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468
B. H. Siddiquee
a
Fig. 19.11 (a, b) Parotid gland carcinoma with skin involvement and facial nerve palsy
facial nerve cannot be pictured by usual ultrasonography. MRI is an excellent imaging for cases
with clinically obvious swellings in parotid gland
with suspicious ndings of malignancy. MRI
offers accurate evidence about the location and
extension of the tumor, even if it is in the deep
lobe or parapharyngeal space. It exposes the scenario of cervical lymph node status. MRI allows
detection of bone invasion, perineural extension,
and meningeal inltration [124]. CT scan may be
advised for staging if MRI is contraindicated or
not available. FDG-PET/CT cannot practically
distinguish malignant, benign, or metastatic
parotid tumors [125] (Fig.19.11).
b
operation time for parotid surgery [127]. Nerve
monitoring is also helpful to elude nerve injury if
the facial nerve is not identied during parotid
surgery.
If the cranial nerve VII is sectioned during surgery, it should be repaired as soon as possible.
Repair under microscope without tension, or
repair with a nerve graft, offers the chance of
good recovery. If the nerve trunk or main branches
are invaded by the tumor but functional, then sacricing overtly involved part of any of the nerves
and primary nerve grafting following radical
resection of the tumor are the prime choice.
19.11 Intraoperative Facial Nerve Monitoring
Electromyographic (EMG) monitoring of facial
nerve is almost in regular use during parotid surgery. But prospective randomized controlled
study regarding usefulness of the EMG monitoring is lacking. One meta-analysis showed that
preoperative EMG monitoring of facial nerve
lessens the chance of facial nerve weakness in
early postoperative period after parotidectomy
[126]. Its role in revision cases and in nal outcome of cranial nerve VII is yet to be elucidated.
It helps to locate the nerve trunk and its branches
while using a combination device for electrostimulation and monitoring. This can reduce the
19.12 Carcinoma ofUnknown
Primary (CUP)
This is a heterogeneous group of metastatic
tumors where even a wide-ranging diagnostic
workup cannot detect the site of origin. Clinically,
CUPs are categorized by a set of unique features
like early metastatic spread of unpredictable pattern, apparently aggressive clinical behavior, and
relatively poor prognosis (Fig.19.12).
The diagnosis of CUP can be made after
through clinical history, physical examination,
laboratory tests, imaging, and a careful review of
the histology with immunohistochemistry (IHC),
and also PET/CT if necessary. IHC staining has
been a standard pathologic practice for evaluation in CUP for the last two decades. CUP
19 Updates andControversies intheManagement ofHead andNeck Malignancy
Three types of neck dissections are generally
offered: (1) radical neck dissection, (2) modied
neck dissection, or (3) selective neck dissection
(levels 1–3). Usually, full-dose radiotherapy (RT)
is advocated. There are no differences in techniques (conventional or IMRT) or dose of radiotherapy, whether the neck dissection has been
performed or not. If the nodes are present in level
V or retropharyngeal space, chance of nasopharyngeal primary is higher [131].
Survival is encouragingly higher, and the recurrence is markedly lower for patients with HPVrelated than non-HPV-induced HNCUP [132,
133]. The survival of patients with CUP in distal
sites like lungs, bones, and other sites is very poor,
usually in months. Overall 5-year survival rate is
still frustrating, although improving reasons for
this development might be the detailed under-
Fig. 19.12 Cervical metastatic carcinoma with unknown
primary (CUP)
standing of different prognostic factors, including
extranodal extension, stage of metastatic lymph
nodes, and HPV involvement [134, 135].
accounts for 3–5% of all cancers. The proportion
of CUP to the cervical lymph nodes (HNCUP)
accounts for around 60% among all such carcinomas. The biology of these cancers is yet to be
well understood. Two opinions regarding the origin of CUP have been put forward. The primary
suggestion is that CUPs are a heterogeneous
cluster of site-specic tumors, which share the
properties of primary site from where they derive,
and the second postulation is that these are distinct entities having a specic genetic asset [128].
