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On cut section, this low-grade apocrine intraductal carcinoma appeared as a cyst with an adjacent solid nodule within the parotid gland
Source publication
Intraductal carcinoma (IDC) is the current designation for a salivary gland neoplasm previously referred to as “low-grade salivary duct carcinoma” and “low-grade cribriform cystadenocarcinoma,” among others. IDC is conceptually believed to be similar to ductal carcinoma in-situ of the breast. Although IDC is one entity in the current WHO Classifica...
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p110α is a catalytic subunit of phosphoinositide 3-kinase (PI3K), a major downstream effector of receptor tyrosine kinase ErbB2, that is amplified and overexpressed in 20–30% of breast cancers, 40% of which have an activating mutation in p110α. Despite the high frequency of PIK3CA gain-of-function mutations, their prognostic value is controversial....
Intraductal carcinoma (IDC) of the salivary glands is a confounding entity, our understanding of which continues to evolve. At least four forms have been elucidated based on histomorphology, immunophenotype, and molecular profile: 1) intercalated duct-like, S100/SOX10 + with frequent NCOA4::RET fusions; 2) oncocytic, S100/SOX10 + with TRIM33::RET,...
Citations
... [6], with a pathogenic HRAS c.181C > A (p.Gln61Lys) mutation in the carcinoma component within the current study, two additional pathogenic mutations were identified: PIK3CA c.1624G > A p.(Glu542Lys) and CHD2 c.4173dup p.(Gln1392ThrfsTer17). This case histologically, immunohistochemically, and genetically resembled salivary gland IC of apocrine subtype, in which the same HRAS and PIK3CA mutations have been reported [19,20]. The final case report described adenocarcinoma arising from branchioma with KRAS and TP53 gene mutations detected [7]. ...
Branchioma is an uncommon benign neoplasm with an adult male predominance, typically occurring in the lower neck region. Different names have been used for this entity in the past (ectopic hamartomatous thymoma, branchial anlage mixed tumor, thymic anlage tumor, biphenotypic branchioma), but currently, the term branchioma has been widely accepted. Branchioma is composed of endodermal and mesodermal lineage derivatives, in particular epithelial islands, spindle cells, and mature adipose tissue without preexistent thymic tissue or evidence of thymic differentiation. Twenty-three branchiomas were evaluated morphologically. Eighteen cases with sufficient tissue were assessed by immunohistochemistry, next-generation sequencing (NGS) using the Illumina Oncology TS500 panel, and fluorescence in situ hybridization (FISH) using an RB1 dual-color probe. All cases showed a biphasic morphology of epithelial and spindle cells with intermingled fatty tissue. Carcinoma arising in branchioma was detected in three cases. The neoplastic cells showed strong AE1/3 immunolabeling (100%), while the spindle cells expressed CD34, p63, and SMA (100%); AR was detected in 40–100% of nuclei (mean, 47%) in 14 cases. Rb1 showed nuclear loss in ≥ 95% of neoplastic cells in 16 cases (89%), while two cases revealed retained expression in 10–20% of tumor cell nuclei. NGS revealed a variable spectrum of likely pathogenic variants (n = 5) or variants of unknown clinical significance (n = 6). Loss of Rb1 was detected by FISH in two cases. Recent developments support branchioma as a true neoplasm, most likely derived from the rudimental embryological structures of endoderm and mesoderm. Frequent Rb1 loss by immunohistochemistry and heterozygous deletion by FISH is a real pitfall and potential confusion with other Rb1-deficient head and neck neoplasms (i.e., spindle cell lipoma), especially in small biopsy specimens.
... In this study, two adenomatype IDLs demonstrated HRAS mutations, analogous to those recurrently identified in EMC [31][32][33]. Of course, HRAS mutations are not entirely specific to EMC in the salivary glands, as they can also be seen in a subset of other tumors including salivary duct carcinoma and apocrine intraductal carcinoma [35][36][37]. As such, it is possible that these adenomatous lesions represent an entirely separate benign salivary gland neoplasm that also happens to have HRAS mutations. ...
