Salivary Gland Cancer From Diagnosis to Tailored Treatment

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Lisa Licitra • Laura D. Locati
Editors

Salivary Gland Cancer

From Diagnosis to Tailored Treatment
Editors
Lisa Licitra Laura D. Locati
Head and Neck Medical Oncology Unit, Head and Neck Medical Oncology Unit,
Fondazione IRCCS Istituto Nazionale dei Fondazione IRCCS Istituto Nazionale dei
Tumori Milan Tumori Milan
Milan Milan
Italy Italy

ISBN 978-3-030-02957-9    ISBN 978-3-030-02958-6 (eBook)

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Contents

1 Management-Based Pathology Assessment of Salivary

Gland Carcinomas ������������������������������������������������������������������������������������   1
Adel K. El-Naggar
2 Molecular Characterization of Salivary Gland Carcinomas ���������������� 17
André Fehr, Jörn Bullerdiek, Thorsten Jaekel, and Thomas Löning
3 The Role of Imaging in Staging and Follow-Up of Salivary
Gland Tumors�������������������������������������������������������������������������������������������� 33
Silvana Sdao, Enrico Civelli, Alessandra Alessi, and Giuseppina
Calareso
4 Surgery for Malignant Parotid Gland Tumours ������������������������������������ 45
Vincent Vander Poorten
5 Surgery for Parapharyngeal Tumors ������������������������������������������������������ 69
Orlando Guntinas-Lichius
6 Surgery for Submandibular and Sublingual Malignant Tumors���������� 85
Natalie L. Silver and Randal S. Weber
7 Surgery for Malignant Tumors of the Minor Salivary Glands���������������� 97
Davide Lombardi, Remo Accorona, Davide Lancini, Vittorio
Rampinelli, Anna Bozzola, and Piero Nicolai
8 Surgical Management of Recurrent Disease ������������������������������������������ 123
M. Guzzo
9 Principles of Reconstruction: Reconstruction of the Parotid Area ������ 127
Silvano Ferrari, Andrea Ferri, Bernardo Bianchi, and Enrico Sesenna
10 Principles of Reconstruction: Palatomaxillary Reconstruction������������ 141
Cesare Piazza, Alberto Paderno, and Piero Nicolai
11 Salivary Gland Tumors: Radiotherapy���������������������������������������������������� 159
Ester Orlandi, Giuseppe Sanguineti, and Carlo Fallai

v
vi Contents

12 Protons and Heavy Ions���������������������������������������������������������������������������� 195

A. D. Jensen and P. Fossati
13 Systemic Therapy in Salivary Gland Carcinoma������������������������������������ 213
Laura D. Locati, S. Alfieri, and Lisa Licitra
Management-Based Pathology
Assessment of Salivary Gland 1
Carcinomas

Adel K. El-Naggar

1.1 Introduction

Salivary gland neoplasms are the most morphologically and clinically diverse solid
epithelial tumors. There are 25 distinct salivary gland tumor types in the current
WHO classification [1]. Given the clinical and management focus of this text,
descriptions of pathologic features will be limited to gross and histopathologic man-
ifestations relevant to surgical and oncologic management. Similarly, brief lineage-­
related biomarkers and genetic findings are present. Although the main focus is on
malignant entities, benign tumors with differential diagnostic importance and those
with potential progression to malignancy are discussed.

1.2 Salivary Gland Development and Tumorigenesis

Salivary glands evolve from the stomatodial surface of embryo at 6–8 weeks through
branching morphogenesis where progressive indentation and elongation of an epi-
thelial cord through the underlying ectomesenchyme leads to the formation of the
ductal acinar unit [2–4]. The inner cellular lining of the ductal segments is epithelial
in lineage except for the terminal duct component in which both epithelial and
basal/myoepithelial cells are present. This fundamental formation in large part
linked to the putative segmental ductal derivation and diversity of salivary gland
neoplasms [5]. In that context, the presence of myoepithelial cells plays a critical
role in the structural polarity and stromal organization in tumors composed of both
cell types. The mechanism for the dual epithelial-myoepithelial neoplastic partici-
pation in some tumors is uncertain. It is, however, possible that an event in

