Basaloid Tumor Research Articles

Basaloid/blue salivary gland tumors

Basaloid tumors are a common diagnostic problem in salivary gland pathology. However, delineating each of these tumor types is facilitated by an algorithmic approach incorporated by tumor border and cell types. This approach greatly diminishes the challenge of separating polymorphous low-grade adenocarcinoma (PLGA) from adenoid cystic carcinoma (ACC). Despite the overlap in growth pattern, ACC is biphasic while PLGA is not. More relevant challenges, namely differentiation of the biphasic basaloid neoplasms including: epithelial–myoepithelial carcinoma (EMCA), cellular pleomorphic adenoma (PA), basal cell adenoma (BCA), and basal cell adenocarcinoma (BCAC), are resolved by a combination of morphologic, immunophenotypic, and to a limited extent, molecular features. Among the most challenging scenarios is high-grade transformation of any of the aforementioned entities. Here, the diagnosis requires recognition of a conventional component and exclusion of metastatic (or in some cases primary) SCC and even select neuroendocrine carcinomas and sarcomas in some cases.

Distinctive Patterns of CTNNB1 (β-Catenin) Alterations in Salivary Gland Basal Cell Adenoma and Basal Cell Adenocarcinoma.

Salivary gland basaloid neoplasms are diagnostically challenging. Limited publications report that some basal cell adenomas harbor CTNNB1 mutations, and nuclear β-catenin expression is prevalent. We evaluated β-catenin expression in basal cell adenomas and adenocarcinomas in comparison with salivary tumors in the differential diagnosis and performed targeted genetic analysis on a subset of cases. β-catenin immunohistochemistry was performed on formalin-fixed, paraffin-embedded whole sections from 73 tumors. Nuclear staining was scored semiquantitatively by extent and intensity. DNA was extracted from 6 formalin-fixed, paraffin-embedded samples (5 basal cell adenomas, 1 basal cell adenocarcinoma) for next-generation sequencing. Nuclear β-catenin staining was present in 18/22 (82%) basal cell adenomas; most were diffuse and strong and predominant in the basal component. Two of 3 basal cell adenocarcinomas were positive (1 moderate focal; 1 moderate multifocal). All adenoid cystic carcinomas (0/20) and pleomorphic adenomas (0/20) were negative; 2/8 epithelial-myoepithelial carcinomas showed focal nuclear staining. Most β-catenin-negative tumors showed diffuse membranous staining in the absence of nuclear staining. Four of 5 basal cell adenomas had exon 3 CTNNB1 mutations, all c.104T>C (p.I35T). Basal cell adenocarcinoma showed a more complex genomic profile, with activating mutations in PIK3CA, biallelic inactivation of NFKBIA, focal CYLD deletion, and without CTNNB1 mutation despite focal β-catenin expression. Nuclear β-catenin expression has moderate sensitivity (82%) for basal cell adenoma but high specificity (96%) in comparison with its morphologic mimics. CTNNB1 mutation was confirmed in most basal cell adenomas tested, and findings in basal cell adenocarcinoma suggest possible tumorigenic mechanisms, including alterations in PI3K and NF-κB pathways and transcriptional regulation.

PLAG1: An Immunohistochemical Marker with Limited Utility in Separating Pleomorphic Adenoma from Other Basaloid Salivary Gland Tumors

Objective: Fine-needle aspiration (FNA) diagnosis of salivary gland neoplasms is often challenging. Differentiating between pleomorphic adenomas (PA) and other basaloid neoplasms, especially basal cell adenoma (BCA) and adenoid cystic carcinoma (AdCC), can be difficult in cellular aspirates. PLAG1 (PA gene 1) is a proto-oncogene, which is frequently rearranged in PAs, leading to the aberrant expression of its protein. PLAG1 IHC expression has been reported to be positive in most PAs. The aim of this study was to evaluate the sensitivity and specificity of PLAG1 to differentiate PA from other basaloid neoplasms. Study Design: Immunohistochemical evaluation of PLAG1 was performed on 125 cases (52 FNAs and 73 surgical excisions). Nuclear staining of tumor cells was scored by the intensity and percentage of positive tumor cells. A combined score of >5 was defined as positive. Results and Conclusion: The sensitivity (55%) and specificity (75%) of PLAG1 in diagnosing PA in FNAs is relatively modest thus limiting its diagnostic utility. BCAs and AdCCs showed PLAG1 false positivity, in surgical excision specimens and less so in FNAs. This may be due to limited sampling or tumor heterogeneity. Hence, PLAG1 is a modest marker for PAs in FNAs.

Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors.

The deubiquitinase-encoding gene Cyld displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant-syndrome (CYLDm-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLDm through K14-Cre-mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9 ). CyldEΔ9/Δ9 mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c-Myc (S62) were markedly elevated in CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome.

Basal Cell Adenocarcinoma of the Parotid Gland

Basal cell adenocarcinoma is low grade malignancy so named in 1990 by Ellis and Wiskovitch. The basal cell adenocarcinomas are rare, accounting for 1-2% of epithelial salivary malignancies. Roughly 77% of them arise de novo with 23% arising within preexisting basal cell adenomas. It is considered as the malign counterpart of the basal cell adenoma. Histological differentiation between the two is difficult and they are often discriminated only by the invasion of local structures or perineural/vascular invasion. It is necessary to differentiate basal cell adenocarcinoma from other basaloid cell tumors of the salivary glands as in the following examples: solid tubuler variant of adenoid cystic carcinoma, polymorphous low grade adenocarcinoma, basaloid type of squamous cell carcinoma, basaloid variant of ameloblastoma and small cell carcinoma for the prognosis and potential differences in the treatment. The standard treatment is wide local excision with or without postoperative radiotherapy. In this article, we present a 75-year-old-female with basal cell adenocarcinoma involving the parotid gland.

A Case of Multiple Desmoplastic Trichoepithelioma.

Dear Editor: A 23-year-old woman presented with multiple, progressively growing, asymptomatic, depressed macules on face for 2 years. Physical examination revealed three yellowish to skin-colored annular atrophic macules 2~5 mm in size without elevated border on both cheeks (Fig. 1). She had no family or past history that scar might occur such as acne, chickenpox, herpes infection or prior laser treatment. Laboratory data including blood cell counts, biochemistry and urinalysis were unremarkable. Histopathology showed narrow strands of basaloid tumor cells in a fibrous stroma with adjacent embedded keratinous cysts (Fig. 2). The tumor strands were distributed from the upper to the deeper dermis. We performed additional exicisional biopsy with immunohistochemical staining in order to differentiate from malignant neoplasms including morpheic basal cell carcinoma (BCC) and microcystic adnexal carcinoma (MAC). Carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), CD23, and CK19 were negative, and CK20 showed focal positive. From these findings, she was diagnosed with desmoplastic trichoepithelioma (DTE), and remaining lesions were completely removed. Fig. 1 (A, B) Cutaneous examination revealed multiple yellowish to skin-colored annular, depressed macules on both cheeks. Fig. 2 (A) Biopsy specimen of left cheek reveals atrophic epidermis with upper and mid dermal cellular infiltration (H&E, ×40). (B) Tumor strands embedded in dense fibrous stroma are composed of small basaloid cells one to two cells thick (H&E, ... DTE is a rare benign skin appendageal neoplasm. It is a distinct variant of trichoepithelioma based upon its unique clinical and histopathological characteristics1. Clinically, it typically shows 3~8 mm diameter, annular, yellowish or skin-colored asymptomatic plaques, with an elevated border and a depressed or atrophic center on face1. It almost develops as a solitary lesion, although rare cases of patients with multiple lesions have been reported2. Histopathologically, DTE is characterized by following features. First, epithelial strands consist of small basaloid cuboidal cells in a one to three-cell-thick layer. Second, many keratinous cysts have a peripheral border of basaloid cuboidal cells, and sometimes have several calcification foci. Finally, stroma appears as dense fibrous stroma1. Differential diagnosis includes MAC, BCC, and scar. Although MAC presents with many horn cysts and epithelial cords, it is distinguished by ductal differentiation and infiltration to the subcutis or deeper structures3. Therefore, when biopsy is superficial, MAC can be misdiagnosed as DTE3. Assessing EMA and CEA immunohistochemistry may identify ductal differentiation and CD23 expression in MAC1. CK19 demarcates follicular bulge stem cells and its positivity favors MAC over DTE4. Both DTE and morpheic BCC can exhibit basaloid cells in strands and sclerotic stroma. However, neither cellular atypia nor peripheral palisading are seen in DTE, and morpheic BCC is not usually associated with horn cyst formation1. Also, in most DTE, retained or increased CK20-positive Merkel cells are found, but not in morpheic BCC5. Scar should be considered if multiple depressed macules appear, but it can be easily differentiated based upon its histopathology. The treatment of choice is surgical excision and Mohs micrographic surgery is recommended to achieve clear surgical margins. In our case, because multiple lesions had developed and tumor strands extended into the deep dermis, total excision was performed to exclude malignancy. Therefore, initial proper biopsy is important to make an accurate diagnosis and treatment in patients with multiple scar-like depressed macules on face. Herein, we report a rare case of multiple DTE, which should be differentiated from malignancy histopathologically.

