Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

NR4A3 Expression Is Consistently Absent in Acinic Cell Carcinomas of the Breast: A Potential Nosologic Shift.

Acinic cell carcinoma (AciCC) is a tumor that is recognized in both the breast and salivary glands. Recently, the recurrent genomic rearrangement, t(4;9)(q13;q31) was identified in salivary AciCC that results in constitutive upregulation of the nuclear transcription factor NR4A3, which can be detected by immunohistochemistry. In this study, we sought to evaluate NR4A3 expression in breast AciCC using immunohistochemistry. Strong and diffuse nuclear staining was considered a positive result. Sixteen AciCCs were studied, including 8 pure AciCCs and 8 AciCCs admixed with other types (invasive carcinoma of no special type in 5 cases and metaplastic carcinoma in 3 cases). All 16 AciCCs showed negative results for NR4A3 expression. Four cases with available material were evaluated for rearrangements of the NR4A3 gene by fluorescence in situ hybridization and no rearrangements were observed. Whole-genome sequencing of 1 AciCC revealed a TP53 splice-site mutation, high levels of genomic instability, and genomic features of homologous recombination DNA repair defects; a structural variant analysis of this case did not reveal the presence of a t(4;9) rearrangement. We conclude that breast AciCCs consistently lack NR4A3 rearrangement or overexpression, unlike most of the salivary AciCCs, and that consistent with previous results, breast AciCCs are associated with genomic alterations more similar to those seen in triple-negative breast carcinomas than salivary gland AciCCs. These results suggest that unlike other salivary gland-like tumors that occur in the breast, the molecular underpinnings of the salivary gland and breast AciCCs are different and that the salivary gland and breast AciCCs likely represent distinct entities.

DNA Methylation Profiling Distinguishes Adamantinoma-Like Ewing Sarcoma From Conventional Ewing Sarcoma.

Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Molecular assessment of paratesticular rhabdomyomas demonstrates recurrent findings, including a novel H3C2 p.K37I mutation.

Rhabdomyomas are benign tumors with skeletal muscle differentiation that are broadly divided into cardiac and extracardiac types. The latter demonstrate a predilection for head and neck and genital locations and are further subclassified into adult-type rhabdomyoma (ATRM), fetal-type rhabdomyoma (FTRM) and genital rhabdomyoma (GRM). Most extracardiac rhabdomyomas that arise in paratesticular tissues have a somewhat distinctive morphology and have been termed sclerosing rhabdomyomas (SRM). Therefore, we hypothesized that these tumors may harbor recurrent genetic alterations. In this study, we assessed 15 paratesticular rhabdomyomas (11 initially classified as SRM, 2 cellular FTRM and 2 ATRM) using massively parallel DNA and RNA sequencing. Five of 14 successfully sequenced cases harbored a novel H3C2 p.K37I mutation (4 SRM and 1 ATRM). This mutation replaced a highly conserved lysine residue that is a target for epigenetic modifications and plays a role in regulation of DNA replication. Moreover, 4 tumors (2 cellular FTRM, 1 case initially diagnosed as SRM and 1 ATRM) had complex copy number profiles characterized by numerous chromosome-level and arm-level copy number gains, consistent with a ploidy shift. Rereview of the SRM with copy number gains demonstrated that it was significantly more cellular and had a more prominent fascicular architecture than the rest of the SRMs included in this series. Therefore, it was retrospectively reclassified as a cellular FTRM. In conclusion, this study demonstrated that paratesticular rhabdomyomas harbor recurrent somatic H3C2 p.K37I mutations and ploidy shifts.

Melanoma arising in extracutaneous cellular blue naevus: report of two cases with comparison to cutaneous counterparts and uveal melanoma.