Background
Intercalated duct lesions (IDLs) are benign salivary gland proliferations that resemble normal intercalated ducts and are subdivided into hyperplastic, adenoma or hybrid types depending on circumscription. While IDLs were historically regarded as non-neoplastic, frequent association with basal cell adenoma (BCA) and epithelial-myoepithelial carcinoma (EMC) has raised the possibility that they are neoplastic precursors.Methods
In this study, we performed β-catenin immunohistochemistry and targeted molecular analysis on IDLs to clarify their pathogenesis.ResultsWe identified 15 IDLs from the parotid glands of eight men and six women with a median age of 65 years (range 42–85 years). These lesions included nine hyperplastic, three adenoma, and three hybrid types. Nuclear β-catenin localization was present in 7 of 13 lesions tested (54%). Next generation sequencing was successfully completed in 12 IDLs, of which seven (58%) had likely oncogenic mutations. These included three recurrent CTNNB1 mutations in hyperplastic (n = 2) and hybrid (n = 1) lesions and two recurrent HRAS hotspot mutations in adenomas.Conclusion
Despite substantial heterogeneity, these findings confirm that a majority of IDLs are genuinely neoplastic, and some demonstrate molecular overlap with both BCA and EMC, supporting their theorized role as precursors to these tumors. Nevertheless, no oncogenic drivers were present in a significant subset of cases, suggesting that some IDLs may be truly reactive and hyperplastic. As such, IDL appear to represent a diverse morphologic and molecular spectrum that include both neoplastic and hyperplastic lesions. Reconsideration of the boundary between IDL and BCA in the future may be necessary to simplify classification.
... 22 As shown in our cohort of IDC cases, alterations in RET have recently been shown to be the most characteristic feature of many IDCs, where certain RET fusions, depending on the specific histologic subtype, are overrepresented. 5,6,23,24 Specific molecular changes identified in IDC include NCOA4-RET (most common in the intercalatedduct type), TRIM27-RET (often in hybrid/mixed IDC), TRIM33-RET (often in oncocytic IDC), BRAF V600E mutations (often in oncocytic IDC), complex molecular alterations of HRAS and PIK3CA (apocrine IDC), and rarely STRN-ALK fusion (rare cases of IDC). 5,6,9,23,24 In our cohort, all LG IDCs with available molecular sequencing data demonstrated NCOA4-RET fusions corresponding to the intercalated-duct type of morphology on histology. ...
... 5,6,23,24 Specific molecular changes identified in IDC include NCOA4-RET (most common in the intercalatedduct type), TRIM27-RET (often in hybrid/mixed IDC), TRIM33-RET (often in oncocytic IDC), BRAF V600E mutations (often in oncocytic IDC), complex molecular alterations of HRAS and PIK3CA (apocrine IDC), and rarely STRN-ALK fusion (rare cases of IDC). 5,6,9,23,24 In our cohort, all LG IDCs with available molecular sequencing data demonstrated NCOA4-RET fusions corresponding to the intercalated-duct type of morphology on histology. A single HG IDC FNA case with molecular sequencing data showed HRAS and PIK3CA alterations, which are consistent with an apocrine-type IDC (Table 3). ...
Background
Intraductal carcinoma of the salivary gland (IDC) is a rare cancer with potential actionable targets, including RET fusions. Histologic and molecular features of IDC were recently reported, but cytomorphologic data are limited. In the largest multi‐institutional fine‐needle aspiration (FNA) series, the authors describe the cytomorphologic features of 13 IDC cases with available clinical, radiologic, histopathologic, and molecular data.
Methods
The cases included 13 FNAs for 9 low‐grade (LG) IDCs and 4 high‐grade (HG) IDCs with corresponding histopathology and available molecular, imaging, and clinical data. Smears and liquid‐based preparations available for 12 FNAs were semiquantitatively scored for key cytomorphologic findings and correlated with the corresponding resection.
Results
LG IDC FNAs showed a cellular, biphasic population of large, atypical ductal cells with mildly pleomorphic nuclei in a clean background and a minor population of small, uniform myoepithelial cells. In contrast, all HG IDC FNAs showed predominantly ductal cells with marked nuclear pleomorphism, coarse chromatin, and necrosis. With the Milan system, most LG and HG IDC FNAs were classified as either salivary gland neoplasms of uncertain malignant potential (54%) or malignant (31%). Immunohistochemistry showed ductal epithelial reactivity with mammaglobin, androgen receptor, and S100, whereas myoepithelial cells were positive for p63 and/or calponin. Among cases with next‐generation sequencing, 4 LG IDCs showed NCOA4‐RET gene fusions, whereas an HG IDC showed HRAS and PIK3CA mutations.