Basal cell adenoma of maxillary sinus mimicking ameloblastoma

Basal cell adenoma (BCA) is a rare basaloid tumor, with only 20% of cases occurring in minor salivary glands. Histologically, BCA is characterized by the presence of basaloid cells and may frequently be mistaken with canalicular adenoma, basal cell adenocarcinoma, adenoid cystic carcinoma and basaloid squamous cell carcinoma. Immunohistochemistry may aid in arriving at a final diagnosis as in the present case. Reported here is a case of locally aggressive BCA. Histologically, the lesion mimicked ameloblastoma and other entities which posed a diagnostic challenge. There are no reports of BCA presenting as an aggressive lesion available in English literature so far; moreover, merely a single case of BCA of maxillary sinus has been previously reported to the best of our cognition. This case report highlights the rarity of this tumor with regards to its site of origin, clinical behavior and histopathological mimics.

Clinical Significance of p53 and p16ink4a Status in a Contemporary North American Penile Carcinoma Cohort

BackgroundBecause of the low incidence of penile carcinoma (PC), the value of p16ink4a, p53, and human papilloma virus (HPV) infection status in clinical practice remains unclear. Herein, we report our experience with potential clinical utility of these markers in men with PC treated at our institution. Patients and MethodsTissue microarrays of 57 cases of invasive penile squamous cell carcinomas were immunohistochemically stained for p16 and p53. HPV in situ hybridization (ISH) for high-risk subtypes was also performed. Association between marker status, nodal disease, overall (OS) and cancer-specific survival (CSS) were assessed. Resultsp16 and HPV ISH were positive in 23 (40%) and 24 (42%) of the cohort, respectively. The proportion of warty, basaloid, or mixed warty basaloid tumor subtypes were significantly greater in the p16-positive patients (48% vs. 3%; P < .01). p53 expression was negative in 31 (54%) cases. Only in p16-negative patients, positive p53 status was associated with pN+ disease (odds ratio, 4.4 [95% confidence interval (CI), 1.04-18.6]). In Kaplan–Meier analysis, the unadjusted estimated OS was insignificantly longer in p16-positive patients (median OS, 75 vs. 27 months; P = .27) and median CSS was not reached (P = .16). In a multivariable Cox proportional hazard model, when controlling for pathological nodal status and adjuvant chemotherapy, p16 status was a significant predictor for improved CSS (hazard ratio, 0.36 [95% CI, 0.13-0.99]). The worst CSS was seen in pN+ patients with double negative p16 and p53 expression (8 vs. 34 months; P = .01). ConclusionIn this current cohort, p53 and p16 status showed clinical utility in predicting nodal disease as well as survival.

A subset of prostatic basal cell carcinomas harbor the MYB rearrangement of adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a basaloid tumor consisting of myoepithelial and ductal cells typically arranged in a cribriform pattern. Adenoid cystic carcinoma is generally regarded as a form of salivary gland carcinoma, but it can arise from sites unassociated with salivary tissue. A rare form of prostate carcinoma exhibits ACC-like features; it is no longer regarded as a true ACC but rather as prostatic basal cell carcinoma (PBCC) and within the spectrum of basaloid prostatic proliferations. True ACCs often harbor MYB translocations resulting in the MYB-NFIB fusion protein. MYB analysis could clarify the true nature of prostatic carcinomas that exhibit ACC features and thus help refine the classification of prostatic basaloid proliferations. Twelve PBCCs were identified from the pathology consultation files of Johns Hopkins Hospital. The histopathologic features were reviewed, and break-apart fluorescence in situ hybridization for MYB was performed. All 12 cases exhibited prominent basaloid histology. Four were purely solid, 7 exhibited a cribriform pattern reminiscent of salivary ACC, and 1 had a mixed pattern. The MYB rearrangement was detected in 2 (29%) of 7 ACC-like carcinomas but in none (0%) of the 5 PBCCs with a prominent solid pattern. True ACCs can arise in the prostate as is evidenced by the presence of the characteristic MYB rearrangement. When dealing with malignant basaloid proliferations in the prostate, recommendations to consolidate ACCs with other tumor types may need to be reassessed, particularly in light of the rapidly advancing field of biologic therapy where the identification of tumor-specific genetic alterations presents novel therapeutic targets.

