Intraoperative Consultation in Head and Neck Pathology
Case 3 -
Polymorphous Low-Grade Adenocarcinoma of
Minor Salivary Gland Origin
Bruce M. Wenig, M.D.
Mary S. Richardson, D.D.S., M.D.
A 32 year old male presented with a palate mass. The result of a
biopsy was that of "salivary gland neoplasm, not further specified" with the recommendation for surgical
At surgery, a 2.5 x 2 x 1.5 cm roughly rectangular tissue
fragment was excised from the palate and sent for frozen section. On gross examination the tissue
fragment had identifiable intact mucosa free of ulceration or a mass lesion. The surgical margins (deep
and lateral) were inked and the specimen was bisected revealing a tan-white, rubbery to firm area within
the submucosa surrounded by skeletal muscle; the more superficial portion of the indurated area appeared
delineated but not encapsulated, while in the deeper aspect of the specimen the lesion appeared
ill-defined. A central through and through section of the specimen was taken, divided into two and
frozen section analysis was performed.
The surface epithelium was intact, composed of
benign keratinizing squamous epithelium, and was free of pathologic changes. Within the submucosa there
was a cellular proliferation showing varied growth patterns, including solid nests, scattered ducts or
glands, focal cribriform pattern and focal papillary architecture. At higher magnification, the
neoplastic cells were composed of round to oval, fairly uniform nuclei with vesicular to stippled
appearing chromatin, mild pleomorphism, and absent mitotic figures. A hyalinized to mucinous stroma was
present. The lesion was unencapsulated and along its superficial aspect was delineated from the
submucosal tissues, as well as from adjacent minor salivary glands. Within the tumor itself isolated
non-neoplastic minor salivary gland parenchyma was identified surrounded by the cellular proliferation.
In the depth of the tumor invasion of skeletal muscle could be seen but neural invasion or lymph-vascular
space invasion was not definitively identified. The neoplastic proliferation extended to the deep margin
Minor salivary gland carcinoma consistent with
polymorphous low-grade adenocarcinoma of minor salivary gland origin extending to the deep margin of
An additional deep margin was resected and on frozen section was
negative for carcinoma.
Diagnosis on Permanent Section:
Polymorphous low-grade adenocarcinoma of
minor salivary gland origin.
Minor salivary gland tumors include all lesions and tumor types found in major salivary glands. The
more common tumor types of minor salivary glands, in particular the oral cavity include benign mixed
tumor (pleomorphic adenoma) and variants thereof, adenoid cystic carcinoma, and polymorphous low-grade
adenocarcinoma (Table 1); other more frequently occurring intraoral minor
salivary gland tumors include adenocarcinoma NOS, mucoepidermoid carcinoma and clear cell adenocarcinoma.
The minor salivary glands have a higher incidence of malignancy as compared to major salivary glands. In
contrast to major salivary gland tumors, all minor salivary gland tumors whether benign or malignant are
unencapsulated. Since there may be overlapping histologic findings (architecture and cytomorphology)
among tumor types, the diagnosis of malignancy in minor salivary gland (oral cavity) tumors is predicated
on the presence or absence of invasion. The importance of identifying invasive growth cannot be
overemphasized and is the key in differentiating benignancy from malignancy in minor salivary gland
tumors. Benign tumors tend to be well circumscribed and usually grow with a broad-based pushing front.
Benign tumors may encircle or displace adjacent normal structures but do not infiltrate these structures.
The presence of invasion irrespective of the morphology of the tumor automatically places the tumor in a
malignant category. Malignant tumors are characterized by the presence of invasion; however, some
malignant salivary gland tumor, including acinic cell adenocarcinoma may havecircumscribed borders. In
this example the diagnosis is based on the histomorphology of the tumor.
Among the key histologic diagnostic features in the overall evaluation of salivary gland tumors
- tumor borders;
- cellular composition;
- architectural arrangement;
- cytologic features;
- stromal components.