A. K. El-Naggar (*)
Department of Pathology, University of Texas MD Anderson Cancer Center,
Houston, TX, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 1

L. Licitra, L. D. Locati (eds.), Salivary Gland Cancer,
https://doi.org/10.1007/978-3-030-02958-6_1
2 A. K. El-Naggar

Hypothetical Evolution of Salivary Malignancy

ACC / EMC Myoepithelial

tumors
Myoepithelial
cell
Early
progenitor BCA/BCadc /
Bipotent
MEC / SDC / Acinic
progenitor Epithelial
cell

UDC
SB
UDC: Undifferentiated Carcinoma; SB: Sialoblastoma; ACC: Adenoid Cystic Carcinoma;
EMC: Epithelial Myoepithelial Carcinoma; PD: Poorly Differentiated; MEC: Mucoepidermoid
Carcinoma; SDC: Salivary Duct Carcinoma; BAC/BCadC: Salivary Basal Cell Adenoma
Carcinoma; MC: Myoepithelial Carcinoma

Fig. 1.1 Empirical diagram of the developmental pathway of the morphologic and cellular origins
of salivary tumors

Table 1.1 Broad clinicopathologic categories of salivary gland carcinomas

Low/Indolent Intermediate Aggressive
• ACC, Tubular and • Predominantly • Salivary Duct Carcinoma
Cribriform Cribriform
• Low grade MEC • Intermediate MEC • Solid—ACC
• EMC • Adenocarcinoma, NOS • High-grade MEC
• Basal Cell • Secretory Ca • High grade transformation of
Adenocarcinoma different low and intermediate grade
carcinomas
• Secretory Carcinoma • Myoepithelial Ca
• Acinic cell carcinoma • Oncocytic Carcinoma • Carcinosarcoma
• Myoepithelial Ca • High-grade adenocarcinoma

uncommitted progenitor early in tumorigenesis gives rise to both epithelial and

basal/myoepithelial cells (Fig. 1.1). In general, purely epithelial and majority of
high-grade carcinoma arise from the main (nonterminal) ductal segments and those
of low grade from the terminal duct-acinar unit.

1.3 Classification

Salivary gland tumors are broadly categorized into benign and malignant subtypes
based on their histopathologic characteristics and the invasive nature of tumor at
presentation. Grossly, benign tumors are well-circumscribed, thinly encapsulated,
and soft to slightly firm in consistency. Histologically, generally these neoplasms
display uniform epithelial and/or myoepithelial cell composition in variable mani-
festations. Malignant tumors, in contrast, present as firm, less mobile, ill-defined,
and invariably infiltrative in nature. Histologically, tumors display heterogeneous
neoplastic cellular and structural features (Table 1.1).
1 Management-Based Pathology Assessment of Salivary Gland Carcinomas 3

Table 1.2 Cytology in Indications Limitations

salivary gland mass • Confirm primary • Differentiation between
evaluation benign and malignant
• Exclusion of • Basaloid, myoepithelial
  − Metastasis • Grade MEC
  − Lymphoreticular disorders • Dx of limited Ca EX PA
  − Reactive
  − Inflammatory

1.4 Pre-surgical Diagnosis of Salivary Gland Tumors

1.4.1 Fine Needle Aspirations (Table 1.2)

Initial assessment of salivary tumors commonly entails a fine needle aspiration

cytology evaluation. The primary purpose of this procedure is to exclude metastasis,
lymphoreticular disorders, infectious processes, and reactive lesions and to ascer-
tain the primary salivary nature of mass. In general, the majority of primary and
malignant tumors can be determined through this procedure. FNA, however, is lim-
ited in delineating benign and malignant nature of basaloid and oncocytic and myo-
epithelial and of carcinoma ex-PA. The procedure is also valuable as a follow-up
tool for harvesting cells for ancillary testing [6–11].

1.4.2 Core Biopsy

Occasionally, core biopsy is performed for salivary tumor diagnosis; however, this
procedure should be limited to non-resectable, recurrent, and metastatic tumors.

1.4.3 Intraoperative Consultations

Although it is unnecessary, intraoperative frozen section can be requested where the

nature of malignancy may alter the surgical plan and if surgical margins are of con-
cern. In these instances, the surgeon and pathologist should be closely interacting
during this process especially for minor salivary tumor resections. In these cases it
is advisable that surgeons submit separate cavity-based margins.

