, Jun Zhang2 and Fan Lin1
(1)
Department of Laboratory Medicine, Geisinger Health System, Danville, PA, USA
(2)
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
Keywords
Salivary glandParotid glandPleomorphic adenomaAdenocarcinoma (ADC)Carcinoma (CA)Adenoid cystic carcinomaPolymorphous low-grade adenocarcinomaMammary analogue secretory carcinomaBasal cell adenomaBasal cell ADCEpithelial-myoepithelial CASialoblastomaMyoepitheliomaMyoepithelial CAWarthin’s tumorOncocytomaSebaceous adenomaLymphadenomaCystadenomaAcinic cell CAMucoepithelial CASalivary ductal CAOncocytic CAMalignant sebaceous CACA ex pleomorphic adenomaLymphomaSarcomaCK7CK20CEAEMACD117DOG1S100p63SOX10SMACalponinGATA3ARGCDFP-15pVHLGFAPSummary of Pearls and Pitfalls
The techniques and applications of biopsy of needle puncture with aspiration were first described in the1930s by Drs. Ellis and Martin at the Memorial Sloan Kettering Cancer Center. However, the widespread application of fine needle aspiration (FNA) in salivary gland and head and neck lesions has only occurred in the past 4+ decades.
The advantages of FNA are its virtually risk-free, convenient, and yet providing sufficient information to triage patients into different treatment groups, such as surgical therapy, medical management, or follow-up without intervention.
The limitations and pitfalls are mainly due to the considerable overlapping cyto- and histomorphology among various tumors of the salivary glands and the heterogeneity within individual tumor entities.
Both false-positive and false-negative rates were reported in the ranges of 1–14%.
Inadequate sampling was the most common cause of false-negative diagnosis.
The sensitivity and specificity for rendering a benign or malignant diagnosis is high, in the range of 81–98%. However, a specific diagnosis may be challenging if not feasible at times.
The objectives of FNA of salivary gland lesions are the following: (a) to distinguish neoplastic from nonneoplastic lesions, (b) to differentiate benign from malignant neoplasms, (c) to identify the lineage of a neoplasm, (d) to separate low-grade from high-grade malignant neoplasms, and (e) to distinguish primary vs metastatic neoplasms.
The indications for FNA include any palpable lesions of the salivary gland or head and neck structures.
The contraindications are few, including bleeding disorder and acute sialadenitis; the latter is due to associated significant pain.
Complications are rare.
Ancillary studies, especially immunohistochemistry (IHC), play a significant role in the confirmation of cell linage, especially in cytology and small biopsy specimens. With the addition of a new generation of biomarkers and molecular genetic discoveries, the diagnostic accuracy of FNA and small biopsy specimens improved significantly.
For other head and neck structures, a specific diagnosis was usually achieved with the aid of ancillary studies, including IHC and flow cytometry studies in particular.
Normal Tissues
Normal salivary gland tissues may be sampled, including normal acinic cells, ductal cells, and occasionally adipocytes.
There are usually scattered clusters of acinic cells forming acini, admixed with benign ductal cells and occasional adipocytes, as illustrated in Fig. 2.1a–c.
Fig. 2.1
(a–c) Normal salivary gland tissues . (a) Normal acinar and ductal unit, Diff-Quik. (b) Normal ductal and acinar unit, Pap stain. (c) Normal acinar cells and adipocytes, Pap stain
Nonneoplastic Salivary Gland Disorders
Acute and Chronic Sialadenitis
Key Clinical Features
Painful
Acute: Often in the parotid gland
Tenderness associated with diffuse or localized swelling, may be fluctuant; usually no discrete mass
Etiology: Postoperative complication, viral or fungal infection, and bacterial infection due to obstruction (such as sialolithiasis)
Chronic: Often in the submandibular gland
Discrete mass
Etiology: sialolithiasis and radiation therapy for head and neck cancer
Cytological Features
Acute:
- 1.
Scant ductal elements in a background of neutrophils and necrotic debris
- 2.
Stone fragments if sialolithiasis is present
- 1.
Chronic:
- 1.
Hypocellular specimen
- 2.
Sparse to absent acinar cells
- 3.
Small sheets and tubules of ductal epithelial cells with sharp borders in a background of blood, proteinaceous debris, mature lymphocytes, and fragments of fibrous tissue (Fig. 2.2a, b)
Fig. 2.2
Chronic sialadenitis . (a) Sparsely cellular specimen showing few reactive ductal cells, fibrous, vascular tissue, and inflammatory cells, mainly lymphocytes, Diff-Quik. (b) Fibrovascular stromal fragment, few benign ductal cells, inflammatory cells, and debris, Diff-Quik
- 1.
