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Emiltatug ledadotin (Emi-Le)

Adenoid cystic carcinoma with solid histology or high-grade transformation

Also known as XMT-1660
Manufacturer
Servier
Regulatory submission
Not announced
Launch
Not announced
Last updated
125 sources

Product information and disease descriptionPlace of product in therapyDisease description

Diagnosis

11 evidence topics · 15 sources

Summary: histologic diagnosis, grading, and molecular testing

ACC is diagnosed by biopsy with histology and immunohistochemistry, after CT or MRI to define local extent and stage. Grading is based on the solid component: the Perzin/Szanto system uses a >30% solid cutoff, the Spiro system >50%, the van Weert system the presence of any solid component, and the WHO notes a worse course when the solid component exceeds one third of the tumor. Interobserver agreement was moderate for the Perzin/Szanto (kappa 0.393) and Spiro (kappa 0.433) systems and 0.990 for the van Weert system. High-grade transformation is distinguished from solid ACC by nuclear enlargement and irregularity, higher mitotic counts, and loss of biphasic differentiation.

Molecular testing supports diagnosis and subtyping. MYB::NFIB FISH had 42.9% sensitivity and 100% specificity, and a MYB RNA in situ hybridization model had 93.2% sensitivity and 97.1% specificity in 79 cases. ACC-I and ACC-II can be assigned with MYC and p63 immunohistochemistry (AUROC 0.99). NOTCH pathway activation can be identified by genomic sequencing or NICD1 immunohistochemistry.

Diagnostic workup: imaging and biopsy with immunohistochemistry

“Radiological investigations like computerized tomography (CT) and magnetic resonance imaging (MRI) are the imaging modalities of choice to help delineate the extension of the primary tumor as well as for staging purposes.” (opens the source at this quote in a new tab)

“A biopsy of the tumor is needed for definitive diagnosis where the characteristic histological features along with the immunohistochemical markers like smooth muscle actin, S100, vimentin, as well as for MYB and CD 117 (c-kit) confirm the diagnosis.” (opens the source at this quote in a new tab)

“It frequently presents with unspecific symptoms, slow growth, the perineural invasion, and it is often problematic to diagnose because of the difficulty in defining its clinical differentiation and distinguishing it from benign tumours” (opens the source at this quote in a new tab)

Histologic grading: Perzin/Szanto, Spiro, and van Weert systems

“Two grading systems most commonly used are those described by Perzin et al./Szanto et al. and Spiro et al., respectively. They report that prognosis of ACC is poor if >30% and >50% of the tumor volume has a solid growth pattern, respectively.” (opens the source at this quote in a new tab)

“Inter-observer concordance for grading ACC according to Perzin et al./Szanto et al. and Spiro et al., proved to be moderate with Kappa Scores of 0.393 and 0.433, respectively. Our alternative grading system yielded inter-observer concordance with a Cohen's kappa result of 0.990.” (opens the source at this quote in a new tab)

“These results suggest to merely register the presence or absence of a solid tumor component since its inter-observer variability is very low, its reproducibility is high and its predictive value is comparable to the traditional grading systems used.” (opens the source at this quote in a new tab)

“According to the current WHO classification for salivary gland tumors, AdCC cases with a solid component constituting more than one third of the tumor may have a worse clinical course.” (opens the source at this quote in a new tab)

“The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate.” (opens the source at this quote in a new tab)

High-grade transformation: diagnostic criteria

“The importance and minimal criteria for distinction from solid (grade III) ACC are not well established.” (opens the source at this quote in a new tab)

“Useful supportive criteria were prominent comedonecrosis and fibrocellular desmoplasia.” (opens the source at this quote in a new tab)

“Ki-67 and p53 labeling indices were elevated in the high-grade components, though c-kit and cyclin-D1 were not.” (opens the source at this quote in a new tab)

“Compared to non-HGT, the HGT cohort exhibited significantly higher rates of lymph node metastasis (39.1% vs. 8.7%; P < 0.05), perineural invasion (60.9% vs. 26.1%; P < 0.05), and increased Ki-67 proliferation index (35.0% vs. 10.0%; P < 0.05).” (opens the source at this quote in a new tab)

Molecular testing: MYB::NFIB FISH and MYB RNA in situ hybridization

“Original scoring criteria yielded a 95.5% sensitivity (Sn), 68.6% specificity (Sp), and 83.5% accuracy. MYB::NFIB FISH yielded a 42.9% sensitivity, 100% specificity, and 60% accuracy.” (opens the source at this quote in a new tab)

“Optimizing for performance, simplicity, and minimal collinearity, our final model was defined as: abluminal pattern and/or % LS > 16.5%, which resulted in a 93.2% Sn, 97.1% Sp, and 94.9% accuracy for ACC diagnosis.” (opens the source at this quote in a new tab)