1.5 Post Surgical Gross Assessment

Salivary tumor resections of major and minor glands should be inspected for gross
infiltration of surrounding host tissue and processed to include tumor/host tissue
interface and different regions of the tumor mass to assess invasion into peri-­
glandular soft tissue. Gross description of salivary resection should include size,
appearance, and consistency, and the relation to surrounding host tissue is required.
4 A. K. El-Naggar

1.5.1 Histopathologic Evaluation

Diagnosis for salivary gland tumors is based on the light-optic evaluation of well-­
prepared hematoxylin- and eosin-stained sections representing lesion and its bound-
aries. Certain immunomarkers may be used in certain instances for differential
diagnosis and assessment of progression.

1.5.2 Pathologic Report

Pathology reports of salivary tumors must primarily include the following informa-
tion: type of surgery, site, size, histologic diagnosis, presence or absence of perineu-
ral spaces, and margin status. Additional relevant findings may include grade if
appropriate, and tumor diathesis, extraglandular extension margin status.

1.6  ommon Benign Salivary Gland Tumors of Differential

C
Diagnostic Significance

Benign salivary gland tumors are the most common in the parotid gland, and the
vast majority pose no diagnostic difficulties. Certain subtypes may pose diagnostic
challenges especially on the initial FNA evaluation. Generally, adenomas present as
well-defined and encapsulated mass.

1.6.1 Pleomorphic Adenoma (PA)

PA is the most common benign salivary neoplasm and manifests a wide range of
cellular and stromal component manifestations within and between tumors. Not
uncommonly rare features such as squamous, sebaceous, and adipose tissue meta-
plasias are present, and this may lead to differential diagnostic challenges. PA gen-
erally presents as an ill-defined presentation and may manifest microscopic satellite
formations that evade detection at the time of surgery leading to frequent recur-
rences. Histologically, tumors can be predominantly myoepithelial, epithelial, or
paucicellular and can mostly be composed of chondroid, fibrotic, or myxoid ele-
ments. Occasionally, the delineation between myoepithelial dominant PA and myo-
epithelioma is difficult, but such distinction is of minimal clinical impact.
Pleomorphic adenomas are also prone to recurrence and rarely distant dissemina-
tion. Metastasizing PA, in general, is histologically benign and typically presents in
patients with multiple recurrence as a result of dislodgment of tumor in vascular
spaces. These cases should be managed based on their presentation. Because of the
not uncommon occurrence of carcinoma in long-standing PA, extensive sampling
and careful examination of these tissues are critical especially in elderly patients
with long-standing history of salivary swelling [12–15].
1 Management-Based Pathology Assessment of Salivary Gland Carcinomas 5

1.6.2 Myoepithelioma

Myoepithelial tumors are either entirely or largely composed of myoepithelial cells

in spindle, plasmacytoid, and epithelioid features. The benign and malignant forms
cannot be distinguished by FNA due to similar histologic features. Only on com-
plete surgical excision the distinction of benign and malignant forms can be made.
Immunohistochemistry may aid in confirming the diagnosis using SMA, p63, and
calponin [16–18]. Their management is similar to pleomorphic adenoma.

1.6.3 Basal Cell Salivary Adenoma

Basal cell salivary tumors are composed of monotonous basal-like cells and classi-
fied into adenoma and adenocarcinoma based on the state of tumor invasion.
Therefore, the initial assessment of these tumors by FNA is difficult if not impos-
sible. Although the majority is cured by surgery, some adenomas may recur locally.
Metastatic dermal basal cell carcinoma may lead to differential diagnostic difficulty
especially in patients with remote history of skin primary. In these instances, immu-
nostaining for keratin, p63, and SMA may confirm the dual cell formation of sali-
vary basal neoplasms. Rarely, recurrence may develop due to multifocality. Not
uncommonly, basaloid adenocarcinoma may evolve from adenoma [19–21].

