An Integrated Cytologic and Histologic Approach to the Diagnosis of Salivary Gland Tumors W.C. Faquin, M.D., Ph.D. Massachusetts General Hospital Massachusetts Eye and Ear Infirmary Boston, MA Celeste N. Powers, M.D., Ph.D. Medical College of Virginia Richmond, VA
An Integrated Cytologic and Histologic Approach to the Diagnosis of Salivary Gland Tumors • INTRODUCTION • 8 FNA CASES WITH CORRESPONDING HISTOLOGY
SALIVARY GLAND FNA Because of the wide range of non-neoplastic and neoplastic lesions, and the cytologic overlap between many benign and malignant tumors, salivary gland FNA is probably the MOST CHALLENGING area of cytopathology.
Salivary Gland Lesions Neoplastic Benign
Non-Neoplastic • • • • • • • • • • •
Acute sialadenitis Chronic sialadenitis LESA HIV-associated lymphoepithelial lesion Reactive lymph nodes Mucocele Mucinous metaplasia Sialadenosis Lipoma Hemangioma Branchial cleft cyst
• • • •
Pleomorphic adenoma Basal cell adenoma Warthin’s tumor Oncocytoma
Low-Grade • • • • • •
Mucoepidermoid carcinoma, low-grade Acinic cell carcinoma Polymorphous low-grade adenocarcinoma Basal cell adenocarcinoma Epithelial-myoepithelial carcinoma MALT lymphoma
High-Grade • • • • • •
*Adenoid cystic carcinoma Salivary duct carcinoma Mucoepidermoid carcinoma, high-grade Ca-ex-pleomorphic adenoma Clear cell carcinoma Large B-cell Lymphoma
SALIVARY GLAND FNA CHALLENGING DIAGNOSTIC ISSUES • Matrix-containing tumors • Oncocytic lesions • Basaloid tumors • Lymphoid lesions • Cystic and mucinous lesions • High-grade carcinomas • Clear cell tumors • Spindle cell lesions
SALIVARY GLAND FNA Rationale and Indications for FNA: – Any unexplained salivary gland mass – Safe, cost-effective, accurate – Guide the clinical management/pre-op strategy: » Non-neoplastic » Benign tumor or low-grade carcinoma » High-grade carcinoma
SALIVARY GLAND FNA Sample Preparation: – Both Romanowsky and Papanicolaou stained preparations are essential !
SALIVARY GLAND FNA Accuracy: • High accuracy for non- neoplastic vs neoplastic • High accuracy for low-grade vs high-grade • Variable accuracy for a specific entity: • High for pleomorphic adenoma • Low for basal cell adenocarcinoma
SALIVARY GLAND FNA Usually Specific Diagnosis
Sometimes Specific Diagnosis
Usually Descriptive Diagnosis
Pleomorphic adenoma
Adenoid cystic carcinoma
Basal cell adenoma, tubulotrabecular and solid types
Warthin’s tumor
LG mucoepidermoid carcinoma
HG mucoepidermoid carcinoma
Acute and chronic sialadenitis
Carcinoma ex PA
Salivary duct carcinoma
Basal cell adenoma, membranous type
Metastasis
Reactive lymph node
Small cell carcinoma
Basal cell adenocarcinoma
Lymphoma
Mucocele
Epithelial-myoepithelial carcinoma
Oncocytoma LESA Acinic cell carcinoma
Polymorphous low-grade adenocarcinoma
FEATURES OF THE NORMAL SALIVARY GLAND
SOME SALIVARY GLAND FACTS • 3 Major glands (ectodermally derived): • Parotid (serous) • Submandibular (mixed seromucinous) • Sublingual (mucinous)
• 500-1000 Minor glands: Submucosa of oral cavity • Seromucinous glands of the nasal cavity, larynx, and bronchi • Tumors: • 0.4-13.5 per 100,000 people • Older adults, females, parotid gland, approx. 75% are benign • Risk of malignancy is inversely proportional to the size of the gland (20% in parotid; 80-89% in oral cavity)
HISTOLOGIC FEATURES OF THE NORMAL SALIVARY GLAND
HISTOLOGIC FEATURES OF THE NORMAL SALIVARY GLAND
HISTOLOGIC FEATURES OF THE NORMAL SALIVARY GLAND
HISTOLOGIC FEATURES OF THE NORMAL SALIVARY GLAND
HISTOLOGIC FEATURES OF THE NORMAL SALIVARY GLAND
FNA OF THE NORMAL SALIVARY GLAND Cytologic Features of the Normal Aspirate • Serous and mucinous-type acinar cells in lobules • Background naked acinar cell nuclei • Few admixed small sheets and tubules of ductal epithelium • Intercalated ducts • Striated ducts • Excretory duct • Adipose tissue
FNA OF THE NORMAL SALIVARY GLAND Polarized grape-like clusters of acinar cells
NORMAL SALIVARY GLAND FNA
Key Pitfall of the Normal Aspirate: • Misinterpreting normal acinar cells as acinic cell carcinoma
FNA OF THE NORMAL SALIVARY GLAND - PITFALL
Normal Salivary Gland
Acinic Cell Carcinoma
SALIVARY GLAND FNA CASES
CASE 1 History: A 31 year old woman with a 1.5 cm nontender right parotid mass that has been slowly enlarging over the past year.