Conclusions
The cytomorphology of IDC overlaps with other benign and malignant salivary gland neoplasms. Immunohistochemistry limits the differential diagnosis, but definitive classification requires molecular analysis. A diagnosis of IDC has potential implications for patient management.
... Although IC is one entity in the current WHO Classification of Head and Neck Tumors, 13 recent studies have suggested that at least 3 subtypes exist: a LG intercalated duct cell (IDC)-like variant with frequent RET rearrangements, 15-17 a LG apocrine and mixed IC with frequent TRIM27-RET fusion, [16][17][18] and an apocrine and mixed IC with SDC-like genetics. 19 Like SPA, apocrine IC may harbor molecular alterations similar to high-grade (HG) SDC with frequent HRAS and PI3K pathway mutations. 19 SDC is a highly aggressive carcinoma that recapitulates invasive ductal breast cancer and it constitutes up to 10% of all salivary gland carcinomas. ...
... 19 Like SPA, apocrine IC may harbor molecular alterations similar to high-grade (HG) SDC with frequent HRAS and PI3K pathway mutations. 19 SDC is a highly aggressive carcinoma that recapitulates invasive ductal breast cancer and it constitutes up to 10% of all salivary gland carcinomas. 20 SDC is characterized by heterogenous molecular abnormalities involving predominantly inactivation of tumor suppressor genes, such as TP53, PTEN, and activation of genes of the PI3K/AKT/mTOR pathway (such as PIK3CA, HRAS, and AKT1). ...
... [21][22][23][24] It has been suggested earlier that apocrine IC and SPA may be related entities. 19 Here, we present an index case of apocrine IC of parotid gland with transformation to SDC arising from SPA. To further explore the nature of SPA and to learn how SPA, apocrine IC and SDC are associated, we decided to study molecular, immunohistochemical and histologic features of 36 cases of SPA, the largest series in the literature so far. ...
Sclerosing polycystic adenoma (SPA) is a rare salivary gland neoplasm originally thought to represent a non-neoplastic lesion. Recently we have encountered an index case of apocrine intraductal carcinoma of parotid gland of 62-year-old man with invasive salivary duct carcinoma component arising from SPA, a combination of tumor entities that has never been published so far. Here, we further explore the nature of SPA by evaluating 36 cases that were identified from the authors' consultation files. The patients were 25 females and 11 males aged 11 to 79 years (mean, 47.8 y). All tumors originated from the parotid gland. Their size ranged from 11 to 70 mm (mean, 28 mm). Histologically, all cases revealed characteristic features of SPA, such as lobulated well-circumscribed growth, focal hyalinized sclerosis, presence of large acinar cells with abundant brightly eosinophilic intracytoplasmic granules, and ductal components with variable cytomorphologic characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. In all cases, there were foci of intraluminal solid and cribriform intercalated duct-like epithelial proliferations with variable dysplasia which were positive for S100 protein and SOX10, and fully enveloped by an intact layer of myoepithelial cells. In addition, 14/36 cases (39%) had focal intraductal cribriform and micropapillary apocrine-type dysplastic epithelial structures composed of cells positive for androgen receptors and negative for S100/SOX10. The intraductal proliferations of both types showed focal mild to severe dysplasia in 17 cases (17/36; 47%). Two cases showed overt malignant morphology ranging from high-grade intraductal carcinoma to invasive carcinoma with an apocrine ductal phenotype. Next generation sequencing using ArcherDX panel targeting RNA of 36 pan-cancer-related genes and/or a TruSight Oncology 170/500 Kit targeting a selection of DNA from 523 genes and RNA from 55 genes was performed. Tumor tissue was available for molecular analysis in 11 cases, and 9 (9/11; 82%) of them harbored genetic alterations in the PI3K pathway. Targeted sequencing revealed HRAS mutations c.37G>C, p.(Gly13Arg) (2 cases) and c.182A>G, p.(Gln61Arg) (2 cases), and PIK3CA mutations c.3140A>G, p.(His1047Arg) (3 cases), c.1633G>A, p.(Glu545Lys) (1 case), and c.1624G>A, p.(Glu542Lys) (1 case). Moreover, mutations in AKT1 c.49G>A, p.(Glu17Lys) and c.51dup, p.(Tyr18ValfsTer15); c.49_50delinsAG, p.(Glu17Arg) (as a double hit) were found (2 cases). In addition, germinal and somatic mutation of PTEN c.1003C>T, p.(Arg335Ter); c.445C>T, p.(Gln149Ter), respectively, were detected. Gene fusions were absent in all cases. These prevalent molecular alterations converging on one major cancer-related pathway support the notion that SPA is a true neoplasm with a significant potential to develop intraluminal epithelial proliferation with apocrine and/or intercalated duct-like phenotype. The name SPA more correctly reflects the true neoplastic nature of this enigmatic lesion.