Indications for Intraoperative Consultation in Minor Salivary Gland Tumors
The indications for intraoperative consultation in minor salivary gland tumors includes:
1) determination of the tumor type for optimal surgical management;
2) evaluation of surgical margins of resection;
3) determination of neural invasion; involvement of the palatine nerves (from the pterygopalatine fossa) is
determined pre-operatively by radiographic imaging studies;
4) determination of bone involvement that may necessitate resection of bone (palatine bone or maxilla);
5) usually a lymph node dissection is not performed for intraoral minor salivary gland tumors unless there
is a pre-operative diagnosis of a high-grade malignancy; if lymph nodes are excised then a frozen section
may be requested to exclude the presence of metastatic disease and the need for a neck dissection.
Surgeons Expectations of the Intraoperative Assessment of Intraoral Minor Salivary Gland Tumors
The surgeon's expectations in the intraoperative assessment of minor salivary gland tumors include:
1) determining benign from malignant;
2) determining the specific type of malignancy, in particular adenoid
cystic carcinoma that may necessitate a wider resection to achieve tumor-free margins;
3) determining adequacy of the resection margins and possible extent
It should be noted that in the oral cavity, the surgeon must consider the possibility of resecting the
lesion with a modest margin. Additional surgical treatment can be accomplished immediately if the frozen
section indicates the need. As with intraoperative consultation of other body sites, frozen section
diagnosis of minor salivary gland lesions requires close interaction between the surgeon and the
- margins for minor salivary gland tumors are
similar to those for other mucosal lesions and include the depth and circumferential excision lines;
- osseous involvement necessitates resection of
the involved bone.
Handling of Resected Tissue
The handling of intraoral minor salivary gland lesions is similar to other mucosal-based lesions.
Careful gross examination of the resection specimen is imperative. In the evaluation of salivary gland
tumors in general the gross inspection of the resection specimen should:
- determine what is the relation between the
lesion and the adjacent tissues; sections submitted for frozen section should show this relationship; the
tissue sample should be taken to include the junction of the tumor and surrounding tissues not just from
the center of the lesion allowing for evaluation of the relationship of the tumor to surrounding
- the frozen section should be taken between
the tumor and the closest line of excision, which allows for determining how far the tumor is from the
surgical resection margin;
Pitfalls in the Intraoperative Assessment of Minor Salivary Gland Tumors
The intraoperative evaluation of salivary gland tumors is potentially problematic. Many surgeons
harbor doubt about the reliability of frozen section diagnosis of salivary gland lesions. However, the
accuracy of frozen section diagnosis of salivary gland tumors is quite good (see later in this section),
and is comparable to the frozen section diagnosis of other tissue sites. The majority of all salivary
gland tumors are benign, so statistically one should not have trouble in the identification of salivary
Regardless of tumor site, the more difficult diagnoses in salivary glands include:
- differentiating mucoepidermoid carcinoma from
chronic sialadenitis and necrotizing sialometaplasia;
- differentiating adenoid cystic carcinoma from
pleomorphic adenomas, monomorphic adenomas and polymorphous low-grade adenocarcinoma.
Mixed Tumor (MT) or Pleomorphic Adenoma (PA) (Table 1)
Benign epithelial-derived tumor composed of cells demonstrating epithelial differentiation (ductal
structures with associated nonductal elements) and mesenchymal differentiation (myxoid, hyaline,
chondroid, and osseous areas).
MT represents the most common neoplasm of salivary glands accounting from 40-70% of all neoplasms of
the parotid, submandibular glands and minor salivary glands. MT of the sublingual glands is rare. MTs
affect women more than men and occurs over a wide age range but is most commonly seen in the 3rd-6th
decades of life. MT is the most common salivary gland tumor in children and adolescents. The most
common site of occurrence is the 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. 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. The most common
site of PA in the upper respiratory tract is by far the nasal cavity. Symptoms vary according to site
but most commonly presents as a slow-growing, painless mass 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. In the parotid, 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 a malignant process. MT appears to be entirely of epithelial origin
with the mesenchymal areas composed predominantly of cells that represent modified myoepithelial cells.
There are no known etiologic factors.
Minor salivary gland tumors are polypoid or lobulated, encapsulated or well-delineated, tan-white
usually measuring 1-2 cm but capable of attaining sizes of 7 cm or more. Recurrent tumors tend to be
MTs of minor salivary gland are generally not encapsulated but are well-demarcated. The histologic
appearance typically includes an admixture of epithelial, myoepithelial and stromal components.
