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Controversies and Emerging Entities in Skull Base
Sinonasal Carcinoma: Crosstalk 3MMorphology, Molecular, Management
Nasal Cavity and Paranasal Sinuses
2005: 76 diagnoses 2017: 39 diagnoses
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MALIGNANT SINONASAL TUMORS
<1.0% of all neoplastic tumors
3.0% of H&N malignancy
Sites:
Maxillary 60%
Nasal Cavity 22%
Ethmoid 15%
Frontal & Sphenoid 3%
Epithelial Mesenchymal Neuroectodermal Stem cells (50%) (30%) (15%) (5%)
Origins
Sinonasal Undifferentiated Carcinoma
(SNUC)
HG malignant epithelial neoplasm of the nasal cavity and paranasal sinuses
uncertain histogenesis
with or without neuroendocrine differentiation
without evidence of squamous or glandular differentiation
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SNUC
Usually unilateral
Nasal obstruction
Epistaxis
Pain
Proptosis
Visual disturbances
CN palsies
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SNUC:Combined modality therapy
Chemoradiotherapy or surgery + chemoradiotherapy is associated with improved survival outcomes.
SNUC multimodality treatment: choice of sequence
Surgical outcomes according to definitive locoregional treatment by response to IC.
Sinonasal Nasopharyngeal-type Undifferentiated
Carcinoma
(aka Lymphoepithelial Carcinoma)
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Distinctive Features:
Geographical distribution
Etiology
Histopathology
Response to therapy
Salivary glands Lung Breast Thymus Bladder Gastric
With prompt recognition and intense therapeutic
management, regardless of the disease stage the
5-year OS is ~ 70% and DSS ~ 78%.25.
Definition: Squamous carcinoma characterized by a distinctive ribbon-like growth pattern with absent to limited maturation.
Synonyms: Schneiderian carcinoma, transitional cell carcinoma, cylindrical cell carcinoma
Epidemiology: 20% of sinonasal SCC
Age: 6th- 7th decades; Sex: M>F
Histology: smooth stromal interface with a pushing border; immature appearance with lack of keratinization; high N>C; peripheral palisading occasionally; numerous mitoses and necrosis
WHO 2017 New Entity Non-keratinizing Squamous Carcinoma
(NKSCC)
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Small percentage of upper aerodigestivemalignancies are associated with translocations involving the nuclear protein of the testis (NUT) gene located at 15q14
The most common translocation involving the NUT gene is the t(15;19) (q13;p13.1)
Translocation fuses the NUT gene on chromosome 15to the BRD4 gene.
Rarely, the NUT gene is fused to the BRD3 gene at 9q34.2
NUT Midline CarcinomaWHO 2017 New Entity
Molecular Genetics
BRD3 and BRD4 are included in the human BET protein family (possessing 2 chromatin-binding bromodomains, and an extraterminal domain of unknown function).
These BRD proteins are known to bind transcriptionally active chromatin.
The bromodomain portions of BRD4 or BRD3 retain the fusion protein in the nucleus, bound to chromatin.
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Patients with NMCs frequently present:
mass related symptoms (including superior vena cava syndrome when the tumors present in mediastinum)
metastases (at the time of diagnosis)
Sinonasal NUT carcinoma centered within R nasal cavity with extension into L nasal cavity.
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Histology The cells have scant amphophilic or eosinophilic
cytoplasm
Nuclei have irregular contours although they tend to be uniform in size (fine to vesicular chromatin and prominent nucleoli)
Mitotic figures and apoptotic bodies are common
Squamous differentiation is frequently seen
Keratinization may seem abrupt (sometimes reminiscent of Hassel corpuscles, with sheets of immature cells juxtaposed to well differentiated, mature squamous nests
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Morphologic mimics of NUT carcinoma
Tumor Distinguishing marker*
Nonkeratinizing SCC HPV
Ewings/PNET CD99
Extra-Gonadal Germ Cell Tumor PLAP, Oct 3/4, β-HCG
Lymphoma/Leukemia LCA
Nasopharyngeal Carcinoma EBV
PD/ Basaloid SCC
Olfactory Neuroblastoma Synaptophysin
Small Cell Carcinoma
SNUC
*All of these markers are negative in NUT Ca
If NUT Ca is not to be missed, any poorly
differentiated, monomorphic, midline
neoplasm that does not stain for lineage
specific markers should be considered
for NUT-rearrangement testing.