Case 1 Pleomorphic Adenoma aka Benign Mixed Tumor
Diff-Quik Stain
Pap Stain
Matrix Tumors Pleomorphic Adenoma Adenoid Cystic Carcinoma Monomorphic Adenomas Carcinoma Ex Pleomorphic Adenoma
Pleomorphic Adenoma z
z
z
z
Most common of all salivary gland tumors in both children and adults 75% of parotid tumors & 50% of all salivary tumors Superficial parotid gland is most common site…esp. the tail of the parotid at jaw angle Firm, moveable, well demarcated (encapsulated), slow growing, painless
Biphasic Tumor Cells Epithelial cells arranged in cohesive, honeycomb groups Myoepithelial cells arranged singly and haphazard clusters. Cells may be plasmacytoid, epithelioid, spindled, or clear
Matrix Fibrillar with frayed, indistinct margins Chrondromyxoid (Metachromatic) Embedded myoepithelial cells
Infarction: Spontaneous vs Aspiration
Pitfalls z
Cellular lesions with sparse or absent matrix – –
z
Focal adenoid cystic–like areas –
z z
Myoepithelial predominant (myoepithelioma) Epithelial predominant (basaloid tumors) Matrix mimics
Cytologic atypia Metaplasia – –
Squamous Mucinous
Squamous Metaplasia
Adenoid Cystic Carcinoma z z
z z z z
4-10% of all salivary gland neoplasms Relatively slow growing with perineural invasion and poor long-term survival Submandibular gland, palate, and parotid 4th to 7th decade, women > men (3:2) FNAB is often reported as painful Cribriform, tubular, and solid forms
Adenoid Cystic Carcinoma Cells Basaloid cells with dark angulated nuclei Variable atypia
Matrix 3-D spheres and branching structures Acellular “hyaline globules” Metachromatic with sharp borders
Adenoid Cystic Carcinoma
Pleomorphic Adenoma vs Adenoid Cystic Carcinoma Pleomorphic Adenoma - predominance of myoepithelial cells - atypia - matrix is fibrillar with ragged edges and myoepithelial cells embedded within
Adenoid Cystic Ca - cells more basaloid in appearance - minimal atypia - unique matrix: acellular, smooth edges, homogeneous “hyaline globules”
Pleomorphic Adenoma vs. Adenoid Cystic Carcinoma
Pleomorphic adenoma
Adenoid cystic carcinoma
Final Comments Pleomorphic adenoma, monomorphic adenoma and adenoid cystic carcinoma can overlap significantly History: slow vs rapid growth presence or absence of pain Matrix: fibrillar arrays +/-embedded cells homogenous acellular globules
CASE 2 History: A 71 year old man with a l.5 cm right nontender submandibular mass that had been slowly increasing in size for 1.5 years.
