Neoplasms of the Salivary Glands

Clinical

• Represents most common neoplasm of salivary glands, accounting for 40% to 70% of all neoplasms of the parotid, submandibular glands, and minor salivary glands; PA of the sublingual glands is rare:

  • 80% occur in parotid gland

  • 10% occur in submandibular gland

  • 10% occur in minor salivary glands

• Slightly more common in women than men; occur over a wide age range but are most com­monly seen in the third through sixth decades of life:

  • Most common salivary gland neoplasm in children and adolescents

• Most common site of occurrence is tail of the parotid gland but it may also occur in the deep lobe of the parotid, in the submandibular and sublingual glands, and in all minor salivary glands throughout the upper and lower respiratory tract:

  • PA of parotid gland occurs primarily (but not exclusively) in the superficial lobe (i.e., superficial plane to facial nerve)

  • PAs of deep lobe of parotid gland may present as a parapharyngeal space mass.

  • Involvement of minor salivary glands occurs most frequently on the palate (hard and soft), but other common sites include the upper lip and buccal mucosa.

  • May occur in the sinonasal tract:

    • –

      Involve the septum (bony or cartilaginous portion) but may arise in the lateral wall

    • –

      Tend to be myoepithelial-predominant neoplasms

• Multiple tumors or bilateral tumors are uncommon.

• Symptoms vary according to site:

  • Most are slow-growing, painless masses present for periods up to several years.

  • Other symptoms, in particular those occurring in the minor salivary glands, may include:

    • –

      Difficulties in chewing, dysphagia, dyspnea, hoarseness, and epistaxis

    • –

      May ulcerate overlying mucosa

• In parotid gland, the tumor typically occurs outside of the facial nerve, and facial nerve involvement typified by facial nerve paralysis is rare and, if present, should be suspicious for malignancy:

  • Infarcted PAs may uncommonly be associated with pain or facial palsy.

• Parapharyngeal space PAs:

  • Represent most common tumor of the parapharyngeal space (followed by peripheral nerve sheath tumors)

  • Usually present as an asymptomatic (cervical or intraoral) mass; other symptoms may include obstruction, unilateral conductive hearing loss, and serous otitis media

  • Parapharyngeal space is a potential space between the lateral wall of the pharynx, internal pterygoid muscle, and cervical vertebrae:

    • –

      Other structures located within this space include cranial nerves IX through XII, great vessels of the neck, mature adipose tissue, and lymph nodes.

• Despite efforts in localization of key proteins using immunohistochemistry, the complex proteomic composition of pleomorphic adenomas (PA) has not yet been characterized.

• Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-imaging):

  • Allows label-free and spatially resolved detection of hundreds of proteins directly from tissue sections and of histomorphologic regions by finding co-localized molecular signals

  • Spatial segmentation of MALDI-imaging data is algorithmic method for finding regions of similar proteomic composition as functionally similar regions.

  • MALDI-imaging of pleomorphic adenoma (two cases reported to date):

    • –

      Spatial segmentation subdivided tissue in good accordance with the tissue histology

    • –

      Numerous molecular signals co-localized with histologically defined tissue regions were found.

    • –

      Highlighted cellular trans-differentiation within the PA

  • Spatial segmentation of MALDI-imaging data represents promising approach in emerging field of digital histologic analysis and characterization of tumors.

• Cause

  • No known etiologic factors

  • Familial occurrence rare

Pathology

Differential Diagnosis ( Table 20-4 )

• In general, diagnosis of pleomorphic adenoma does not present difficulties; however, in cellular tumors with a variety of growth patterns, particularly involving minor salivary glands (i.e., intraoral), pleomorphic adenomas may prove difficult to differentiate from other tumors including:

  • Monomorphic adenoma (MA):

    • –

      Presence or absence of mesenchymal component differentiates PA from MA.

    • –

      Identification of mesenchymal component in any given case can be problematic, but in such a situation decision is between two benign neoplasms so treatment and prognosis are similar.

  • Polymorphous low-grade adenocarcinoma (PLGA) of minor salivary gland origin:

    • –

      Many overlapping findings with PAs so in limited sampling will be problematic in differentiating it from PA (see immediately below for use of p63/p40 immunostaining in the differential diagnosis)

  • Adenoid cystic carcinoma:

    • –

      In contrast to PAs, adenoid cystic carcinomas reported to have:

      • ▪

        Increased proliferation indices

      • ▪

        Increase in p53 staining

      • ▪

        Strong bcl-2 staining

  • Further IHC findings including pairing p63 and p40 reported to assist in differentiating PA from polymorphous low-grade adenocarcinoma (PLGA) and adenoid cystic carcinoma (AdCC) include:

    • –

      PA: p63 + (68%; 21/31) and p40+ (42%; 13/31) immunophenotype

    • –

      Discordant p63+/p40− staining pattern seen only in overtly mesenchymal chondromyxoid stroma

    • –

      Cellular PA: concordant p63+/p40+ or p63−/p40− immunophenotypes

    • –

      PLGA: consistent p63+ (100%; 11/11) and p40− (100%; 11/11) immunophenotype

    • –

      AdCC: p63 + (90%; 91 of 101) and p40+ (89%; 90/101) immunophenotype

      • ▪

        Single discordant p63+/p40− case was solid variant with high-grade features

    • –

      Proliferation indices (Ki67):

      • ▪

        Low proliferation indices seen in association with PA, cellular PA, and PLGA typically less than 5%

      • ▪

        Proliferative indices reported to be significantly higher in AdCC (up to approximately 20%)

        • □

          Increased proliferation indices may not be present in all cases of AdCC and by itself does not unequivocally differentiate it from PA, cellular PA, and PLGA.

CAUTIONARY NOTE: Although a p63/p40 immunohistochemical panel can be a valuable tool for making distinction between PA, PLGA, and AdCC, it is not infallible and any given example may demonstrate divergence from the reported p63/p40 immunophenotype.