Differential Diagnosis
Acute: Rarely aspirated, usually a clinical diagnosis; microbiologic workup should be ordered. If a neoplastic process is suspected clinically, a repeat aspiration is warranted after the resolution of acute inflammation.
Chronic:
- 1.
Lymphoepithelial sialadenitis (LESA) : the presence of lymphoepithelial lesions and germinal center fragments.
- 2.
Warthin’s tumor : the presence of cohesive groups of oncocytes with lymphocytes and a cystic background.
- 3.
Carcinoma: chronic sialadenitis is separated from carcinoma by its scant cellularity; small, angulated, tightly cohesive clusters of ductal cells; lack of marked atypia; and rare single epithelial cells in the background .
- 1.
Histology
Acute: Acute inflammation accompanied by edema and hyperemia. Peri- and intraductal collections of neutrophils are evident, with associated destruction of ductal epithelium and loss of acini. There may be microabscesses.
Chronic: Depending on the etiologies, there are histomorphologic variations. However, the basic histology is chronic inflammatory cell infiltration, including lymphocytes, histiocytes, and plasma cells, with occasional neutrophils; stromal fibrosis; acinar atrophy of various degrees; and ductal dilatation with squamous, mucous, and oncocytic metaplasia. A granulomatous inflammatory response may be seen, with extravasation of saliva secondary to duct rupture .
Immunohistochemistry :
Rarely utilized in this setting; however, if an exuberant lymphoid population is present, flow cytometry study may be performed .
Granulomatous Sialadenitis
Key Clinical Features
A form of chronic sialadenitis
Caused by infection (fungi, mycobacteria, the agent of cat-scratch disease), cyst rupture, sarcoidosis or Wegener’s involving the parotid gland , or rarely neoplasia (Hodgkin lymphoma , T-cell lymphoma , or metastatic carcinoma)
Cytological Features
Aggregates of epithelioid histiocytes and multinucleated forms in a variable background of granular, necrotic cell debris and inflammation (Fig. 2.3a, b).
Fig. 2.3
Granulomatous sialadenitis . (a) Aggregate of epithelioid histiocytes and multinucleated form in a background of inflammatory cells and debris, Diff-Quik. (b) Multinucleated giant cell and crystal debris, Diff-Quik
In sarcoidosis: asteroid bodies, Schaumann bodies, and calcium oxalate crystals may be present .
Differential Diagnosis
The findings are not specific; an infectious etiology must be excluded by special stains and/or microbiologic cultures.
Histology
Noncaseating granulomas are often seen in cases of sarcoidosis; in contrast, necrotizing granulomas are usually identified in cases with mycobacterial or fungal infection.
Special stains for fungus (Grocott’s methenamine silver [GMS]) and acid-fast bacilli (AFB) should be performed in cases of necrotizing granulomas.
Additionally, Wegener’s granulomatosis, in which necrotizing arteritis is the fundamental feature, must also be considered.
Elastic stain may aid in identifying remnants of vessels in tissue damaged by inflammation and necrosis .
Immunohistochemistry :
Usually not applied
Lymphoepithelial Sialadenitis (Mikulicz Disease , Benign Lymphoepithelial Lesion , Myoepithelial Sialadenitis )
Clinical Features
Women, 90%; average age at diagnosis of 50.
Often bilateral parotid gland enlargement, painless; a minority of cases involve the submandibular gland.
Autoimmune disorder, seen in patients with Sjogren’s syndrome, or other connective tissue disorder .
Sialographic Features
Punctate cavitary defects filled with radiopaque contrast medium, described as a “fruit-laden, branchless tree”
Cytological Features
Cellular specimen.
Lymphoepithelial islands and germinal center fragments in a background of a mixed population of lymphocytes, plasma cells, and tangible-body macrophages.
Acinar cells are rarely present .
Differential Diagnosis
Chronic sialadenitis: sparsely cellular specimen with fewer lymphocytes and germinal center fragments; no characteristic lymphoepithelial islands.
Lymphoepithelial cyst.
Human immunodeficiency virus (HIV)-associated cystic lymphoepithelial lesions.
Warthin’s tumor : the presence of oncocytic epithelium.
Extranodal marginal zone B-cell lymphoma (EMZBCL ) of mucosa-associated lymphoid tissue (MALT): large numbers of monocytoid B-cells present. Flow cytometry and immunocytochemistry studies should be performed .
Nonneoplastic Cysts
Squamous Epithelial-Lined Cyst
Key Clinical Features
Including congenital cysts (dermoid cyst and branchial cleft cyst) and sporadic lymphoepithelial cyst:
Lymphoepithelial cyst : common in the parotid gland ; unilateral and solitary, occasionally bilateral (HIV-associated); usually painless swelling; common in middle-aged men (no association with HIV or Sjogren’s syndrome) or children (HIV-associated is the most common presentation); facial nerve dysfunction may occur when the parotid gland is involved.