Case 2 Acinic Cell Carcinoma
Acinic Cell Carcinoma Second most common salivary gland malignancy z 2-6% of all salivary gland neoplasms z Low-grade malignancy z
recapitulating growth of normal acinous cells 6.5% of neoplasms, 18% of malignant F>M, 90% parotid
Acinic Cell Carcinoma z
Well demarcated/encapsulated, lobulated, Slow growing
z
Growth patterns Solid & microcystic (common); papillary-cystic; follicular variants
z
Complete surgical excision 12% local recurrence; 8% mets, 6% pts die
Acinic Cell Carcinoma Cells (high cellularity) Serous type acinar cells, predominate Intercalated duct cells
Background Naked nuclei + lymphocytes “Clean” may be “cystic” Psammoma bodies (papillary) Capillary meshwork
Acinic Cell Carcinoma Serous type acinar cells Sheets and dyshesive 3-D clusters Large polygonal cells with abundant finely vacuolated to granular basophilic cytoplasm PAS+D resistant cytoplasmic zymogen granules Bland nuclear cytologic features…some are higher grade. Intercalated duct cells Cohesive ductal cells with moderate to scant cytoplasm
Acinic Cell Carcinoma
Papanicolaou stain
Diff Quik stain
Acinic Cell Carcinoma, papillary-papillocystic
Pitfalls z
Misinterpreting normal acinar cells as acinic cell carcinoma
z
Misinterpreting metastatic carcinoma as acinic cell carcinoma
Normal Salivary Gland vs. Acinic Cell Carcinoma
Normal Salivary Gland
Acinic Cell Carcinoma
Metastatic Tumors Uncommon Intraparotid lymph nodes Clinical history in 70% of cases Skin cancers (SCC, basal cell, MM) Head and neck SCC Sebaceous carcinoma Small cell carcinoma Lymphoma Renal cell carcinoma
Metastatic Renal Cell Carcinoma vs. Acinic Cell Carcinoma z
Renal cell carcinoma: – Clinical history of cancer – Evidence of lymph node
involvement – CD10+, RCC+, EMA+, CK7-, PAS+
z
Acinic cell carcinoma: – Primary salivary tumor – May have lymphocytes – CD10-, RCC-, EMA +, CK7+,
PAS + D granules
Metastatic Renal Cell Carcinoma vs. Acinic Cell Carcinoma
Acinic Cell Carcinoma
Renal Cell Carcinoma
Oncocytic Tumors Acinic Cell Carcinoma Warthin Tumor Oncocytoma Mucoepidermoid carcinoma (oncocytic variant) Metastatic Renal Cell Carcinoma
Warthin Tumor z z z z z
Second most common salivary gland tumor 5-10% of all salivary gland neoplasms Bilateral, men> women, fluctuant mass Doughy on palpation Thick brown-green granular fluid “machine oil”
Warthin Tumor Cells Oncocytic, 2-D sheets Lymphocytes, germinal centers
Background Mucoid, mucinous or watery Granular or “dirty” or “machine oil” Cholesterol crystals
Warthin Tumor Variable cellularity Oncocytes large cells, abundant cytoplasm (squamous/glandular metaplasia eccentric nuclei, prominent nucleoli
Lymphocytes heterogeneous (plasma cells, small lymphs) occasional germinal centers, DNA artifact
Warthin Tumor
Papanicolaou Stain
Diff-Quik Stain
Pitfalls z
Squamous metaplasia in Warthin Tumor may be mistaken for squamous cell carcinoma W
z
WT lacks overtly malignant features of SCCa
Abundant oncocytes in Warthin Tumor may be mistaken for an oncocytic neoplasm
Squamous Metaplasia
Oncocytoma z z z z
Circumscribed nodule Fibrous capsule Parotid gland May be bilateral
Cells Oncocytes 2-D and 3-D groups Homogeneous granular cytoplasm without vacuoles
Background No lymphocytes Clean
Oncocytoma
Acinic Cell Carcinoma vs. Oncocytoma Acinic Cell Carcinoma – Vacuolated cytoplasm – Delicate, slightly
basophilic cytoplasm – Variable atypia – PAS + D granules – PTAH negative
Oncocytoma No cytoplasmic vacuoles Dense, granular eosinophilic cytoplasm Minimal to absent atypia No PAS + D granules PTAH positive
Final Comments z
Common problem Normal vs Warthin tumor vs Acinic cell ca
z
Clinical information is very helpful History of primary Fluctuant, recurrent vs firm and fixed
z
Pattern vs cytomorphology Monomorphic vs biphasic population Sheets vs papillae Granular vs vacuolated cytoplasm
CASE 3 History: A 45 yo man with a 6 month history of a 3.7 cm mildly painful, enlarging left parotid gland mass. An MRI showed a nodular, slightly irregular lesion with variable signal intensity located in the superficial parotid gland just lateral to the facial nerve. An FNA was performed.