Reflectance confocal microscopy in the diagnosis of solitary pink skin tumours: review of diagnostic clues.

Reflectance confocal microscopy (RCM) is a noninvasive tool that can be helpful in the diagnosis of nonpigmented skin tumours. As RCM enables visualization of architectural and cytological structures at near-histological resolution, it can improve the diagnostic accuracy of dermoscopically equivocal solitary pink neoplasms. For management decisions, it is important to identify specific morphological clues that allow bedside classification of nonpigmented skin neoplasms into benign vs. malignant and melanocytic vs. nonmelanocytic. More specifically, the presence of a nested melanocytic proliferation at the dermoepidermal junction or dermis level permits the clinician to ascribe a given lesion as melanocytic; the identification of basaloid bright tumour islands is a key RCM feature for the diagnosis of basal cell carcinoma; and the presence of disarrayed epidermis along with small demarcated papillae is suggestive for the diagnosis of squamous cell carcinoma. The present review offers a comprehensive description of the main RCM diagnostic clues for solitary pink neoplasms that direct clinicians to the correct diagnosis and that may serve as groundwork for future prospective studies.

Dermpath Quiz.

A 52-year-old woman with no significant past medical history presented to her dermatologist with a long-standing history of multiple, small papules on her face. These had remained stable in size. The remainder of the physical examination and laboratory investigations was unremarkable. A biopsy of one of the papules was taken from the right side of her hairline. THE LESION MOST LIKELY REPRESENTS? Trichoepithelioma Trichoblastoma Basaloid follicular hamartoma (BFH) Fibroepithelioma of Pinkus (FOP) Infundibulocystic basal cell carcinoma (IFBCC) ANSWER C. Basaloid follicular hamartoma DISCUSSION Basaloid follicular hamartoma is a rare, benign follicular tumor that recapitulates portions of the normal hair follicle. It demonstrates a spectrum of clinical presentations, including multiple lesions with a generalized or localized distribution, blaschkoid distribution, or as a solitary stable lesion. The generalized form may be sporadic, acquired, familial or congenital. The sporadic form consists of multiple lesions without systemic disease. The acquired form occurs in females and is associated with alopecia, myasthenia gravis and systemic lupus erythematosus. The familial form is an autosomal dominant disease and can be found in association with hypotrichosis and hypohidrosis. Finally, the generalized congenital form is associated with cystic fibrosis and alopecia.[12] Patients have been described with overlap between BFH syndrome and Gorlin's syndrome and both are associated with PTCH mutations. Histopathological examination reveals nests and cords of basaloid cells within the superficial dermis, embedded in a scant to abundant fibromucinous stroma [Figures 1 and 2]. Horn cysts and hair follicle-like structures are present [Figure 3]. And clefting may be noted within the stroma, but unlike other benign pilar tumors, BFH rarely demonstrates a concentric fibroblast-rich stroma or papillary mesenchymal bodies.Figure 1: The lesion is composed of basaloid cells with horn cysts and peripheral palisading (H and E, ×40)Figure 2: Anastomosing strands of basaloid cells are noted. The intervening stroma is scant with myxoid areas and clefting within the stroma (H and E, ×100)Figure 3: Prominent horn cysts with keratin are identified. Peripheral palisading is prominent (H and E, ×200)The differential diagnosis includes trichoepithelioma, trichoblastoma, FOP and IFBCC.[23] Trichoepitheliomas are usually larger than BFH and are composed of tumor islands of basaloid cells in a distinct lace-like or “swiss-cheese” pattern. In addition, the stroma of trichoepithelioma is more cellular with concentric fibroblasts, papillary mesenchymal bodies and more prominent stroma clefting.[1] Trichoblastomas are circumscribed, large, basaloid neoplasms which, unlike BFH, are located in the deep dermis or subcutis, without any connection to the surface epithelium. Trichoblastomas, like related trichoepitheliomas, have a cellular stroma with prominent papillary mesenchymal bodies. Fibroepithelioma of Pinkus is a variant of basal cell carcinoma, which is characterized by arborizing cords of basaloid cells from the epidermis. Islands of fibromucinous stroma are surrounded by the reticular epithelial network, and eccrine ducts are present within the pink strands of epithelium. Blue basaloid buds are noted at the tips of the pink strands.[14] The most important differential diagnosis of BFH is IFBCC. IFBCC is characterized by cords and strands of basaloid cells embedded in a scant, fibromyxoid stroma, as in BFH. Horn cysts, clefts within stroma and no epidermal changes are also common to both lesions.[23] While IFBCC can have a greater degree of cellular atypia, mitotic activity, necrosis, deep infiltration, and epidermal ulceration, the two tumors may be identical histologically and often can only be distinguishable based on clinical features and biological behavior. At the molecular level, both lesions have abnormal PTCH (patched) signaling pathways.[135] Surgical excision is usually not required for BFH, except for cosmetic reasons or to exclude other skin tumors. When multiple BFH lesions are present, clinicians should be aware of the possibility of systemic disease.[123]

