Common and rare carcinomas of the thymus Roden, Anja C.; Szolkowska, Malgorzata
Virchows Archiv : an international journal of pathology,
2021/1, Letnik:
478, Številka:
1
Journal Article
Recenzirano
Thymic carcinoma encompasses a diverse group of rare tumors that occur almost exclusively in the prevascular (anterior) mediastinum. Thymic carcinomas have a worse outcome than thymomas with a median ...time to death of under 3 years. These tumors lack the typical lobulation of thymomas, exhibit commonly more cytologic atypia, are associated with a desmoplastic stromal reaction, and lack thymocytes, features that distinguish them from thymomas. The most common thymic carcinoma is squamous cell carcinoma; other subtypes include mucoepidermoid carcinoma, NUT carcinoma, and adenocarcinoma, among others. Largely due to multi-institutional and global efforts and meta-analysis of case reports and series, some of the thymic carcinoma subtypes have been studied in more detail and molecular studies have also been performed. Morphology and immunophenotype for the vast majority of thymic carcinoma subtypes are similar to their counterparts in other organs. Therefore, the distinction between thymic carcinoma and metastatic disease, which is relatively common in the prevascular mediastinum, can be challenging and in general requires clinical and radiologic correlation. Although surgical resection is the treatment of choice, only 46 to 68% of patients with thymic carcinoma can undergo resection as many other tumors present at high stage with infiltration into vital neighboring organs. These patients are usually treated with chemotherapy and/or radiation. The search for better biomarkers for prognosis and treatment of thymic carcinomas is important for improved management of these patients and possible targeted therapy.
Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous inflammation with necrotizing vasculitis predominantly affecting small to medium vessels. The survival rates have ...drastically improved; however, GPA can be lethal, with older patients having a worse prognosis and higher mortality than younger patients. Moreover, the incidence of various cancers has been reported to increase in patients with GPA. We aimed to discuss possible associations between GPA and lung cancer and emphasize the associated diagnostic challenges.
We encountered three older patients with chronic GPA who developed lung cancer during long-term follow-up. Two of the patients had a smoking history, with one having silicosis and the other having chronic obstructive pulmonary disease. Furthermore, all of them had radiation exposure from repeated radiography/computed tomography. All the patients had confirmed GPA, and vasculitis relapse was first suspected when new lung lesions were noted during follow-up. However, they had no new clinical symptoms, and serum ANCA titer increased only in one patient. All the patients received standard immunosuppressive treatment but eventually died.
Lung cancer is uncommon in patients with GPA; however, the similarity between the imaging findings of lung cancer and GPA may pose a diagnostic challenge. Clinicians should be particularly vigilant when treating older patients with an increased risk of cancer, as they are often asymptomatic or have poorly apparent clinical features.
Thymic carcinomas are rare malignancies that in general arise in the prevascular (anterior) mediastinum. These tumors are usually invasive, often present at advanced stages, and typically behave ...aggressively. Studies are hampered by the paucity of these tumors, the large variety of carcinoma subtypes, and the lack of unique morphologic and immunophenotypic features. Despite these challenges, advances in diagnostic imaging, surgical approaches, systemic therapies, and radiation therapy techniques have been made. The WHO classification of thymic epithelial tumors has been updated in 2021, and the eighth tumor nodal metastasis staging by the American Joint Committee on Cancer/Union for International Cancer Control included thymic carcinomas in 2017. Molecular alterations that provide more insight into the pathogenesis of these tumors and that potentially permit use of novel targeted therapies are increasingly being identified. New approaches to radiation therapy, chemotherapy, and immunotherapy are under evaluation. International societies, including the International Thymic Malignancy Interest Group, European Society of Thoracic Surgeons, and Japanese, Chinese, and Korean thymic associations, have been critical in organizing and conducting multi-institutional clinical studies. Herein, we review contemporary multidisciplinary perspectives in diagnosis and management of thymic carcinoma.
Primary mediastinal large B-cell lymphoma (PMBL) cells depend on the constitutive activity of NF-κB and STAT transcription factors, which drive expression of multiple molecules essential for their ...survival. In a molecularly related B-cell malignant tumor (classic Hodgkin lymphoma), tumor Reed-Sternberg cells overexpress oncogenic (proviral integration site for Moloney murine leukemia virus (PIM) 1, 2, and 3 kinases in a NF-κB– and STAT-dependent manner and PIMs enhance survival and expression of immunomodulatory molecules. Given the multiple overlapping characteristics of Reed-Sternberg and PMBL cells, we hypothesized that PIM kinases may be overexpressed in PMBL and involved in PMBL pathogenesis. The expression of PIM kinases in PMBL diagnostic biopsy specimens was assessed and their role in survival and immune escape of the tumor cells was determined. PIMs were abundantly expressed in primary tumors and PMBL cell lines. Inhibition of PIM kinases was toxic to PMBL cells, attenuated protein translation, and down-regulated NF-κB– and STAT-dependent transcription of prosurvival factors BCL2A1, BCL2L1, and FCER2. Furthermore, PIM inhibition decreased expression of molecules engaged in shaping the immunosuppressive microenvironment, including programmed death ligand 1/2 and chemokine (C-C motif) ligand 17. Taken together, our data indicate that PIMs support PMBL cell survival and immune escape and identify PIMs as promising therapeutic targets for PMBL.
A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing ...(NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.