CASE 3 CYTOLOGIC DIAGNOSIS: BASALOID NEOPLASM WITH MILD ATYPIA, FAVOR BASAL CELL ADENOMA. SEE NOTE. Note: The differential diagnosis includes basal cell adenoma and basal cell adenocarcinoma; however, a more aggressive basaloid neoplasm cannot be entirely excluded.
CASE 3 SURGICAL RESECTION: Superficial parotidectomy was performed. A frozen section performed at the time of surgery also favored a basal cell adenoma.
CASE 3 HISTOLOGIC DIAGNOSIS: BASAL CELL ADENOCARCINOMA, 3.7 CM, SOLID TYPE.
Clinical follow-up: The patient has been free of disease for 6 years.
BASAL CELL ADENOCARCINOMA •Rare, low-grade salivary gland neoplasm °Approximately 2% of malignant salivary gland tumors °Parotid gland, rarely in submandibular gland °Average age: 60 years (range: 27-92 years)
•Good prognosis: –Local recurrence (35%), infrequent metastatic disease (10%), and low mortality (3%)
•Complete surgical excision with disease-free margins
BASAL CELL ADENOCARCINOMA •Malignant counterpart of basal cell adenoma (aka monomorphic adenoma) •Distinguished by histologic evidence of invasion – CANNOT DISTINGUISH BY FNA! •3 Patterns: –Solid, tubulotrabecular, and membranous
•May be associated with synchronous dermal tumors
BASAL CELL ADENOMA & ADENOCARCINOMA Histologic Features: •Basaloid cells •Small dark cells - usually peripheral •Larger pale cells
•Palisading of the small dark cells • Conspicuous hyaline membranes of basal lamina surround nests •Intercellular hyaline droplets •Small tubules lined by cuboidal cells •Squamous morules
BASAL CELL ADENOMA & ADENOCARCINOMA: Membranous Type
BASAL CELL ADENOMA & ADENOCARCINOMA: Membranous Type
BASAL CELL ADENOMA & ADENOCARCINOMA: Synchronous Cutaneous Cylindroma
BASAL CELL ADENOMA & ADENOCARCINOMA: Tubulotrabecular Type
BASAL CELL ADENOMA & ADENOCARCINOMA:
BASAL CELL ADENOMA & ADENOCARCINOMA: Solid Type
BASAL CELL ADENOMA & ADENOCARCINOMA
Peripheral palisading
BASAL CELL ADENOMA & ADENOCARCINOMA
BASAL CELL ADENOMA & ADENOCARCINOMA
Squamous morule
BASAL CELL ADENOMA & ADENOCARCINOMA
BASAL CELL ADENOMA & ADENOCARCINOMA: Myoepithelial Markers Calponin Keratin SM Actin S100 P63
BASAL CELL ADENOMA VS. ADENOCARCINOMA Malignancy is based upon finding histologic evidence of infiltrative growth into salivary gland parenchyma and soft tissue. 25% of carcinomas show perineural or lymphovascular invasion.