Morphologic variability can be seen within a single neoplasm. The epithelial component may have a
variety of growth patterns, including solid, cystic, trabecular or papillary consisting of a
proliferation of duct-lining epithelial cells and myoepithelial cells. The duct-lining epithelial cells
form the inner layer of acini or tubules and appear flattened, cuboidal or columnar with round to oval
nuclei and a variable amount of cytoplasm appearing eosinophilic to amphophilic. The myoepithelial
component forms the outer layer and is spindle-shaped in appearance with hyperchromatic nuclei and may be
more than one cell layer thick. The stromal component, the product of myoepithelial cells, varies in
appearance from myxoid to chondroid to myxochondroid and may also appear fibrous and vascular. Any one
or all of these components may coexist in the same neoplasm. In a given tumor, any of the components may
predominate so that tumors may be diagnosed as epithelial-, myoepithelial- or stromal-predominant MT.
However, all components must be identified in order to diagnose a MT. Extracellular crystalloids may be
identified, particularly in the nonepithelial areas. Crystalloids are more often present in MT than in
any other salivary gland tumor, but can be found in other tumors as well (e.g., polymorphous low-grade
adenocarcinoma). Other findings may include the presence of keratinization, squamous cells, mucous
cells, clear cells, spindle cells, plasmacytoid cells, and sebaceous cells. Mixed tumors of the nasal
cavity (particularly the septum) tend to have an increased plasmacytoid-appearing myoepithelial
component. Additional features may include oncocytic metaplasia, calcification and fat.
The immunohistochemistry staining pattern seen in MT includes cytokeratins, S-100 protein, calponin,
p63, smooth muscle action (SMA), vimentin (variable), glial fibrillary acidic protein (variable) and
carcinoembryonic antigen (variable).
Treatment and Prognosis
Complete surgical excision is the treatment of choice and should include an adequate margin of
uninvolved tissue. MT of minor salivary glands require complete but conservative excision. Incomplete
excision results in recurrent tumor. As compared to major glands, minor salivary gland MTs are less
likely to recur. The overall prognosis for MT is excellent with 5- and 10-year recurrence free rates are
97 and 94%, respectively. Complications include malignant transformation (carcinoma ex pleomorphic
adenoma) and the rare occurrence of so-called "benign" metastasizing mixed tumor.
Polymorphous Low-Grade Adenocarcinoma of Minor Salivary Gland Origin (Table 1)
Polymorphous low-grade adenocarcinoma (PLGA) of minor salivary gland origin is a malignant epithelial
neoplasm arising from the minor salivary glands, characterized by a varied architecture (polymorphous),
bland cytomorphology, infiltrative growth and indolent biologic behavior. Synonyms include lobular
carcinoma and terminal duct carcinoma. Lobular carcinoma was used because PLGA demonstrated areas of an
infiltrative "Indian-file" growth pattern identical to that of the lobular carcinoma of the breast.
Terminal duct carcinoma was used to emphasize the proposed histogenesis of the tumor, thought to be the
progenitor cell of the distal or terminal duct portions of the salivary gland unit, that is, the
intercalated duct reserve cell.
PLGA is considered an uncommon type of salivary gland malignant tumor but is becoming more widely
recognized. PLGA affects women more than men; occurs over a wide age range but is most frequently seen
in the 7th decade of life. PLGA is predominantly a tumor of minor salivary glands and is almost
exclusively identified in the oral cavity where the palate represents the most frequent site of
occurrence. In descending order of frequency the other intraoral sites include: buccal mucosa > lip
> retromolar pad > cheek > tongue > maxillary area > mandibular mucosal area >
posterior trigone region. Involvement of non-oral minor salivary gland sites is rare and includes the
nasal cavity and nasopharynx. Until recently, PLGA had not been identified in major salivary glands
except as the malignant epithelial component in a carcinoma ex pleomorphic adenoma. However, over the
last few years there are reports identifying PLGA in major salivary glands. The most common symptom is a
painless mass or swelling occasionally associated with bleeding, increase in size or discomfort. Other
less frequently identified symptoms include otalgia, odynophagia, tinnitus and airway obstruction. The
duration of symptoms is quite variable ranging from as short as 2 weeks to a 20 to 30 year history of a
mass lesion. There may be a predilection for PLGA to occur in blacks. There are no known predisposing
factors associated with this neoplasm.