Lymphangioleiomyomatosis (LAM) is a rare interstitial lung disease characterized by abnormal smooth muscle-like cell (LAM cell) proliferation in the lung stroma. The origin of LAM cells is still ...unknown. The gold-standard immunohistochemical diagnostic for LAM is an immunopositive reaction to the HMB-45 antibody.
We aimed to evaluate 15 diagnostic open-lung biopsy specimens of pulmonary LAM. Based on the LAM histologic score (LHS), we distinguished two groups of histological severity: early- and advanced-stage LAM. The expression of HMB-45, estrogen receptor (ER), progesterone receptor (PR), β-catenin, E-cadherin, podoplanin (D2-40), mini-chromosome maintenance protein 3 (MCM3), and epidermal growth factor receptor (EGFR) was evaluated immunohistochemically. Fluorescence in situ hybridization (FISH) was performed in order to investigate amplification of the EGFR gene in LAM cells.
The expression of ER and EGFR was significantly higher in advanced than in early-stage LAM. Amplification of the EGFR gene was not detected in any of the 15 studied cases. There was a strong-positive correlation between the expression of PR, ER, β-catenin, E-cadherin, and the standard marker of LAM, HMB45.
We conclude that together with LHS, ER may be considered a useful tool for evaluating the progression of LAM. β-Catenin and E-cadherin seem to be new potential specific markers of LAM cells. The increased expression of EGFR in LAM cells is not associated with EGFR gene amplification, although it may be a marker of disease progression; the role of this receptor in LAM pathogenesis should be further investigated. Positive reaction of LAM cells with podoplain demonstrates the existence of an additional lymphatic endothelial lineage in LAM cells.
Background
Thymic epithelial tumors constitute a morphologically and clinically diverse group of rare neoplasm of the anterior mediastinum.
Methods
Here, we present an analysis of 188 patients ...diagnosed with primary thymic tumors between 1995 and 2015. The prognostic value of selected clinical and morphological factors was assessed in relation to overall survival and recurrence‐free survival.
Results
The risk of recurrence increased significantly in thymic carcinoma diagnosis (P = 0.0036), co‐occurrence of other diseases, and weight loss (P = 0.0012 and 0.0348, respectively). Multivariate analysis showed that the most important independent risk factor for disease recurrence was clinical stage IV (P = 0.0036). A total of 63 patients (33.5%) died. In the univariate analysis, the following factors were considered as independent prognostic factors for overall survival: clinical stage (P < 0.0001), histological type (P < 0.0001), lymph node involvement (P < 0.001), WHO performance status 2 (P < 0.0001), anemia (Hb <9.5 g/dL; P = 0.0002), leucocytosis (>12.5 G/L; P = 0.0011), LDH level (>185 U/L; P < 0.0001), concomitant diseases (P = 0.0012) and weight loss (P < 0.0001).The strongest independent risk factor for death was stage IV disease (P < 0.001).
Conclusions
The results confirmed a fairly good prognosis for patients with thymic epithelial tumors. Clinical stage was the most important prognostic factor, but, some additional clinical factors may also have prognostic value.
We present an analysis of 188 patients diagnosed with primary thymic tumours. The prognostic value of selected clinical and morphological factors was assessed in relation to survival. Multivariate analysis showed that the most important independent risk factor was CS IV. The risk of recurrence increased significantly in thymic carcinoma, comorbidities occurrence and weight loss. Some additional clinical factors including LDH elevation, leucocytosis, anemia may have prognostic value.
This study was an epidemiological analysis of all primary mediastinal neoplasms (PMNs) diagnosed between 2000 and 2016 at the National Tuberculosis and Lung Diseases Research Institute, Poland.
All ...patients with any mediastinal abnormality were included in the analysis. The patients' age and gender were obtained from the institutional database.
From a cohort of 5,108 patients, 3,691 primary mediastinal lesions were found, including 1,005 (19%) PMNs: lymphomas (533, 53% of PMNs), thymomas (215, 21%), neurogenic tumors (NTs) (100, 10%), germ cell tumors (GCTs) (62, 6%), soft tissue tumors (STTs) (47, 5%) and thymic carcinomas/thymic neuroendocrine tumors (TCs/TNETs) (37 in total, 4%). The most frequent lymphomas were classical Hodgkin lymphomas 256 and primary mediastinal large B-cell lymphomas 163. Type AB 73 predominated in thymomas and squamous cell carcinomas 9 and carcinoids 10 in TCs/TNETs. NTs encompassed mainly schwannomas 49, ganglioneuromas 21 and neurofibromas 10. The most frequent STTs were hemangiomas 13 and lymphangiomas 11. Lymphomas, thymomas and NT were more often in women, TCs/TNETs in men (P<0.001). Lymphomas predominated between the 2
and 4
decade of life, NTs under the 3
decade and thymic epithelial tumors between the 6
and 8
decade (P<0.001). There was no correlation between the subtypes of thymomas and the patients' gender (P=0.389) but it was found between histology and patients' age: in patients <30 years of age type B2 and B3 thymomas and >70 years of age AB type and micronodular thymomas with lymphoid stroma (P<0.001) predominated. In the group of GCTs half of them were malignant and these were noted exclusively in men. No correlation between subtypes of NTs or TCs/TNETs and patients' age and gender was found (P>0.05).
PMNs are rare conditions thus awareness of basic epidemiology may be very helpful for final diagnosis.
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