AIMS: Blue naevi are benign melanocytic lesions that typically occur in the dermis. Melanoma arising in blue naevus is rare, and shows a molecular profile distinct from conventional forms of cutaneous melanoma and more similar to uveal melanoma and central nervous system (CNS) melanocytomas. In contrast to conventional cutaneous melanoma, these tumour types typically show activating driver mutations in GNAQ or GNA11, a low mutational burden without evidence of a UV signature and a reproducible pattern of chromosomal copy number changes. Blue naevi can also occur at extracutaneous sites. Here we report two cases of melanoma arising in extracutaneous blue naevus and compare their molecular features to cohorts of melanoma arising in cutaneous blue naevus (five patients) and uveal melanoma (six patients). METHODS AND RESULTS: We describe the clinical, histomorphological, immunohistochemical and molecular findings in these two cases of melanoma arising in extracutaneous blue naevus. We compare their molecular profiles to melanomas arising in cutaneous blue naevus and uveal melanoma using a targeted next-generation DNA sequencing platform and find striking similarities between all three groups. CONCLUSIONS: The close relationship between blue naevus-associated melanomas, regardless of their anatomical site, supports and validates the concept of melanoma arising in extracutaneous blue naevus and suggests that the two groups share common pathogenic mechanisms. The similarity of both groups to uveal melanoma in turn supports the close relationship between blue naevus-associated melanoma, uveal melanoma and CNS melanocytoma, and their distinction from conventional UV-associated melanoma. These findings have important implications for prognosis and therapy.

Pseudosarcomatous myofibroblastic proliferations of the urinary bladder are neoplasms characterized by recurrent FN1-ALK fusions.

Pseudosarcomatous myofibroblastic proliferation is a descriptive term that designates a group of clinically indolent genitourinary lesions that most commonly arise in the urinary bladder. Given that pseudosarcomatous myofibroblastic proliferation may show morphologic overlap with inflammatory myofibroblastic tumor, the relationship, if any, between the two entities has been unclear. Moreover, pseudosarcomatous myofibroblastic proliferations are known to be positive for ALK immunohistochemistry in a subset of cases, although an inconsistent association with ALK rearrangement (ranging from 0 to 60%) has been reported. The objectives of this study were to determine the frequency of ALK rearrangement and to identify fusion partners using fluorescence in situ hybridization (FISH) and targeted RNA sequencing studies in a contemporary series of 30 pseudosarcomatous myofibroblastic proliferations of the urinary bladder, as well as to investigate ROS1 status by immunohistochemistry. ALK immunohistochemistry was positive in 70% (21/30) of pseudosarcomatous myofibroblastic proliferations; ROS1 immunohistochemistry was consistently negative (0/28). ALK rearrangements were detected by FISH in 86% (18/21) of cases, correlating with ALK immunohistochemical positivity in all but 3 cases. Of eight cases confirmed to be ALK rearranged by FISH, targeted RNA-sequencing detected FN1-ALK fusions in seven (88%) cases, which involved exons 20-26 of FN1 (5') and exon 18-19 of ALK (3'). In conclusion, ALK rearrangements are frequent in pseudosarcomatous myofibroblastic proliferations, typically involving exon 19, and FN1 appears to be a consistent fusion partner. Given the significant clinicopathologic differences between inflammatory myofibroblastic tumor and pseudosarcomatous myofibroblastic proliferation, our findings provide further support for classification of pseudosarcomatous myofibroblastic proliferation as a distinct clinicopathologic entity, and propose the alternate terminology "pseudosarcomatous myofibroblastic neoplasm of the genitourinary tract."

Imaging of IgG4-Related Disease in the Head and Neck: A Systematic Review, Case Series, and Pathophysiology Update.

This systematic review aims to clarify and comprehensively detail the sometimes variable published imaging features as well as the pathogenesis, clinical diagnostic criteria, and treatment options of IgG4-Related Diseases (IgG4-RD) in the head and neck to aid the radiologist in diagnosing relapse and new sites of disease. A literature search in PubMed and EMBASE for reported cases of IgG4-RD was performed in December 2019. Case reports or series of IgG4-RD in the head and neck in adults that included sufficient imaging and pathology findings were included. This yielded 50 reports. IgG4-RD locations included the orbits, thyroid, pituitary gland, paranasal sinuses, salivary and parotid glands, larynx, pharynx, cervical lymph nodes, meninges, and skull base. Most lesions demonstrated non-specific homogenous CT attenuation, diffuse enhancement, isointense/low T2 signal intensity, and low T1 signal intensity. 6 cases from our institution followed previously reported imaging patterns.