• Mucoepidermoid carcinoma (MEC):

  • In those examples of PA with squamous and mucinous cell metaplasia differentiation from MEC can be somewhat problematic:

    • –

      Presence of keratinization and intercellular bridges associated with squamous metaplasia of PA contrasts to the epidermoid component of MEC typically lacking keratinization and intercellular bridges.

    • –

      Metaplastic PAs do not harbor translocations t(11;19) and anticipated t(11;15) resulting in CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts, respectively, and/or MAML2 gene rearrangement found in association with MEC.

• Deep-seated dermal adnexal neoplasm

• Mesenchymal neoplasm:

  • Peripheral nerve sheath tumor

  • Smooth muscle neoplasms

Treatment and Prognosis

• Complete surgical excision is preferred treatment:

  • Parotid gland tumors usually require lobectomy with preservation of the facial nerve.

  • Submandibular gland tumors usually necessitate complete removal.

  • Minor salivary glands neoplasms require complete but conservative excision.

• Incomplete excision irrespective of site results in recurrent tumor:

• Increase risk of recurrence associated with:

  • Inadequate surgery:

    • –

      Enucleation

    • –

      Rupture or spillage during surgery

  • Chondromyxoid-predominant PAs:

    • –

      Diffluent nature results in “spillage.”

  • Variable capsular thickness coupled with tendency of tumor to invade capsule and/or bulge through capsule

  • Young age

• Recurrent tumors may be multifocal and in some cases may be widely distributed throughout the soft tissues of the neck, precluding surgical resection to control local disease:

  • Low-dose radiation may be used in this situation.

  • Presence of scar tissue in association with the recurrent tumor may present difficulties relative to the facial nerve with adherence to the nerve.

  • Preservation of the nerve with excision of the scar tissue and the entire parotid gland is recommended for recurrent tumor.

• Overall prognosis for PA is excellent with:

  • 5-year recurrence-free rate of 97%

  • 10-year recurrence-free rate of 94%

• Complications include malignant transformation (carcinoma ex pleomorphic adenoma) and the rare occurrence of so-called benign metastasizing pleomorphic adenoma.

• Surgical complications may include nerve damage and Frey syndrome (gustatory sweating).

• Features that may indicate a greater likelihood of malignant transformation include:

  • Occurrence in submandibular gland

  • Older patient age

  • Long-standing tumor

  • Larger tumor size

  • Prominent areas of acellular hyalinization

  • Increased mitotic activity including atypical mitoses

• Any salivary gland PA may show histologic features that raise concern for malignancy:

  • Neoplastic tissue within or extending through the fibrous capsule causes concern for malignant transformation; however, by itself capsular involvement in an otherwise unremarkable PA is acceptable and is not an indication of malignant transformation.

  • Rare cases of PA may show vascular permeation but by itself this feature is not indicative of malignancy.

  • Recurrent PA often have multiple foci of tumor within the normal salivary gland but these foci are usually discrete and circumscribed without cytologic atypia (they may show a prominent chondromyxoid stroma).

• Treatment for an atypical pleomorphic adenoma is similar to “conventional” pleomorphic adenoma albeit perhaps with more vigilant follow-up.

Clinical

• Represents second most common benign salivary gland tumor (following pleomorphic adenoma) accounting for approximately 5% to 6% of all salivary gland tumors and up to 12% of benign parotid gland tumors

• More common in men than in women:

  • Recent evidence shows marked decline in incidence in men with increased prevalence in women.

  • These demographic changes have been linked to smoking habits with a decline in use by men and an increase of use in women.

  • Smoking has been considered as an established risk factor for the development of Warthin tumor.

• Occurs over a wide age range but is most common in the fifth through seventh decades of life; uncommon to occur in the first three decades of life

• Almost exclusively involves parotid gland, particularly in the superficial lobe along the inferior pole adjacent to the angle of the mandible; rare cases reported in submandibular gland, palate, lip, tonsil, larynx, and maxillary sinus

• Bilateral tumors can be seen in up to 10% of cases and multifocal tumors in up to 12% of cases:

  • Bilateral or multifocal tumors may occur synchronously or metachronously.

• Most common symptom is painless mass; rarely is pain an associated complaint.

• May occur synchronously or metachronously with other salivary gland tumors, including:

  • Pleomorphic adenoma (most common), monomorphic adenomas, oncocytoma, basal cell adenoma, acinic cell adenocarcinoma, ductal adenocarcinoma, and adenoid cystic carcinoma

• Radiology:

  • CT scan:

    • –

      Well-defined area of increased density in the posteroinferior segment of the superficial lobe of the parotid

  • Radionucleotide imaging:

    • –

      Increased uptake of technetium-99m, which does not wash out following dialogue administration; this finding plays an important role in diagnosis and is related to the presence of oncocytes and their increased mitochondrial content.

• Cause:

  • Strong link with cigarette smoking

  • Radiation exposure has been linked as a tumorigenetic factor.

  • Role of Epstein-Barr virus (EBV) in the development of Warthin tumor is controversial:

    • –

      Some studies document the presence of EBV in the cytoplasm of luminal cells of WT, whereas other studies do not identify EBV in WT.

    • –

      No substantiation that EBV plays a role in development of WT.