BASAL CELL ADENOMA & ADENOCARCINOMA Cytologic Features: •Two populations of basaloid cells •Small oval cells with scant cytoplasm •Bland dark nuclei •Haphazard arrangement in cohesive groups •Absence of marked nuclear atypia
•Peripheral palisading •Squamous morules • Peripheral ribbons & intercellular droplets of dense, nonfibrillary, acellular matrix •Metachromatic by Romanowsky stains, cyanophilic by Pap stain
Basal Cell Adenoma & Adenocarcinoma: 3 Subtypes - Solid, tubulotrabecular and membranous
BASAL CELL ADENOMA & ADENOCARCINOMA: Membranous Type
BASAL CELL ADENOMA & ADENOCARCINOMA: Solid Type
Squamous Morule
BASAL CELL ADENOMA & ADENOCARCINOMA DIFFERENTIAL DIAGNOSIS •Adenoid cystic carcinoma •Polymorphous low-grade adenocarcinoma •Cellular pleomorphic adenoma •Chronic sialadenitis •Cutaneous basal cell carcinoma •Metastatic basaloid squamous carcinoma
Basal Cell Tumor vs Adenoid Cystic Carcinoma Features favoring basal cell tumor: • Peripheral bands of matrix • Intercellular matrix globules • Dual cell population • Peripheral palisading • Squamous morules • Bland cytology
Solid Basal Cell Tumor vs Solid Adenoid Cystic Carcinoma Basal cell adenoma
Adenoid cystic carcinoma
BASAL CELL ADENOMA & ADENOCARCINOMA In the final analysis, it may not always be possible to make a specific diagnosis. Rather, a diagnosis favoring a basal cell tumor with a note explaining the differential diagnosis.
Polymorphous Low-Grade Adenocarcinoma • Minor salivary glands, esp. palate • Circumscribed subepithelial mass • Resembles infiltrating lobular breast carcinoma
Histologic Features: • Diverse architecture: solid, trabecular, cords/single file, ductular, tubular, papillary, cystic, cribriform • Concentric whorling appearance • Few myoepithelial cells, minimal atypia, & absence of myxochondroid matrix • Infiltrative growth • Prominent neurotropism without necrosis
Polymorphous Low-Grade Adenocarcinoma
Polymorphous Low-Grade Adenocarcinoma
Polymorphous Low-Grade Adenocarcinoma
Polymorphous Low-Grade Adenocarcinoma
Polymorphous Low-Grade Adenocarcinoma
Polymorphous Low-Grade Adenocarcinoma
Cellular Pleomorphic Adenoma Features favoring PA: • Matrix is fibrillar and contains cells • Absence of peripheral palisading • Predominance of myoepithelial cells/Absence of two basaloid cell populations
Chronic Sialadenitis: Kuttner Tumor
Chronic Sialadenitis
Hypocellular with small basaloid groups and background chronic inflammation.
Final Comments •Most difficult diagnostic problem in the salivary gland •Often a descriptive diagnosis •Basal cell adenocarcinoma and adenoma are cytologically indistinguishable: –2 populations of basaloid cells –Peripheral matrix ribbons and intercellular globules –Squamous morules –Palisading
•The DDX includes adenoid cystic carcinoma.
CASE 4 History: A 49 year-old woman with a several year history of rheumatoid arthritis presents with a markedly enlarged left parotid gland. By clinical exam, the parotid gland was diffusely firm; however, a discrete mass was not identified. An FNA was performed.
The initial working diagnosis based upon rapid interpretation included reactive lymph node, chronic sialadenitis, LESA, and lymphoma. Therefore material for flow cytometry was sent and was negative for lymphoma.