The Benefits of Adjuvant Trastuzumab for HER-2-Positive Salivary Gland Cancers.

BACKGROUND: Although high-grade salivary gland cancers (SGCs) often express androgen receptor (AR) and/or HER-2/neu, therapeutically targeting these receptors in SGC remains investigational. We investigated the prevalence of receptor expression and the benefit of adjuvant HER-2 directed therapy in the high-risk postoperative setting and explored the clinical utility of sequentially targeting these receptors in the setting of advanced disease. MATERIALS AND METHODS: We clinically annotated 95 patients with SGC (excluding adenoid cystic carcinoma) treated at our institution from 2002 to 2019 and recorded AR, HER-2/neu status, and tumor genomic profiling results when available. Clinicopathologic information was then integrated with outcomes. RESULTS: Of 95 patients, most had high-risk histologies, with salivary duct carcinoma (SDC) as the most frequent diagnosis (43, 45%). Thirty-five (37%) experienced recurrence (51% SDC). HER-2/neu was positive (1-3+) by immunostaining in 34 of 52 (65%) evaluable cases. There was no difference in survival based on HER-2/neu or AR expression. Nine of 17 (53%) patients with HER-2+ SDC received adjuvant chemoradiation with trastuzumab. Median disease-free survival (DFS) and overall survival (OS) were longer among patients with HER-2/neu 3+ staining tumors who received adjuvant trastuzumab versus those who did not (DFS, 117 vs. 9 months; p = .02; OS, 74 vs. 43 months; p = .02), with no difference among other HER-2/neu subgroups (0-2+). Two of nine (22%) patients treated with adjuvant trastuzumab demonstrated recurrence, both with low HER-2/neu staining intensity (1+). Longer time to recurrence (hazard ratio, 0.94; p = .01) predicted improved outcomes. Both androgen deprivation and HER-2-directed therapies had clinical benefit beyond the first-line metastatic setting, with partial response observed beyond second-line use. CONCLUSION: Although prospective data are lacking, the use of adjuvant trastuzumab in high-risk patients with SGC appears beneficial, particularly among patients with tumors exhibiting HER-2/neu 3+ immunostaining. IMPLICATIONS FOR PRACTICE: Results of this study showed an improved disease-free and overall survival in patients treated with adjuvant trastuzumab for high-risk salivary gland cancers with strong HER-2/neu staining intensity. Following recurrence or metastatic spread, sequential HER-2, and androgen-directed therapies may benefit certain patients with salivary gland cancer.

PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells.

Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor frequently displaying gene fusions, most of which affect the PHF1 gene. PHF1 encodes plant homeodomain finger protein 1, which is involved in various processes regulating gene transcription, including those orchestrated by the polycomb repressor complex 2. Here, a series of 37 OFMTs, including 18 typical, 9 atypical, and 10 malignant variants, was analyzed with regard to transcriptomic features, gene fusion and copy number status, and/or single-nucleotide variants. The effects on gene expression and chromatin accessibility of three detected fusions (EP400-PHF1, MEAF6-PHF1, and PHF1-TFE3) were further evaluated in fibroblasts. Genomic imbalances showed a progression-related pattern, with more extensive copy number changes among atypical/malignant lesions than among typical OFMTs; loss of the RB1 gene was restricted to atypical/malignant OFMTs, occurring in one-third of the cases. RNA sequencing identified fusion transcripts in >80% of the cases analyzed, including a novel CSMD1-MEAF6. The gene-expression profile of OFMT was distinct from that of other soft tissue tumors, with extensive transcriptional upregulation of genes in OFMT. These findings were largely recapitulated in gene fusion-expressing fibroblast lines, suggesting that genes involved in, e.g., Wnt signaling and/or being regulated through trimethylation of lysine 27 in histone 3 (H3K27me3) are pivotal for OFMT development. The genes showing differentially higher expression in fusion-expressing cells paralleled increased chromatin accessibility, as revealed by ATAC sequencing. Thus, the present study suggests that OFMT develops through gene fusions that have extensive epigenetic consequences.

MYC expression has limited utility in the distinction of undifferentiated radiation-associated sarcomas from sporadic sarcomas and sarcomatoid carcinoma.