... In addition to morphologic features, these two main phenotypes can largely be distinguished by their mutually exclusive immunohistochemical profiles, namely, positive staining for S100, SOX10, and mammaglobin in intercalated duct IC, and nuclear positive androgen receptor (AR) in apocrine IC. More recently, studies have shown that apocrine IC with low-grade histology has similar immunohistochemical and molecular features as its higher grade apocrine counterpart [10] and that the molecular findings in IC with partial or pure oncocytic morphology include alterations in RET and BRAF [11]. ...
... Over the past 15 years, significant studies have led to the recognition of a distinct salivary gland neoplasm that is predominantly noninvasive, with unique morphological features and predictable molecular alterations, culminating in its inclusion and classification as IC in the 2017 WHO Blue Book [1]. Since this classification, there has been increased focus on IC, with published series highlighting its features for pathologic diagnostic recognition [7][8][9][10][20][21][22][23]. At our institution, increased awareness of IC has led to a higher frequency of identification in our patient cohort over the last few years, and as noted in our cohort, some in retrospective review. ...
... Among low-grade intraductal tumors with a nonspecific ductal appearance, the cells will have variable amounts of cytoplasm, secreted material in luminal spaces, and typically an S100-, SOX10-, and mammaglobinpositive immunohistochemical profile. Although the presence of p63-positive myoepithelial rimming is a helpful clue in the differential diagnosis [6,7], the differentiation between SC with intraductal growth and intercalated duct IC with invasive growth can be confounding [7][8][9][10]. Oncocytic morphology in IC has been increasingly reported in recent studies, and identification of a RET fusion, including TRIM33-RET and NCOA4-RET, or a BRAF p.V600E variant can further support the diagnosis of IC. ...
Following the publication of the 2017 WHO Classification of Head and Neck Tumours, there has been increasing interest in the classification of newly categorized intraductal carcinomas. Intraductal carcinoma (IC) is an indolent tumor, typically arising in the parotid gland, with an intact myoepithelial layer and a cystic, papillary, often cribriform architecture. Early studies of IC identified a heterogeneous group of molecular alterations driving neoplasia, and recent studies have defined three primary morphological/immunohistochemical variants, subsequently linking these morphologic variants with defined molecular signatures. While studies to date have pointed toward distinct molecular alterations following histological classification, this study used a novel approach, focusing primarily on six cases of IC with NCOA4-RET gene rearrangement as determined by next-generation sequencing, and describing the spectrum of clinicopathologic findings within that molecularly-defined group, among them a unique association between the NCOA4-RET fusion and hybrid variant IC and the first case of IC arising in association with a pleomorphic adenoma. RET-rearranged IC show histological and immunohistochemical overlap with the more widely recognized secretory carcinoma, including low-grade morphology, a lumen-forming or microcystic growth pattern, and co-expression of S100, SOX10, and mammaglobin, findings undoubtedly leading to misdiagnosis. Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of 6 NCOA4-RET fusion-positive IC compared with 4 cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications.