The tumors are polypoid or raised, round to oval, mucosal-covered masses ranging in size from 1.0 to
6.0 cm in greatest dimension. In general, the mucosa remains intact; however, scattered surface
ulceration may occur.
The histologic appearance is that of a well-circumscribed but unencapsulated tumor
characterized by morphologic diversity, cytologic uniformity and infiltrative growth. The polymorphic
nature of these lesions refers to the variety of growth patterns that include solid, trabecular,
glandular, ductular, and tubular; cribriform and cystic patterns can be seen but generally do not
predominate. These patterns may be identified within the same lesion and from lesion to lesion. The
presence of small tubular structures with a distinct central lumen lined by a single layer of cuboidal
cells is a characteristic feature. A pattern of cell growth in which the cells are arranged in a single
row termed "Indian-file" can be seen and is often located at the periphery of the tumor. A focal
papillary pattern can be identified. There has been some controversy in the literature relative to the
presence and importance of a prominent papillary component. Some authorities feel that PLGA does not
demonstrate a predominant papillary growth and would consider tumors with prominent papillary growth as
papillary cystadenocarcinomas. This is also based on the differences in biologic behavior with papillary
cystadenocarcinomas associated with local recurrence, regional cervical lymph node metastases, distant
(visceral) metastases, and mortality, all findings that are unusual for PLGA. However, other authorities
believe in a papillary and non-papillary variants of PLGA with the papillary variant associated with a
more aggressive biologic behavior than the non-papillary counterpart. Recently, Evans and Luna reported
40 cases of PLGA and evaluated for the importance of tumors with prominent papillary areas. These
authors found that those PLGA with "papillary areas of more than focal extent" (17 cases) showed a
statistically significant relationship with regional lymph node metastasis and between positive or
unknown surgical margins and local recurrence. However, there was no statistical significance with
patient survival. As such, focal or more extensive papillary growth occurs in PLGA but those tumors with
a predominate or exclusive papillary pattern and do not show other characteristics of PLGA, are best
classified as papillary cystadenocarcinomas or another carcinoma depending on the overall features.
PLGA is composed of cuboidal to columnar isomorphic cells with indistinct cell borders which have
uniform ovoid to spindle-shaped nuclei and small and inconspicuous nucleoli. The nuclear chromatin
pattern varies from vesicular to stippled but basophilic nuclei can also be identified. Scant to
moderate amounts of eosinophilic to amphophilic cytoplasm can be seen, and occasionally clear cytoplasmic
changes predominate. The tumor stroma varies from mucoid to hyaline to mucohyaline, and in some cases
tumor nests are separated by a fibrovascular stroma. Neurotropism (peri- and intraneural) is found in
the majority of tumors; perivascular invasion can also be seen with tumor nests often arranged in
concentric fashion around these structures. In addition, the tumor may infiltrate the surface
epithelium, residual minor salivary glands and/or connective tissue components (bone, cartilage, muscle,
and adipose tissue). Mitotic figures are rare and necrosis is not seen. Other histologic changes that
may be identified include: intratubular calcifications (psammoma-like bodies), pseudoepitheliomatous
hyperplasia of the surface epithelium and squamous metaplasia within the tumor. Squamous metaplasia can
be identified following fine-needle aspiration biopsy.
Intraluminal mucin can be identified by diastase-resistant, PAS-positive material; however, only focal
intracytoplasmic mucin is seen. The immunohistochemical reactive pattern for PLGA includes
immunoreactivity with antibodies to cytokeratin, vimentin, muscle specific action, epithelial membrane
antigen (EMA), carcinoembryonic antigen (CEA) and glial fibrillary acidic protein (GFAP). Electron
microscopic findings include the presence of glandular differentiation, junctional complexes (desmosomes,
tight junctions), lumina, and microvilli.
