphetamine (MA) and ONJ. CASE REPORT: A 44-year-old male with extended osteonecrosis of the maxilla admitted chronic abuse and synthesis of MA for at least the previous two decades. Furthermore, he confessed self-extracting teeth since he became addicted to MA. However at presentation, he had been successfully cured of his addiction to MA. A step-by-step surgical treatment was planned using computer-aided design/computer-aided manufacturing techniques. After resection of necrotic bone, a vascularized osteomyocutaneous fibular flap was applied secondarily. DISCUSSION: Two possible mechanisms, alone or in combination, could possibly lead to MA-related ONJ. Self-extraction of teeth as a psychopathologic behavior of self-destruction among MA abusers results in wounds that allow unhindered invasion of microorganisms causing osteomyelitis and ONJ, while on the other hand, the heating of white phosphor releases toxic phosphorous vapor, which could be inhaled and consequently cause ONJ of the maxilla. However, since the worldwide prevalence of MA abuse is remarkably high, a relationship between MA abuse and ONJ will offer a new aspect in the etiology of ONJ and might present a further therapeutic challenge.

Adenoid cystic carcinoma of the skull base mimicking temporomandibular disorder.

BACKGROUND: Temporomandibular disorder (TMD) involves problems of the temporomandibular joint and its adjacent muscular system. Because TMD prevalence is high among Western populations, complaints in these regions are generally attributed to TMD. However, in rare cases, TMD symptoms are mimicked by malignant tumors of the head. CASE REPORT: Upon first presentation, an 18-year-old female complained about typical symptoms of TMD. After an initial splint therapy and physiotherapy, painful symptoms increased significantly. Twelve weeks after initial diagnosis, further diagnostic imaging revealed a tumor formation at the skull base with infiltration of the infratemporal fossa. Histological evaluation confirmed the diagnosis of adenoid cystic carcinoma. Two years after resection of the tumor, lung metastases were detected with no option of curative treatment. CONCLUSION: TMD symptoms, which are refractory to treatment or exhibit significant worsening during therapy, should be regarded as warning signals and as an indication that early further diagnostic imaging is warranted.

Pathology of tracheal tumors.

Malignant involvement of the trachea predominantly results from direct spread of neighboring tumors to the tracheal wall. Primary tracheal malignancies show a low incidence of approximately 0.1 in every 100,000 persons per year, squamous cell carcinomas and adenoid cystic carcinomas accounting for about two-thirds of adult primary tracheal tumors. The etiology of squamous cell carcinoma and its premalignant lesions is strongly associated with tobacco smoking. Patients with tracheal malignancies show an unfavorable prognosis, with reported 5- and 10-year survival rates of 5% to 15% and 6% to 7%, respectively, for all types of tracheal carcinoma.

Microcystic adnexal carcinoma of the upper lip misdiagnosed benign desmoplastic trichoepithelioma.

BACKGROUND: Desmoplastic trichoepithelioma (DT) is a benign appendageal tumour predominately localized on the facial skin. The histological diagnosis can be difficult in some cases. Partial malignant transformation of a DT is a rarity and a complete transformation has never been described in literature. CASE REPORT: A DT of the upper lip was diagnosed histologically by a small biopsy 4 years previously. At presentation, the tumour had enlarged and had partly infiltrated the left side of the upper lip and subnasal region. Histological evaluation confirmed a microcystic adnexal carcinoma but without evidence of malignant transformation of the DT. It appeared that a too-small initial biopsy had led to the incorrect histological diagnosis of a benign tumour. Thus, it was necessary to perform a tumour resection and reconstruction using a two-flap technique including a rotation flap and an Abbé flap. Functional and aesthetic outcomes were good after 6 months. There were no recurrences during a 12-month follow-up. CONCLUSION: A facial DT should be resected completely. Patients should be attended for follow-ups, keeping in mind the difficulty of making a proper histological diagnosis from small biopsies or excisions and the consequences of ablative facial surgery. However, in particular cases, subtotal defects of the upper lip region are amenable to reconstruction without gross functional or aesthetic deficits.

Activation of the two microRNA clusters C19MC and miR-371-3 does not play prominent role in thyroid cancer.

Chromosomal rearrangements of band 19q13.4 are frequent cytogenetic alterations in benign thyroid adenomas. Apparently, these alterations lead to the upregulation of genes encoding microRNAs of two clusters mapping to the breakpoint region, i.e. miR-371-3 and C19MC. Since members of both clusters have been associated with neoplastic growth in other tumor entities the question arises whether or not their upregulation predisposes to malignant transformation of follicular cells of the thyroid. To address this question we have quantified the expression of miR-372 and miR-520c-3p in samples of 114 thyroid cancers including eight anaplastic thyroid carcinomas, 25 follicular thyroid carcinomas, 78 papillary thyroid carcinomas (including 13 follicular variants thereof), two medullary thyroid carcinomas and one oncocytic thyroid carcinoma. Additionally, we quantified miR-371a-3p and miR-519a-3p in selected samples. While in neither of the cases miR-520c-3p and miR-519a-3p were found to be upregulated, one papillary and one anaplastic thyroid carcinoma, respectively, showed upregulation of miR-372 and miR-371a-3p. However, in these cases fluorescence in situ hybridization did not reveal rearrangements of the common breakpoint region as affected in adenomas. Thus, these rearrangements do apparently not play a major role as first steps in malignant transformation of the thyroid epithelium. Moreover, there is no evidence that 19q13.4 rearrangements characterize a subgroup of thyroid adenomas associated with a higher risk to undergo malignant transformation. Vice versa, the mechanisms by which 19q13.4 rearrangements contribute to benign tumorigenesis in the thyroid remain to be elucidated.

Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ATS/ERS classification.

The International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed a classification for lung adenocarcinomas (ADC) based on the predominant growth pattern. This classification has been shown to have prognostic and maybe even predictive impact. However, until now, the reproducibility of this classification has not been sufficiently demonstrated. Digital images of 40 selected ADC cases were shown twice to members of the Pulmonary Pathology Working Group of the German Society of Pathology. Each time a teledialogue-based survey on the classification was performed. Between the voting procedures, salient features of the novel classification were presented and discussed in detail by its members. The mean percentages of consensual votes per pattern ranged between 59.6 and 75 %, with lepidic and solid being the pattern with the most discordant and concordant votes, respectively. The other patterns ranged in between (papillary 65.8 %; acinar 67.8 %; micropapillary 74.2 %). The extent of disagreement decreased after the educational session. This decrease, however, was heterogeneous for the different patterns with acinar being the pattern with the strongest improvement. The overall number of abstentions decreased significantly after the educational session (p < 0.001) as well. The IASLC/ATS/ERS classification of lung ADC can be applied with reasonable consensus even for difficult cases in a nationwide context. The reproducibility evidently improves following educational sessions, even among experienced lung pathologists. Worldwide harmonization is clearly the next step on the way to a clinically meaningful, internationally accepted use of this novel prognostic and potentially predictive tool in lung pathology.

Talcum induced pneumoconiosis following inhalation of adulterated marijuana, a case report.

BACKGROUND: Talcosis, a granulomatous inflammation of the lungs caused by inhalation of talcum dust, is a rare form of pneumoconiosis. Besides inhalative occupational exposure, intravenous abuse of adulterated drugs is a major cause for this condition. Minerals such as talcum (magnesium silicate) and sand (predominant silicon dioxide) are used to increase both volume and weight of illicit substances. In intravenous heroin-abuse, talcosis is a well-known complication. Here we describe a case of talcosis caused by inhalative abuse of adulterated marijuana. CLINICAL HISTORY: A 29-year old man presented with persistent fever, dyspnea and cervical emphysema. He admitted consumption of 'cut' marijuana for several years, preferentially by water pipe smoking. MORPHOLOGIC FINDINGS: Lung-biopsies showed chronic interstitial lung disease, anthracotic pigments and birefringent material. Energy dispersive x-ray spectroscopy revealed silicon-containing particles (1-2 µm) and fine aluminum particles (< 1 µm), magnesium and several other elements forming a spectrum compatible with the stated water pipe smoking of talcum-adulterated marijuana. CONCLUSIONS: The exacerbated chronic interstitial lung disease in a 29-year old patient could be attributed to his prolonged abuse of talcum-adulterated marjuana by histopathology and x-ray spectroscopy. Since cannabis consumption is widely spread among young adults, it seems to be justified to raise attention to this form of interstitial pulmonary disease. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnomx.eu/vs/krause/html/start.html.

Detection of PAX8-PPARG fusion transcripts in archival thyroid carcinoma samples by conventional RT-PCR.

The t(2;3)(q13;p25) occurs in a subgroup of follicular-patterned thyroid tumors and leads to a fusion of the genes encoding for the thyroid-specific transcription factor paired box 8 (PAX8) and the peroxisome proliferator-activated receptor gamma (PPARγ). Although initially discovered in follicular carcinomas (FTC), the fusion transcripts were also detected in a small fraction of follicular adenomas and rarely in follicular variants of papillary carcinomas (FV-PTC). In most RT-PCR based studies, fresh or snap-frozen tissue samples were used. The aim of the present study was to develop a method for the detection of chimeric PAX8-PPARG transcripts in formalin-fixed paraffin-embedded (FFPE) thyroid tumor samples by conventional RT-PCR. For this purpose, RNA from FFPE samples of 21 FTC, seven FV-PTC, and one bone metastasis derived from an FTC was subjected to RT-PCR with subsequent gel electrophoretic separation of the products. Fusion transcripts were detected in 2/21 primary FTC (9.5%) and in the bone metastasis, but they were undetectable in all seven FV-PTC under investigation. The RT-PCR approach described herein allows to detect all known variants of PAX8-PPARG fusion transcripts and is applicable to FFPE tissues. Thus, it can be used to screen archival thyroid tumor samples for the gene fusion.

Interphase fluorescence in situ hybridization analysis detects a much higher rate of thyroid tumors with clonal cytogenetic deviations of the main cytogenetic subgroups than conventional cytogenetics.

In benign thyroid lesions, three main cytogenetic subgroups, characterized by trisomy 7 or structural aberrations involving either chromosomal region 19q13.4 or 2p21, can be distinguished by conventional cytogenetics (CC). As a rule, these aberrations seem to be mutually exclusive. Interphase fluorescence in situ hybridization (I-FISH) analysis on benign as well as malignant thyroid neoplasias has been performed in the past, but rarely in combination with CC. In the present paper, we have analyzed 161 benign thyroid lesions both with CC and I-FISH on touch preparations by using a multi-target, triple-color FISH assay as well as dual-color break-apart probes for detection of the main cytogenetic subgroups. Within the samples, I-FISH detected tumors belonging to either of the subgroups more frequently than CC (23 vs. 11.4%), either due to small subpopulations of aberrant cells or to cryptic chromosomal rearrangements (three cases). Thus, I-FISH seems to be more sensitive than CC, particularly in the detection of subpopulations of cells harboring cytogenetic aberrations that may be overlooked by CC. In summary, I-FISH on touch preparations of benign thyroid lesions seems to be a favorable method for cytogenetic subtyping of thyroid lesions.