• Pathogenesis

  • Thought to develop from neoplastic transformation of entrapped salivary duct epithelium within intra- and periparotid lymph nodes during embryologic development; in support of this theory includes:

    • –

      Ontogenically, parotid gland is last of the salivary glands to be encapsulated, resulting in either incorporation/entrapment of lymphoid tissue within the parotid or incorporation/entrapment of parotid ducts and acini within the periparotid lymph node epithelium

    • –

      Identification in some cases of subcapsular sinuses, a normal feature of lymph nodes and not a normal feature of non-lymph node tissues (i.e., salivary glands)

    • –

      Occurrence in periparotid lymph nodes

    • –

      Presence of B- and T-cell markers in the lymphoid component of Warthin tumors

Pathology

Differential Diagnosis

• Histology of WT so characteristic that its diagnosis presents limited difficulty

• Cystadenoma

• Oncocytic papillary cystadenoma (for those cases identified in unusual sites)

• Salivary gland tumors/lesions with oncocytic cells either focally or a predominant component including:

  • Oncocytoma; oncocytosis; mucoepidermoid carcinoma, acinic cell carcinoma, others

• Mucoepidermoid carcinoma:

  • In those examples of WT with squamous and mucinous cell metaplasia differentiation from MEC can be somewhat problematic:

    • –

      Metaplastic WTs do not harbor translocations t(11;19) and anticipated t(11;15) resulting in CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts, respectively, and/or MAML2 gene rearrangement found in association with MEC.

Treatment and Prognosis

• Complete surgical excision is the preferred treatment and should include an adequate margin of uninvolved tissue as well as preservation of facial nerve.

• Locally recurrent tumor may occur and is related to inadequate excision or to multicentrically occurring neoplasms.

• Transformation to malignant Warthin tumor is exceedingly rare with an incidence of less than 0.1% and may include the:

  • Epithelial component (carcinoma ex Warthin tumor):

    • –

      Squamous cell carcinoma (most common), oncocytic carcinoma, adenocarcinoma not otherwise specified, undifferentiated carcinoma, mucoepidermoid carcinoma, Merkel cell carcinoma:

      • ▪

        Metastasis to regional lymph nodes may occur.

      • ▪

        Rarely, distant metastasis may occur.

  • Lymphoid component:

    • –

      Malignant lymphoma, usually non-Hodgkin type

Fine-Needle Aspiration Cytology (FNAB)

• FNAB diagnosis may be problematic given overlapping features with pleomorphic adenoma, adenoid cystic carcinoma, and basal cell adenocarcinoma.

• Cellular aspirate including sheets, trabeculae, and tubular structures composed of uniform cells with hyperchromatic round to oval nuclei and scanty cytoplasm:

  • Cells are small with high nuclear-to-cytoplasmic ratio.

• Stromal component tends to be scanty.

• Extracellular basement membrane–like material may be present, especially in the membranous type of basal cell adenoma, appearing as amorphous eosinophilic material, including spheric globules, findings that may raise the diagnosis of adenoid cystic carcinoma.

• Collagenous stroma interdigitates with adjacent tumor cells:

  • This feature has been suggested as useful in differentiating basal cell adenoma from adenoid cystic carcinoma.

Gross

• Major glands:

  • Encapsulated, tan-white to red-pink, solid mass measuring up to 4 cm in diameter

• Minor salivary glands:

  • Similar to those of major salivary glands except that, although well circumscribed, they often are unencapsulated

  • May be associated with surface ulceration

Histology

• Encapsulated neoplasm that may show variety of growth patterns allowing for subclassification into:

  • Solid

  • Trabecular

  • Tubular

  • Membranous types

  • Combination of patterns can be seen in any given case.

  • Cribriform growth may be present.

• Irrespective of growth composed of two cell types:

  • Small cells with hyperchromatic nuclei and indistinct cytoplasm usually (but not always) seen at the periphery of the cell nests:

    • –

      These cells may be arranged in a palisading pattern around the periphery of tumor cords or islands in manner similar to cutaneous basal cell carcinomas but usually without retraction artifact from the surrounding stroma.

  • Larger polygonal-shaped cells with pale-staining nuclei, more abundant but indistinct cytoplasm usually more centrally located in cell nests

  • In addition, these cells may form squamous whorls or eddies.

• Myoepithelial rich stroma may be present in some cases characterized by:

  • Stromal spindle-shaped cells

  • S100 positive but p63 and actin negative

  • Presence of stromal myoepithelial cells assists in differentiation from adenoid cystic carcinoma, which lacks such stromal cells

• Solid basal cell adenoma:

  • Most common histologic variant

  • Solid masses of basal cells composed of small, isomorphic cells with uniform, hyperchromatic, round to oval nuclei and indistinct cytoplasm

  • Peripheral aspect of these nests are characterized by nuclear palisading

  • Scant stroma is present from which the epithelial islands are sharply demarcated by an intact membrane.

  • Squamous cells and squamous whorled eddies (“keratin pearls”) can be seen as a terminal expansion of the epithelial islands.

  • Mitoses are generally absent.

• Trabecular basal cell adenoma:

  • Basal cell proliferation growing in elongated, ribbon-like (trabecular) pattern with the cell islands separated by proliferation of a prominent vascular (capillary) stroma.

• Tubular basal cell adenoma:

  • Basal cell proliferation composed of multiple small duct-like structures lined by columnar-appearing cells with uniform, hyperchromatic, round to oval nuclei

  • Tubules are well-demarcated from the stroma by an intact membrane.

  • Stroma is noteworthy for the presence of prominent vascular pattern consisting of capillaries and venules.

  • Mitoses are generally absent.

• Tubular-trabecular adenoma:

  • Presence of tubular and trabecular patterns

  • Cellular stroma composed of myoepithelial cells

• Membranous basal cell adenoma:

  • In contrast to the other types, the membranous basal cell adenoma may be multilobular and frequently unencapsulated (present in only approximately 50% of cases).

  • Characterized by the presence of thick eosinophilic hyalin membranes surrounding and separating cell islands and creating a jigsaw puzzle appearance; this material represents reduplicated basal lamina and its appearance is similar to that of the dermal cylindroma, prompting the synonym of dermal analogue tumor.

  • Eosinophilic hyalin material can also be seen within the tumor islands and is diastase-resistant periodic acid-Schiff positive.

  • Tumor nests are often separated by normal salivary gland parenchyma, giving the appearance of multifocal growth.

  • Mitoses are generally absent.