Diagnosis
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From January 1993 to
December 2014- total
of 107 patients with
NUT carcinoma
International NUT Midline Carcinoma Registryhttp://www.nmcregistry.org
45% HN NUT carcinoma (48/ 107)
Median age: 21.9 years (0.1-81.7 yo)
Female predominance (1.5:1)
Tumor site:• sinonasal origin- 57%• other sites- the nasopharynx (n=3), the oropharynx (n=1),
the hypopharynx (n=1), the larynx (n=1), salivary gland (n=2), and an unknown primary (n=5).
The BRD4-NUT fusion was found in 86%.
Histology:• Carcinoma with squamous differentiation (49%)• Carcinoma without squamous differentiation (43%) • Other histology (8%)
HN NUT carcinoma
Details of treatment available for 39 of the 48 patients.
All patients received surgery, radiation, or
chemotherapy either as single agents or in combination as
part of their initial management.
Outcome data were available for 40 of the 48 cases.
• The median PFS was 6.6 months (range, 4.7-8.4 months).
• The median OS was 9.7 months (range, 6.6-15.6 months).
• The 2-year PFS rate was 26% (95% CI, 13%-40%).
HN NUT carcinoma
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No statistically significant difference in PFS or OS by age, sex, tumor location, size, histology, LN metastasis, or BRD4-NUT.
Survival affected by the treatment selection and the initial therapeutic sequencing strategy.
HN NUT carcinoma
Initial surgical resection and the extent of surgical resection (negative margins) significantly associated with PFS and OS.
HN NUT carcinoma
NUT Ca- Summary Points
NUT carcinoma is a genetically defined, highly aggressive, and incurable (squamous) carcinoma associated with chromosomal rearrangements of NUT, most commonly resulting in BRD4-NUT fusion oncogenes or, less commonly, BRD3-NUT or NUT-variant fusion oncogenes.
The karyotype of NUT carcinoma is uniquely simplecompared with that of other squamous cell carcinomas, suggesting that it arises through a genetic or epigenetic shortcut to the phenotype of squamous cell carcinoma.
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NUT Ca- Summary Points (cont)
NUT carcinoma is now diagnosable in most cases by IHC staining with an anti-NUT monoclonal antibody.
BRD-NUT chimeric oncoproteins include the acetyl histone–binding bromodomains and the protein-binding ET domain of BRDs, as well as an acidic domain in NUT that binds p300.
HDACi and BETi reverse the effects of BRD-NUT fusion proteins through mechanisms that remain to be elucidated.
Ongoing Issues: NUT-Carcinoma
Targeted inhibitors - more effective therapy/ clinical trials anticipated in the near future.
Whole genome/ exome – sequencing.
Clinical trials that employ a combinatorial approach.
Neuroendocrine Carcinoma
Small cell neuroendocrine carcinoma (SmCC)
Large cell neuroendocrine carcinoma (LCNEC)WHO 2017 New Entity
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NEC Carcinoma High-grade carcinoma with morphologic and
immunohistochemical differentiation, that includes small cell and large cell neuroendocrine carcinoma
Rare: 3% of sinonasal tumors
Age: mid to older aged men
Site: ethmoid>nasal cavity>maxillary& sphenoid
No significant association with smoking
Non-specific symptoms, rarely paraneoplastic syndrome
Advanced local disease with regional or distant metastasis at presentation
SmCC-NEC
LC-NEC
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Neuroendocrine Tumors – Overall Survival
0
.2
.4
.6
.8
1
Ove
rall
Su
rviv
al
0 60 120 180Time (months)
ONB
NEC
SNUC
SmCC
p=0.0029
5y-OS93.1%
64.2%62.5%
28.6%
Courtesy of Dr. Ehab Y. Hanna, MDACC
Uncommon tumors with overlapping histological features.
The natural history and biological behavior varies in this group of tumors.
Morphological diagnosis coupled with grading/staging are important for prognostication.