1.6.4 Oncocytic Salivary Lesion

Oncocytic lesion/tumors are unique entities composed of mitochondrial-rich cells

and are classified into hyperplastic and neoplastic lesions. The hyperplastic form is
typically diagnosed as nodular oncocytic hyperplasia and may present unilaterally
or bilaterally. These lesions regardless of their histologic classification are com-
posed of monotonous epithelial cells with abundant eosinophilic cytoplasm and
central nuclei. Histologic examination reveals the multinodular formation in vari-
able sizes. The neoplastic types are classified into adenoma and carcinoma based on
the status of the invasiveness [22–24].

1.6.5 Warthin’s Tumor (WT)

Warthin’s tumor can be presented bilaterally as single mass and rarely multifocally
within intraparotid lymph nodes. The differential diagnosis of Warthin’s tumors
should be considered in oncocytic tumors and mucoepidermoid carcinoma, espe-
cially on FNA materials. Thorough examination of Warthin’s tumors must be per-
formed to exclude the latter possibility. Grossly, Warthin’s tumor presents as a brown
bulging and pliable soft mass. Histologically, lesions are formed of eosinophilic epi-
thelial cell lining lymphoid nodules in distinct structural formation [25–27].
6 A. K. El-Naggar

1.7 Malignant Salivary Tumors

1.7.1 Mucoepidermoid Carcinoma (MEC)

MEC is the most common salivary carcinoma of minor and major salivary glands in
adults and children. MEC is also the only salivary cancer where histologic grading
is associated with clinical behavior. Accurate diagnosis is difficult on FNA material
and can be confused with cystic lesions and Warthin’s tumor. Grossly, MEC pres-
ents as ill-defined cystic, partially cystic, or solid light tan and mucinous.
Histologically, tumors are composed of mucinous, epidermoid (epithelial squamous-­
like), and transitioned (intermediate) cells in variable structural forms. Tumors are
graded into low grade (grade 1), intermediate (grade 2), or poorly differentiated
(grade 3) based on the extent of cystic and cellular manifestations. MEC may dis-
play oncocytic, clear, and transitional cell features of invariable proportion and pat-
terns and display sclerotic. Mucoepidermoid carcinoma can rarely be associated
with protracted radioactive iodine treatment in patients with papillary thyroid carci-
noma. Low-grade cystic MEC is cured by complete surgery in major salivary gland.
The most common grade is grade 2 where subjectivity plays a major role. Regardless
of the reported grading systems, broadly speaking low-grade MECs are mainly cys-
tic with limited foci of cellular proliferation, while intermediate grade displays
more cellular formations with less cystic structure and the high-grade manifests
markedly cellular with no cystic formation and focal intracellular mucin production
[28–32].
Minor salivary gland MECs may pose surgical challenges if incompletely
excised. Ancillary staining is rarely used in the diagnosis. Occasionally mucicar-
mine stain can be helpful in the diagnosis of poorly differentiated tumors. MEC is
characterized by reciprocal translocations of chromosome 11p and 19q that lead to
the formations of the CTRC1-MAML-2 fusion transcript [33–35]. Currently, there
is no diagnostic, prognostic, and/or therapeutic validated evidence for this event.
Mucoepidermoid carcinoma rarely shows keratin formation. Carcinoma with dis-
tinct keratin component and mucinous differentiation should be categorized as ade-
nosquamous carcinoma. If metastasis is excluded, definitive distinction between
these tumors should not influence the surgical management.
Complete surgical excision with free margins is the primary treatment for all
grades of MEC. Post-operative XRT may be considered in case with close surgical
margins and /or perineural invasion [32].

1.7.2 Adenoid Cystic Carcinoma (ACC)

ACC is the second most common and relentless salivary carcinoma subtype. ACC is
assumed to develop from the terminal segment of the ductal-acinar unit and is
formed of dual cell composition of outer myoepithelial and inner ductal cells [36].
The initial FNA diagnosis may not reliably be achieved, and definitive diagnosis can
only be made on either excision biopsy, especially of minor salivary glands, or
1 Management-Based Pathology Assessment of Salivary Gland Carcinomas 7