  • Perineural invasion is not seen.

• Cribriform basal cell adenoma

  • Composed of jigsaw puzzle–like lobules with multiple cystic spaces (cribriform growth) in at least 30% of a given tumor

  • Merge with more characteristic foci of basal cell adenoma

  • Absence of invasive growth

  • May be mistaken for adenoid cystic carcinoma

• Immunohistochemistry:

  • Staining patterns support ductal and myoepithelial differentiation, including:

    • –

      Epithelial cells:

      • ▪

        Cytokeratin (low molecular weight), CEA, EMA positive

    • –

      Myoepithelial cells:

      • ▪

        p63, calponin, S100 protein, actin and vimentin positive

  • Nuclear β-catenin staining may be present.

  • bcl-2 and c-kit (CD117) reactivity may be present.

• Electron microscopy:

  • Ductal cells:

    • –

      Microvilli, tight junctions, desmosomes

  • Myoepithelial cells:

    • –

      Abundant microfilaments, desmosomes, junctional complexes, reduplicated basal lamina

• Cytogenetics and molecular genetics:

  • Presence of CTNNB1 (β-catenin) gene mutation

  • Loss of heterozygosity at 16q12-13:

    • –

      Similar finding as seen in dermal cylindroma

• Association of Basal Cell Adenoma and Intercalated Duct Lesions (IDL)

  • IDL found to coexist with salivary and nonsalivary neoplasms.

  • Among salivary tumors, basal cell adenoma appears to be associated most frequently with IDL.

  • Tubular variant most commonly associated with IDL:

    • –

      Less frequently, nontubular variants of basal cell adenoma may harbor foci of IDL.

  • Unique hybrid lesion containing basal cell adenoma and IDL with transitional area described

  • These findings have led to the hypothesis that IDL could be a precursor of basal cell adenoma.

Fine-Needle Aspiration

• Cellular aspirate that may include elongated, duct-like structures or tubules lined by columnar-appearing cells

Gross

• Circumscribed and/or encapsulated, tan-pink to yellow-brown, rubbery to firm nodule measuring from 0.5 to 3 cm in diameter

• Surface ulceration may be seen but is not common.

• Cystic spaces and a gelatinous mucoid material may be identified in transecting the tumor.

Histology

• Encapsulated or well-circumscribed nodules

• Not infrequently include multifocal nodules

  • Scattered nodules may be small (clinically undetectable) and may be unencapsulated.

• Consistent pattern of growth (unlike basal cell adenoma and other tumor types) and includes:

  • Double rows of columnar (basaloid) epithelial cells forming branching and interconnecting cords

    • –

      Somewhat parallel arrangement of the rows of cells forms elongated duct-like structures resembling canals, hence the terminology of canalicular adenoma

  • Cystic dilatation of the canalicular structures may be present and may even be prominent in a given tumor.

  • Cords cut in cross-section may result in the presence of isolated tubules.

  • Alternating areas of tubules separated with closely apposed tubules is referred to as “beading,” creating an image of “beads on a string.”

• Elongated duct-like structures or tubules are lined by cuboidal to columnar cells with uniform, hyperchromatic, round to oval nuclei, variable amount of eosinophilic to amphophilic cytoplasm, and indistinct cell borders; mitoses are generally absent.

• Tubules are well demarcated from stroma by an intact membrane.

• Stroma is edematous and noteworthy for the relative absence of cellularity (scattered fibroblasts are present) and for the presence of prominent vascular pattern consisting of capillaries and venules, some with an eosinophilic cuff likely representing basal lamina and collagen.

• Histochemistry:

  • Diastase-sensitive, PAS-positive cytoplasmic granularity is seen.

• Immunohistochemistry:

  • Cytokeratins (pancytokeratin, CK7, CK13), S100 protein and vimentin positive

  • Variable EMA reactivity

  • Distinctive GFAP linear immunoreactive pattern among cells in proximity to connective tissue interface reported

  • Little to no myoepithelial differentiation: absence of p63, calponin, smooth muscle actin, smooth muscle myosin heavy chain

  • Recent evidence based on morphologic, immunohistochemical, and ultrastructural findings support a cell of origin demonstrating features of intercalated duct cells and striated duct luminal epithelial cells, including:

    • –

      IHC:

      • ▪

        Positive nuclear staining for S100 protein, absence of CEA and GFAP

    • –

      EM:

      • ▪

        Abundant junctional complexes, including desmosomes and hemidesmosomes

      • ▪

        Junctional complexes are associated with large aggregates of cytoplasmic intermediate filaments.

      • ▪

        Focal microvillus projections forming intercellular lumina lined by abundant junctional complexes

      • ▪

        Abundant cytoplasmic rough endoplasmic reticulum (rER) adjacent to the intercellular lumina and in apical aspects of the cells; rER is also seen near the basal lamina

Clinical

• Rare tumor composing less than 1% of all salivary gland neoplasms

• No gender predilection; most commonly occurs in the sixth to eighth decades of life

• Most frequently involves parotid gland but may also occur in the submandibular gland as well as in minor salivary glands throughout respiratory tract

• Symptoms vary according to the site of occurrence and most frequently present as a painless mass; other symptoms include nasal or airway obstruction.

• May occur synchronously with Warthin tumor

• Radiology:

  • Similar to Warthin tumors and as a result of the mitochondrial hyperplasia, radionucleotide imaging demonstrates increased uptake of technetium-99m.

• Stimulus for induction of oncocytic change is unknown but generally considered age related, rarely seen under 50 years of age and nearly always present above 70 years old:

  • Oncocytic cell changes are not limited to salivary glands but are seen in other organs, including:

    • –

      Thyroid gland, parathyroid glands, adrenal glands, kidney, pancreas, others

• Pathogenesis remains unclear. Some theories support a neoplastic growth, whereas others suggest a hyperplastic/metaplastic phenomenon:

  • Oncocytic tumorigenesis secondary to acquired mitochondrial dysfunction has been proposed as a plausible mechanism, but few tumors harbor mtDNA alterations within the control region to support this theory.