Primary Sinonasal Neuroendocrine Tumors (STND)
Small Blue Round Cell Tumors DDX
MR. SLOPE
Melanoma
Rhabdomyosarcoma
SNUC
Lymphoma
Olfactory neuroblastoma
Pituitary adenoma/ Plasmacytoma/ Paraganglioma
Ewings Sarcoma/ PNET
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Basaloid Squamous Carcinoma with Adenoid-like Cystic Features
aka
HPV-related carcinoma with adenoid cystic-like features
HPV-related Multiphenotypic Sinonasal Carcinoma
WHO 2017 Provisional Entity(part of NKSCC)
Definition
A distinctive HPV-related carcinoma of the sinonasal tract with
histologic and immunophenotypic features of both surface-
derived and salivary gland carcinoma.
Etiology:
HPV type 33; HPV 16, 18 negative
Localization:
exclusively in the nasal cavity and/or paranasal sinuses
(ethmoid, maxillary sinus, sphenoid) with occasional secondary
extension into the orbit.
Macroscopy:
the tumors usually appear as tan-white, fleshy masses
undermining normal-appearing sinonasal mucosa.
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Microscopy:
Highly cellular proliferations of basaloid cells (solid nests, with focal cribriform structures with cylindromatousmicrocystic spaces, à la AdCC).
The predominant basaloid cells have hyperchromatic and slightly angulated nuclei and a high nuclear-to-cytoplasmic ratio; cell spindling and clearing is sometimes seen.
These tumors also demonstrate ductal formations comprised of eosinophilic cuboidal cells within some of the nests.
Squamous differentiation is not seen within the invasive tumor, but most cases demonstrate squamous dysplasia of the surface epithelium.
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p63
p16
C-kit
HPV-hr
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LEF1
MYB
MRI- mass in the right frontal sinus compressing the right orbit.
nasal endoscopy and biopsy of the right paranasal sinus mass.
64 yo F with drooping eyelid and diplopia
WHO 2017Provisional Entity (part of the SNUC)
SMARCB-1 (INI-1)-Deficient Sinonasal Carcinoma
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Pan-CK
Synaptophysin
p63
Diagnosis:Sinonasal Undifferentiated Carcinoma (SNUC)
PTEN
INI-1 (BAF 47)
Reclassified as
SMARCB-1 (INI-1) Deficient Sinonasal Carcinoma
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SMARCB1 (INI1)A member of SWI/SNF chromatin remolding complexes, involving in epigenetic regulation of gene expression
Pawel BR, et al. Pediatr Dev Pathol. 2018
TSG (chromosome 22q11.2)
Its gene product is ubiquitously expressed in nuclei of all normal tissues.
SMARCB1 gene inactivation: pathogenesis of malignant neoplasms that tend to share “rhabdoid”cytomorphology.
The SWI/SNF ATPase subunit genes are frequently mutated in specific types of human cancers
Cancer Genetics, Volume 207, Issue 9, 2014, 365 - 372
Cancer-related effects of SMARCB1 loss
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SMARCB1 (INI1)-Deficient Tumors
Malignant rhabdoid tumor
Atypical teratoid/rhabdoid tumor
Epithelioid sarcoma
Renal medullary carcinoma
Epithelioid MPNST
Myoepithelial tumors
Extraskeletal myxoid chondrosarcoma
SMARCB1 (IN1)-Deficient Sinonasal Carcinoma
Nests of basaloid cells, peripheral palisading
Variable amount of rhabdoid cells
IHC: INI1 (BAF 47) antibody
SMARCB1 gene alteration
Aggressive clinical course
Clinical trial: EZH2 Inhibitor
IFN or polo-like kinase (PLK1) inhibitors
Agaimy A, et al. AJSP, 2014Bishop , et al. AJSP, 2014Bell D., et al. Virchows Arch. 2015
Agaimy, et al. AJSP 2017
SMARCA4- Deficient Carcinoma
Agaimy Al., Head Neck Pathol. 2017
A member of SWI/SNF chromatin remodeling complexes
Loss of SMARCA4 associated with small cell carcinoma of the ovary, hypercalcemic type, and a subset of aggressive thoracic/lung malignancies, etc.