AIMS: MYC is a proto-oncogene that is frequently dysregulated in various malignancies, through translocation or amplification. Radiation-associated angiosarcoma frequently shows MYC amplification, and immunohistochemical expression has been shown to be a reliable surrogate marker for amplification, but less is known about MYC expression in other sarcoma types, despite reports of MYC amplification in some undifferentiated/unclassified radiation-associated sarcomas (RASs). Distinguishing putative RAS from non-radiation-associated sarcoma or sarcomatoid carcinoma can be difficult. The aim of this study was to determine the prevalence and potential diagnostic utility of MYC in this context, by evaluating MYC expression in a cohort of RASs, non-radiation-associated sarcomas, and sarcomatoid carcinomas. METHODS AND RESULTS: Three hundred and eighty-five neoplasms were evaluated, including 81 RASs (18 angiosarcomas; 57 undifferentiated sarcomas; three leiomyosarcomas; and three malignant peripheral nerve sheath tumours), 267 non-radiation-associated sarcomas, and 37 sarcomatoid carcinomas. Immunohistochemistry was performed with a monoclonal anti-MYC antibody. Staining in tumour cells was scored on the basis of extent (focal, 1-4%; multifocal, 5-49%; and diffuse, ≥50%) and intensity (strong, moderate, and weak). One hundred percent of radiation-associated angiosarcomas expressed MYC diffusely. Expression was infrequent among other types of RAS (9.5%), and the frequency was similar to that in non-radiation-associated sarcomas (9.7%). MYC expression was more common in sarcomatoid carcinomas, occurring in 43%. The extent and intensity of staining were variable in all groups. CONCLUSION: MYC expression is infrequent among RASs other than angiosarcoma, and has a similar prevalence in sporadic sarcomas. Given the frequency of expression in sarcomatoid carcinomas, MYC expression outside the context of radiation-associated angiosarcoma is of limited diagnostic utility, and should be interpreted with caution after exclusion of sarcomatoid carcinoma where relevant.

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma.

BACKGROUND: Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker-stratified clinical trials; however, the clinical utility and U.S.-centric financial sustainability of integrated next-generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. MATERIALS AND METHODS: In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS-based mutation and fusion detection, with MYB break-apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. RESULTS: Among 181 consecutive ACC cases (2011-2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB-NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1-NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression-free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.-based) and international levels of reimbursement. CONCLUSION: Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. IMPLICATIONS FOR PRACTICE: Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.

Immunohistochemistry with a pan-TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma.

AIMS: Secretory carcinoma (previously known as mammary analogue secretory carcinoma) is characterised by ETV6 rearrangements, most often ETV6-NTRK3 fusion. Given its histological overlap with other salivary gland tumours, secretory carcinoma can be difficult to diagnose without genetic confirmation. A recently developed pan-TRK antibody shows promise for identifying tumours with NTRK fusions. The aim of this study was to evaluate the utility of pan-TRK immunohistochemistry in distinguishing secretory carcinoma from mimics. METHODS AND RESULTS: We examined whole-tissue sections from 86 tumours, including 14 secretory carcinomas (12 parotid primaries and one buccal primary, and one metastasis; five with ETV6 rearrangement confirmed by fluorescence in-situ hybridisation, and one with ETV6-NTRK3 fusion and one with ETV6-RET fusion detected by targeted sequencing), 14 acinic cell carcinomas, 18 polymorphous adenocarcinomas, 20 low-grade mucoepidermoid carcinomas, and 20 pleomorphic adenomas. Immunohistochemistry was performed with a pan-TRK rabbit monoclonal antibody. Pan-TRK staining was detected in nine (64%) secretory carcinomas, all with a nuclear pattern and four with diffuse staining (>50% of cells). Among other tumour types, pan-TRK immunoreactivity was observed in all (100%) pleomorphic adenomas (particularly myoepithelial cell-rich, myxoid areas), 15 (83%) polymorphous adenocarcinomas, and four (20%) low-grade mucoepidermoid carcinomas, all with predominantly membranous/cytoplasmic immunoreactivity; only six cases showed focal (<10%) nuclear staining. All acinic cell carcinomas were entirely negative. CONCLUSIONS: Although pan-TRK expression is not entirely sensitive or specific for secretory carcinoma, nuclear staining distinguishes secretory carcinoma from mimics. Acinic cell carcinomas are negative for pan-TRK, though membranous expression of TRK is common in other salivary gland neoplasms. The lack of pan-TRK immunoreactivity in a subset of secretory carcinomas may suggest non-NTRK fusion partners.