Basaloid Laringyeal Carcinoma on o Patient with Pneumonectomy Due to Advanced Tuberculosis.

The basaloid carcinoma is a rare and distinct type of squamous carcinoma. Of all the squamous carcinomas, the basaloid tumor is noted for its high aggressivity and fast replication rate. It is usually discovered within the upper levels of the larynx (supraglottis), the tongue base or the piriform sinuses in male patients ranging from sixty to eighty years old. The aggressivity of the tumor also means its discovery is usually a late event thus associating a relatively low survival rate within the first 5 years. The current paper presents the case of a patient diagnosed with a malign tumor of the larynx which is then identified as being a squamous basaloid carcinoma. The medical review of the patient reveals a long history of smoking and also pulmonary tuberculosis, for which the patient underwent left pneumonectomy.

P16 Protein and Gigaxonin Are Associated with the Ubiquitination of NFκB in Cisplatin-induced Senescence of Cancer Cells

The molecular mechanism of p16-mediated senescence in cisplatin-treated cancer cells is not fully understood. Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFκB. Chromatin immunoprecipitation assays show that this modification is associated with the inhibition of NFκB interacting with its DNA binding sequences, leading to decreased expression of NFκB-transcribed proteins. LCMS proteomic analysis of LAP-TAP-purified proteins from HeLa cells containing a tetracycline-inducible GFP-S peptide-NFκB expression system identified gigaxonin, an ubiquitin E3 ligase adaptor, as an NFκB-interacting protein. Immunoblotting and siRNA studies confirmed the NFκB-gigaxonin interaction and the dependence of this binding on p16-NFκB binding. Using gel shift assays, we have confirmed p16-NFκB and gigaxonin-NFκB interactions. Furthermore, we have observed increased NFκB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression. Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0.0000542), indicating the importance of nuclear p16 expression in prognosis. Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors. However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors. These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFκB.

Lung squamous cell carcinomas with basaloid histology represent a specific molecular entity.

The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient. To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed). Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n = 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR = 2.45; P = 0.000001). This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies.

Basal cell adenoma mimicking adenoid cystic carcinoma on FNAC- A Case Report

A 40-year-old-female presented with a right parotid swelling. It was diagnosed as adenoid cystic carcinoma on FNAC. On histopathology final diagnosis of basal cell adenoma was made. Basal cell adenoma is a rare and benign basaloid neoplasm of the salivary gland. The other basaloid neoplasms are pleomorphic adenoma, basal cell adenocarcinoma, adenoid cystic carcinoma, metastatic basal cell carcinoma, metastatic squamous cell carcinoma and small cell carcinoma. Differentiating basaloid neoplasms on FNAC pose diagnostic difficulties. The goal is to discuss problems and pitfalls in FNAC diagnosis of basal cell adenoma and to emphasize on cautious approach while diagnosing basaloid neoplasm on cytology.