Vargas et al reported that the staining patterns with Ki-67 (MIB1), S-100 protein and BCL2 may be
useful in differentiating PLGA from mixed tumor and adenoid cystic carcinoma. These authors found that:
1) PLGA: low Ki-67, p53 and BCL2 immunostaining but strong S-100 protein reactivity; 2) mixed tumors:
low Ki-67, p53 and BCL2 immunostaining but strong S-100 protein reactivity; 3) adenoid cystic carcinomas:
high Ki-67 and more intense BCL2 reactivity, the percentage of p53 staining increased with increasing
histograde and less intense and less frequent S-100 protein staining as compared with PLGA and mixed
Some authors advocate that PLGA represents the low-grade or less aggressive variant of adenoid cystic
carcinoma based on the morphologic similarities as well as common derivation from the intercalated duct
region. However, cytologic, immunohistochemical, and biologic differences do not support this
contention. Recently, high-grade transformation of PLGA characterized by a predominantly solid growth
pattern, nuclear atypia with prominent nucleoli and foci of necrosis has been reported with the
recommendation PLGA with these histologic features not be included under the designation of "typical
Treatment and Prognosis
Conservative but complete surgical excision is the treatment of choice. Depending on whether there is
involvement of bone (e.g., maxilla or mandible), as may occur in palatal or retromolar tumors, en bloc
resection of the involved bone may or may not be necessary. Neck dissections are unwarranted unless
there is clinical evidence of cervical lymph node metastasis. Post-operative radiotherapy and
chemotherapy have been used, but there is no evidence to substantiate any benefit of these modalities in
conjunction with surgery. PLGA is a slow-growing, indolent malignant neoplasm that has a good prognosis
following complete surgical excision. PLGA may recurrence from months to years after the diagnosis. The
rate of tumor recurrence is quite variable and probably correlates with the ability to completely excise
the tumor. Metastasis to regional cervical lymph nodes may occur (< 10% of patients) but distant
metastasis has not been reported. Death attributable to PLGA is extremely rare but has been reported.
Adenoid Cystic Carcinoma (ACC) (Table 1)
ACC is a malignant epithelial salivary gland neoplasm characterized by its histologic appearance,
tendency to invade nerves and its protracted but nonetheless relentless clinical course. With the
recognition of new types of salivary gland tumors, including such tumors as polymorphous low-grade
adenocarcinoma, a histologic simulator of adenoid cystic carcinoma, the incidence of ACC has been
ACC is felt to represent approximately 7.5 percent of all salivary gland epithelial malignancies and 4
percent of all salivary gland neoplasms. In major salivary glands, ACC primarily involve the parotid and
submandibular glands. Fifty-five percent of ACC occur in these sites. ACC is the most frequently
encountered malignant neoplasm of the submandibular gland. Minor salivary gland involvement may occur
throughout the upper respiratory tract where it most frequently involves the palate; other intraoral
sites of involvement include the tongue, lower lip, retromolar-tonsillar pillar region and the sublingual
gland. ACC may also occur in ceruminal glands of the external auditory canal as well as representing 50
percent of all lacrimal gland neoplasms.
ACCs are usually firm and tan white. Small tumors may be circumscribed but encapsulation is rare.
Circumscribed tumors may be deceptive because infiltration beyond the tumor margin is often present tumor
but difficult to appreciate by gross examination.
The histologic appearance of ACC is that of an unencapsulated, infiltrating neoplasm with varied
growth patterns consisting of cribriform, tubular/ductular, and solid. Individual neoplasms may have a
single growth but characteristically are composed of multiple patterns any one of which may predominate.
The most common pattern is the cribriform type, considered the "classic" pattern demonstrating
arrangement of cells in a "Swiss cheese" configuration with many oval or circular spaces. These spaces
contain basophilic mucinous substance or hyalinized eosinophilic material. The tubular type has cells
arranged in ducts or tubules. The ducts or tubules contain faintly eosinophilic mucinous material.
Cribriform and tubular patterns often occur together. The least common pattern is the solid type,
composed of neoplastic cells arranged in sheets or nests of varying size and shape. There is little
tendency to form cystic spaces, tubules or ducts.