“MYB IHC was soon touted as an inexpensive practical alternative to FISH or other molecular testing. However, again, evidence to date suggest that the sensitivity and specificity are somewhat limited” (opens the source at this quote in a new tab)

Molecular subtyping: MYC and p63 immunohistochemistry

“Furthermore, immunohistochemical staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions.” (opens the source at this quote in a new tab)

“To assess the clinical utility of these biomarkers, we performed IHC for both markers and found they could robustly stratify ACC tumors by subtype (AUROC = 0.99” (opens the source at this quote in a new tab)

“Prognostic separation was consistent across RNA sequencing and immunohistochemistry-based classification methods.” (opens the source at this quote in a new tab)

“However, histologic grading suffers from interobserver variability and fails to fully explain the marked heterogeneity in survival observed among patients with similar clinicopathologic features” (opens the source at this quote in a new tab)

Molecular testing: NOTCH pathway activation

“NOTCH pathway activation was assessed through genomic analysis for NOTCH‐activating mutations or immunohistochemistry for NOTCH1 intracellular domain (NICD1).” (opens the source at this quote in a new tab)

“NOTCH‐activating mutations were identified in 82% of patients, and 95% showed positive NICD1 staining.” (opens the source at this quote in a new tab)

“NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining (P = .004).” (opens the source at this quote in a new tab)

Assignment of ACC-I and ACC-II by MYC and TP63 expression

“High- versus low-transcriptional expression of MYC and TP63 were defined by median expression level of each gene for stratification. Samples with high MYC/low TP63 were categorized as ACC-I, whereas those with high TP63/low MYC were categorized as ACC-II” (opens the source at this quote in a new tab)

“Intermediate classification denotes a situation in which both genes are concurrently up or downregulated.” (opens the source at this quote in a new tab)

“Further, NOTCH1 mutations were observed in 46.0% versus 3.5% (P < 0.0001) of ACC-I and ACC-II cases, respectively.” (opens the source at this quote in a new tab)

Distinguishing high-grade transformation from solid-pattern ACC

“It is mainly the cytomorphologic features that allow for a distinction between AdCC-HGT and the solid pattern of AdCC.” (opens the source at this quote in a new tab)

“Although a higher degree of nuclear atypia, a higher number of mitotic figures, and focal necrosis can be encountered in solid AdCCs, the neoplastic cells still have scanty cytoplasm and rather uniform nuclear features. In contrast, the cells of AdCC-HGT display a noticeable variation of nuclear size and shape, vesicular chromatin, increased nucleolar size, and more abundant cytoplasm.” (opens the source at this quote in a new tab)

“The Ki-67 index is significantly increased in the HG component compared with conventional tubular and cribriform AdCC (Fig. 3D).” (opens the source at this quote in a new tab)

Diagnostic criteria for high-grade transformation applied in a 412-case series

“The diagnosis of HGT was established based on the criteria delineated by Seethala et al.” (opens the source at this quote in a new tab)

“Microscopically, HGT components were deemed 'focal' if below 10% and 'diffuse' if above 10%.” (opens the source at this quote in a new tab)

“In the subsequent 5th (2022) edition of the WHO classification of head and neck tumors, specific morphological descriptions distinguishing HGT from conventional salivary gland carcinomas have been incorporated. These descriptions emphasize features like cellular pleomorphism, high mitotic activity, and necrosis. All HGT cases in this study met the aforementioned diagnostic criteria (Fig. 6).” (opens the source at this quote in a new tab)

“the distinguishing features of HGT include significant cellular atypia, vesicular nuclei, prominent nucleoli, high mitotic activity, frequent necrosis (including comedonecrosis), desmoplastic proliferation, and calcification, along with the occasional occurrence of squamous metaplasia and micropapillary architecture” (opens the source at this quote in a new tab)

Histologic grading by proportion of solid pattern, and limits of fine needle aspiration cytology

“Classic AdCC often shows a combination of cribriform and tubular patterns. In most studies, a solid growth pattern is associated with worse prognosis, advanced stage and development of distant metastases” (opens the source at this quote in a new tab)

“proposed a histologic grading scheme for AdCCs based on the degree of solid pattern. Three grades were suggested: Grade I, tumors with tubular and cribriform areas, but without solid components; Grade II, cribriform tumors that were purely or mixed with >30% of solid areas; and Grade III, tumors with a predominantly solid pattern.” (opens the source at this quote in a new tab)

“Fine needle aspiration cytology (FNAC) can be used for diagnostic purposes. The finding of large globules of extracellular matrix, partially surrounded by basaloid cells, suggests AdCC” (opens the source at this quote in a new tab)

“However, diagnosis of salivary cancers by FNAC is notoriously difficult and is often compromised by false negative evaluations” (opens the source at this quote in a new tab)