Pathology

Differential Diagnosis

• Oncocytic metaplasia:

  • Transformation of ductal and acinar epithelium to oncocytes

  • Metaplastic process is an aging phenomenon and as such oncocytic metaplasia is generally not seen in patients less than 50 years of age from which time the percentage of the population with oncocytic metaplasia increases

  • In contrast to oncocytoma, oncocytic metaplasia represents non–mass-forming focal or limited changes in one or more areas within the salivary gland.

  • May be seen in tumor cells of nearly all salivary gland tumors, including most commonly in pleomorphic adenoma and mucoepidermoid carcinoma

• Oncocytosis (also referred to as oncocytic [adenomatous] hyperplasia):

  • Proliferation of oncocytic cells within the salivary gland

  • Typically appear as nodular foci referred to as nodular oncocytic hyperplasia or nodular oncocytosis

  • May represent a diffuse alteration in the affected salivary gland referred to as diffuse oncocytosis

  • In either nodular or diffuse form may present as a clinically detectable mass lesion, presenting difficulties in differentiation from oncocytoma; the differentiation of oncocytosis from oncocytoma may not be possible due to overlapping histologic features and this differentiation may be more of an academic than practical issue because treatment and prognosis are essentially similar; however, features seen in oncocytosis that may assist in differentiating it from oncocytoma include:

    • –

      Multiple separate nodules (two or more)

    • –

      Unencapsulation

    • –

      Presence within the oncocytic nodules of residual nononcocytic salivary gland parenchyma, including ductular epithelium and serous acinar cells

  • Warthin tumor

  • Papillary oncocytic cystadenoma

  • Pleomorphic adenoma

  • A number of usual salivary gland carcinomas may have oncocytic cells as either a part of the tumor or as the predominant cell type; these tumors are included in the differential diagnosis of oncocytoma, including:

    • –

      Oncocytic carcinoma

    • –

      Mucoepidermoid carcinoma

    • –

      Acinic cell adenocarcinoma

    • –

      Adenoid cystic carcinoma

• Clear cell carcinoma

• Metastatic renal cell carcinoma and thyroid carcinoma

Treatment and Prognosis

• Complete surgical excision is the preferred treatment.

• Radiotherapy is not indicated as oncocytes are radioresistant.

• Prognosis is excellent following removal.

• Locally recurrent tumors are uncommon.

• Transformation to an oncocytic carcinoma is rare.

Clinical

• Accounts for approximately 2% of all salivary gland neoplasms

• No gender predilection; occurs over a wide age range but is most commonly seen in the third to sixth decades of life

• Although all salivary gland sites may be affected, the most common site of involvement is the parotid gland.

  • Second most common site is the palate (hard and soft palate)

  • Other sites may include the submandibular gland and oral minor salivary glands (e.g., retromolar region, upper lip).

• Most commonly present as a slow-growing, painless mass

Pathology

Differential Diagnosis

• Myoepithelial-predominant pleomorphic adenoma:

  • Although myoepithelial cells predominate, residual foci of pleomorphic adenoma in the form of myxochondroid stroma are present.

• Basal cell adenoma

• Myoepithelial carcinoma

• Epithelial-myoepithelial carcinoma

• Extracranial meningioma

• Peripheral nerve sheath tumors (i.e., neurilemmoma and malignant schwannoma)

• Smooth muscle tumors (i.e., leiomyoma and leiomyosarcoma)

• Extramedullary plasmacytoma

• Spindle cell squamous carcinoma

• For clear cell dominant or exclusive tumors, the differential diagnosis may include metastatic renal cell carcinoma or thyroid carcinoma.

Treatment and Prognosis

• Complete surgical excision is the preferred treatment and should include a portion of surrounding uninvolved tissue; if appropriate, a superficial parotidectomy should be performed.

• Local recurrence is related to inadequate excision.

• There is no relationship between cell type (e.g., spindle, plasmacytoid, epithelioid, clear) and prognosis.

• Malignant transformation is rare and occurs in the setting of a long-standing tumor and/or multiply recurrent tumor.

Clinical

• Uncommon lesion

• More common in women than in men; occurs over wide age range from the first to the tenth decades of life with a mean of 33 years

• Most common site of occurrence is parotid gland:

  • Much less often submandibular gland and intraoral salivary minor glands are affected.

  • Rare cases reported in other sites, including sinonasal tract

• Patients present with a slow-growing asymptomatic mass; rarely, pain and/or a “tingling” sensation have been described.

• Majority of cases present as a de novo process but a few cases have been described in association with recurrent pleomorphic adenomas or recurrent chronic parotitis

• Familial occurrence reported in two sisters, suggesting genetic predisposition

Pathology

Differential Diagnosis

• Polycystic (dysgenetic) disease (see Chapter 19 ):

  • Lobular collection of cystic ducts frequently with apocrine metaplasia

  • Unlike SPA, polycystic disease is usually:

    • –

      Bilateral

    • –

      Involves entire gland

    • –

      Shows no acinar proliferation and has minimal fibrosis and inflammation

• Sclerosing sialadenitis:

  • Shows similarities to SPA including presence of fibrosis and inflammation

  • In contrast to SPA, fibrosis is not nodular nor are xanthomatous cells seen in association with the duct ectasia.

Treatment and Prognosis

• Complete surgical resection is preferred treatment:

  • Facial nerve sacrifice not indicated

• Recurrence of the lesion may occur following incomplete excision:

  • 30% recurrence rate reported in some studies.

• Prognosis is very good with the caveat that until longer follow-up becomes available in these patients the biologic behavior may not be completely known.

• To date, no reported metastatic disease or death due to disease reported

Clinical

• Rare tumor type

• More common in women than in men; occurs over a wide age range from the second to ninth decades but most common in the sixth decade of life; rarely occur in the first two decades of life.