Irrespective of the growth pattern, the neoplastic components are the same consisting of fairly
uniform sized cells with small, hyperchromatic round to oval to angulated nuclei, scant amphophilic to
clear cytoplasm and indistinct cell borders. The nuclear to cytoplasmic ratio is about 1 to 1. The
majority of the neoplastic cells are abluminal type cells of myoepithelial differentiation. The cystic
spaces seen in the cribriform or classic type are pseudocysts which are extracellular and lined by
replicated basement membrane. Scattered among these abluminal cells are ductal cells which surround
small true lumens (glands). True duct like lumens are an infrequent feature of ACC but are most
frequently seen in the ACC with a tubular growth. In the solid pattern, the cell population is dominated
by the basaloid myoepithelial cells. The interstitial stroma, from which the epithelial component is
sharply demarcated, varies in appearance from myxoid to hyalinized. Cellular and nuclear pleomorphism,
necrosis and mitotic activity are limited in the cribriform and tubular patterns. However, these
features are more frequently seen in the solid pattern. Common to all histologic variants is the
proclivity for nerve invasion (neurotropism), including peri- and intraneural invasion, as well as
invasion of adjacent issue structures can also be seen. Squamous differentiation is a decidedly uncommon
feature in ACC.
The histochemical features of ACC include the presence of diastase-resistant, PAS-positive and
mucicarmine positive material within the pseudocysts. Alcian blue staining is also present within the
pseudocysts. Immunohistochemistry of ACC vary depending the cellular component with the myoepithelial
cells showing cytokeratin, vimentin, S-100 protein, actin (muscle specific) positivity with variable and
glial fibrillary acidic protein reactivity. The ductal cells showing cytokeratin, epithelial membrane
antigen (EMA) and carcinoembryonic antigen (CEA) positivity. Ultrastructural studies show the presence
of cells with bidirectional differentiation, including the luminal or ductal cells, and the abluminal or
Treatment and Prognosis
The treatment of choice for ACC is wide local surgical excision and postoperative radiotherapy.
Problems confronting the surgical removal of ACC relate to the infiltrative nature of these neoplasms
with tendency to extend along nerve segments further compounded by their deceptively circumscribed
macroscopic appearance. Recurrence rates are high and directly relate to inadequate surgical excision.
Adenoid cystic carcinomas are radiosensitive and radiotherapy is particularly useful in controlling
microscopic disease after initial surgery, in treating locally recurrent disease or as palliation
management in unresectable tumors. Radiotherapy is not curative. The short term prognosis is generally
good corresponding to the slow-growth leading to prolonged survivals, the long term prognosis is poor.
These facts are reflected in the 5-year and 20-year survival rates of adenoid cystic carcinomas of all
head and neck sites of 75 percent and 13 percent, respectively. The solid type of ACC, is felt by most
authorities to have the most aggressive clinical course with early metastasis and poor 5-year survival
rates. Both Szanto et al and Greiner et al found worse cumulative survival rates in patients who had ACC
with greater than 30 percent solid growth. Spiro and Huvos reported that clinical staging plays a more
decisive role than histologic grading in predicting prognosis in ACC. These authors report a cumulative
10-year survival of 75 percent, 43 percent and 15 percent for patients with Stage I, II, and III and IV,
Necrotizing Sialometaplasia (NS)
NS represents a benign, self-healing (reactive) inflammatory process of salivary gland tissue which
clinically and histologically may be mistaken for a malignant neoplasm. NS most commonly involves the
intraoral minor salivary glands particularly involving the palate. However, major salivary glands as
well as the minor salivary glands of virtually every site in the upper aerodigestive tract can be
affected. The larynx may be affected but is a rare site of occurrence.
NS tends to affect men more than women and it occurs over a wide age range with the average age of
occurrence in the 5th and 6th decades of life. The most common presenting problem is that of a painless
ulcerated lesion or a nodular swelling which is usually unilateral but may be bilateral. The lesions are
usually asymptomatic but may be associated with pain, numbness or a burning sensation, and
The pathogenesis for NS is felt to iatrogenically-induced following an operative procedures, trauma or
radiotherapy. The inciting event is primarily but not exclusively thought to be due to
ischemia. There is a mean duration of 18 days from the time of the insult to the development of the
lesion. NS may occur de novo unassociated with a traumatic event or it may occur in association with a
neoplasm (benign or malignant).