Dermoid cyst : usually in the oral, orbital, and nasal area, occasionally in the neck; usually paramidline, can be lateral, in submandibular triangle; benign squamous epithelial cells, keratin debris, and sebaceous glands.
Branchial cleft cyst : painless nodule located along the anterior border of the sternocleidomastoid muscle from the hyoid bone to the suprasternal notch; tender mass with secondary infection; equal male-to-female ratio, 20–40 years old .
Cytological Features
Cellular specimen.
Small clusters of squamous (and/or columnar) cyst lining cells in a background of keratin debris/anucleate squames, histiocytes, and mixed population of lymphocytes (Fig. 2.4a, b).
Fig. 2.4
Branchial cleft cyst . (a) Squamous cells, histiocytes, inflammatory cells, and debris, Pap stain. (b) Ciliated columnar cells, Diff-Quik
Germinal center fragments with tangible-body macrophages may be present.
No lymphoepithelial lesions, except in HIV-associated cases and cystic LESA . Figure 2.5a, b show a lymphoepithelial cyst in an HIV patient .
Fig. 2.5
A lymphoepithelial cyst in a patient with HIV infection. (a) Cyst contents with degenerated foam histiocytes, lymphocytes, squamous epithelial cells (many anucleated), rare columnar-shaped ductal epithelial cells, crystals, and mucinous debris, Diff-Quik; (b) cyst contents with squamous cells, lymphocytes, histiocytes, and debris, Diff-Quik
Differential Diagnosis
Cystic metastatic squamous cell carcinoma :
Chronic sialadenitis
Pure lymphoid lesions (intraparotid lymph node, lymphoma)
Cystic salivary gland neoplasms (Warthin’s tumor , acinic cell carcinoma [AciCC], MEC)
Histology
Lymphoepithelial Cyst :
Usually an encapsulated, unilocular cyst with a stratified squamous epithelial lining.
Cuboidal, columnar, mucous, and sebaceous cells may be present.
The cyst contents can be fluid to mucoid to caseous.
There are dense lymphoid infiltrates in the cyst wall.
Bronchial Cleft Cyst :
Usually in the lateral neck, with histological features similar to benign lymphoepithelial cyst
Dermoid Cyst :
Generally is midline in the floor of the mouth.
A squamous epithelial-lined cyst with skin adnexa.
Immunohistochemistry :
Usually not applied
Mucus-Containing Cysts
Acquired cysts, including mucoceles and retention cysts, are often the result of ductal obstruction (such as a stone) or ductal disruption due to trauma.
Key Clinical Features
Often in minor salivary glands: the submandibular and sublingual glands
Mucocele: pseudocysts, no epithelial lining
Mucus retention cysts: lined by squamous, columnar, or oncocytic epithelium
Cytological Features
Histiocytes and some inflammatory cells in a background of thick mucus.
Rare metaplastic epithelium and normal salivary gland cells may be seen.
Calcifications and dirty debris .
Figure 2.6a–d.
Fig. 2.6
Mucus retention cyst of the submandibular gland in setting of chronic sialadenitis, cytology. (a, b) Thick, inspissated mucinous secretion containing scant macrophages, inflammatory cells, ductal epithelial cells, and rare mucous cells, Diff-Quik. (c, d) Pap stain
Differential Diagnosis
Low-grade MEC
Chronic sialadenitis with mucinous metaplasia of ducts
Histology
Mucocele:
A pseudocyst resulting from the rupture of minor salivary gland ducts to cause mucus extravasation.
A pool of mucin containing inflammatory cells and mucin-laden macrophages surrounded by granulation tissue without lining cells.
The background salivary gland tissue often exhibits chronic inflammation .
Mucus Retention Cyst :
Usually unicystic but can be a multicystic lesion with lining epithelium, including cuboidal to columnar cells, mucous cells, squamous cells, and rarely oncocytoid cells.
The cyst contents are comprised of inspissated mucinous secretions containing scant inflammatory cells, ductal epithelial cells with or without metaplastic changes, or microliths.
The background salivary gland tissue often exhibits chronic inflammation and possibly ectasia of adjacent ducts (in cases of multicystic lesions).
Representative images are illustrated in Fig. 2.7a, b.
Fig. 2.7
Mucus retention cyst of the submandibular gland in setting of chronic sialadenitis, surgical resection. (a) True cystic space lined by ductal epithelium, showing mucous cells and focal squamoid changes, with adjacent tissue showing chronic inflammation, H&E; (b) the inspissated mucinous secretion containing scant macrophages, inflammatory cells, ductal epithelial cells with squamous metaplastic changes, and microlith with debris, H&E
Immunohistochemistry :
Usually plays no role in this setting.