post-­excision [37]. ACC is not graded due to the invariable presence of at least two
histologic forms in any given tumor [38]. The tubular and the cribriform are com-
posed of dual epithelial and myoepithelial cell. These forms retain the structural
polarity, and pursue slow and progressive clinical course. Loss of myoepithelial
component leads to epithelial solid form [39].
Solid epithelial development is typically associated with loss of myoepithelial
cells and clinical progression. Solid myoepithelial transformation is typically of
low-grade nature. ACC is characterized by translation between chromosomes (6;q)
and (8;q) resulting in fusion genes of MY13 and MYBL1 genes with the NFIB
genes in more than 60% of tumors. No definitive association between fusion and
outcome has been established [40–45]. ACC of minor salivary glands, particularly
the sin0-nasal sites, is difficult to eradicate unless clear margins are achieved
intraoperatively.

1.7.3  alivary Duct Carcinoma (De Novo and Ex-pleomorphic

S
Adenoma)

Salivary duct carcinoma is one of the most aggressive malignancies of salivary

glands and presents as de novo primary or as a malignant transformation of pleo-
morphic adenoma [46–49]. It is important that the carcinoma subtype be clearly
stipulated in the diagnosis of this entity ex-PA. Generally, tumors histopathologi-
cally resemble high-grade mammary adenocarcinoma and share overlapping molec-
ular and biomarker characteristics, an issue of differential diagnostic relevance in
female patient. Multiple cytomorphologic features have been described including
oncocytic, apocrine, rhabdoid, and squamoid. These morphologic forms have no
clinical significance. SDC typically presents at high stage and wide surgical exci-
sion with neck lymph node dissection with radiotherapy and/or chemotherapy is the
primary management [50–52].
Certain biomarkers may aid non-surgical therapy of these tumors including
EGFR, AR and PTEN, and HER-2 [53, 54]. High AR nuclear expression is found in
approximately 70% of males and 50% of female tumors. Recently, presence of AR
isoform A7 has also been reported in AR-positive tumors of male and females [55–
57]. Androgen deprivation treatment has been empirically used with variable and
inconsistent results. PTEN expression is frequently lost in SDC and directly or indi-
rectly is associated to PI3K pathway activation [58, 59].

1.7.4 Polymorphous Adenocarcinoma (PAC)

In the current WHO classification of head and neck tumors, the “low-grade” desig-
nation has been omitted due to the aggressive behaviors of some of these tumors. As
the descriptive term implies, the tumor manifests variable neoplastic manifestation
including lobular, trabecular, papillary, microcystic, and/or solid features. PAC is
the second most common malignancy in the oral cavity, palate, and base of the
8 A. K. El-Naggar

tongue [60–63]. PAC has also been reported to occur in major salivary glands, the
lacrimal gland, minor glands of the nasopharynx, and the nasal cavity. Grossly
tumor presents as unencapsulated, light tan and soft with variable appearance and
occasional hemorrhagic regions. A salient morphologic feature is the presence of
distinctive cellular structures (eddy-like formation) along with the tubular, trabecu-
lar, and/or lobular structure. A reported subset with dominant cribriform and micro-
cytic patterns has been reported as a separate entity but currently represents a variant
of PAC [64]. Although a majority of these tumors pursue a good behavior with
complete excision, not uncommonly recurrent and metastatic disease is encountered
especially those of minor glands and base of tongue locations. This entity can be
misclassified as adenoid cystic and epimyoepithelial carcinomas due to occasional
overlapping features and definitive distinction may not be possible on small materi-
als. Definitive diagnosis may not be achieved on biopsy materials and should not
affect the surgical management. Rarely PAC may undergo high-grade undifferenti-
ated transformation, and these cases typically pursue a more aggressive behavior
[39, 65].

1.7.5 Acinic Cell Carcinoma

Acinic cell carcinoma is a distinctive entity composed of neoplastic cells of aci-

nar cell features and coarse granules and afflicts a wide age range with no signifi-
cant sex predilection. Acinic cell carcinoma is the second most common cancer
in children and occurs mainly in the parotid and occasionally in mixed serious
and mucinous glands. The tumor may rarely be encountered in mixed major and
minor salivary glands [66–68]. Acinic cell carcinoma, as in Warthin’s tumor and
oncocytic and mucoepidermoid carcinoma, may develop in intraparotid lymph
nodes and can be multifocal. Grossly acinic cell carcinoma is typically well-­
circumscribed with a brownish, mahogany color, soft, and can be cystic.
Histopathologically, they are readily recognized by well-trained pathologists and
may display variable phenotype patterns microcystic followed by macrocystic
with papillary formation. In general, acinic cell carcinoma has a low to interme-
diate grade but occasionally displays solid transformation and poor differentia-
tion. Patients with high grade transformation should be managed as other high
salivary carcinomas [67, 69, 70].