... In addition, nextgeneration sequencing has shown that these 2 tumors are very similar at the molecular level. 21 The additional proliferative ductules and altered acini seen in SPA are not present in pure intraductal carcinoma. Admittedly, the difference between these 2 lesions is not practically important, because they both behave in a benign manner in the absence of stromal invasion. ...
Sclerosing polycystic adenoma (SPA) is the more appropriate name for sclerosing polycystic adenosis. SPA is an uncommon salivary gland lesion with a constellation of unusual histologic findings that were originally interpreted as analogous to breast fibrocystic changes. The histologic findings in SPA include fibrosis, cystic alterations, apocrine metaplasia, and proliferations of ducts, acini, and myoepithelial cells in variable proportions. Because of its unusual mixed histology, SPA may be confused with a variety of lesions, ranging from reactive conditions to benign or even malignant neoplasms. The features of SPA are reviewed, with an emphasis on resolving its differential diagnosis.
... Recent studies have placed IDC into at least three variants based on morphology and immunohistochemistry: the intercalated duct-like type, which is positive for S100 protein and SOX10; the apocrine type, which expresses AR and GCDFP; and a hybrid or mixed type which demonstrates both intercalated duct-like and apocrine features [7][8][9][10]. Emerging molecular data suggests that these variants also have distinct molecular profiles, with recurrent NCOA4-RET rearrangements in the majority of cases with intercalated duct differentiation, TRIM27-RET fusions in cases with hybrid features, and a complex genetic profile including HRAS and PIK3CA hotspot mutations in the apocrine type [7][8][9][11][12][13][14]. ...
... Furthermore, although the purely apocrine subtype of IDC has an excellent prognosis in the absence of high-grade cytology or invasive growth, its molecular profile demonstrates more similarities to salivary duct carcinoma (SDC) than other IDC variants [15][16][17]. Both Bishop, et al. and Hsieh, et al. recently argued that these findings make lowgrade apocrine IDC distinct from tumors with intercalated duct-like features, although its relationship to high-grade apocrine IDC and SDC remains clouded [11,13]. ...
... TRIM27-RET fusions have also been reported as a recurrent genetic event in a few cases of IDC, occurring in those tumors with hybrid intercalated duct and apocrine features [7,8,14]. Meanwhile, IDC with pure apocrine differentiation often show more complex genetic profiles with multiple mutations including PIK3CA and HRAS hotspot mutations that overlap with those seen in SDC [9,11,13]. Only rare cases with alternate fusions have been reported to date, including a TUT1-ETV5 fusion in a tumor with intercalated duct-like differentiation and a KIAA1217-RET fusion in a tumor with hybrid intercalated duct and apocrine features [7]. ...
Intraductal carcinoma (IDC) is a rare salivary gland tumor that is considered analogous to ductal carcinoma in-situ of the breast, demonstrating a complex neoplastic epithelial proliferation surrounded by a continuous layer of presumed non-neoplastic myoepithelial cells. It is subcategorized into intercalated duct, apocrine, and hybrid subtypes based on morphologic and immunohistochemical features, with frequent NCOA4-RET and TRIM27-RET fusions, respectively, seen in intercalated duct and hybrid tumors. However, as an expanding clinicopathologic spectrum of IDC has been documented, controversy has emerged as to whether this tumor type is best defined by its intraductal growth pattern or distinctive molecular and immunophenotypic differentiation. Here, we further explore the nature of IDC by evaluating four cases that arose within intraparotid lymph nodes. These intercalated-duct phenotype tumors with diffuse S100 protein expression demonstrated a crowded and complex epithelial proliferation arranged in cystic, cribriform, and micropapillary architecture, surrounded by an intact myoepithelial cell layer, and were completely intranodal. Of two tumors with tissue available for molecular analysis, one demonstrated a NCOA4-RET fusion and one harbored a STRN-ALK fusion that is novel to IDC. Not only does the intranodal presence of IDC present a challenging differential diagnosis, but the complex nature of this proliferation within lymph node tissue raises questions as to whether the myoepithelial component of IDC is actually non-neoplastic in nature. Furthermore, identification of a STRN-ALK fusion expands the genetic spectrum of IDC and adds to evidence of an emerging role for ALK in salivary gland tumors. Further attention to the nature of the myoepithelial cells and documentation of alternate fusion events in IDC may inform continued discussion about its appropriate classification.