Neoplasms of the Salivary Gland
Salivary gland tumors are uncommon, with an annual incidence worldwide of 0.4–13.5/per 100,000 population, representing approximately 3% of head and neck neoplasms. The following are general features of salivary gland neoplasms:
- 1.
Female-predominant except Warthin’s tumor and high-grade carcinomas
- 2.
Benign in a majority, the most common being pleomorphic adenoma (PA)
- 3.
Parotid gland being the most common site of tumor origin, 80% benign
- 4.
Less commonly arising from an intraoral location; however, with the highest chance of being malignant (86–90%)
- 5.
Rare in children; however, approaching 50% malignant in patients younger than 18
- 6.
Bilaterality in 12% of tumors, commonly seen in AciCCs, Warthin’s tumor s, and oncocytomas .
Salivary gland tumors show a predilection for major or minor glands, as summarized in Table 2.1.
Table 2.1
Summary of tumors with predilection for major or minor salivary glands (SG)
Exclusive in major SGs | Exclusive in minor SGs |
|---|---|
Warthin’s tumor AciCC MASC Basal cell adenoma /ADC Oncocytoma/oncocytic CA Epithelial-myoepithelial CA Salivary duct CA Lymphoepithelial | Lip, buccal mucosa: Canalicular adenoma Cystadenoma /cystadenocarcinoma Inverted papilloma Intraductal papilloma Palate: PLGA Sialadenoma papilliform Oral mucosa: Cribriform ADC of minor SGs (also tongue) Signet ring cell ADC |
Salivary glands exhibit a two-tiered organization comprising luminal cells (acinar and ductal cells) and abluminal cells (myoepithelial cells and basal cells). The secretory acini and intercalated ducts are wrapped by myoepithelial cells, while the striated ducts and subsequent conducting ducts are supported by basal cells. Tumors of the salivary glands exhibit extraordinary diversity and heterogeneity in cyto- and histomorphology as well as tumor composition. For practical purposes, the common tumors of salivary glands can be categorized into four major groups:
- 1.
Tumors with mixed luminal and myoepithelial cell differentiation, as well as abundant mesenchymal metaplasia, characterized by chondromyxoid matrix material.
- 2.
Tumors with biphasic cell populations (luminal and abluminal cells without significant matrix material.
- 3.
Tumors with myoepithelial/basal cell proliferation.
- 4.
Tumors lacking myoepithelial cell differentiation .
- 5.
See summary in Table 2.2.
Table 2.2
Summary of salivary gland tumors based on cell lineage or tumor composition
Benign
Malignant
Mixed luminal and myoepithelial cells as well as abundant mesenchymal metaplasia
PA
CA ex pleomorphic adenoma
Biphasic cell populations without significant matrix material
Basal cell adenoma
Basal cell ADC
Epithelial-myoepithelial CA
AdCC
Sialoblastoma
Myoepithelial cell differentiation only
Myoepithelioma
Myoepithelial CA
Tumors lacking myoepithelial cell differentiation
Warthin’s tumor
Oncocytoma
Sebaceous adenoma
Lymphadenoma
Cystadenoma
PLGA
Acinic cell CA
Mucoepithelial CA
MASC
Salivary ductal CA
Oncocytic CA
Malignant sebaceous CA
ADC, NOS
The diagnostic approach for tumors of the salivary gland in cytology and small biopsy specimens aims to define the cell population of the tumor, that is, to demonstrate the presence or absence of myoepithelial cells or luminal cells and to apply newly discovered tumor-specific biomarkers or molecular cytogenetic assays to render as specific a diagnosis as possible. IHC plays a significant role in this regard, especially in cytology and small biopsy specimens. The commonly used immunomarkers for luminal or abluminal cell differentiation are summarized in Table 2.3.
Table 2.3
Commonly used biomarkers for the identification of cell differentiation in salivary gland neoplasms
Markers of luminal cells | Markers of myoepithelial or basal cells |
|---|---|
Acinar and ductal cells LMWCK, pan-cytokeratin (AE1/AE3) CEA EMA CD117 a DOG1 b SOX10 b Acinar cells Amylase PAS-D Ductal cells CK7 GCDFP-15 pVHL | Myoepithelial and basal cells HMWCK (including CK14) Pan-cytokeratin (AE1/AE3) Vimentin P63 Myoepithelial cells SMA Calponin MSA GFAP (variable) S100 protein (variable) Maspin (variable) CD10 (variable) SOX10 (myoepithelial cells of intercalated ducts) |
The relatively tumor-specific biomarkers and the new discovery of molecular genetic abnormalities of individual tumors will be discussed under each entity.
The World Health Organization (WHO) classification of tumors of salivary glands is summarized in Table 2.4.