1.7.6 Secretory Carcinoma

Secretory carcinoma is a newly recognized subtype with similar morphology to

their mammary gland counterpart. This new entity has been extracted from acinic
cell carcinoma following the recognition of a morphologically similar subset of
secretory carcinoma in a review of acinic cell carcinomas of the mammary gland
[71, 72]. As in mammary and acinic cell carcinomas, they are low to intermediate in
grade and typically managed similarly to acinic cell carcinoma. A subset of this
1 Management-Based Pathology Assessment of Salivary Gland Carcinomas 9

entity, as in mammary tumors, manifests (12, 15) resulting in gene fusion transcript
of the ETV6 and the NTRK3 genes [73–75]. Although this fusion has not been
reported in other salivary gland carcinomas, it has been detected in multiple tumor
entities of diverse cell origins including carcinoma, lymphoma, thyroid, and rare
lung tumors. The incorporation of this fusion in the diagnosis and differential diag-
nosis of primary and metastatic salivary tumors must supersede the morphologic
diagnosis. The diagnostic and biological significance of this fusion is currently
uncertain and must await large studies with long-term follow-up. The clinical course
and management is similar to acinic cell carcinoma [76].

1.7.7 Adenocarcinoma: Not Otherwise Specified (NOS)

Adenocarcinoma, NOS, is defined as a salivary gland malignancy with ductal and

glandular features that cannot be categorized as epithelial salivary carcinomas. This
entity includes adenocarcinoma, NOS, cribriform adenocarcinoma, and mucinous,
papillary, and intestinal carcinoma subtypes. The majority of tumors are of parotid
origin, but minor and major salivary glands can be the source. In general, they can
be considered intermediate in grade and behavior. Surgical excision remains to be
the primary treatment [77–80].

1.7.8 Basal Cell Adenocarcinoma (BCAC)

BCAC, a distinctive low-grade malignancy of salivary glands, is characterized by

uniform basaloid cell composition forming ductal, acinar, and tubular structures.
Their pathologic classification into benign and malignant forms is based on the
presence of lack of infiltrative extension into host tissue. BCAC may present as de
novo or as carcinoma arising from basal cell salivary adenoma especially the mem-
branous form [81–83]. Some of these tumors share striking resemblance to dermal
adnexal tumors, and both types of tumors may occur in the same patient. Tumors
should be differentiated from metastatic basal cell carcinoma of the skin, and sialo-
blastoma in infants. Complete excision with clear margins is generally curative.
Recurrence may occur if close margins or satellite nodules are reported. Neck dis-
section is rarely recommended. Not uncommonly, carcinoma may arise from pre-­
existing adenoma and may manifest high-grade features. Patients with these tumors
should be managed similar to a high-grade salivary malignancy.

1.7.9 Clear Cell Carcinoma (CCC)

CCC is a rare entity typically composed of clear epithelial cells with and without
fibrosis. Among tumors that may exhibit significant clear cell features are mucoepi-
dermoid, oncocytic, and myoepithelial carcinomas. Grossly, tumors are generally
less well-circumscribed, soft, and tan with and without visible sclerosis. The most
10 A. K. El-Naggar

common site for these tumors is the oral cavity. Females are thought to be more
affected than males, but the rarity of these tumors precludes confirmation. Complete
excision of this low−/intermediate-grade tumor is curative. Rarely nodal metastasis
and recurrence may occur [84–87].