CASE 4 Cytologic Diagnosis: LYMPHOEPITHELIAL SIALADENITIS (LESA)
LYMPHOEPITHELIAL SIALADENITIS (LESA) •Variety of names: •Benign lymphoepithelial lesion •Myoepithelial sialadenitis (MESA) •Mikulicz’s disease
•Often associated with Sjogren’s syndrome, rheumatoid arthritis or other autoimmune disorders •Can be unilateral, bilateral, solid, or cystic •Increased risk of B-cell lymphoma, esp. MALT-type
LYMPHOEPITHELIAL SIALADENITIS (LESA) Histologic Features: •Lymphocytic infiltration of gland with parenchymal atrophy •T-lymphocytes, plasma cells, and monocytoid B-cells •Variable germinal center formation •Ductal hyperplasia to form lymphoepithelial lesions
LYMPHOEPITHELIAL SIALADENITIS (LESA)
LYMPHOEPITHELIAL SIALADENITIS (LESA) Cytologic Features: •Cellular aspirate •Mixed population of lymphocytes and plasma cells •Germinal center fragments •Tingible body macrophages •Lymphoepithelial lesions •Absence of acinar cells
A key pitfall in the diagnosis of LESA is metastatic squamous cell carcinoma. SCC
LESA
Differential Diagnosis of LESA • • • • •
Chronic sialadenitis Reactive intraparotid lymph node Lymphoepithelial carcinoma Metastatic squamous cell carcinoma B-cell lymphoma – MALT – Follicular – Diffuse large B-cell
Epithelial Salivary Gland Tumors with Lymphocytes • • • • •
Warthin tumor Mucoepidermoid carcinoma Acinic cell carcinoma Lymphoepithelial carcinoma Metastatic carcinoma
LESA vs. Chronic Sialadenitis Chronic Sialadenitis differs from LESA by: •Hypocellularity •Fewer lymphocytes and germinal centers •Smaller angulated groups rather than sheets •Absence of lymphoepithelial lesions
LESA vs. Lymphoma
Immunophenotyping is essential for distinguishing LESA from lymphoma, especially MALT lymphoma.
Salivary Gland Lymphomas • • • • • •
2-5% of salivary gland neoplasms Parotid is most frequently involved Most are B-cell NHL MALT is the most common DLBCL Follicular lymphoma – primarily in parotid LNs
MALT LYMPHOMA
MALT LYMPHOMA
Salivary Gland Lymphomas MALT
•Small lymphs, centrocytes, monocytoid B cells •Slight nuclear atypia •CD20+, 23-, 10-, 5-, cyclin D1-, bcl2+, bcl6-
Follicular
•Mixed small & large •Notched and grooved nuclei •CD20+, 23-, 10+, 5-, bcl2+, bcl-6+ •May be CD10•T(14:18) by FISH
DLBCL
•Large size: Immunoblasts & centroblasts •Marked atypia •CD20+, keratin -, S-100-
Final Comments •A characteristic feature of LESA is the lymphoepithelial lesion. •The differential diagnosis of lymphoid lesions in the salivary gland includes non-neoplastic and benign conditions, B-cell lymphoma, and carcinoma. •Without ancillary studies, LESA can be impossible to distinguish from MALT lymphoma.
Case 5 History: A 58 year old man with a 2.0 cm nontender, enlarging left parotid gland mass.
Case 5 Mucoepidermoid Carcinoma
Mucoepidermoid Carcinoma Low Grade z z z z z
Most common salivary gland in children Second only to PA in frequency in adults M=F; Age range: 20-50 years Usually slow growing and painless Residual mass post aspiration
Mucoepidermoid Carcinoma Low Grade Cells (variable cellularity, sheets) Mucous containing epithelial cells Epidermoid cells (squamous features) Intermediate cells (low N/C ratio) Background Mucinous often with cellular debris
Low-Grade Mucoepidermoid Carcinoma
Low-Grade Mucoepidermoid Carcinoma
Low-Grade Mucoepidermoid Carcinoma
Intermediate cells
Cystic Lesions Low grade mucoepidermoid carcinoma Branchial cleft cyst Lymphoepithelial cyst Salivary duct cyst/retention cyst Cystic squamous cell carcinoma
Mucocele/Retention Cyst
Low-Grade Mucoepidermoid Carcinoma vs Mucocele Low grade mucoepidermoid carcinoma is the most common cause of false negative salivary gland diagnoses: Low cellularity due to cyst Bland cytology of cells Mucin cells resemble foamy histiocytes
Branchial Cleft Cyst z z
z
Usually present in young adults Lateral neck along SCM muscle, around external ear 1st branchial cleft (parotid) – –
z
Type I ectodermal only Type II ectodermal and mesodermal (cartilage)
Non tender fluctuant masses
Branchial Cleft Cyst
Pap Stain
Diff-Quik Stain
Final Comments z
z
Search for three cell types (mucus, intermediate, squamous) to distinguish LG MEC from Tumors with squamous or mucinous metaplasia Beware making a definitive diagnosis when aspirates are hypocellular
Case 6 History: 52 year old man presented with a rapidly enlarging right parotid gland mass. The lesion is painful, and the patient has symptoms of facial nerve involvement.