MYB Gene Abnormalities t(6;9) in Adenoid Cystic Carcinoma Fine-Needle Aspiration Biopsy Using Fluorescence In Situ Hybridization

Fine-needle aspiration (FNA) biopsy of salivary gland neoplasms can have a variety of overlapping appearances. Basaloid neoplasms can be a diagnostic challenge, and FNA cytomorphology alone cannot always provide a definitive diagnosis. To examine the incidence and potential utility of detecting a MYB translocation by fluorescence in situ hybridization (FISH) in adenoid cystic carcinomas (AdCCs) and pleomorphic adenoma FNA smears with known surgical outcomes. Patients who underwent FNA biopsy for surgically confirmed AdCCs and pleomorphic adenomas were identified. Fluorescence in situ hybridization, using commercially available fluorescent-labeled probes, hybridizing to MYB-telomeric and MYB-centromeric, was used to identify the MYB gene and to evaluate it for abnormalities and translocation. Using a fluorescent microscope, 4',6-diamidino-2-phenylindole (DAPI)-stained, nonoverlapping cells were counted, and 10% or greater abnormal cells were considered positive. The 10 AdCC and 13 pleomorphic adenoma FNA cases had FISH evaluations performed; 50% (5 of 10) of the AdCC cases showed a MYB abnormality by FISH; 40% (4 of 10) AdCCs showed a positive break-apart signal in most cells (48%-84%). One case (10%) of AdCC showed a trisomy MYB signal pattern without the break-apart translocation pattern. Of the 13 pleomorphic adenomas, none (0%) of the cases showed a MYB translocation or abnormality by FISH. MYB FISH abnormalities showed a 100% positive predictive value, 50% sensitivity, and 100% specificity, when differentiating AdCC from pleomorphic adenoma. MYB gene abnormalities were present in 50% (5 of 10) of the AdCC cases. This corresponds to the reported prevalence in formalin-fixed, paraffin-embedded tissue for AdCC surgical resections. Using FISH testing for detecting MYB gene abnormalities in the salivary gland of FNA biopsies has the potential to provide additional, helpful ancillary information in diagnosing AdCC.

Abstract IA09: Squamous cell carcinoma pathology, etiology, and molecular drivers.

Abstract Squamous cell carcinoma (SCC) accounts for approximately 20% of all lung cancers in the United States and 30% in Europe [1-3]. It is a model of smokers related tumors with SCLC. The frequency of peripheral lung involvement has increased as compared to central squamous cell carcinoma. Morphologically, squamous differentiation is identified by inter-cellular bridging, squamous pearl formation and individual cell keratinisation. The intensity of these features characterizes well differentiated squamous cell carcinoma, versus poorly differentiated tumors that lack clear squamous morphology, are more difficult to differentiate from large cell carcinoma or from non cell lung carcinoma on small biopsies. In this cases the molecular marker P63 and/or P40 (the delta-N deleted P63 isoform) and negativity of TTF1 allows for a tumor to be classified as SCC. With high concordance q with the genomic prediction from exome sequencing (D.Seidel et al,Science Translational Medicine 2013 in press ) In addition to keratinized (well differentiated) and non keratinized (poorly differentiated) squamous cell carcinoma, basaloid carcinoma represent a third class recently identified as a specific molecular entity among SCC on gene expression profiling (WHO 2004 Travis , E. Brambilla, submitted 2013), with a significantly dismal prognosis among SCC. Basaloid carcinoma carries 95 % P53 mutation (G-T transversion). Supervised analyses reveal that basaloïd SCC significantly display a specific mRNA profile. Genes related to cell cycle, transcription factors, germ cells specific signatures, mRNA spliceosome, chromatin modification, and stemness are shown to be overexpressed in pure basaloid tumors, while genes related to squamous differentiation are shown to be underexpressed. This is highly coherent with the poorly differentiated status fast growth and aggressiveness of these tumors. Moreover, unsupervised analyses identify a molecular subgroup corresponding to pure basaloïd tumors. The transcription factor SOX4 showed 100% specificity and 50% sensitivity to discriminate basaloïd tumors in our cohort confirmed by immunohistochemical analysis. Using a centroid-based predictor, this molecular subtype was found in 8 independent public datasets (n=58/533), and was shown associated to a very poor survival as compared to other SCC (adjusted HR =2.45, p =0.00001 SCC. In addition to gene copy number alterations common to all SCC at the single gene level, gains of MYB, JUN, FGFR1, PIK3C3, DSC/DSG genes were found more frequent in pure basaloïd tumors. First identification of genomic druggable oncogene target were FGFR1 amplification [4] sensitive to a specific FGFR inhibitor [5] and DDR2 (Discoidin domain receptor) mutation [6] sensitive to dasatinib. Recently significant knowledge of genomics of SCC has been provided by comprehensive analysis of genetic alteration as part of the cancer gene genome atlas (TGA) [7] which transformed the landscape of genomic and epigenomic alterations. Among specific genetic alterations discovered as driver oncogenes targetable by specific therapies, FGFR1 amplification to 25 % of SCC even smokers restricted to those cases exposed to tobacco carcinogens (upper and lower airways) exclusively, DDR2 mutation accounting for 3 % of SCCand PIK3 amplication (PIK3CA inhibitors). The PIK3CA is amplified in 20-30 % of SCC. In addition, frequent mutation has been discovered on CDKN2/P16 gene, PTEN, PIK3CA, KEAP1 and other NRF2 complex (NRF2, Cul3) and MLL2, as well as significant copy number alterations including amplifications on SOX2, confirming previous description of a 3q 26 amplicon in all subtypes triggering high expression of SOX2 ,TP63 and PIK3CA [8, 9] and deletion of CDKN2/P16. Many of the somatic alterations identified in SCC were drivers of pathway important for initiation and tumor progression even those not yet but potentially targetable like SOX2. Therapeutic targets are ready for DDR2 mutation (dasatinib) and FRGR1 amplification (FGFR TKI) with anticipated approval for a target for PIK3CA. All together about 60 % of squamous cell carcinoma are potentially targetable with specific therapies [7,10]. Citation Format: Elisabeth Brambilla. Squamous cell carcinoma pathology, etiology, and molecular drivers. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA09.

