High-grade Transformation Research Articles

High-grade transformation of low-grade biphenotypic sinonasal sarcoma: Radiological, morphophenotypic variation and confirmatory molecular analysis

Biphenotypic sinonasal sarcoma (BSNS) is a recently described spindle cell sarcoma with neural and myogenic differentiation which arises exclusively in the sinonasal region.A man presented with swelling of left eyelid, and history of resection of a low-grade spindle cell mesenchymal tumor of left sinonasal cavity performed 15 years before. The original diagnosis was synovial sarcoma. Current MRI showed left supraorbital mass with intracranial extension. IR biopsy confirmed recurrence, and a left orbital craniotomy was done. NGS identified PAX3-MAML3 fusion in both, current and original tumor. The sarcoma was reclassified as BSNS, recurrent, with higher grade transformation. While the morphology, phenotype and molecular signature were in keeping with BSNS, the tumor showed biological progression towards a high-grade sarcoma.High-grade transformation of low-grade BSNS has not been described so far. High-grade transformation was not appreciated at the time of initial diagnosis, and it occurred in the local recurrence 15 years after.

Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report

BackgroundSecretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC.Case presentationThree cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30–32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis.ConclusionsHigh-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type.

Lacrimal gland extranodal marginal zone B-cell lymphoma (EMZL) with high-grade transformation: A case report

Introduction: Non-Hodgkin’s lymphoma (NHL) comprises a diverse collection of hematologic malignancies that is commonly prevalent worldwide. Although the survival rate of NHL has improved with early detection, treatment, and preventative measures; NHLs can still present within various locations involving the lymphatic system.

A case of adenoid cystic carcinoma with high-grade transformation in the palate with early poor prognosis

A case of adenoid cystic carcinoma with high-grade transformation in the palate with early poor prognosis

A case of suspected epithelial myoepithelial carcinoma in the parotid gland with high-grade transformation in which an <i>HRAS</i> mutation was detected

A case of suspected epithelial myoepithelial carcinoma in the parotid gland with high-grade transformation in which an <i>HRAS</i> mutation was detected

A Case Report of Mammary Analogue Secretory Carcinoma with Aggressive Clinical and Histological Presentation

Mammary analogue secretory carcinoma is a rare salivary gland tumor that has a wide range of clinical presentation ranging from indolent, local and slowly growing tumors to a very aggressive, infiltrative and widely metastasizing forms. We report a case of an unfortunate patient whose tumor had a very quick ominous disease course with aggressive clinical and histological presentation. This case is the first case, to our knowledge, to be reported in the literature from Saudi Arabia of MASC with features of high grade transformation

Prognostic factors in acinic cell carcinoma of the head and neck: The Amsterdam experience

IntroductionThe aim was to analyse prognosticators in acinic cell carcinoma (AciCC) in two head and neck referral centers in Amsterdam, the Netherlands. Materials and methodsEighty- nine cases of AciCC treated between 1979 and 2016 were retrospectively reviewed. Five, − 10 -and 20- year estimates of survival were executed as well as univariate analysis of prognosticators. ResultsThe majority of AciCC were T1-T2; 89%. Two percent had nodal disease (2%). The most affected organ was the parotid gland (84%) with a female preponderance (67%). Mean age was 52 years with most cases diagnosed in the fourth to sixth decade. The majority of patients received adjuvant radiotherapy. Elective neck dissection (END) in the N0 neck showed no metastases. High grade transformation (HGT) was found in 21% of cases. Median follow up was 101.9 months. Median time to recurrence was 26 months. Nine patients developed distant metastases (DM) of whom 6 had HGT-AciCC. Median survival with DM was 7 months. Five,- ten -and twenty- year estimates were 84%, 81% and 81% for recurrence free survival respectively. Negative clinical features were advanced stage disease and tumour size > 2.6 cm. Negative histological features were a high mitotic rate, HGT, close and involved surgical margins and necrosis. ConclusionAciCC- HGT excluded- of the head and neck has an excellent prognosis and shows acceptable long term results. END can be considered as part of the standard treatment due to the relative high incidence of HGT- AciCC and low accuracy of cytology.