Case 6 Salivary Duct Carcinoma
Diff-Quik Stain
Pap Stain
Salivary Duct Carcinoma z z z z
Uncommon Clinically aggressive Parotid in elderly men Resembles high-grade comedo-type ductal carcinoma of the breast
Salivary Duct Carcinoma Cells Overtly malignant cytomorphology Sheets, clusters, papillae, cribriform groupings Polygonal with abundant vacuolated cytoplasm Large hyperchromatic, pleomorphic nuclei Prominent nucleoli Background Necrosis
Salivary Gland Duct Ca
High-Grade Carcinomas Salivary Duct Carcinoma Mucoepidermoid Carcinoma Carcinoma Ex Pleomorphic Adenoma Squamous Cell Carcinoma
High-grade carcinomas
Salivary duct ca
High-grade MEC
Ca Ex PA
Mucoepidermoid Carcinoma HighGrade z
z
z z
Most common malignant salivary gland tumor (2nd in frequency to PA) Clinically aggressive: rapidly enlarging and painful Parotid in elderly men Resembles high-grade comedo-type ductal carcinoma of the breast
Mucoepidermoid Carcinoma HighGrade Cells High cellularity, obvious malignant features Epithelial cells in clusters and singly Little distinction between squamous and glandular cells Pleomorphism, prominent nucleoli
Background Variable necrosis and/or cystic component (mucinous)
Malignant Mixed Tumor z
z z
z
Rare, occurs in 5-9% of pleomorphic adenomas Pre-existent pleomorphic adenoma Sudden rapid growth in salivary gland mass present for considerable time Three types Carcinoma ex pleomorphic adenoma Carcinosarcoma Metastasizing mixed tumor
Carcinoma Ex Pleomorphic Adenoma Cells High-grade carcinoma with pre-existent PA Sheets and aggregates of malignant cells
Background Matrix (associated with PA) associated with HG Carcinoma
Necrosis
Squamous Cell Carcinoma z z z
Rare salivary gland primary Metastases from H&N often cystic High-grade non-keratinizing squamous cell carcinoma often indistiguishable from high-grade primaries (esp. MEC)
Squamous Cell Carcinoma, High-Grade Cells Sheets and aggregates of malignant cells Pleomorphic nuclei with coarse chromatin Distinct nucleoli
Background Necrosis and cell debris (+/- keratin) Inflammation
Squamous Cell Carcinoma, Primary
Squamous Cell Carcinoma, Metastatic
Final Comments z z
z z
The presence of matrix suggests Ca ex PA The combination of squamoid cells and rare mucin+ cells favors MEC (cell block is useful) Keratinization favors a metastasis over MEC Salivary duct carcinomas resemble high-grade breast cancers with comedo necrosis – they can be mucin +
CASE 7 History: A 69 year-old woman presented with a slowly enlarging, non-tender, 2.0 cm parotid gland mass. An FNA was performed.
CASE 7 Cytologic Diagnosis: LOW-GRADE BIPHASIC SALIVARY GLAND NEOPLASM WITH ABUNDANT MYOEPITHELIAL CELLS. SEE NOTE. Note: The DDX includes epithelial-myoepithelial carcinoma and cellular pleomorphic adenoma.
The tumor was surgically excised by superficial parotidectomy.