Table 2.4
WHO histological classification of tumors of the salivary glands, 2017
Malignant tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Polymorphous adenocarcinoma Clear cell carcinoma Basal cell adenocarcinoma Intraductal carcinoma Adenocarcinoma, NOS Salivary duct carcinoma Myoepithelial carcinoma Epithelial-myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Secretory carcinoma Sebaceous adenocarcinoma Carcinosarcoma Poorly differentiated carcinoma Undifferentiated carcinoma Large cell neuroendocrine carcinoma Small cell neuroendocrine carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Oncocytic carcinoma Uncertain malignant potential Sialoblastoma Benign tumors Pleomorphic adenoma | Myoepithelioma Basal cell adenoma Warthin’s tumor Oncocytoma Lymphadenoma Cystadenoma Sialadenoma papilliferum Ductal papillomas Sebaceous adenoma s Canalicular adenoma and other ductal adenomas Nonneoplastic epithelial lesions Sclerosing polycystic adenosis Nodular oncocytic hyperplasia Lymphoepithelial sialadenitis Intercalated duct hyperplasia Benign soft tissue lesions Hemangioma Lipoma/sialolipoma Nodular fasciitis Hematolymphoid tumors Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT Lymphoma) |
Benign Epithelial Tumors
Pleomorphic Adenoma (Benign Mixed Tumor )
Key Clinical Features
The most common neoplasm of the salivary glands
Parotid gland (the vast majority) > the minor salivary glands (especially the palate) > the submandibular gland
In adults, 3rd to 6th decades of life, female predominant; in children and adolescents, peak at age 5–15 years, more frequent in males
Presents as a solitary, slow-growing, well-circumscribed, painless firm mass
Key Radiological Features
Ultrasound: typically a hypoechoic, homogenous, well-circumscribed mass with posterior acoustic enhancement.
Magnetic resonance imaging (MRI): intermediate or low T1 signal; variable T2-weighted signal, high in cellular areas to very high in myxoid areas.
Computed tomography (CT): typically a well-circumscribed mass of soft tissue density, either heterogeneous or homogeneous contrast enhancement.
Radiologic findings are not specific, unable to distinguish PA from other benign tumors, such as myoepithelioma and basal cell adenoma .
Cytological Features
Three components in varying proportions:
Ductal cells: small, cuboidal, bland nuclei may show moderate atypia.
Myoepithelial cells: spindled or plasmacytoid, entrapped in the matrix.
Chondromyxoid matrix: magenta on Diff-Quik and pale and gray to cyanophilic on Papanicolaou (Pap) stain.
Occasionally, radiating, cauliflower-shaped tyrosine-rich crystals are present.
Examples are shown in Fig. 2.8a–i.
Fig. 2.8
Pleomorphic adenoma of the parotid gland , cytology. (a) Magenta chondromyxoid matrix with embedded and background myoepithelial cells and few ductal epithelial cells, Diff-Quik. (b) Pale and gray to cyanophilic chondromyxoid matrix and myoepithelial cells, Pap stain. (c, d) Abundant chondromyxoid matrix with few myoepithelial cells and ductal epithelial cells, Diff-Qiuk and Pap stain. (e) Magenta chondromyxoid matrix with embedded and background myoepithelial cells and few ductal epithelial cells, Diff-Qiuk. (f) Background myoepithelial cells, Diff-Quik. (g) Ductal epithelial cells, myoepithelial cells, and pale to gray matrix, Pap stain. (h) Tyrosine-rich crystals, Pap stain. (i) Cell block, H&E
Differential Diagnosis
Low-grade MEC
Adenoid cystic carcinoma (AdCC)
Polymorphous low-grade adenocarcinoma (PLGA )
Plasmacytoma or plasmacytoid malignant lymphoma
Myoepithelioma
Histology
Usually an encapsulated tumor that may be multinodular with satellite nodule.
PA is comprised of three basic cellular components, including luminal cells, abluminal cells (myoepithelial cells), and stroma, often arranged in various proportions to produce a variety of growth patterns, such as tubular structures of luminal cells with enveloped myoepithelial cells embedded in a chondromyxoid stroma or sheets, islands, and single myoepithelial cells melting into a myxoid matrix stroma. A focal pattern resembling AdCC may be seen.
The luminal cells may undergo metaplastic changes to squamous, sebaceous, oncocytic, or clear cells or rarely to goblet or mucous cells. The latter, in association with squamous epithelium, can lead to an erroneous interpretation of MEC.
Myoepithelial cells can be cuboidal, spindled, stellate, plasmacytoid hyaline, or hydropic clear cells and often form sheets, trabeculae, or cribriform structures.
The identification of plasmacytoid hyaline cells is diagnostic for PA and myoepithelioma .
Rarely skeletal muscle differentiation can be identified.
The extracellular stroma is often a mixture of chondroid, myxoid, chondromyxoid, and hyaline matrix, rarely osseous and adipose tissues. The chondromyxoid stroma is a characteristic for PA.