Molecular evidence of type 2 mosaicism in Gorlin syndrome

We present a 12-year-old girl with a family history of Gorlin syndrome who had unilateral, segmentally arranged basaloid skin tumours present since birth, ipsilateral, palmoplantar pits of rather large size distributed along Blaschko lines, and an ipsilateral odontogenic keratocyst. The patient and her father were heterozygous for a germline mutation in the form of a single-base substitution in exon 18 of the PTCH1 gene. In the patient's lesional skin, a microdeletion in exon 3 of PTCH1 was detected, giving rise to a truncated protein. This additional mutation was ruled out in the contralateral skin and in blood lymphocytes, thus confirming its mosaic state. In this way we provide for the first time molecular proof of a type 2 segmental involvement of this autosomal dominant trait.

Expression of Cytokeratin Subtypes

Basaloid squamous cell carcinoma (BSCC) is rare variant of oral squamous cell carcinoma (OSCC) with predilection for upper aerodigestive tract. Although it is characterized by distinct histologic features it is often confused with conventional OSCC and other basaloid tumors. The study aims to establish differentiating features of BSCC with oral basaloid tumors using immunohistochemical (IHC) markers. This retrospective study included 34 cases, including BSCC, OSCC, and basaloid tumors. IHC staining was performed with primary antibodies against cytokeratin (CK) 19, 14, 8/18, α-smooth muscle actin (αSMA), p53, and MMP-9. A prominent CK 19, 14, and 8/18 expression was observed in BSCC as compared with basaloid tumors suggesting of basal cell origin with undifferentiated type of tumor cells. Expression of αSMA was intense in tumor cells of myoepithelial differentiation but lacked in BSCC. The intense expression of p53 and MMP-9 was noted in all basaloid malignancies. Considering standard histologic criteria in diagnosing BSCC, when in confusion with other basaloid tumors, IHC markers gain importance. Hence, enhanced expression of CK 19, 8/18, and 14 and coexistence of p53 and MMP-9 expression and negativity for αSMA suggest an accurate diagnosis of BSCC.

Basaloid Squamous Cell Carcinoma of the Rectum: A Rare Entity

We report a case of a 33-year old woman with a squamous-cell carcinoma of the rectum, of the basaloid subtype, infiltrating the uterus. The pathologic data and imaging findings that document the presence of the primary tumor of the rectum are presented in detail. Basaloid tumor is a histologic subtype of squamous-cell carcinoma arising usually in the anal canal. In this article we present a case of basaloid carcinoma of the rectum outside the anal canal with a bibliographical review of this rare clinical entity. J Med Cases. 2013;4(8):535-539 doi: http://dx.doi.org/10.4021/ jmc1386e