• Majority occurs in minor salivary glands, including:

  • Lips > cheek > palate

  • Slightly less than half (approximately 45%) occur in the parotid gland

  • Minority of cases (less than 10%) occur in submandibular gland.

• Majority present as slowly growing, painless masses; minor salivary gland lesions appear as mucosa-covered smooth nodules resembling mucoceles.

Pathology

Differential Diagnosis

• Cystic lesions associated with duct obstruction:

  • Such lesions include duct ectasia, as well as salivary duct cyst.

  • Typically, duct obstruction primarily affects submandibular gland

  • Secondary changes to duct obstruction include fibrosis, acinar atrophy, squamous metaplasia, chronic inflammation, and periductal hyalinization.

  • In comparison with cystadenoma, the ectatic or cystic ducts in obstructive lesions are widely separated, may be seen connected to or tracking to the obstructed duct, and usually lack the greater cytologic variability of the intraluminal epithelial proliferation seen in cystadenoma.

• Warthin tumor:

  • Characteristic bilayered epithelial layer and prominent dense lymphoid stroma with germinal centers of Warthin tumor not seen in cystadenoma, including papillary oncocytic cystadenoma

• Intraductal papilloma:

  • Almost invariable a unicystic lesion

  • Occurs in association with a dilated salivary gland duct

  • Intraluminal papillations are more complex and numerous than papillae of cystadenoma.

• Cystadenocarcinoma:

  • Presence of invasive growth differentiates cystadenoma from cystadenocarcinoma.

• Mucoepidermoid carcinoma, low-grade:

  • May share overlapping features with cystadenoma

  • Noncystic epithelial component of mucoepidermoid carcinoma includes an admixture of mucous, epidermoid, intermediate cells, which are absent in cystadenoma

  • Invasive growth, a feature often (but not always) seen in mucoepidermoid carcinoma absent in cystadenoma

• Polycystic (dysgenetic) disease:

  • Presence of diffuse involvement of the affected gland, apocrine lining epithelial cells and spheroliths seen in polycystic (dysgenetic) disease assists in differentiating it from cystadenoma.

Treatment and Prognosis

• Complete (conservative) surgical resection is curative.

• Recurrent tumor and malignant transformation rarely occur.

Clinical

• Uncommon tumor

• More common in men than in women; occurs over a wide age range but is most frequently seen in the sixth to seventh decades of life.

• Most common site of occurrence is the palate (greater than 80%), particularly at junction of the hard and soft palates.

  • Other minor salivary glands sites of involvement include buccal mucosa, retromolar region, tonsillar pillar, lip, and nasopharynx (adenoids).

  • Major gland involvement is rare and in major glands parotid gland is most commonly affected.

• Usually presents as an asymptomatic (painless) lesion generally discovered incidentally; clinical appearance often mistaken for a papilloma; duration of symptoms may be from months to years.

• Origin is disputed; evidence supports salivary gland excretory duct rather than intercalated duct origin.

Pathology

Differential Diagnosis

• Papilloma of surface epithelial origin

• Inverted ductal papilloma

• Warty dyskeratoma

• Verrucous carcinoma

• Mucoepidermoid carcinoma, low grade

Treatment and Prognosis

• Complete conservative surgical excision is the preferred treatment and is curative.

• Recurrence rarely occurs.

• Rare examples of malignant transformation reported, including:

  • Epithelial-myoepithelial carcinoma

  • Mucoepidermoid carcinoma

  • Carcinoma in situ

Clinical

• Uncommon tumor

• No gender predilection; affects primarily adults, oc­­curring in the fourth through seventh decades of life

• Intraoral minor salivary glands most frequently involved:

  • Buccal mucosa and lips are most commonly affected.

  • Other sites of occurrence include floor of mouth, soft palate, and tongue.

  • Involvement of major glands is rare.

• Symptoms relate to a painless, well-delineated, and solitary (submucosal) mass.

Pathology

Differential Diagnosis

• Inverted ductal papilloma

• Papillary cystadenoma

• Low-grade papillary adenocarcinoma of the nasopharynx

Treatment and Prognosis

• Complete conservative surgical excision is the preferred treatment and is curative.

Clinical

• Rare neoplasm

• No gender predilection; occurs primarily in adults over a wide age range but is most frequently seen in the sixth decade of life

• Most common sites of occurrence include:

  • Lower lip and the buccal (vestibular) mucosa

  • Other sites of involvement include the upper lip, floor of mouth, and soft palate.

• Generally asymptomatic and presents as a slow-growing painless, nodular submucosal swelling

Pathology

Differential Diagnosis

• Inverted papilloma

• Sialadenoma papilliferum

• Mucoepidermoid carcinoma

Treatment and Prognosis

• Conservative but complete local excision is the preferred treatment and is curative.

Clinical

• Rare tumor type with very few reported cases

• Most common site of occurrence is parotid gland

  • May occur less often in minor salivary glands (palate)

• Present as a palpable mass

Pathology

• Well-circumscribed to encapsulated lesion ranging in size from 0.5 to 3.0 cm

• Composed of closely apposed small ducts with minimal intervening stroma admixed with cystic ductal spaces that may include:

  • Prominent areas with cystic changes containing colloid-like luminal contents with scalloped edges reminiscent of thyroid parenchyma

  • Focal cysts

  • Absence of cystic spaces

• Ductal epithelial cells:

  • Single layer of cuboidal to columnar eosinophilic cells with bland nuclei, eosinophilic cytoplasm, and prominent cell membranes similar to striations of normal striated ducts:

    • –

      Eosinophilic intranuclear inclusions may be seen.

    • –

      Focal clear cell cytoplasmic change may be present.