Atypical lipomatous tumour/well-differentiated liposarcoma and de-differentiated liposarcoma in patients aged ≤ 40 years: a study of 116 patients.

AIMS: Limited data exist on atypical lipomatous tumour (ALT)/well-differentiated liposarcoma (WDL) and de-differentiated liposarcoma (DDLPS) in children and young adults. METHODS AND RESULTS: Cases of ALT/WDL/DDLPS arising in patients aged ≤ 40 years were collected from multiple institutional and consultation archives. A total of 116 cases of ALT/WDL (75) and DDLPS (41) were identified, representing fewer than 5% of these tumours seen at our institutions during this time-period. The patients (59 male/57 female) ranged in age from 8 to 40 years. Sites included deep central (abdomen/retroperitoneum/pelvis/groin) (n = 60), extremity (n = 42), trunk (n = 5), head/neck (n = 8) and mediastinum (n = 1). De-differentiated patterns included: high-grade pleomorphic sarcoma, myxofibrosarcoma-like, heterologous rhabdomyoblastic differentiation, low-grade spindle cell sarcoma and homologous lipoblastic differentiation. Forty-one patients experienced a local recurrence and 11 patients with DDLPS developed metastasis. ALT arising in the extremities had lower recurrence rates than deep central WDL (5-year recurrence-free survival 88.9% versus 59.0%; P = 0.002), while patients with deep central DDLPS experienced significantly more adverse events compared to WDL at this site (5-year event-free survival 11.9% versus 59.0%) (P < 0.0001). Seven (of eight) head/neck tumours had follow-up available; five recurred, and one patient (DDLPS) with recurrence also experienced a metastasis. The single mediastinal tumour (DDLPS) recurred and metastasised. CONCLUSION: ALT/WDL and DDLPS occurring in patients aged ≤ 40 years is rare, but exhibits similar morphological features to its counterparts in older adults, including potential for heterologous and homologous de-differentiation in the latter. Although case numbers are limited, tumours arising in the head and neck exhibit high rates of adverse events, suggesting that classification as WDL rather than ALT is more appropriate.

Pleomorphic liposarcoma: Updates and current differential diagnosis.

Pleomorphic liposarcoma is the least common but most aggressive subtype of liposarcoma. Tumors most commonly arise in the deep soft tissues of the extremities in adult patients. Pleomorphic liposarcoma has no specific immunohistochemical or molecular genetic features, and the presence of lipoblasts remains the sole diagnostic criterion. Diagnostic challenges include the identification of lipoblasts, which are often scarce or focal, and the distinction from other pleomorphic sarcomas, including dedifferentiated liposarcoma with homologous lipoblastic differentiation. This review provides an updated overview of the clinicopathologic features of pleomorphic liposarcoma, with discussion of its morphologic variants, differential diagnosis, and the role of small biopsy samples.

Surgical Management of Primary Retroperitoneal Sarcomas: Rationale for Selective Organ Resection.

