Medullary thyroid carcinoma (MTC) is a rare nonfollicular cell-derived tumor. A robust grading system may help better stratify patients at risk for recurrence and death from disease. In total, 144 ...MTC between 1988 and 2018 were subjected to a detailed histopathologic evaluation. Clinical and pathologic data were correlated with disease specific survival (DSS), local recurrence free survival (LRFS) and distant metastasis free survival (DMFS). Median age was 53 years (range: 3–88). Median tumor size was 1.8 cm (range: 0.2–11). Lymph node metastases were present in 84 (58%) cases while distant metastases at presentation were found in 9 (6%) patients. Seven (5%) had ≥5 mitoses/10 HPFs. Tumor necrosis was present in 30 cases (20%) while lymphovascular invasion occurred in 41 (28%) of tumors. Extra-thyroidal extension was found in 44 (31%) and positive margins were seen in 19 (14%). There was a strong correlation between increasing tumor size and tumor necrosis (p < 0.001). Median follow up was 39 months. In univariate analysis, male gender, higher American Joint Committee on Cancer (AJCC) stage group, larger tumor size, tumor necrosis, high mitotic index (≥5/10 HPF), nodal status, size of largest nodal metastasis, and elevated postoperative serum calcitonin predicted worse DSS, LRFS, and DMFS (p < 0.05). Extra-thyroidal extension correlated with DSS and DMFS while positive margins and distant metastasis at presentation imparted worse DSS (p < 0.05). In multivariate analysis, tumor necrosis and mitotic activity (5 mitosis/10 HPFs as the cutoff) were the only independent predictors for DSS (p = 0.008 and 0.026, respectively). Tumor necrosis was the sole independent prognostic factor for LRFS and DMFS (p = 0.001 and 0.003, respectively). The presence of tumor necrosis and high mitotic rate are powerful independent prognostic factors in MTC and outperform serum calcitonin and stage. We propose a grading system based on tumor necrosis and mitotic activity to better stratify MTC patients for counseling, post-resection surveillance, and therapy.
Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT ...cancers have not been reported.
We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC.
There was a very high prevalence of
promoter mutations, comparable with that of ATC, and these co-occurred with
and
mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes
-
and
-
were identified. There was a high frequency of mutations in
and these were mutually exclusive to
promoter mutations and also to
and
mutations. In addition, a high frequency of mutations in
was identified and these co-occurred with
mutations and
mutations. Compared with the PTCs in TCGA, there were higher frequencies of mutations in
pathway effectors,
subunits, and histone methyltransferases.
These data support a model, whereby fatal NAT cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of
promoter mutations,
mutations,
mutations, and chromosome 1q gain highlight their likely association with tumor virulence.
.
Perivascular epithelioid cell neoplasms (PEComas) include the common renal angiomyolipoma, pulmonary clear cell sugar tumor, lymphangioleiomyomatosis, and less common neoplasms of soft tissue, ...gynecologic, and gastrointestinal tracts. Recently, aberrant immunoreactivity for TFE3 protein (a sensitive and specific marker of neoplasms harboring TFE3 gene fusions) has been reported in as many as 100% of PEComas; however, TFE3 gene status in these neoplasms has not been systematically investigated. We used a fluorescence in situ hybridization (FISH) break-apart assay to evaluate for evidence of TFE3 gene fusions in archival material from 29 PEComas. These cases included 2 earlier published TFE3 immunoreactive nonrenal PEComas, 14 additional nonrenal PEComas, and 13 renal angiomyolipomas with predominantly spindle or epithelioid morphology. Four nonrenal PEComas (mean patient age 24 y) showed TFE3 gene rearrangements by FISH, and all 4 of these showed strong positive (3+) TFE3 immunoreactivity using the original validated overnight incubation protocol. Two of these cases had adequate mRNA for RT-PCR analysis, but neither harbored the PSF-TFE3 gene fusion reported earlier in 1 PEComa. In addition, a lung metastasis of a uterine PEComa showed TFE3 gene amplification, an earlier unreported phenomenon. None of the other 24 PEComas (mean patient age 54 y) showed TFE3 gene alterations, though 4 exhibited moderate positive (2+) TFE3 immunoreactivity. In contrast, using an automated stainer, 2 of these 4 cases exhibited strong (3+) TFE3 immunoreactivity. All PEComas with TFE3 genetic alterations immunolabeled strongly for Cathepsin K, similar to other PEComas. In conclusion, a subset of lesions currently classified as PEComas harbors TFE3 gene fusions. Although numbers are small, distinctive features of these cases include a tendency to young age, the absence of association with tuberous sclerosis, predominant alveolar architecture and epithelioid cytology, minimal immunoreactivity for muscle markers, and strong (3+) TFE3 immunoreactivity. Despite significant morphologic and immunohistochemical overlap with other PEComas, PEComas harboring TFE3 gene fusions may represent a distinctive entity.