  • Absence of epithelial “beading” pattern with abundant stroma seen in canalicular adenoma

  • Absence of chondromyxoid stroma, basal lamina-like material

  • Absence of mitotic activity and necrosis

  • Absence of visible bilayering composed of ductal cells surrounded by basal or myoepithelial cells:

    • –

      In contrast, normal excretory and intercalated ducts contain diffuse bilayering with basal or myoepithelial markers.

• Psammoma bodies and an associated adipocytic component may be identified.

• Immunohistochemistry:

  • • Keratins (CK7, pankeratin) consistently present

    • S100 protein in >80%

    • CK5/6 (75%)

    • Generally devoid of myoepithelial cells:

      • –

        Smooth muscle actin (SMA) negative

      • –

        Isolated cells may be p63 positive

        • ▪

          Pattern identical to striated ducts

      • –

        Focal calponin and smooth muscle myosin heavy chain may be present, forming incomplete rim around ducts

    • Thyroglobulin and TTF1 negative

• Highly vascular lesions with numerous small capillaries, some containing large ecstatic staghorn vessels

Treatment and Prognosis

• Complete resection curative

• No recurrence or metastases

Pathology

• Presence of discrete, rounded, partially to completely encapsulated nodules with well-defined contours

  • Fibrous capsule may vary in thickness and may contain entrapped, irregular-appearing ducts.

• Composed of intercalated ducts lined by single layer of cuboidal to columnar cells with small round nuclei and eosinophilic to amphophilic cytoplasm:

  • There is an absence of nuclear pleomorphism or increased mitotic activity.

  • Minimal intervening stroma present

• Occasionally acinic cells may be interspersed among the ductular structures.

• Immunohistochemistry:

  • Luminal cells reactive for cytokeratin (CK7), DOG1 (apical and membranous), S100 protein, and lysozyme

  • Basal/myoepithelial markers including p63, calponin, CK14, or smooth muscle actin highlight thin layer of myoepithelial cells around ducts:

    • –

      Basal/myoepithelial cells are indistinct by light microscopy.

Clinical

• Uncommon tumor type but more common than sebaceous lymphadenoma

• No gender predilection; primarily disease of adults

• Most commonly arises in parotid gland:

  • Less commonly arises in submandibular gland

Pathology

• Solid or cystic epithelial tumor islands:

  • Solid foci may show trabecular growth or tubules surrounded by a basement membrane–like material.

  • Cystic foci may contain proteinaceous material.

  • Papillary architecture may occasionally be seen.

  • Cells types include squamous cells in the solid nests, cuboidal to columnar cells lining cysts, but an absence of sebaceous cells.

  • Cellular components are rather bland, lacking atypical features, significant increase in mitotic activity, and an absence of necrosis.

  • Epithelial components are intimately associated with a lymphoid stroma that includes a dense mature lymphocytic cell infiltrate with identifiable lymphoid follicles; this lymphoid component is believed to represent the tumor-associated lymphoid stroma, a finding that can be seen in association with other salivary gland tumors.

  • Absence of atypical features, mitotic activity, and necrosis assists in differentiating lymphadenoma from a malignancy (either a primary salivary gland carcinoma or metastatic adenocarcinoma).

Treatment and Prognosis

• Surgical excision is curative.

Clinical

• Rare tumor type

• No gender predilection; occurs over wide age range, including pediatric and adult ages

• To date, all cases limited to parotid gland

• Present as slowly growing tumors

Pathology

• Cut surface shows multilocular cystic lesions filled with keratin materials.

• Histologically:

  • Multicystic spaces and solid epithelial islands containing lamellated-appearing keratin

  • Lined by stratified squamous epithelium with keratinization, including orthokeratosis and parakeratosis but absence of granular layer

  • Stratification of epithelium always regularly oriented from the outer basal to the inner keratotic cell layer

  • Basal cell layer demarcated by basement membrane from surrounding inflamed fibrous stroma

  • Focally, outer layer shows bud-like protrusions.

  • Solid squamous cell islands surrounded by basement membrane enveloped within collagenous stroma may be present.

  • Cystic and solid structures randomly distributed without definite lobular architecture

  • Lesional cells composed of uniform, bland nuclei and abundant eosinophilic cytoplasm

  • Scattered mitotic figures may be seen usually limited to outer epithelial layer; atypical mitoses not present

  • Foreign-body giant cell reaction to keratin debris may be present.

  • Immunoreactivity for cytokeratins (AE1/AE3, CK5/6, CK14) but negative for CAM5.2, S100 protein, actin, and calponin

Treatment and Prognosis

• Complete surgical resection is curative.

• No recurrences reported

Clinical

• More common in men than in women; occurs over a wide age range from third to eighth decades

• Arises primarily in parotid gland:

  • Less often may occur in submandibular gland and oral minor salivary glands

Pathology

• Solitary and well-circumscribed with light brown to yellow appearance on cut section

• Histologically, composed of an admixture of cells, including:

  • Mature adipose tissue:

    • –

      Usually dominates, representing more than 90% but reported in as little as 5% of a given tumor

  • Benign salivary gland epithelial parenchymal components:

    • –

      Sharply demarcated from fat

    • –

      Composed of ducts and acini:

      • ▪

        Ductal dilatation may be present.

    • –

      Extensive oncocytic cell population often present

    • –

      Other cell types may include sebaceous cells and squamous cells.

    • –

      Irrespective of cellular components there is an absence of cytologic atypia.

• Other common features include the presence of serous acini, ductal elements, sebaceous glands, and a patchy chronic inflammation.

Treatment and Prognosis

• Complete surgical resection is curative.

• No recurrences reported

Clinical

• Rare tumor accounting for 0.1% of all salivary gland tumors.

• More common in men than in women; occur over a wide age range from the third to tenth decades of life, and a mean in the sixth decade of life

• Most common site of occurrence is parotid gland

  • Other sites of occurrence include the submandibular gland and oral cavity:

    • –

      Sites of involvement in oral cavity include the buccal mucosa and posterior mandibular region.