BACKGROUND: Recently, some have argued for routine resection of adjacent but uninvolved organs in patients with retroperitoneal sarcoma (RPS) without stipulating the rationale for such organ resection (beyond the need to achieve a macroscopically complete resection) or examining histopathologic organ invasion (HOI). This study reviewed the authors' experience with primary RPS to investigate the rate and rationale for individual organ resection and the rate of HOI. METHODS: Operative and pathology reports for patients with primary RPS who underwent resection at our institution were retrospectively reviewed. Histopathologic organ invasion was confirmed by a dedicated sarcoma pathologist. RESULTS: From 2002 through 2011, 118 patients underwent resection of a primary RPS, and 99 of these patients (84%) had at least one organ resected. Kidney (n = 57), colon (n = 51), and adrenal (n = 41) were the most commonly resected organs. For the 302 organs removed, the perioperative clinical rationale for the resection was suspected invasion or tumor origin (n = 52, 17%), involved end-organ vasculature (n = 39, 13%), organ encasement (n = 42, 14%), tumor adherence (n = 127, 42%), resection required for R0/R1 resection (n = 25, 8%), or other (n = 17, 6%). The presence of HOI was found in 77 (25%) of the 302 organs resected. In the reviewed studies, HOI was identified in 34 (65%) of 52 organs suspected of invasion or tumor origin, in 19% of organs resected due to tumor encasement, and in 26% of organs with adherent tumor, even when not suspected intraoperatively, but was never identified in organs resected purely as part of a liberal en bloc resection of adjacent organs. When invasion was suspected intraoperatively, HOI was confirmed in 50, 78, and 100% of resected organs respectively for well-dedifferentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), and leiomyosarcoma (LMS). CONCLUSIONS: Histologic organ invasion was observed more commonly in organs resected with suspicion of invasion than in organs resected simply to achieve a negative margin, although this reflects a degree of subjectivity and selection bias. In more than one-fourth of adherent organs, HOI was present even when not suspected intraoperatively. Histologic subtype may predict HOI because DDLPS and LMS are associated with high rates of HOI when invasion is suspected intraoperatively. Development of a data-driven, histology-specific rationale for adjacent organ resection is critical.

Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma.

Sinonasal undifferentiated carcinoma is a rare and aggressive malignancy. Sinonasal undifferentiated carcinoma has long been considered a diagnosis of exclusion; to date, the molecular pathogenetic basis for sinonasal undifferentiated carcinoma is unknown. To identify potential oncogenic drivers in sinonasal undifferentiated carcinoma, targeted next-generation sequencing of 300 cancer-related genes was performed on 11 cases of sinonasal undifferentiated carcinoma. We identified IDH2 R172X mutations in 55% of sinonasal undifferentiated carcinomas including R172S, R172T, and R172M. Multispecific mutant IDH1/2 immunohistochemistry was performed and identified mutant-specific protein expression in all cases with available tissue: 3/3 sinonasal undifferentiated carcinomas with R172 mutations were positive and 4/4 wild-type cases were negative. Review of sequencing data for our institutional head and neck cohorts (n=412) confirmed the absence of IDH-activating mutations in other tumor types. Alterations in the IDH2-wild-type sinonasal undifferentiated carcinomas included SMARCA4 loss-of-function with confirmed loss of immunohistochemical expression, NOTCH1 gain-of-function, and TET2 loss-of-function. We demonstrate that the majority of histologically defined sinonasal undifferentiated carcinomas are characterized by IDH2 R172X mutations and overexpression of mutant protein. IDH2 R172X mutations are specific to sinonasal undifferentiated carcinoma among carcinomas of the head and neck, confirming this tumor type as a distinct clinicopathologic entity. These findings have significant implications for diagnosis and therapy with IDH inhibitors for patients with this rare and poorly understood tumor.

HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex-pleomorphic adenoma.

AIMS: Accurate classification of salivary gland neoplasms may be challenging, owing to morphological overlap, particularly in small biopsies. Recurrent translocations involving the high-mobility group AT-hook 2 (HMGA2) gene are present in a subset of pleomorphic adenomas (PAs) and carcinoma ex-pleomorphic adenomas (CA ex-PAs). The aim of this study was to evaluate immunohistochemical HMGA2 expression in 225 salivary gland tumours, including 56 PAs, 37 CA ex-PAs, and 132 potential histological mimics, to determine its diagnostic utility. METHODS AND RESULTS: HMGA2 expression was identified in 19 PAs (33.9%) and nine CA ex-PAs (24.3%). Expression was strong and diffuse throughout all PAs, and in four of nine positive CA ex-PAs. In five CA ex-PAs, HMGA2 showed weak-to-strong multifocal staining within the carcinomatous component, and strong diffuse HMGA2 expression in the residual PA. Among histological mimics, six de-novo salivary duct carcinomas (28.5%), three epithelial-myoepithelial carcinomas (33.3%) and one case each of myoepithelioma and basal cell adenoma expressed HMGA2. Fluorescence in-situ hybridization for HMGA2 rearrangement performed on a subset of tumours that showed diffuse HMGA2 expression in PAs and CA ex-PAs was frequently associated with rearrangement of the HMGA2 locus, whereas cases of de-novo salivary duct carcinoma, or CA ex-PA with limited or no HMGA2 expression, had an intact HMGA2 locus. CONCLUSIONS: HMGA2 expression is a highly specific (96.2%), but low-sensitivity (29.8%), marker for PA and CA ex-PA when compared with histological mimics, and is frequently associated with rearrangement of the HMGA2 locus.