Clinical Implications of the Mitotic Index as a Predictive Factor for Malignant Transformation of Atypical Meningiomas.

ObjectiveIntracranial atypical meningiomas have a poor prognosis and high rates of recurrence. Moreover, up to one-third of the recurrences undergo high-grade transformation into malignant meningiomas. We aimed to investigate the clinical factors that can predict the propensity of malignant transformation from atypical to anaplastic meningiomas. MethodsBetween 2001 and 2018, all patients with atypical meningioma, in whom the tumors had undergone malignant transformation to anaplastic meningioma, were included. The patients’ medical records documenting the diagnosis of atypical meningioma prior to malignant transformation were reviewed to identify the predictors of transformation. The control group comprised 56 patients with atypical meningiomas who were first diagnosed between January 2017 and December 2018 and had no malignant transformation. ResultsNine patients in whom the atypical meningiomas underwent malignant transformation were included. The median time interval from diagnosis of atypical meningioma to malignant transformation was 19 months (range, 7–78). The study group showed a significant difference in heterogeneous enhancement (77.8% vs. 33.9%), bone invasion (55.6% vs. 12.5%), mitotic index (MI; 14.8±4.9 vs. 3.5±3.9), and Ki-67 index (20.7±13.9 vs. 9.5±7.1) compared with the control group. In multivariate analysis, increased MI (odds ratio, 1.436; 95% confidence interval, 1.127–1.900; p=0.004) was the only significant factor for predicting malignant transformation. ConclusionAn increased MI within atypical meningiomas might be used as a predictor of malignant transformation. Tumors at high risk for malignant transformation might require more attentive surveillance and management than other atypical meningiomas.

Metatypical Adenoid Cystic Carcinoma: A Variant Showing Prominent Squamous Differentiation With a Predilection for the Sinonasal Tract and Skull Base.

Adenoid cystic carcinoma is a malignant salivary gland neoplasm, commonly involving the major and minor salivary glands. Adenoid cystic carcinoma arising in the skull base region is considerably less common and is characterized by aggressive clinical behavior, perineural invasion, and intracranial extension. Classically, these tumors are composed of ductal and myoepithelial cells, arranged as tubules and cribriform structures, as well as in a solid pattern when higher in grade. The distinctive molecular findings in this tumor are the gene fusions involving the MYB/MYBL1 and NFIB genes. Squamous differentiation, trabecular, and macrocystic growth patterns are exceedingly rare in these tumors and when present can cause significant diagnostic challenges. Squamous differentiation, in particular, is considered by many to be an exclusion criterion for adenoid cystic carcinoma outside of cases with high-grade transformation. In addition, a similar-appearing tumor with squamous differentiation, namely human papillomavirus-related multiphenotypic sinonasal carcinoma, has recently been defined, further complicating this differential diagnosis. Recently, we have come across 3 cases of adenoid cystic carcinomas involving the sinonasal tract and skull base having extensive interconnecting trabecular growth, macrocysts, and squamous differentiation, yet demonstrating the signature fusions involving MYB-NFIB and MYBL1-NFIB by RNA sequencing. In this article, we describe the clinical, histomorphologic, and imaging findings of these cases and propose the appellation "metatypical adenoid cystic carcinoma" for this uncommon variant morphology.

Dominant cell type analysis predicts head and neck adenoid cystic carcinoma outcomes

Traditional histological grading for predicting adenoid cystic carcinoma (ACC) outcomes is challenging and unreliable. We explored the relationship between dominant cell type (DCT) and outcomes for ACC of the head and neck to develop a new approach to predicting prognosis. Clinicopathological data were obtained from a retrospective cohort of 167 patients with primary ACC of the head and neck. Using immunohistochemistry markers to determine DCT, tumors were subclassified into three distinct subtypes, epithelial-predominant (E-ACC), myoepithelial-predominant (M-ACC), and conventional (C-ACC). Differences in clinicopathological parameters and clinical outcomes among these subtypes were then analyzed. Compared to that of M-ACC and C-ACC, E-ACC exhibited more aggressive clinicopathological features with predominantly solid components, high-grade transformation, lymphovascular invasion, tumor necrosis (TN), Ki-67 ≥ 30%, and advanced stage of disease. Both E-ACC and M-ACC could present as solid morphological forms, but E-ACC had a significantly worse prognosis than M-ACC. DCT, TN, and disease stage were independent predictors of recurrence-free survival. DCT, TN, age ≥ 50 years, and disease stage were independent predictors for overall survival. In conclusion, DCT was an independent prognostic indicator for both recurrence-free and overall survival for ACC. Our results provide a new approach to predicting prognosis in ACC and a strong pathological basis for clinically optimizing treatment.