CASE 7 Histologic Diagnosis: EPITHELIAL-MYOEPITHELIAL CARCINOMA
Epithelial-Myoepithelial Carcinoma •Rare - 1% of all salivary gland tumors •Parotid gland •Average age: 62 years (range: 31-89 years) •M:F = 1:2 •Low-grade malignancy; locally aggressive •Excellent prognosis
Epithelial-Myoepithelial Carcinoma Histologic Features: •Biphasic: myoepithelial cells and intercalated duct-type cells •Multinodular and hyalinized stroma •Eosinophilic, PAS+ luminal material •Solid, organoid, cystic, and nested patterns •Infiltrative growth •Variable atypia, necrosis, and mitoses
Epithelial-Myoepithelial Carcinoma
Epithelial-Myoepithelial Carcinoma
Epithelial-Myoepithelial Carcinoma
Epithelial-Myoepithelial Carcinoma
Epithelial-Myoepithelial Carcinoma Cytologic Features: •Cellular •Biphasic: sheets and spheres of cells: •Myoepithelial cells -Polygonal with abundant clear cytoplasm -Bland oval nucleus with pale chromatin -Small distinct nucleolus -PAS+ for glycogen
•Ductal cells -Cuboidal -Round nuclei with dark chromatin -Scant granular cytoplasm
•Background stripped myoepithelial nuclei •Acellular matrix material and proteincaceous secretions
In some cases, the clear myoepithelial cells predominate to the near exclusion of the ductal component.
Epithelial-Myoepithelial Carcinoma Special Studies: •Cell block can be used to demonstrate the biphasic features of the tumor: •PAS+ to demonstrate abundant glycogen •IPX for WS keratins for ductal cells •IPX for smooth muscle actin, calponin, S-100 for myoepithelial cells
Epithelial-Myoepithelial Carcinoma: The DDX includes other tumors with clear cells DIFFERENTIAL DIAGNOSIS: •Myoepithelioma/carcinoma •Acinic cell carcinoma •Oncocytoma •Sebaceous adenoma/carcinoma •Clear cell carcinoma •Lipoma •Metastatic renal cell carcinoma •Mucoepidermoid carcinoma, low-grade
Epithelial-Myoepithelial Carcinoma: The DDX includes other tumors with clear cells What is in the clear cytoplasm?: •Glycogen •Lipid •Condensed mitochondria •Mucin
Clear Cell Tumors: Myoepithelioma/Carcinoma •Monophasic pattern •Less abundant glycogenrich cytoplasm •May contain fibrillar matrix with embedded cells •High-grade when malignant
Myoepithelioma
Myoepithelial carcinoma
Clear Cell Tumors: Myoepithelioma/Carcinoma Myoepithelioma
Myoepithelial Carcinoma
Clear Cell Tumors: Sebaceous Adenoma/Lymphadenoma •Very rare •Clear cells and squamous cells •Highly vacuolated cytoplasm •Background lymphocytes •Cytoplasm contains fat: oil red-o + on air-dried Fat Stain +
Sebaceous Lymphadenoma
Can be confused with LG MEC, but it lacks mucin.
Clear Cell Tumors: Acinic Cell Carcinoma •Lacks myoepithelial cells •Lacks biphasic pattern •Contains PAS + D zyomogen granules
Clear Cell Tumors: Clear Cell Carcinoma •Usually palatal •Lacks ductal structures •Lacks myoepithelial differentiation •Diagnosis of exclusion
Final Comments • Epithelial-myoepithelial carcinoma is a rare lowgrade biphasic tumor with a predominance of large clear myoepithelial cells. • Histology is unique; cytology is more challenging! • The DDX includes numerous other clear cell tumors, but none matches the biphasic pattern of epithelialmyoepithelial carcinoma. • Ancillary studies can be helpful
CASE 8
A 48 year-old female presented with a 1.5 cm tender, rapidly enlarging lesion of the left parotid. An FNA was performed.
CASE 8 Cytologic Diagnosis:
SPINDLE CELL LESION, FAVOR BENIGN. SEE NOTE. Note: The differential diagnosis includes nodular fasciitis, schwannoma, and pleomorphic adenoma.
The nodule was surgically excised by superficial parotidectomy.
Immunohistochemistry for Vimentin
Immunohistochemistry for Smooth Muscle Actin
CASE 8 • Summary of immunohistochemistry: – – – – –
Vimentin + Smooth muscle actin + S-100 Keratin CD34 -
CASE 8 Histologic Diagnosis:
NODULAR FASCIITIS
Nodular Fasciitis • First reported in 1955 (Konwaler et al.) • Reactive myofibroblastic lesion in young adults (20-40 year-old) • Rapidly enlarging, often tender subcutaneous nodule (