IHC: BRG1 antibody
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These carcinomas tend to grow as epithelioid nests in the sinonasalsubmucosa, architecturally mimicking the much more common squamous carcinoma.
Occasionally the tumor may extend down seromucinous ducts and exhibit papillary or pseudopapillary growth - architectural features that are reminiscent of sinonasal papilloma.
Tumor necrosis is usually seen, and the mitotic rate is typically high. These tumors are usually highly infiltrative, with frequent bone invasion.
At the cellular level, each SMARCB1 (INI-1) deficient sinonasal carcinoma contained some rhabdoid or plasmacytoid cells.
While the tumor cell cytoplasm is variable in quality, the tumor nuclei of these carcinomas tend to be uniformly round with open chromatin and a prominent nucleolus.
Histology:
IHC
SMARCB1 (INI-1) deficient carcinoma have strong/ diffuse CK expression along with a complete absence of SMARCB1 (INI-1) immunostaining.
focally positive for synaptophysin, p63 and p40, p16 negative for actin, desmin, chromogranin, and NUT-1. negative for high risk HPV by in situ hybridization or PCR.
Differential Diagnosis
Non-keratinizing or basaloid SCC SNUC (diagnosis of exclusion))SNUC) Myoepithelial carcinoma (salivary gland or soft tissue
origin). Epithelioid sarcoma
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SMARC- Deficient Sinonasal Carcinoma(SDSC)
Expanding spectrum!!
To date, about 73 SDSC reported (~6% of sinonasal carcinomas).
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IDH-mutant SNUC
Recently discovered molecular subtype (~25 reported cases).
IDH-mutant SNUC
No morphologic or immunohistochemical differences, except of cytoplasmic expression of a polyclonal antibody targeting IDH1/2 R132/R172 genetic alterations in IDH-mutant SNUC.
Mutation of IDH2 along the R172 hotspot, including R172S, R172T, and R172 M.
Pathways linking IDH to tumorigenesis are well understood (identified in several cancers).
IDH1 and IDH2 encode metabolic enzymesinvolving the Krebs cycle.
Testing for IDH mutation should be considered because these patients might also benefit from targeted IDH inhibitors.
Malignant neoplasm; complex histologic pattern
Combining features of teratoma and carcinosarcoma
Benign and malignant Epithelial
Neural
Mesenchymal
Embryonal carcinoma, choriocarcinoma and seminoma are absent
Teratocarcinosarcoma
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Epithelial element
“Fetal oral mucosa”
Squamous nests with clear cytoplasm
neural element
pseudorosettes
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primitive component
Cartilage
Rhabdomyoblasts
mesenchymal
elements
Teratocarcinosarcoma
1984 - Heffner and Hyams
Sinonasal tract
Case reports in nasopharynx and pharynx
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Total: 63 cases Sharma et al. 35 cases (1998)
26 cases from literature
2 case reports
8:1 male to female ratio
Mean age: 61 years
Sinonasal tract (56)
Ethmoid sinus and nasal cavity (24)
Nasal cavity (18)
Ethmoid sinus (8)
Maxillary sinus (6)
Nasopharynx (6), pharynx (2), oral cavity (1)
Primitive cells: CD99, S-100 protein
Mesenchymal spindle cells: Vimentin, focal desmin, myogenin, SMA
Neuroepithelium: NSE, synaptophysin, chromogranin
Epithelium: Cytokeratin
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TCS: Prognosis and Treatment
Highly malignant
Mean survival ~ 2 years
Recurrences within 3 years
Complete resection
Followed by radiotherapy
Adequate sampling is paramount
Carcinosarcoma Single malignant epithelial / mesenchymal
Malignant germ cell tumor Seminoma, embryonal, choriocarcinoma, YST
Teratoma Lack malignant component
TCS: Differential Diagnosis
Undersampling or small incisional biopsies
– Olfactory neuroblastoma
Squamous carcinoma
Neuroendocrine carcinoma
Adenocarcinoma
Sarcoma
TCS: Differential Diagnosis
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Teratoid appearance Epithelial, mesenchymal, and neuroepithelial
Epithelium Nests of squamous cells
Glandular structures lined by columnar ciliated cells
Primitive cells Rhabdomyoblasts, chondroid, small primitive cells
TCS- morphology