Primary cutaneous adenoid cystic carcinoma: a clinicopathologic, immunohistochemical, and fluorescence in-situ hybridisation study of 13 cases.

This study aimed to investigate the clinical, histological, immunohistochemical and chromosomal features of primary cutaneous adenoid cystic carcinoma (PCACC). We retrospectively analysed 13 cases identified on their clinicopathological features and performed fluorescence in-situ hybridisation (FISH) on six available cases. Head and neck (46.2%) were most commonly involved. The median age was 53 years, with a male predilection. Histologically, tumours were classified as grades 1 (eight), 2 (four) and 3 with high-grade transformation (HGT) (one). The HGT component was demonstrated as poorly differentiated carcinoma with multifocal necrosis and myoepithelial differentiation. Patients with one of the following factors: longest diameter of the lesion (≥ 1 cm), involvement of subcutaneous fat tissue and widely infiltrative border had a relatively higher rate of local recurrence, distant metastasis and death. Five of six cases were confirmed to have MYB translocation, while nuclear staining for MYB proto-oncogene, transcription factor (MYB) protein was found in four cases. During the follow-up (median = 64 months), two patients experienced local recurrences. One patient, who was classified as grade III PCACC with HGT, developed multiple metastases and died of disease. Another patient was alive with multiple metastases. This is the largest single-institution study, to our knowledge, of PCACC in an Asian population. We describe the first case of scalp PCACC with HGT, which is the only death case in our series. PCACC tends to recur locally and has metastatic potential. PCACC with HGT has a poor prognosis.

Long-Term Outcome of Conjunctival Extranodal Marginal Zone Lymphoma: A Large Single-Institution Analysis