Salivary duct carcinoma (SDC) is a high-grade salivary gland carcinoma that is associated with frequent metastasis and poor outcome. Androgen receptor (AR) immunoexpression in SDC is reported in 69% ...to 100% of SDC. Androgen deprivation therapy (ADT) has shown a response rate of 18% to 42% in SDC. Therefore, AR immunoexpression may serve as a diagnostic and predictive marker for ADT response in SDC. We investigated AR immunopositivity and staining pattern in a large retrospective cohort of 188 SDCs from 163 patients, including 22 paired primary and metastatic SDCs from the same patients, focusing specifically on staining heterogeneity and concordance. A control cohort of 61 non-SDC salivary gland carcinomas was also included. AR immunopositivity defined as ≥1% of tumor cell nuclear staining was found in 94% (177/188) of SDCs, including 95% of primary tumors, 100% of regional metastases, and 90% of distant metastases. Most of the cases (75%, 86/114) showed homogeneous and diffuse AR positivity. However, a subset (25%) exhibited focal or heterogeneous AR staining pattern. Although most metastases (21/22, 95%) had concordant AR expression with the primary tumors, one treatment-naïve tumor (5%) had complete loss of AR immunoexpression in the metastasis without detectable molecular alterations in AR or AR co-regulators. AR positive staining in non-SDC salivary carcinomas was infrequent (15%, 9/61), and mostly heterogeneous or focal. AR immunoexpression is highly prevalent in SDC, in both primary (94%) and metastatic tumors (93%). The cumulative AR immunopositivity rate in SDC is 90% based on data from the current study and previous literature. A small subset may show intratumoral AR heterogeneity and discordant AR expression in metastasis. AR immunoexpression may be seen in non-SDC salivary gland carcinomas but it is uncommon and usually focal.
•AR immunoexpression is highly prevalent in primary and metastatic SDC.•The cumulative AR immunopositivity rate in SDC is 90%.•A small subset of SDC may show intratumoral AR heterogeneity and discordant AR expression in metastasis.•AR immunoexpression is uncommon and usually focal in non-SDC salivary gland carcinoma.
ETV6–NTRK3 fusion was identified in several cancers including the recently described mammary analog secretory carcinoma (MASC) of the salivary glands and a minority of papillary thyroid carcinomas. ...We describe three cases of primary MASC of the thyroid gland and provide a detailed clinical and pathological characterization of the tumor morphology, immunoprofile, and genetic background. Immunohistochemistry for PAX8, TTF-1, thyroglobulin, mammaglobin, GCDFP-15, S-100 protein, and p63 was used to define the tumor immunophenotype. Fluorescence in situ hybridization for ETV6 rearrangement was performed in three, and the next-generation sequencing assay MSK-IMPACT™ (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) was performed in two cases. Primary MASC of the thyroid occurred in two women and one man, age 47–72 years. All patients presented with high T stage, infiltrative, locally aggressive tumors with extrathyroidal extension. Two cases were associated with well-differentiated papillary thyroid carcinoma. Histologically, they appeared as low-grade tumors, resembling MASC of the salivary glands and labeled positive for mammaglobin, GCDFP-15, S-100 protein, p63, weakly positive for PAX8, and negative for TTF-1 and thyroglobulin. Fluorescence in situ hybridization revealed ETV6 rearrangement in all cases. In two tested cases MSK-IMPACT™ confirmed the presence of ETV6–NTRK3 gene fusion. Two patients had at least two local recurrences, one was alive with disease, and one was alive and free of disease after 14 and 17 years, respectively. The third patient was alive and free of disease after 2 years. MASC of the thyroid is histologically, immunophenotypically, and genetically similar to its salivary gland counterpart. Thyroid MASC can be associated with a well-differentiated papillary thyroid carcinoma component, supporting follicular cell origin. Clinically, these carcinomas may show frequent recurrences but are associated with long-term survival. Patients with MASC of the thyroid may potentially benefit from Trk molecular-targeted therapy.
•Next-generation sequencing is gaining importance in treating thoracic malignancies.•However, NGS requires high DNA input for hybrid capture assays.•EBUS-TBNA reliably provided adequate specimens for ...NGS.•Success improved over time, possibly due to surgical technique or tissue processing.
Next-generation sequencing (NGS) allows for the identification of a growing number of therapeutic and prognostic molecular targets. However, NGS typically requires greater quantities of DNA than traditional molecular testing does. Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure used to sample central thoracic lesions, but it is not well established whether this technique provides sufficient material for NGS.
We performed a retrospective review of EBUS-TBNA at our institution (3/1/14-9/28/16). NGS was performed using a comprehensive hybrid-capture based assay (MSK-IMPACT) that detects >340 gene mutations. Samples found to be diagnostic for malignancy and for which MSK-IMPACT had been attempted were identified. Pathologic and clinical data were obtained from the medical record, and the results of MSK-IMPACT were examined.