... This entity has undergone several nomenclature revisions, with the recent WHO classification of head and neck tumors using the term intraductal carcinoma. 8,28 This tumor is an intraductal proliferation of neoplastic cells surrounded by a myoepithelial cell layer, similar to DCIS of breast. 8,28 Intraductal carcinoma can be low, intermediate, or high grade, with high-grade forms entering the differential diagnosis with SDC. ...
... 8,28 This tumor is an intraductal proliferation of neoplastic cells surrounded by a myoepithelial cell layer, similar to DCIS of breast. 8,28 Intraductal carcinoma can be low, intermediate, or high grade, with high-grade forms entering the differential diagnosis with SDC. Classic intercalated duct-like intraductal carcinoma is S100 and SOX10 positive and AR negative, but an apocrine variant exists that is S100 and SOX10 negative and AR positive. ...
... Such cases of high-grade apocrine intraductal carcinoma are distinguished from SDC by the presence of a surrounding myoepithelial cell layer highlighted by p40/p63 or SMA. 6,28 This apocrine variant of intraductal carcinoma may represent a precursor lesion to more widely invasive SDC because there are also some genetic similarities. 28 Small areas of invasion may be seen in tumors classifiable as intraductal carcinoma, but the significance of this remains to be determined and intraductal carcinomas are generally indolent with an excellent prognosis after complete excision. ...
... morphologic subtypes of IDC: the intercalated duct type, apocrine type, and hybrid or mixed type (consisting of an admixture of intercalated duct type and apocrine features). 4,5 Additionally, a small series of 5 cases by Nakaguro and colleagues 6 also has proposed the so-called oncocytic variant of intraductal carcinoma due to its prominent oncocytic features. Significantly, the increasing molecular profiling of intraductal carcinomas is demonstrating recurrent molecular alterations, which appear to be specific to each subtype, such as the NCOA4-RET rearrangements in the intercalated duct type and TRIM27-RET rearrangements predominantly in the mixed subtype. ...
... Although most reports in the literature recognize these as distinct tumor entities, recent literature has demonstrated a potential molecular connection between the so-called low-grade apocrine intraductal carcinoma and high-grade conventional salivary duct carcinoma. 4 The fact that many of these cases show microinvasion and rarely show extensive invasion also suggests a potential link to salivary duct carcinoma in some cases. ...
... The size may range anywhere between 0.6 cm and 4.6 cm. 2,4,11,12 ...
Intraductal carcinoma of the salivary gland is a rare tumor characterized by intracystic proliferations of papillary, cribriform, and solid architecture of small uniform epithelial cells, reminiscent of ductal carcinoma in situ of the breast. Recent literature has identified 4 distinctive subtypes: the intercalated duct type, apocrine type, mixed/hybrid type, and oncocytic type, all with corresponding immunohistochemical and molecular findings. Although these tumors are typically in situ, as evidenced by a retained myoepithelial layer, they can demonstrate minimal invasion or, rarely, widespread invasive growth. Their overall prognosis is favorable, with few reported cases of recurrences and nodal metastases but no evidence of distant metastases.
Background
Salivary gland cystadenoma (SGCA) is a rare benign tumor that predominantly occurs in the parotid gland. SGCAs affecting the minor salivary glands are uncommon and often resemble, clinically and histopathologically, other salivary gland lesions.
Methods
This study aimed to describe a series of four cases of SGCA affecting intraoral sites and performed a literature review of well-reported SGCA published in the English-language literature.
Results
SGCA cases included in this series were diagnosed in the buccal mucosa, lip, and hard palate of female patients aged between 19 and 78 years. All cases underwent excisional biopsy and were histologically characterized by a multicystic growth with variable degrees of capsule formation and were lined by several types of epithelium, including some cell types that are infrequently reported in SGCA. In some cases, a small collection of lymphocytes was observed adjacent to cystic formations. All SGCA were positive for periodic acid-Schiff, and immunohistochemical reactions were positive for CK7 and p63. The follow-up time ranged widely from 3 to 53 months, and to date, no recurrence has been observed.
Conclusion
The literature review revealed a total of 33 published studies accounting for 55 SGCA cases.