BackgroundThe most common subtype of B-cell lymphomas presenting in the conjunctiva is extranodal marginal zone lymphoma (EMZL), accounting for ~80% of cases. Most patients (pts) present with localized disease, and radiation therapy (RT) is the preferred treatment strategy. We aimed to retrospectively analyze our single-institution experience to provide further insight into the characteristics and long-term outcomes of conjunctival EMZL.MethodsWe evaluated 72 pts diagnosed with conjunctival EMZL between 01/1995 and 12/2020 at the University of Miami. Pts' characteristics included age, sex, TNM-AJCC ocular lymphoma and Ann Arbor staging systems, MALT-IPI score, treatment (RT, chemotherapy, rituximab), and treatment response (complete response (CR), partial response, stable disease, progression of disease). Primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method, and compared using the log rank test and the univariable Cox regression analysis. We also performed a competing risk univariable analysis (UVA) assessing predictors of cumulative incidence of relapse/progression, with death without relapse as a competing risk, using the Fine and Gray regression analysis.ResultsAmong all 72 pts, mean age was 59.9 yrs (7-93) with 38 (52.8%) being >60 yrs old, 46 (63.9%) were female, 56 (77.8%) had unilateral conjunctival disease, localized disease (T1N0M0 and Ann Arbor stage I) was present in 63 (87.5%), 6 (8.3%) had disseminated disease with more than 1 extranodal site involved, and 29 (40.3%) had a MALT-IPI of 1 or 2. After biopsy and surgical removal, 65 (90.2%) received additional treatment, while 6 (8.3%) were followed only, and in one case therapy information was not available . RT was the most common treatment (53 pts [73.6%], with 46 [86.8%] of those treated with ≥ 30 Gy). In two of these patients RT was combined with chemotherapy. Other treated pts received immunochemotherapy (12 [16.7%], including rituximab in 8). Five pts with stage II-IV disease received systemic therapy. CR was achieved in 63 (87.5%) after first line treatment, and no high-grade lymphoma transformation was seen. With a median follow up of 6.67 yrs (0.56-24.13), there were 14 relapses (19.4%). Among 53 pts treated with RT there were 8 relapses (15.1%), only one (1.9%) within the RT field. There were 23 progression events (31.9%, 14 relapses and 9 deaths without documented relapse), and a total of 14 deaths (19.4%).Mean PFS and OS were 6.69 yrs (0.49-20.37, SD 4.95) and 7.81 yrs (0.56-24.13, SD 5.40), respectively. The 10-yr PFS and OS were 68.4% (95%CI 52.8, 79.8%) and 89.4% (95%CI 77.4, 95.2%), respectively. Variables associated with shorter PFS in UVA Cox model were age > 60 yrs (HR=2.93, 95%CI 1.08, 7.95; p=0.035), high MALT-IPI (1-2) (HR=2.42, 95%CI 1.01, 5.78; p=0.048), and use of chemotherapy only (HR=2.73, 95%CI 1.13, 6.56; p=0.025). Variables associated with shorter OS included age >60 yrs (HR=9.07, 95%CI 1.17, 70.26; p=0.035) and high MALT-IPI (HR=6.19, 95%CI 1.35, 28.33; p=0.019). CR after frontline therapy was associated with longer PFS (HR=0.13, 95%CI 0.04, 0.45; p=0.001) but not OS. PFS of MALT-IPI 0 vs 1-2 was significantly longer (p=0.042), with 10-yr PFS 80.9% (95%CI 63.4%, 90.6%) vs 55.6% (95%CI 32.1%, 73.8%). Similarly, longer OS was observed in MALT-IPI 0 pts (p=0.0077; 10-yr OS 95.2% [95%CI 82.2%, 98.8%] vs 80.6% [95%CI 55.6%, 92.4%]) (Figure).A subset UVA Cox analysis of patients with Ann Arbor stage I showed longer PFS associated with CR after frontline therapy (HR 0.15, 95%CI 0.04, 0.58; p=0.006) with no significant association with age >60 yrs, high MALT-IPI or use of chemotherapy. Variables associated with shorter OS were age >60 yrs (HR 8.01, 95%CI 1.00, 63.98; p=0.05) and high MALT-IPI (HR 13.41, 95%CI 1.67, 107.99; p=0.015), similarly to the primary analysis.On univariable Fine and Gray regression models with death without relapse/progression as a competing risk, RT (SHR=0.33, 95%CI 0.12, 0.96; p=0.041) and CR-post frontline therapy (SHR=0.11, 95%CI 0.03, 0.36; p<0.001) were associated with lower risk of relapse. Conversely, chemotherapy (SHR=3.47, 95%CI 1.20, 10.0; p=0.022) was associated with higher risk of relapse.ConclusionPatients with conjunctival EMZL exhibit excellent long-term survival, and RT remains the most effective frontline therapy. MALT-IPI appropriately identifies patients at risk for treatment failure. [Display omitted] DisclosuresAlderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; NCI: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; NIH grants: Research Funding; University of Miami: Current Employment.

A single-center analysis of patients with extranodal marginal zone lymphoma of the breast

Breast extranodal marginal zone lymphoma (EMZL) is a rare malignancy. We performed the largest published to date single-center retrospective analysis of 13 patients with breast EMZL focusing on clinical characteristics and treatment-related outcomes. The rarity of this disease at our center was concordant with the prevalence reported in the literature, with breast EMZL comprising 2% of 654 MZL cases. Most patients presented with stage I-II disease however four (30.8%) patients had stage IV disease mostly due to occult bone marrow (BM) involvement. Interestingly, EMZL was frequently non-FDG avid (66.7%) on staging PET/CT. With a median follow-up of 3.1 years (range 5 months to 10.2 years), the 3-year progression free survival was 68.7% (95%CI 30.2%–88.9%) and overall survival 80.2% (95%CI 40.3%-94.8%). No patient experienced higher-grade transformation. Herein we show that localized breast EMZL can be effectively treated with radiation therapy providing long term disease control.