    • –

      Given the presence of sebaceous cells in oral mucosa (unassociated with minor salivary gland), a definitive minor salivary gland origin cannot be confirmed.

• Generally asymptomatic and presents as a slow-growing, painless, firm mass; duration of symptoms may be from months to years.

Pathology

Differential Diagnosis

• Sebaceous lymphadenoma

• Sebaceous carcinoma

• Mucoepidermoid carcinoma

Treatment and Prognosis

• Conservative but complete surgical resection is curative.

• Unlike their cutaneous counterparts, salivary gland sebaceous adenomas not associated with increased risk of visceral carcinomas as may occur in Muir-Torre syndrome

Clinical

• Rare tumor

• No gender predilection; occurs primarily in the sixth to eighth decades of life

• Majority (more than 90%) occur in parotid gland or in periparotid region

  • Other much less sites of occurrence include anterior midline neck and oral cavity.

• Generally asymptomatic presenting as slow-growing, painless mass; duration of symptoms may be from months to years.

• Association with Warthin tumor and basal cell adenoma, membranous type reported

• Similar to Warthin tumor, the suggestion has been made that sebaceous lymphadenoma may arise in salivary gland inclusions within a lymph node; however, there is no definitive proof that this tumor is arising in a lymph node but rather represents the so-called tumor-associated lymphoid stroma (TALP), a phenomenon that can be seen in association with other salivary gland tumors (e.g., acinic cell carcinoma, mucoepidermoid carcinoma, others).

Pathology

Differential Diagnosis

• Sebaceous adenoma

• Lymphadenoma, nonsebaceous, of salivary gland origin:

  • Similar to sebaceous lymphadenoma but lacks sebaceous cell component

  • See previously in chapter for more complete discussion.

• Warthin tumor

• Lymphoepithelial sialadenitis

• Mucoepidermoid carcinoma

• Lymphoepithelial carcinoma

• Metastatic adenocarcinoma to periparotid or intraparotid lymph node

Treatment and Prognosis

• Conservative but complete surgical resection is curative.

• Rarely, single cases of malignant transformation to sebaceous carcinoma and basal cell adenocarcinoma reported

Clinical

• Common benign vascular tumor of infancy (affecting approximately 4% of children)

• Approximately 60% occur in head and neck.

  • Most common in the skin and subcutis

  • May occur in other locations, including salivary (parotid) glands

• Represents most common salivary gland tumor in pediatric population, accounting for greater than 90% of parotid gland tumors in children less than 1 year old

• More common in females than in males; may occur over a wide age range but most frequently seen in the first decade of life

• Almost exclusively involves parotid gland:

  • Occasionally the submandibular gland may be affected.

• Usually discovered at birth as a unilateral, compressible mass and bluish discoloration of overlying skin that may be accentuated during crying

  • Rapid enlargement and facial asymmetry may be seen, raising clinical suspicion for a malignancy

  • Extension to adjacent sites such as the hypopharynx may occur.

  • Ulceration of the overlying skin may occur.

• Generally appearing within weeks after birth, proliferate rapidly during the first year of life, and then spontaneously involute over a period of several years

• No association with:

  • Familial disorders such as von Hippel-Lindau syndrome or hereditary telangiectasia

  • Consumptive coagulopathy disorder (i.e., Kasabach-Merritt syndrome)

• Intraparotid hemangiomas in adults are uncommon.

Pathology

Differential Diagnosis

• “Adult” hemangiomas:

  • May uncommonly be identified in salivary glands and are noted for:

    • –

      Tendency to occur in older children and adults

    • –

      Female predilection

    • –

      Primarily involve parotid gland

    • –

      Involve the extralobular connective tissue

    • –

      Characterized by presence of dilated, thin-walled vessels lined by flattened endothelial cells

    • –

      GLUT1 negative

    • –

      Do not regress and therefore requires complete surgical excision

• Lymphatic malformation (lymphangioma/cystic hygroma):

  • See Section 4, Neck, for more complete discussion.

  • Involvement of the parotid gland is less common than hemangiomas.

  • Most occur during childhood.

  • Histology is similar to lymphangiomas of more common locations, including the presence of variably sized, endothelial-lined spaces with or without intraluminal eosinophilic material, and surrounding collagenous stromal tissue

  • Complete surgical resection is the preferred treatment.

• Epithelioid hemangioma:

  • Formerly referred to as angiolymphoid hyperplasia with eosinophilia

  • Rarely involves salivary glands

  • See Section 7, Ear and Temporal Bone, for complete discussion.

• Angiosarcoma

• Kaposi sarcoma

• Hemangioendothelioma

Treatment and Prognosis

• Majority (75% to 90%) involute by 7 years of age; current recommendation in absence of an enlarging neoplasm with compromise of external ear canal and/or facial distortion, is delay surgery until an older age in the hope that the tumor will involute (spontaneously regress) over time.

  • Regression (involution) may occur in phases, initially slowly over the first 5 years of life and then with continuous regression through the first decade of life.

• Variable success has been reported with the use of corticosteroids, interferon, and compression therapy.

• (Oral) propranolol has replaced corticosteroids as preferred first-line therapy for management of infantile hemangiomas:

  • • –

      >94% of patients demonstrate response to treatment with size reduction, color changes, softened texture, and/or healing of ulceration.

    • –

      Topical β-blocker timolol now an alternative to oral propranolol with watchful waiting for smaller infantile hemangiomas

• In presence of a rapidly enlarging lesion and/or disfiguring lesion complete surgical excision is preferred treatment with preservation of the facial nerve

  • Facial nerve in infants is in a more superficial location than in an older age; therefore surgical intervention in infancy may be associated with a greater incidence of damage to the facial nerve.

• Rarely, life-threatening growth may occur:

  • In this situation, preoperative combined radiation and chemotherapy may be indicated.

• Malignant transformation does not occur.