Occasional tumors may have very scant or no extracellular stroma . Those tumors can be designated as “cellular PAs.”
Elastic fibers are present in variable amounts in most PAs and especially abundant in long-standing lesions. These thick elastic fibers are diagnostically helpful because they are rare in other salivary gland tumors.
Various histologic patterns of PAs are illustrated in Fig. 2.9a–h.
Fig. 2.9
Pleomorphic adenoma of parotid gland , histology . (a) Well-circumscribed, thinly encapsulated, lobulated growth pattern, H&E. (b) Tubular structure enveloped by myoepithelial cells, focal chondromyxoid stroma, and a few sebaceous cells seen, H&E. (c, d) Myoepithelial cells merging into chondromyxoid stroma, H&E. (e) Tubules and cords of cells merging into chondromyxoid stroma; focal thick elastic fibers are seen, H&E. (f) Plasmacytoid hyaline cells, H&E. (g) CD117 decorates luminal cells; (h) p63 highlights abluminal myoepithelial cells
Immunohistochemistry :
In cytology or small biopsy specimens, IHC may be applied to demonstrate the coexistence of luminal and abluminal (myoepithelial) cells.
The luminal cells are decorated by epithelial membrane antigen (EMA ), carcinoembryonic antigen (CEA ), and CD117 .
The abluminal cells are positive for p63 , calponin , S100 , and sex determining region Y box (SOX) 10.
Pleomorphic adenoma gene 1 (PLAG1) was reported in 94.4% of PAs, all myoepithelioma s (low intensity), 25% (2/8) of PLGAs, and one salivary ductal carcinoma ex pleomorphic adenoma , but was negative in other common salivary gland tumors including AdCC, MEC, and AciCC.
In addition, Ki67, p53, and Bcl2 may help in the differential diagnosis of PA from AdCC. PA shows a low proliferative index (1.6%), rare p53 reactivity (1.2%), and weak Bcl2 staining; while AdCC has been reported to have a mean proliferative index of 20.5–54% depending on tumor grades, p53 of 4.3–24%, and strong diffuse staining for Bcl2 .
Discovered on GIST-1 (DOG1 ) was reported mostly negative in PAs.
Representative images are shown in Fig. 2.9g, h.
The majority of PAs exhibit a translocation t(3;8)(p21;q12) involving PLAG1 and one of several other fusion partners, commonly catenin (cadherin-associated protein), β1 (CTNNB1), which is the gene coding for β-catenin. This gene rearrangement is specific for PAs and its malignant counterpart, the carcinoma ex pleomorphic adenoma , leading to overexpression of PLAG1 by immunoassay. Approximately 10% of PAs show rearrangement at 12q13–15 involving high-mobility group AT hook 2 (HMGA2). The characteristic translocations involving PLAG1 or HMGA2 with associated immunoexpression of PLAG1 in PAs have also been observed in myoepitheliomas but not in basal cell adenomas .
Monomorphic Adenoma/Basal Cell Adenoma
Key Clinical Features
Less than 5% of all salivary gland tumors, 75% in the parotid gland .
Slightly more common in females than in males.
Presents as an asymptomatic, solitary, slow-growing mass.
The membranous pattern of basal cell adenoma often affects males .
Key Radiological Features
Similar to PA (benign mixed tumor)
Cytological Features
Numerous small blue cells associated with variable amounts of collagenous stroma (Fig. 2.10a–c).
Fig. 2.10
Monomorphic adenoma (basal cell adenoma), cytology. (a, b) Angulated, usually sharp bordered groups of cytologically bland basaloid ductal epithelial cells with appreciable peripheral palisading and clinging of collagenous stroma, (a) Diff-Quik. (b) Pap stain. (c) Scattered plasmacytoid myoepithelial cells entrapped in matrix, Pap stain
Naked nuclei and single cells may be numerous.
Arborizing stroma contains fibroblast-like spindle cells and capillaries .
Differential Diagnosis
AdCC, solid variant
Basal cell carcinoma
Histology
Comprised of two cell types, the basaloid cells (basal cells or myoepithelial cells) and luminal cells, sharply delineated from the stroma by basement membrane-like material, differing greatly from the centrifugal or “melting” growth of PA.
Chondromyxoid stroma is absent .
The tumor cells are often predominated by basaloid cells, typically arranged in anastomosing jigsaw puzzle-like islands and trabeculae with peripheral palisading.
Small ductal structures with luminal cell lining may be appreciated.
Cribriform pattern is rarely present; however, the spaces lack luminal cells.
For tumors with myoepithelial-derived stroma, there are plump spindle cells in the stroma.