O04 Orbital lymphoma in a 72-year-old lady with rheumatoid arthritis: an argument for rituximab

O04 Orbital lymphoma in a 72-year-old lady with rheumatoid arthritis: an argument for rituximab

Static permeability assessment method to distinguish brain tumour recurrence from pseudoprogression

Abstract Aims It is common to have adjuvant chemo-radiotherapy after primary brain tumour resection. It is a known side effect that enhancing lesion could be seen in radiation territory after treatment, termed as pseudoprogression. It has been a difficult task to distinguish brain between tumour recurrence from pseudoprogression after radiotherapy. Timing of occurrence of these can overlap. It is important to distinguish the two as management is completely different. Early intervention in recurrence could improve survival time while pseudoprogression could be self-limiting. Surgical resection of pseudoprogression could be counter-productive. The radiological approach has been relying on multimodality investigation and close follow up. It has come to our institution notice that there is a new technique which could distinguish the two conditions efficiently. That's static permeability assessment method, also known as treatment response assessment maps (TRAMs). Our experience with it so far has been beneficial. Method This is a retrospective case series review of primary brain tumour treatment in our neurosurgical institution in 2020. Two high resolution 3D T1-weighted brain MRI images were acquired after a standard dose of gadolinium based contrast agent was injected. The first acquisition began five minutes after injection, and the second began 60 – 105 minutes post contrast injection. The TRAMs technique is based on image subtraction that is post processed after acquisition. The resultant subtracted image set was mapped to grey scale values, where voxels showing contrast clearance were light grey/white, and those showing contrast accumulation were dark grey/black. The zero value (i.e. no clearance or accumulation) was therefore mid-grey. Those with contrast clearance is associated with tumour recurrence. TRAMs images were compared to serial follow up imaging and histopathology results to determine the diagnostic accuracy of the technique. Results We have identified 21 patients in this period who had concern of either of pseudoprogression or tumour recurrence/progression. There were 6 females and 15 males, mean age 51. There were 14 glioblastoma multiforme (GBM), 5 astrocytoma, 1 oligodendroglioma and 1 post radiotherapy arteriovenous malformation. 17 cases were found to have clear cut recurrence, pseudoprogression or mixture of both in TRAMS. These findings are backed up by histology or repeated follow up scan. 4 cases were considered as equivocal. In retrospect, these cases have challenging interpretation due to poor case selection. TRAMs could distinguish high grade transformation as well as detecting recurrence. In some difficult cases, it is found that both pseudoprogression and recurrence could happen together. Conclusion TRAMs is a useful adjunct to the multimodalities of diagnostic techniques in tricky situation. This has provided an efficient and easy to use tool for radiologists to come up with the answer. We are the first independent centre to report on this technique. This is still early days and fine-tuning of its use is still undergoing. It is clear this has saved precious resources and has given patients more suitable care. We think it would be beneficial for us to share our experience with others and hope to get future collaboration with other centres.

DEK-AFF2 fusion-associated papillary squamous cell carcinoma of the sinonasal tract: clinicopathologic characterization of seven cases with deceptively bland morphology