Comprehensive genetic analysis of a paediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of the RB1 gene.

AIMS: Pleomorphic myxoid liposarcoma (PML) is an exceptionally rare and poorly studied subtype of liposarcoma, occurring typically in children and adolescents. The few previous genetic studies have shown that PML lacks the gene fusions and amplifications that characterize myxoid liposarcoma, atypical lipomatous tumour and de-differentiated liposarcoma. To learn more about its pathogenesis, we performed a comprehensive genetic analysis, including chromosome banding, fluorescence in-situ hybridization, single nucleotide polymorphism (SNP) array analysis, deep sequencing of the exome (WES) complemented by targeted sequencing of hot-spot regions of selected cancer-associated genes and transcriptome sequencing (RNA-seq) of a PML in a 10-year-old boy. METHODS AND RESULTS: Banding analysis revealed a hyperdiploid/hypotriploid karyotype that at SNP array analysis could be shown to derive from a near-haploid ancestral clone. Structural imbalances were few, but included homozygous loss of the RB1 locus; no fusion transcripts were identified at RNA-seq, no somatic mutations were seen at gene panel analysis and the most interesting mutation detected at WES involved KMT2D. CONCLUSION: The results support the notion that PML is a distinct type of liposarcoma, associated with a spectrum of somatic mutations that is different from that in other liposarcoma subtypes. The findings in the present case, combined with previous data, suggest that PML develops through combinations of numerical chromosome aberrations, possibly initialized by haploidization. The results also suggest that inactivation of RB1 is pathogenetically important.

Soft tissue tumors of the sinonasal tract.

Primary soft tissue tumors arising in the sinonasal tract are rare. While many mesenchymal neoplasms have been reported in the nasal cavity, sinuses, and nasopharynx, few are distinctive to this anatomic region. Some tumor types are relatively more common in this area, such as schwannoma and rhabdomyosarcoma. Nasopharyngeal angiofibroma and sinonasal hemangiopericytoma are unique entities of the sinonasal tract, as well as the recently characterized biphenotypic sinonasal sarcoma. This review discusses the clinical, morphologic, and immunohistochemical features and currently known molecular data of the more frequently encountered soft tissue tumors of the sinonasal tract.

Dermatofibrosarcoma Protuberans in a Patient With Cowden Syndrome: Revisiting the PTEN and PDGF Pathways.

PTEN hamartoma tumor syndrome, of which Cowden syndrome (CS) is the most recognized variant, is characterized by multiple benign and malignant tumors of ectodermal, mesodermal, and endodermal origins, secondary to germline mutation in the phosphatase and tensin homolog (PTEN) gene. Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive malignant fibroblastic/myofibroblastic tumor of the skin, characterized by the t(17:22)(q22:q13) translocation resulting in fusion of the COL1A1 and PDGFB genes. An association between CS and DFSP has not been reported in the literature to date. The authors have encountered a male patient with CS and a history of DFSP that developed adjacent to a sclerotic fibroma on the parietal scalp, both excised at age 7. He presented at age 21 with an enlarging pink nodule at the same site on the parietal scalp. Excision revealed a dermal and subcutaneous storiform spindle cell proliferation with fat entrapment and positive staining for CD34, consistent with DFSP. Fluorescence in situ hybridization confirmed PDGFB gene rearrangement. PTEN expression in the patient's recurrent DFSP was nearly absent when compared with that of sporadic DFSP. To our knowledge, this is the first report of DFSP in a patient with CS. Although the association is likely to be coincidental, the authors revisited the PTEN and the PDGF pathways to speculate any possible interplay of the 2 conditions on a molecular level.