For the membranous variant of basal cell adenoma, the smooth-contoured basaloid tumor islands are surrounded by thick, eosinophilic, periodic acid-Schiff (PAS)-positive hyaline basal lamina material. This variant often grows in a multinodular fashion with entrapped normal salivary gland tissue to mimic tumor invasion.
Representative images are illustrated in Fig. 2.11a, b.
Fig. 2.11
Monomorphic adenoma (basal cell adenoma), histology . (a) Well-circumscribed, encapsulated border, H&E. (b) Jigsaw puzzle-like islands and trabecular of basaloid cells with peripheral palisading and thick basement membrane material surrounding, H&E. (c) Aberrant nuclear expression for β-catenin was reported in about 50% of cases. The current case shows patchy nuclear staining for β-catenin. (d) S100 decorates the plump spindle cells in the stroma; tumor cells are negative
Immunohistochemistry :
The luminal cells are positive for CD117 , CK AE1/AE3, CEA , and EMA .
The basaloid cells are reactive to p63 , calponin , glial fibrillary acidic protein (GFAP ), and S100 .
For the tumors with myoepithelial-derived stroma, the plump spindle cells in the stroma are decorated by S100 , not p63 .
Studies also reported nuclear expression of β-catenin in about 50% of cases, corresponding to mutations in CTNNB1 (β-catenin) in basal cell adenomas/adenocarcinomas (ADCs).
Representative images are shown in Fig. 2.11c, d.
Warthin’s Tumor (Papillary Cystadenoma Lymphomatosum)
Key Clinical Features
The second most common benign salivary gland tumor, exclusively in the parotid gland , occasionally in periparotid lymph nodes.
Smokers, commonly found in males in the 6th to 7th decades of life; found in whites and Asians more frequently than in Hispanic and African Americans.
Presents as a painless, slow-growing, fluctuant cystic mass over the angle of the mandible.
Bilaterality (5–14%) and multifocality (12–20%) occur more frequently than others .
Key Radiological Features
CT scanning may demonstrate a well-defined mass in the posterior inferior segment of the superficial lobe of the parotid.
Radiosialography shows increased activity due to high mitochondrial contents in oncocytes.
Cytological Features
Three components in varying proportions:
Oncocytic epithelium: usually in flat sheets, with abundant granular cytoplasm and may have prominent nucleoli; also seen in papillary structures
Lymphocytes: a mixed population of lymphoid cells and germinal center fragments
Cyst fluid: foam macrophages and debris, giving a “dirty” background
Figure 2.12a–f
Fig. 2.12
Warthin’s tumor of the parotid gland , cytology. (a) Sheet of oncocytic epithelium with abundant eosinophilic, granular cytoplasm and intraepithelial lymphocytes in a background of cyst debris and lymphocytes, Diff-Quik. (b) The oncocytes are cytologically bland in a dirty background, Diff-Quik. (c) A Mixed population of lymphocytes with germinal center sampling, Diff-Quik. (d, e) Oncocytes with an appreciable double layer in a background of lymphocytes and cystic debris, Pap stain. (f) Oncocytes with papillary architecture, intraepithelial and background lymphocytes, Pap stain
Differential Diagnosis
Cystic salivary gland lesions: when only non-specific cyst fluid present, a repeat aspiration may be useful.
Oncocytic neoplasms usually do not have a cystic background and have very limited lymphoid cells.
Low-grade MEC.
Low-grade malignant lymphoma: when lymphocytes are the most prominent elements, cell marker studies should be performed.
Squamous cell carcinoma: squamous metaplasia with marked individual keratosis and degenerative atypia often present in Warthin’s tumor and may mimic squamous cell carcinoma. In questionable cases, a repeat aspiration or concentrating any recovered fluid to search for oncocytes should be considered.
AciCC, oncocytic variant .
Histology
Irregular cystic structures lined by double-layer oncocytic epithelium, often with a papillary proliferation, occasionally metaplasia to squamous or mucous or ciliated cells in a lymphoid stroma.
Germinal centers and rare granulomatous reactions may be seen.
Representative images are shown in Fig. 2.13a–c.
Fig. 2.13
Warthin’s tumor of the parotid gland , surgical resection . (a) Irregular cystic structures with papillary folds of double-layered oncocytic epithelium and underlying dense lymphoid stroma, H&E. (b) High power showing oncocytic columnar cells with brightly eosinophilic granular cytoplasm, H&E. (c) Focal mucous cell metaplasia, H&E
Immunohistochemistry :
The oncocytes show luminal ductal cell differentiation and are therefore positive for low molecular weight cytokeratin (LMWCK), pan-cytokeratin, EMA , and CEA .
No myoepithelial cell differentiation is identified, leading to negative staining for p63 and calponin .
DOG1 and SOX10 expressions are often lacking.
S100 and mammaglobin are nonreactive.
