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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

19

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