Benign Mixed Tumor

Synonyms: Pleomorphic Adenoma

Typical variation in cellularity, cellular arrangement and matrix

Definition

Neoplasm of epithelial and myoepithelial differentiation, varied architectural and cytologic features and mucoid, myxoid or chondroid stroma.

Clinical Features

Most common neoplasm of salivary glands
Most frequent in women in fourth decade of life1
≈ 10× more common in parotid than submaxillary gland
Very rare in sublingual gland
Origin in parotid:
- mainly superficial lobe:
  - 50% tail
  - 25% anterior portion
- remaining 25% deep lobe
  - often present as pharyngeal mass without external evidence of tumor2

Metastases

Rarely to:
- lymph nodes
- lungs
- bone
- other organs:
  - a number have presented as isolated masses in kidney3
- Appear as benign as original tumor4–6
- Sometimes occur in immunologically compromised patients:
  - a rapidly aggressive clinical course 7
- Usually preceded by one or more local recurrences8

Gross Pathology

A rubbery resilient mass with a bosselated surface
May be large
Consistency depends on:
- relative amount of:
  - epithelial cells
  - stroma
- type of stroma
Tends to be well circumscribed (Fig. 1
Fig. 1: Gross appearance of benign mixed tumor of parotid gland. Note the sharply outlined character and predominantly solid cut surface.
)
Small extensions protrude into adjacent normal tissue
Cut surface:
- appearance depends on relative proportion of:
  - epithelium
  - stroma
- islands of cartilage have a glistening, translucent appearance (Figs 2 and 3
  Fig. 2: Gross appearance of benign mixed tumor of parotid gland. Note the sharply outlined character and predominantly solid cut surface. The glistening surface is indicative of cartilaginous differentiation.
  Fig. 3: Gross appearance of benign mixed tumor of parotid gland. Note the sharply outlined character and predominantly solid cut surface. The glistening surface is indicative of cartilaginous differentiation.
  )
- rarely foci of mature bone

Histopathology

Bewildering pattern:
- extreme cellularity
- scattered bizarre tumor cells9
- partial penetration of capsule:
  - capsule tends to be thicker and less likely to be penetrated by tumor in deep lobe10
- occasionally clusters of tumor cells in vascular lumina11
Typically biphasic appearance due to intimate admixture of:
- epithelium
- stroma
Epithelial component:
- mostly glandular
- commonly foci of squamous metaplasia
- sometimes keratinized epithelial plugs in lumen
- lining of neoplastic glands composed of two cell types:
  - basally located cells:
    - display morphologic features of myoepithelial cells12
    - may be cuboidal, flattened, clear, spindle shaped, or ‘hyaline'13 (Fig. 4
      Fig. 4: Microscopic appearance of benign mixed tumor. Epithelial and myoepithelial cells can be easily distinguished.
      )
Stroma:
- may have nonspecific fibromyxoid appearance
- sometimes contains:
  - abundant elastic tissue14
  - extensive adipose tissue15
- usually areas of clear-cut cartilaginous differentiation (Fig. 5
  Fig. 5: Benign mixed tumor. The myoepithelial cells are undergoing cartilaginous metaplasia.
  ):16
  - more common and prominent in parotid and submaxillary tumors than in those of minor salivary glands
- evidence suggests that these mesenchymal elements:
  - share same origin as epithelial cells17–19
  - represent modified myoepithelial cells 20,21
- often transitions between basally located myoepithelial cells and myxochondroid cells of stroma
Mucin:
- two types:
  - connective tissue type 20,22 containing sulfated and nonsulfated glycosaminoglycans 23–25
- probably secreted by cells of epithelial derivation 26
Sometimes other extracellular substances:
- tyrosine-rich crystalloids in myxoid areas27,28
- collagenous spherules 29
- calcium oxalate crystals
- amyloid30
- intraductal birefringent crystalloids of unknown chemical composition31,32
Sometimes:
- extremely cellular and tumor cells are round or spindle shaped (Fig. 6
  Fig. 6: Benign mixed tumor with a markedly hypercellular appearance.
  )
- cytologic atypia in form of scattered large hyperchromatic nuclei (shown to be polyploid)33,34
  - do not behave differently from ordinary variety
  - rarity of mitotic figures and absence of necrosis aid in differential diagnosis with true malignant neoplasms
- foci that superficially resemble adenoid cystic carcinoma pattern
  - do not influence prognosis
Recurrences:
- usually microscopic pattern exactly mimics original neoplasm
Ultrastructurally:
- a continuum of cytoplasmic features from epithelial to mesenchymal cells 35–37

Special Stains and Immunohistochemistry

Ductal epithelial component:
- positive for:
- amylase usually absent 42
- similar to normal intercalated duct cells, particularly regarding expression of lactoferrin and secretory component42
In ≈ 50% cells reactive for:
- prostate-specific antigen (PSA)
- prostate-specific acid phosphatase (PSAP)48
Myoepithelial component:
- immunoreactive for:
  - keratin
  - actin
  - myosin
  - other smooth muscle-specific proteins
  - fibronectin
  - S-100 protein:49–55
    - also strongly expressed in:
      cartilaginous areas
      a subtype of epithelial ductal cells
Cartilaginous foci:
- abundant expression of:
  - (pericellularly) type IV collagen 56
- expression of:
  - bone morphogenetic proteins57
  - S-100 protein
- Sometimes demonstration of:
  - two glial markers – glial fibrillary acidic protein and astroprotein
    - difficult to explain58,59
    - suggested to be result of cross-reactivity with other intermediate filaments of similar structure and chemical composition 60
    - seems to be related to capacity for cartilaginous differentiation
    - may be useful in differential diagnosis with adenoid cystic carcinoma and basal cell adenoma61,62
- Basement membrane proteins:
  - consistently present, e.g.:
    - laminin 63
  - linear quality when related to epithelial ductular cells
  - thicker more ‘membranous’ appearance when connected with myoepithelial cells64
  - expressed in connection with chondroid areas:
    - type II collagen
    - tenascin65,66

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Benign Mixed Tumor

Adenoid cystic carcinoma
Basal cell adenoma61

Genetics

Cell proliferation index low67–69
Cytogenetically three major subgroups:
- rearrangements of 12q14–15 70,71
Overexpression of p53 rare 72

Management

Total surgical removal with a margin of normal salivary tissue
Superficial parotidectomy with preservation of facial nerve:
- standard for tumors in superficial lobe of parotid
- incidence of recurrence almost zero
Recurrence rate:
- depends almost entirely on adequacy of primary excision73
- very high if tumor removed by a simple enucleation (Fig. 7
  Fig. 7: Distribution of recurrent tumor nodules (shown as purple dots) as demonstrated by careful histologic study of re-excision of benign mixed tumor of parotid gland, which at time of first operation had apparently been enucleated. Surgical scar measured 3.5 cm. (Courtesy of Dr F. Leidler, Houston)
  ):
  - because small inconspicuous nodules attached by threadlike filaments of neoplastic tissue surrounding main mass may be left behind and provide nidus for recurrence:74–76
    - may have shape and appearance of lymph nodes and be mistaken for nodal metastases
- most recurrences during first 18 months after surgery
- others supervene over years (may be >50 years)
Immediate radiation therapy:
- to minimize recurrence 77
Surgery for recurrent tumor:
- often fails
- further recurrences in ≈ 25%, often as multiple foci78

Prognosis

Long-term prognosis excellent if properly treated79

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Last updated: 6 Jan 2006