GATA-binding protein 3 (GATA3 ) is positive in 100% of cases, with weak to moderate intensity .
Oncocytoma
Key Clinical Features
Less than 1% of all salivary gland tumors, 80–90% in the parotid
No gender predilection, older adults, peak in the 7th–9th decades, common in Caucasians
Multifocal and bilateral in 70% of cases
Presents as a soft, well-circumscribed, slow-growing painless mass
Key Radiological Features
Radiosialography: high uptake of technetium-99 m due to high mitochondrial content of oncocytes
Ultrasound: non-specific, a hypoechoic mass with well-defined margins
CT: a well-defined mass showing homogeneous enhancement
MRI: T1 and T2 hypointensities with homogeneous contrast enhancement
Cytological Features
Monotonous population of large cells with abundant densely granular cytoplasm, discernible cell borders, and occasional nucleoli (Fig. 2.14a, b.)
Fig. 2.14
Oncocytoma . (a) Population of oncocytes with abundant densely granular cytoplasm, relatively defined cell borders, and focally discernible nucleoli in a clean background without lymphocytes, Diff-Quik. (b) The same, Pap stain. (c) Well-circumscribed, thinly encapsulated border, H&E. (d) Polygonal oncocytes with abundant eosinophilic granular cytoplasm and central round nuclei containing distinct nucleoli, H&E. (e) Positive for pVHL stain, also note the normal duct in adjacent is positive for pVHL, but not the acinar cells. (f) Tumor cells are negative for p63, and only residual myoepithelial cells are positive
Clean background without lymphocytes.
Most are benign regardless of pleomorphism .
Differential Diagnosis
Warthin’s tumor: cohesive groups of oncocytic epithelium, lymphocytes, and a cystic background.
AciCC: loosely cohesive groups and single cells; the tumor cells usually have round nuclei with a smooth nuclear membrane and prominent nucleoli; the cytoplasm is coarsely granular, with indistinct cell border; many naked nuclei with the same nuclear features; granular debris in the background; delicate vasculatures; may contain abundant lymphocytes.
Malignant oncocytoma: significant cytologic atypia, mitotic activity, and necrosis.
Metastatic renal cell carcinoma: more cytologic atypia; IHC aids differential diagnosis.
MEC .
Histology
Usually solid but may have a cystic component.
The tumor cells are uniform, polygonal or cuboidal, and contain a centrally placed round nucleus with nucleoli and abundant eosinophilic granular or clear cytoplasm arranged in trabeculae, packets, sheets, or rarely glands, separated by scanty loose vascular stroma.
Focal sebaceous, goblet cell, or squamous differentiation may be present.
For tumors with predominant clear cells, the designation of clear cell oncocytoma is applied. Those tumors carry a higher frequency for bilaterality and recurrence.
Oncocytoma is prone to infarction, either spontaneously or after FNA.
Representative images are illustrated in Fig. 2.14c, d.
Immunohistochemistry :
The diagnosis of oncocytoma is straightforward in the majority of cases; Immunohistochemical assay is not necessary.
In cases of small biopsy or FNA cellblock material, immunohistochemical assay may be applied to confirm cell lineage.
The neoplastic oncocytes are usually positive for cytokeratin, von Hippel von tumor suppressor (pVHL ), CD117 , and CK20 and negative for myoepithelial markers (including p63 , calponin , S100 ), SOX10 , and DOG1 .
GATA3 is positive in 100% of cases with variable intensity.
Representative images are illustrated in Fig. 2.14e, f.
Myoepithelioma
Key Clinical Features
An unusual salivary gland tumor (<1% of all tumors), considered a monomorphic variant of PA.
50% occur in the parotid, followed by minor salivary glands (especially the palate).
No gender predilection, mean age in early to mid-40s.
Presents as slowly enlarging, painless masses, usually 1–5 cm in diameter.
Key Radiological Features
Similar to PA (benign mixed tumor)
Cytological Features
Loosely cohesive and single cells with spindled, clear cell, epithelioid, and/or plasmacytoid appearance (Fig. 2.15a)
Fig. 2.15
Myoepithelioma . (a) Loosely cohesive clusters of fusiform, spindly to focally plump myoepithelial cells in a clean background, devoid of stroma, Pap stain. (b) Spindled cells in a myxoid background, H&E. (c) Spindled myoepithelial cells in a solid sheet, H&E. (d) Desmin positive, IHC
No matrix material or honeycombed epithelial sheets
Differential Diagnosis
Myoepithelial-rich PA: the discrimination between myoepithelial-cell-rich PA and myoepithelioma is of little biological consequence.
Schwannoma: difficult to distinguish from spindle cell myoepithelioma morphologically; IHC has great value; positive for cytokeratin, smooth muscle actin (SMA ), and calponin in myoepithelioma; S100 and SOX10 are positive in both.
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