Acinic Cell Adenocarcinoma with High-Grade Transformation
Beth Israel Medical Center
New York, NY
69 year old women with a left parotid gland mass measuring 3 cm in greatest dimension.
The tumor was rapidly growing with associated facial nerve weakness. An enlarged left cervical neck
(Level II) was also present. A radical parotidectomy and neck dissection was performed.
Acinic cell adenocarcinoma with high-grade transformation
("dedifferentiated" acinic cell adenocarcinoma).
Acinic Cell Adenocarcinoma (ACC)
Malignant epithelial salivary gland neoplasm characterized by a variety of histologic growth patterns
and the tendency for at least some of the neoplastic cells to recapitulate the appearance of normal
serous acinous cells characterized by the presence of cytoplasmic (zymogen type) secretory granules.
Synonyms have included acinous or acinic cell tumor considered an inappropriate designation given the
malignant biologic potential of this neoplasm.
ACC represents approximately 18% of all malignant salivary gland neoplasms and 6.5% of
all salivary gland neoplasms. ACC is slightly more common in women than in men; occurs over a wide age
range with a peak incidence in the 7th decade of life:
The majority of cases (>80%) arise in the parotid gland. Uncommonly, ACC may also be identified
in the submandibular and sublingual glands, as well as in all minor salivary glands, especially those of
intraoral sites; the most common intraoral sites include the buccal mucosa and upper lip. Bilateral
parotid gland, and less often bilateral submandibular gland involvement, may uncommonly occur. The most
common clinical presentation is that of a slow-growing, solitary mass without fixation to surrounding
structures. Associated pain may or may not be present. Facial paralysis may occur in up to 10% of
patients and fixation to surrounding structures may uncommonly occur. The duration of symptoms typically
are less than a year but may occur up from several years to decades.
- approximately 4% occur in children;
- in children, the majority of cases occur in
the second decade of life;
- in children, acinic cell adenocarcinoma is
the second most common malignant epithelial neoplasm second to mucoepidermoid carcinoma;
There are no known etiologic factors.
Fine Needle Aspiration Biopsy
Aspirates of ACC tend to be cellular except for the papillary-cystic and follicular
variants, which may have low numbers of serous acinar cells. The cytologic diagnosis of ACC rests on the
presence of identifying serous acinar cells characterized by the presence of:
Serous acinar cells may be mistaken for oncocytic cells and in conjunction with a lymphocytic cell
infiltrate may be misdiagnosed as a Warthin tumor.
- large cells with round, relatively uniform
dark staining nuclei, inconspicuous to conspicuous nucleoli and abundant, granular appearing cytoplasm;
- appear in clusters resembling normal acini or
as individual cells;
- stripped or naked nuclei may be present in
the background, and may be mistaken for lymphocytes;
- in contrast to normal (nonneoplastic) serous
acinar cells in which the cells have basally oriented nuclei, the nuclei in neoplastic acinar cells tend
to be centrally situated lacking polarity;
- the histology of acinar cell adenocarcinoma
often includes the presence of a lymphocytic cell infiltrate, which may be apparent in aspirates of this
ACCs are well-demarcated and/or encapsulated, round or multilobulated, soft to rubbery,
tan-gray to yellow or pink mass usually measuring from 1-3 cm in greatest diameter but occasionally may
reach sizes up to 13 cm. Most neoplasms have a homogenous appearance but may be cystic and hemorrhagic.
Recurrent neoplasms are less well-demarcated and tend to be multinodular in appearance.
ACCs often are circumscribed tumors and may be encapsulated or may be infiltrative. ACCs
are polymorphic tumors characterized by a variety of growth patterns including solid, microcystic,
papillary-cystic and follicular.
1) Solid and microcystic :
- most common patterns and often seen in
association with each other;
- solid growth consists of sheets or aggregates
of tumor cells in lobules or organoid arrangement;
- microcystic consists of numerous small cystic
spaces; microcysts may appear as empty spaces or may contain eosinophilic to basophilic material.
- less common patterns than solid and
microcystic but more common than follicular pattern;
- papillary-cystic consists of variable-sized
cystic spaces associated with papillary projections supported by a thin fibrovascular core:
- epithelial proliferation may appear to be
"floating" in cystic spaces;
- epithelial cells may bulge into the lumen in an
uneven manner resulting in a "tombstone row" appearance.
3) Follicular pattern :
- follicular pattern resembles thyroid parenchyma with epithelial-lined lumens containing
eosinophilic proteinaceous material lined by cuboidal to columnar cells.
ACCs are also noteworthy for their cytologic variation including:
1) Acinic or acinar cells : these cells are diagnostic (pathognomonic)
appear polyhedral in shape with small dark eccentrically placed nuclei and characteristic abundant
basophilic cytoplasm with cytoplasmic (zymogen-like secretory) granules; the zymogen-like secretory
granules define these as acinar cells. These cells may predominate in well-differentiated tumors, but in
any given tumor they may represent a minority of the neoplastic cells; in the latter situation,
histochemical stains are helpful in the diagnosis (see below). These cells may be vacuolated and in
contrast to vacuolated (non-acinar) cells retain their cytoplasmic diastase-resistant, PAS-positivity.