NS typical appears as a deep, crater-like ulcerative lesion measuring from 1-3 cm. However, the
lesion may appear as a submucosal nodular swelling that may slough leaving a crater-like ulcer. The
histologic appearance is that of lobular necrosis of the salivary glands with preservation of the lobular
architecture of the minor salivary glands. The histologic hallmark is squamous metaplasia of residual
acinar and ductal elements. The necrotic lobules consist of acinus-sized pools of mucin which may extend
into adjacent tissue eliciting a granulation tissue reaction with associated acute and chronic
inflammation. The lobular architecture is maintained and the metaplastic lobules vary slightly to
moderately in size and shape, and have smooth edges surrounded by granulation tissue and an intense mixed
acute and chronic inflammatory reaction. The squamous cells are bland in appearance with uniform nuclei
and abundant eosinophilic cytoplasm with occasional preservation of ductal lumina or scattered mucocytes.
Muci-carminophilic material is seen within lumina and within the cytoplasm of residual mucocytes. With
regeneration, mitoses, individual cell necrosis, enlarged nuclei and prominent nucleoli can be seen.
Associated findings include ulcerated mucosa and pseudo-epitheliomatous hyperplasia (PEH). PEH results
when the metaplastic lobules present in excretory ducts and merge with surface epithelium. This reaction
may be so striking presenting a diagnostic nightmare in separation from an infiltrating squamous cell
The differential diagnosis includes mucoepidermoid carcinoma and invasive squamous cell carcinoma.
However, retention of the overall lobular architecture, bland appearance of the squamous nests with
rounded or smooth edges, and retention of residual ductal lumina and mucocytes help in differentiating NS
from these malignant neoplasms.
Treatment and Prognosis
NS are self-limiting lesions which heal by secondary intention. Depending on the size of the lesion,
the healing process in most cases occurs from 3-12 weeks. Debridement and saline rinses may aid in the
healing process. Recurrences do not usually occur.
Accuracy of Intraoperative Diagnosis
Among a variety of studies evaluating the accuracy of frozen section diagnosis in large numbers of
salivary gland neoplasms, it has been consistently shown that the frozen-section diagnosis of salivary
gland tumors is reliable and clinically valuable with accuracy rates over ranging from 90-98%. False
positive, false negative and deferral rates are reported to be as high as 2%, 12% and 10%, respectively.
Sampling errors represent a primary reason for false-negative errors. Clinically significant error rates
are probably lower than reported as a proportion of these tumor "errors" are classification changes
within the same category.
Table 1: Intraoral Minor Salivary Glands: Selective Differential Diagnosis
MT – Mixed Tumor; CMT – Cellular Mixed Tumor MPMT – Myoepithelial Predominant Mixed Tumor; PLGA –
Polymorphous Low-Grade Adenocarcinoma; ACC – Adenoid Cystic Carcinoma
|Tumor ||Encapsulation ||Growth Patterns ||Cytomorphology ||Stroma ||Invasion|
|MT ||Absent ||Tubules, ribbons, sheets, cords, cysts, trabeculae ||Dual cell population: ducts/glands and myoepithelial cells; no necrosis or increased mitotic activity; intercellular hyaline material may be present ||Chondromyxoid; crystalloids may be present ||Non-invasive|
|CMT ||Absent ||Tubules, ribbons, sheets, cords, cysts, trabeculae ||Dual cell population: ducts/glands and myoepithelial cells although the latter is limited; no necrosis or increased mitotic activity; intercellular hyaline material may be present ||Scanty but identifiable myxochondroid stroma; crystalloids may be present ||Non-invasive|
|MPMT ||Absent ||Solid, trabecular, fascicular, anastomosing cords ||Spindle-shaped and plasmacytoid predominate but glands focally seen; minimal pleomorphism; no necrosis or increased mitotic activity; intercellular hyaline material may be present ||Scanty to absent stromal component; crystalloids may be present ||Non-invasive|
|PLGA ||Absent ||Tubular/ductules, cribriform, solid, linear single cell, "streaming", papillary ||Isomorphic cells with minimal pleomorphism; no necrosis or increased mitotic activity; intercellular hyaline material may be present ||Chondromyxoid; crystalloids may be present ||Invasive|
|ACC ||Absent ||Tubular/ductules, islands, cysts, nests, cords, cribriform, solid ||Basaloid cells with uniform, angulated, hyperchromatic nuclei, scanty cytoplasm; no necrosis or increased mitotic activity; intercellular hyaline material present ||Myxoid-hyaline stroma ||Invasive|
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