A novel DEK-AFF2 fusion has been recently identified in four cases of basaloid to nonkeratinizing squamous cell carcinoma (SCC) in the sinonasal tract and middle ear with high-grade morphology. The exceptional response to immune checkpoint inhibitor in the first reported case highlights the potential clinical importance of identifying tumors with DEK-AFF2 fusions. We herein reported the first series of seven cases of DEK-AFF2 fusion-associated sinonasal SCC with deceptively bland morphology, including four cases of low-grade papillary Schneiderian carcinoma, which is a recently described tumor type with unknown molecular underpinnings. The DEK gene rearrangement was confirmed by DEK break-apart fluorescence in situ hybridization and DEK-AFF2 fusion transcripts were detected by reverse transcription polymerase chain reaction. In contrast to the previously reported DEK-AFF2 fusion-positive high-grade carcinomas, these tumors had a monotonous and bland morphology and were all initially diagnosed as sinonasal papilloma (SP) of various types, with or without dysplasia or carcinoma in situ. The tumor was characterized by mixed exophytic and inverted patterns, broad papillary fronds, acantholytic change, cellular monotony, dense neutrophilic infiltrates, and peripheral palisading. All tumors were diffusely positive for p40 or p63 and negative for NUT and p16. Molecular drivers associated with SP, including EGFR and KRAS mutations and both high and low-risk human papillomavirus infection, were negative in all cases. Although there was no overt stromal invasion or desmoplastic reaction in the initial specimens, these tumors tended to progress locoregionally through a prolonged clinical course and occasionally develop lymph node metastases, high-grade transformation, or extensively local destruction eventually leading to death. These justify more aggressive clinical management. Therefore, we propose the new terminology “DEK-AFF2 fusion-associated papillary SCC of the sinonasal tract” to better describe this clinicopathologically and molecularly distinct entity.

NR4A3 Immunostain Is a Highly Sensitive and Specific Marker for Acinic Cell Carcinoma in Cytologic and Surgical Specimens.

Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers. Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining. Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case. NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens.

High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases

PurposeSalivary Gland cancer (SGC) is a rare and heterogenous group of tumors. Standard therapeutic options achieve high local but poor distant control rates, especially in high-grade SGC. The aim of this monocentric study was to evaluate patterns of recurrence and its treatment options (local ablative vs. systemic) in a homogenously treated patient population with high-grade SGC after surgery and radio(chemo)therapy.MethodsMonocentric, retrospective study of patients with newly diagnosed high-grade salivary gland cancer. We retrospectively reviewed clinical reports from 69 patients with high-grade salivary gland cancer in a single-center audit. Survival rates were calculated using the Kaplan–Meier method and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox regression analysis).ResultsThe median time of follow-up was 31 months. After 5 years, the cumulative overall survival was 65.2%, cumulative incidence of local recurrence was 7.2%, whereas the cumulative incidence of distant metastases was 43.5% after 5 years. 30 of 69 patients developed distant metastases during the time of follow-up, especially patients with adenoid cystic carcinoma, salivary duct carcinoma, adenocarcinoma NOS and acinic cell carcinoma with high-grade transformation. The most common type of therapy therefore was chemotherapy (50%). 85.7% of patients with local ablative therapy of distant metastases show disease progression during follow-up afterwards.ConclusionWith surgery and radio-chemotherapy, a high rate of loco-regional control is reached, but over 40% of patients develop distant metastases in the further follow-up which usually present a diffuse pattern involving in a diffuse metastases. Therefore, in the future, intensified interdisciplinary combination therapies even in the first-line treatment in certain subtypes of high-grade SGC should be investigated.

Cytopathology of acinic cell carcinoma: A study of 50 cases, including 9 with high-grade transformation.

Although largely readily recognizable in tissue sections, acinic cell carcinoma (ACC) remains diagnostically problematic in fine-needle aspiration (FNA) cytopathology. The authors undertook an analysis of a large series of ACC aspirates, including acinic cell carcinoma with high-grade transformation (ACC-HGT). The authors searched their cytopathology files for ACC cases with histopathologic confirmation. FNA biopsy was performed according to standard techniques. Fifty FNA biopsy cases of ACC (including 36 of parotid origin [72%]) from 41 patients (female to male ratio, 1.4:1; age range, 23-84 years; average, 54 years) met the study inclusion requirements. Primary neoplasm aspirates were most common (72%), and they were followed by recurrent tumors (16%) and metastases (12%). A precise cytologic diagnosis was made for 64%. Three of 9 ACC-HGT cases (33%) were correctly interpreted as such; 98% of conventional ACC cases were correctly graded as low-grade. With the Milan classification system, 74% fit into the malignant category. Ancillary testing was performed for only 36%. Conventional ACC had moderately to highly cellular smears; monotonous cells in aggregates and single forms; rounded nuclei; and microvacuolated, finely granular, oncocyte-like, or nonspecific cytoplasm. ACC-HGT smears contained larger nuclei, high nuclear to cytoplasmic ratios, coarse nuclear chromatin, and a loss of cytoplasmic granules/vacuoles. A correct diagnosis of ACC via FNA biopsy was made in almost two-thirds of the cases. With the Milan classification, 84% of the cases would have been classified as malignant or suspicious for malignancy. An absence of conventional serous acinar cell morphology in some cases as well as an absence of ancillary immunohistochemistry testing in almost two-thirds of the cases prevented even better diagnostic performance.