2) Intercalated duct-like cells : these cells are cuboidal or columnar
with centrally placed small dark nuclei and eosinophilic to amphophilic cytoplasm. They are found in the
majority of tumors but usually represent a smaller percentage of the cellular components; may predominate
in about 1/3 of cases.
3) Vacuolated cells : contain clear cytoplasmic vacuoles which may be
numerous, vary in size and distend the cell membranes. These cells are more commonly seen in ACC than in
other salivary gland neoplasms, but they are not in and of themselves diagnostic for acinic cell
4) Clear cells : appear round to oval cells with distinct cell borders,
peripherally-placed, small, dark nuclei and the hallmark clear cytoplasm; result from fixation and/or
tissue processing. These cells are considered an uncommon cell type in acinar cell adenocarcinomas.
Likely "pure" clear cell variant of acinic cell adenocarcinoma doesn't exist.
5) Nonspecific glandular cells : lack specific features seen in the other
cell types and appear round to polygonal with round nuclei, amphophilic to eosinophilic cytoplasm and
indistinct or ill-defined cell borders; tend to be more cellular and pleomorphic with a syncytial growth.
While a single growth pattern and cell type may predominate in any given tumor, it is not
uncommon to see multiple growth patterns and cell types in a single tumor. In the majority of ACCs,
there is minimal cellular pleomorphism and low to absent mitotic activity. Typically, the stroma is
scant but occasionally may be dense and hyalinized. A prominent lymphoid component with germinal centers
is present in many ACCs and has been referred to as Tumor-Associated Lymphoid Proliferation (TALP). The
presence of TALP, including germinal centers may suggest involvement of a periparotid or intraparotid
lymph node; the presence or absence of subcapsular sinuses assist in differentiating TALP from a bona
fide lymph node. TALP is not unique to ACC and can be seen in a variety of salivary gland neoplasms.
Occasionally, psammomatoid concretions similar to those seen in thyroid papillary carcinoma may be
present. Hemorrhage may be present including in connective tissue and within epithelial cells;
intracytoplasmic hemosiderin pigment appears finely granular. Of note that invasive growth is not a
prerequisite for a diagnosis of ACC and the diagnosis can (and should) be even in the absence of invasive
growth on the basis of the architectural and cytomorphologic features. As far as is currently known,
there is no benign counterpart for ACC.
Acinar cells and intercalated duct cells show the presence of intracytoplasmic
diastase-resistant, PAS-positive granules; mucicarmine and alcian blue staining are typically negative
but may be weakly positive in any given case. The presence of some intracytoplasmic mucicarminophilic
material can be seen in ACC and does not exclude the diagnosis. All of the other cell types including
vacuolated cells, clear cells and non-specific glandular cells may show diastase-sensitive, PAS-positive
intracytoplasmic material, and are mucicarmine and alcian blue negative.
Relative to specific patterns, in the microcystic pattern eosinophilic to basophilic
material may stain for PAS and mucicarmine; in the papillary-cystic pattern, intraluminal and
extracellular PAS positive and mucicarmine positive material may be present; in the follicular pattern,
luminal material may be PAS positive and weakly mucicarmine positive.
Immunostaining is non-specific in the diagnosis and differential diagnosis of ACC.
Cytokeratins are consistently positive. While normal acinar cells are reactive for anti-amylase,
neoplastic acinar cells are usually nonreactive. Variable immunoreactivity is seen with S-100 protein
and vimentin. p63, calponin and actins (smooth muscle and muscle specific) are negative. There may be a
high expression of p53 and bcl-2, and a low labeling index with Ki-67 (MIB1).
Electron microscopy :
Ultrastructural findings are characterized by the presence of numerous round, electron
dense cytoplasmic secretory granules; rough endoplasmic reticulum and mitochondria are present;
junctional complexes and microvilli may be identified; basal lamina separates tumor cells from stroma.
Cytogenetics and Molecular Biology :
To date, there have been only a few studies on cytogenetics and molecular biology showing
the presence of alterations of chromosome 4p, 5q, 6p and 17p, as well as loss of heterozygosity (LOH) in
at least one of the 20 loci on chromosomes 1, 4, 5, 6, and 17.
Treatment and Prognosis
The treatment for ACC includes complete surgical excision and may consist of either
conservative parotidectomy when the tumor is limited to the superficial lobe or total parotidectomy when
the deep lobe of the parotid is involved. For non-parotid gland sites of involvement, conservative but
complete surgical resection to include tumor-free margins is indicated. Adjunctive
radiation therapy is generally not used as a primary mode of treatment but may be utilized for tumors
that cannot be completely resected or in the presence of metastatic disease. ACCs are indolent neoplasms
generally cured by complete surgical removal. ACCs have a 5-year disease specific survival of 91%.