In total, 784 EBUS-TBNA procedures were performed during the study period. MSK-IMPACT was requested for 115 malignant samples and was successful for 99 (86.1%), identifying an average of 12.7 mutations at a mean coverage depth of 806X. NGS was performed on paraffin-embedded cell blocks in 93 cases (93.9%) and on cell-free DNA in needle rinse fluid in 6 cases. The success rate of the assay improved significantly from the first third of cases (76.3%), to 92.3% for the final one-third of cases (p < 0.05).
EBUS-TBNA reliably provided adequate tissue for hybrid capture NGS, and is a suitable option for comprehensive NGS testing in patients with thoracic malignancies.
Spindle cell squamous cell carcinoma (SpC-SCC) is rare, accounting for 0.4–4% of head and neck (HN) SCCs. Better understanding of HN SpC-SCC clinicopathologic characteristics, especially features ...that predict outcome, is needed. We present a clinicopathologic review of 71 HN mucosal SpC-SCC from three tertiary centers. The patient population showed a median age of 63 years (range 20–91), slight male predominance (M:F = 1.6:1), and a preponderance of smokers/ex-smokers (45/71, 64%). Most lesions involved oral cavity (42/71, 59%), especially oral tongue (
n
= 18), and larynx (
n
= 20, 28%). Polypoid/exophytic growth and surface ulceration were seen in 60% and 86% of cases, respectively. Histologically, most tumors showed sarcoma-like pattern (65/70, 93%), the remaining exhibiting granulation tissue-like or fibromatosis-like patterns, and 5 lesions showed osteosarcomatous/chondrosarcomatous elements. Most tumors (53/71, 74%) showed a conventional SCC (C-SCC) component, keratinizing (86%) or non-keratinizing/basaloid (14%). Nodal metastases, seen in 22 (31%) of resection specimens, showed SpC-SCC and/or C-SCC histomorphology. By immunohistochemistry, 76% of lesions showed immunoreactivity for keratin and 62/60% of lesions were p40/p63 positive. Ki-67 proliferation index ranged from 5 to 70%. Follow-up was available on 69 patients, median of 1.1 years from the time of SpC-SCC diagnosis. The 3-, 5-, and 10-year disease-specific survival (DSS) was 62, 37, and 12%, respectively. AJCC pN stage was an independent prognostic factor for DSS and distant metastasis-free survival (DMFS), whereas the presence of C-SCC was independently associated with improved DMFS. HN SpC-SCC is rare and might be diagnostically challenging. AJCC pN stage and co-existing C-SCC component appear to be prognostically relevant.
We report a case of crystal storing histiocytosis (CSH) of the upper lip and cheek in a 51-year-old woman and review the clinicopathologic features of 80 cases in the literature. These occurred in 41 ...men and 39 women with a respective mean age of 59 and 61 years (range 17–81 years). Forty-six patients (58%) had localized CSH, and, of these, 16 (35%) occurred in the head and neck, with the most common site being the eye/orbit. The remaining 34 patients (42%) had generalized CSH primarily involving bone marrow, liver, lymph nodes, spleen and/or kidney. Regardless of whether the CSH was localized or generalized, the vast majority of patients (90%) had an underlying lymphoproliferative or plasma cell disorder, especially multiple myeloma, lymphoplasmacytic lymphoma, or monoclonal gammopathy of undetermined significance. In 7 cases (8.8%), the CSH was associated with a variety of benign disorders, often with an inflammatory background, and no evidence of a clonal lymphoproliferative or plasma cell disorder. Treatment and prognosis varied according to the underlying disease. A classification of CSH based on etiology and/or associated disease and chemical composition of the crystal is proposed, rare non-immunoglobulin variants of CSH are discussed, and a differential diagnosis of other potentially confusing lesions is provided.
Purpose
Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid cancer with most patients dying of their disease within a few months. Only a very small percentage of long-term survivors ...(LTS) are alive for 2 years or longer. In this retrospective case-control study, we provided a comprehensive comparison between 46 ATC LTSs and 75 ATC control patients who suffered disease-specific mortality within 2 years, aiming to identify factors that may be associated with prolonged survival in ATC.
Methods
A comprehensive clinicopathologic and molecular comparison was performed between 46 ATC LTSs and 75 ATC control patients. Peripheral neutrophil count and neutrophil-to-lymphocyte ratio (NLR) were recorded. The composition of the tumor microenvironment was compared using immunohistochemistry.
Results
Compared with ATC control patients, ATC LTSs were characterized by 1) higher frequency of (primary) resection as well as clinicopathologic parameters attributed to resectability; 2) lower rate of concurrent
RAS/BRAF
and
TERT
promoter mutations; 3) lower peripheral neutrophil count and NLR; and 4) lower number of tumor-infiltrating neutrophils/myeloid-derived suppressor cells (MDSC). The survival benefits of low peripheral neutrophil counts and low NLR persisted even when controlling for distant metastasis status at presentation.
Conclusions
In addition to traditional beneficial prognostic factors, e.g., surgical resection, factors attributed to resectability, and absence of co-existing
RAS/BRAF
and
TERT
promoter mutations, we herein show that tumor-infiltrating and circulating neutrophils/MDSC are adverse prognostic factors in ATC.
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