1.7.10 Myoepithelial Carcinoma

Myoepithelial carcinoma, similar to myoepithelioma, is composed entirely of

malignant myoepithelial cells of hybrid epithelial and smooth muscle characteris-
tics. Pre-surgical classification into benign and myoepithelial-rich PA may not be
possible by FNA screening. Grossly, tumors are generally ill-defined, gray to tan in
color, and firm in consistency. Histopathologically, they may display spindle, epi-
thelioid, plasmacytoid, and/or mixed cell composition with infiltrative and ill-­
defined boundaries. The differentiation from the benign tumor is largely based on
the infiltrative nature and extension into surrounding soft tissue. Myoepithelial car-
cinoma presents either in a pure form or as the malignant component of long-­
standing pleomorphic adenomas. These tumors are generally low grade and
managed by complete surgical excision. Infiltrative spindle cell forms can be prone
to recurrence [88–91].

1.7.11 Epithelial-Myoepithelial Carcinoma (EMC)

EMC is a low-grade salivary malignancy composed of dual cell types; outer clear
myoepithelial and inner epithelial cells in ductal and nesting formation. EMC is
uncommon with an estimated incidence of 5% of salivary malignancies. The most
common sites of these tumor types are the parotid and the submandibular glands.
The majority is of low-intermediate grade and is generally cured by complete surgi-
cal excision. Because of their dual cell formation, they may cause differential diag-
nostic difficulties with adenoid cystic, myoepithelial, and clear cell carcinomas.
High-grade transformation has been reported and should be managed as high-grade
malignancy [92–94].

1.7.12 Carcinosarcoma

Carcinosarcoma is a rare salivary malignancy composed of two distinct high-grade

epithelial carcinoma and heterologous mesenchymal derived components. The epi-
thelial form in commonly high-grade adenocarcinoma and the mesenchyme form is
osteo-chrondro rhabdo and/or angiosarcoma subtypes. Tumors are large and grossly
variable with solid, hemorrhagic, and osteo-chondromatous features with extension
into surrounding host tissue. Generally, they are de novo in presentation but may
rarely originate from pleomorphic adenoma and both instances are managed in a
multidisciplinary setting. These tumors should be considered high-grade
1 Management-Based Pathology Assessment of Salivary Gland Carcinomas 11

malignancy and if not surgically eradicated can be managed by either sarcoma or

carcinoma medical oncology [95–98].

1.7.13 Poorly Differentiated and Undifferentiated Carcinomas

Primary poorly differentiated carcinoma may exhibit either small (slightly larger
than lymphocytes) or large cell formation typically in cohesive sheets and nests.
These tumors may manifest neuroendocrine differentiation and can be diagnosed as
poorly differentiated carcinoma with neuroendocrine features or small- and large-­
cell neuroendocrine carcinoma. The latter tumors, particularly, should be differenti-
ated from metastatic or unknown primary Merkel cell carcinoma. Tumors typically
run aggressive clinically and frequently show lymph node metastasis. Management
remains to be initial surgery with postoperative XRT and/or chemotherapy
[99–101].

1.7.14 Undifferentiated (Lymphoepithelial) Carcinoma

Morphologically these tumors mimic nasopharyngeal carcinoma and are rare in

Caucasian populations. Tumor is characteristically composed of malignant epithe-
lial cells forming synthetial nests with intra- and peritumoral lymphoid infiltrate of
undifferentiated tumor cells. Primary intraparotid tumor may arise de novo or from
lymphoepithelial lesions. Tumor may or may not be positive for EBV. The tumor
may present with lymph node metastasis. Surgical treatment is the primary approach
with postoperative radiation and/or chemotherapy [102–105].

1.7.15 Primary Squamous Carcinoma

Primary squamous carcinoma of the salivary gland is exceedingly rare, and the
diagnosis mostly only is made after the exclusion of dermal squamous malignancy
even if remote. Primary squamous carcinoma can rarely occur in patients with long-­
standing sialolithiasis and chronic inflammation and squamous metaplasia of the
main duct that primary squamous diagnosis can develop. The differential diagnosis
from tumors with squamous features includes MEC and salivary duct carcinomas.
Proximity to the main duct with evidence of squamous metaplasia and/or dysplasia
is necessary to confirm the primary origin. Typically they are well to moderately
differentiated and their surgical excision is curative [106–108].

1.7.16 Sialoblastoma

This is a tumor of infancy and has, until recently, been considered of uncertain
malignant potential. In the fourth WHO edition of H&N tumor classification, it was