However, there is an approximately 35% recurrence rate, approximately 16% metastatic rate and
approximately 16% disease-associated death rate. Depending on the primary site of occurrence regional
lymph node metatsasis may include the pre-auricular lymph nodes (parotid tumor), submandibular and upper
jugular chain lymph nodes (submandibular tumor), submental lymph nodes (lip tumor), base of skull (palate
tumor), submandibular, post-auricular and level II accessory lymph nodes (intraoral tumors). Distant
visceral spread include the lungs, liver, bone and brain. Most recurrences and metastases occur within 5
years of the initial therapy; however, recurrent tumor and metastatic disease may occur years after the
Favorable prognostic factors include: occurrence in minor salivary glands, longer
duration of symptoms, and patient's under 30 years of age. Adverse prognostic factors include multiple
recurrences and metastasis (regional lymph nodes, distant visceral), short duration of symptoms,
submandibular tumors more aggressive than parotid tumors and patient's over 30 years of age.
Histologic features (i.e., growth patterns, cell type) are not predictive of prognosis (except for
dedifferentiation, see below). Despite attempts to separate acinic cell adenocarcinomas into low- and
high-grade, the histologic pattern and cytologic appearance do not correlate with either a favorable or
poor clinical outcome. Clinical staging is a better predictor of prognosis than histology with poorer
outcome associated with large size and infiltrative growth, involvement of the deep lobe of parotid and
Acinic Cell Adenocarcinoma with High-Grade Transformation or "Dedifferentiated" Acinic Cell Adenocarcinoma
Acinic cell adenocarcinoma with high-grade transformation includes those tumors showing the presence
of histomorphologically "conventional" ACC associated with areas of undifferentiated carcinoma. Similar
high-grade transformation may occur in other salivary gland neoplasms including pleomorphic/monomorphic
adenoma (i.e., carcinoma ex pleomorphic/monomorphic adenoma) mucoepidermoid carcinoma, adenoid cystic
carcinoma, polymorphous low-grade adenocarcinoma, epithelial-myoepithelial carcinoma and others.
High-grade transformation in ACC is a rare phenomenon. There is no gender predilection; tends to
occur in older adults. Preferentially occurs in the parotid gland but rarely may occur in other sites.
While there may be a known prior (long-standing) history of ACC, most ACCs with high-grade transformation
occur de novo. Patients present with a mass lesion with or without associated pain. These tumors tend
to be large with most measuring over 3 to 4 cm in greatest dimension. Metastatic disease may be present
at the time of presentation and may represent the primary clinical complaint. Metastatic disease may be
locoregional to cervical lymph nodes or distant metastases including to the lungs, brain and abdomen.
There are no known etiologic factors in association with high-grade transformation of ACC. There has
not been a correlation to prior irradiation therapy.
The differentiated or low-grade is composed of conventional ACC. This component may be readily
identifiable or may be extremely limited in extent. The high-grade component is characterized by the
presence of sheets of epithelial cells lacking evidence of cellular differentiation with marked nuclear
pleomorphism, increased nuclear-to-cytoplasmic ratio, increased mitotic figures including atypical
mitoses, and necrosis (individual cell and confluent [comedotype] areas). The neoplasm is extensively
infiltrative including invading of residual salivary gland parenchyma, neurotropism and lymph-vascular
space invasion. A desmoplastic stroma may be present. The high-grade component is devoid of any
evidence of acinar cell differentiation and typically lacks an associated lymphoid proliferation.
Histochemical stains may show the presence of intracytoplasmic diastase-sensitive, PAS- positive
material; mucicarmine staining is negative.
Immunohistochemical stains show the lesional cells to be variably reactive for cytokeratins (AE1/AE3,
CAM5.2) but negative for p63, calponin, S100 protein, actins, trypsin, amylase and lysozyme. Other
stains including EGFR, CD117, androgens and Her-2/neu have not been consistently reported in the
literature but are usually negative. Recently, strong beta-catenin (membranous) staining has been
reported (Skalova et al). Ki-67 (MIB1) staining will show a high proliferation index. Staining for p53
and cyclin D1 are increased in the high-grade component.
Treatment and Prognosis
Given the limited number of cases reported in the literature, there are no set guidelines for the
treatment of high-grade transformation of ACC; however, since these are aggressively behaving
carcinomas, therapy should be equally aggressive. Treatment includes complete surgical resection,
including neck dissection given the propensity of this carcinoma to metastasize to regional lymph nodes
plus adjunctive radiotherapy. Chemotherapy is added in patients with distant metastasis. High-grade
transformation of ACC is associated with an accelerated clinical course with early wide dissemination and
high mortality rates.
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