Proteomic analysis of lacrimal gland adenoid cystic carcinoma with high-grade transformation

Objective: To analyze the protein expression differences of lacrimal gland adenoid cystic carcinoma (LACC) with high-grade transformation (HGT). Methods: Experimental study. A total of 8 paraffin tissue samples were collected in Tianjin Medical University Eye Hospital from December 2012 to January 2019. According to pathological examination, the samples were divided into the LACC group and the LACC-HGT group, with 4 cases in each group. The LACC group included 2 male samples and 2 female samples, with an average age of 53 years. The LACC-HGT group included 2 male samples and 2 female samples, with an average age of 44 years. Primary cells were cultured from fresh tumor tissue. Isobaric tags for relative and absolute quantification techniques were used to screen the differentially expressed proteins between the two groups, and bioinformatics analysis was conducted for the differentially expressed proteins. Microarray was used to screen differentially expressed mRNAs between LACC and LACC-HGT primary cells. The mass spectrum data were intersected with mRNA microarray data, and quantitative real-time (qRT) PCR was performed to verify the results. Proteomics and microarray data were compared using the independent sample t test. The qRT-PCR data were compared pairwise by one-way analysis of variance. Results: A total of 105 HGT-related differential proteins were detected in this study, including 50 up-regulated proteins and 55 down-regulated proteins. The significantly up-regulated proteins included hemoglobin subunit beta, hemoglobin subunit alpha 1, and collagen type Ⅵ alpha 2 chain; the significantly down-regulated proteins included Cereblon, adenosylhomocysteinase like 2, and ribosomal protein L39 pseudogene 5. Gene ontology analysis results showed that the LACC-HGT differential proteins were mainly located in the cytoplasm, vesicle cavity, and extracellular matrix, had organic acid binding and molecular carrier activity, and participated in the regulation of extracellular matrix composition, immunity, inflammation, apoptosis, and other biological processes. Pathway analysis showed that the LACC-HGT differential proteins were mainly involved in signal pathways such as mitogen-activated protein kinase signal pathway and extracellular matrix proteoglycans and glycan metabolism signal pathway. Protein complex prediction analysis screened out 4 up-regulated protein complexes and 1 down-regulated protein complex. There were 15 LACC-HGT differential proteins that overlapped with mRNA chip differential genes, of which 6 were tumor-related proteins including collagen type XIV alpha 1 chain (COL14A1), EMAP like 4 (EML4), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), NDRG family member 2 (NDRG2), osteoglycin (OGN) an Ras homolog family member C (RhoC). The main function was the movement and migration of tumor cells. The qRT-PCR results showed that the relative expression levels of COL14A1, EML4, ITIH4, NDRG2, OGN, and RhoC in primary LACC-1, LACC-2, LACC-HGT-1, and LACC-HGT-2 cells were significantly different (F=1 675.98, 38.53, 27.37, 16.47, 13.38, 25.22, all P<0.01). For example, the relative expression of COL14A1 in primary LACC-HGT-1 (16.09±0.51) and LACC-HGT-2 (9.96±0.34) cells was significantly higher than that in primary LACC-1 (1.00±0.13) and LACC-2 (0.67±0.08) cells (all P<0.05). Conclusion: There are differentially expressed proteins between LACC-HGT and LACC, among which COL14A1, EML4, ITIH4, NDRG2, OGN, and RhoC may play an important role in LACC-HGT and can be used as potential targets of LACC-HGT in further study. (Chin J Ophthalmol, 2021, 57: 531-539).