Advanced age, advanced N stage (N3, N2b, and
N2c), and ECS (extracapsular spread from metastatic lymph nodes) are negative prognostic factors, and HPV-induced origin is considered as a
positive prognostic factor. Diagnostic criteria or
treatment policies so far recognized remain unaltered [129, 130].
Treatment of HNCUP is yet to reach consensus; some studies have revealed higher survival
rate for treatment comprising neck dissection
[136, 137]. But indication for neck dissection
was questioned by a few, as no substantial variation in survival could be shown between cases
with or without neck dissection [138]. Precise
gene expression proles can be identied in most
cancers relating to the site of origin. These different expression proles reect their tissues of origin. Gene expression proling assays, called
molecular cancer classier assays (MCCAs), are
competent to ascertain around 40 cancers and
cancer subtypes [139, 140]. The fast advancement of immune checkpoint inhibitors (targeted
therapy) and other immune-modulatory agents is
likely to be promising for treating patients with
CUP.Right now, only few case reports are available about these treatments [141].
469
19.12.1 Treatment
There are two treatment options:
1. Neck dissection and postoperative adjuvant
radiation
2. Primary radiation or chemoradiation (CRT)
19.13 Parapharyngeal Space Tumors (PPS)
The parapharyngeal space is a structurally composite region. Tumors arising in this area are not
very common, and surgery is considered as a
470
B. H. Siddiquee
preferable option in the majority of cases. Various
operating approaches have been practiced by surgeons. Most of the parapharyngeal space tumors
are of neurogenic or salivary tissue origin.
Ectopic salivary tissue tumors originate in the
PPS, and deep lobe tumors from parotid gland
may extend to the PPS.Schwannoma or neurobroma is a common neurogenic tumor. These
may become large enough before giving rise to
symptoms. Because of the close proximity with
the internal carotid artery and lower cranial
nerves, precise information about tumor location
and its relation, adhesion, and invasion to the
vital structures is crucial for surgery. The trans-
a
b
cervical route, transparotid route, or a combination of these two is the standard surgical approach
[142] (Fig.19.13).
Mandibulotomy is rarely necessary nowadays,
and most of the cases can be handled via transcervical approach with endoscopic assistance.
This allows meticulous clearance and better
hemostasis (Fig.19.14).
Minimally invasive robotic-endoscopic techniques are coming up as effective alternatives in
some cases. TORS has been used for removing
smaller lesions, especially salivary tumors perorally and via a transcervical route for bigger
tumors, likely to be fragmented during removal.
c
Fig. 19.13 (a–c) Imaging of parapharyngeal tumors (different patients). (a) CT scan (malignant tumor). (b) MRI. (c)
CT angiogram
a
Fig. 19.14 (a) Transmandibular approach. (b) Endoscopic removal via cervical approach
b
19 Updates andControversies intheManagement ofHead andNeck Malignancy
471
TORS is also indorsed for taking tissue for biopsy
from adversely located PPS tumors with suspicious manifestation, which are inaccessible without a mandibulotomy [143]. Cases of neurogenic
tumors from the difcult area like retrostyloid
space treated with TORS have also been reported.
Safety and feasibility of the TORS for PPS
tumors achieve a high local control with low peroperative/postoperative complication rate [144].
19.14 Ongoing Controversies
inManagement ofHNSCC
19.14.1 Controversy inStaging
System
In the eighth edition of the AJCC’s TNM staging
system, the depth of invasion (DOI) of the primary OCSCC has been integrated into the T category and has been considered as a major
constituent in the staging system. But how efciently this new system will reect prognosis in
respect to survival, occult metastasis, and recurrence is controversial. According to the eighth
edition staging system, DOI 5mm is the cut margin for upgrading from T1 to T2 and 10mm for
upgrading to T3. This is debatable because
research-based opinion prevailing on 3 or 4mm is
crucial. DOI >4mm is associated with high risk
of locoregional spread and poor prognosis [145].
19.14.2 Diagnostic Controversy
The opinion varies regarding diagnostic strategies
for many HNSCCs, especially after the availability of 18-FDG-PET/CT.Should it be a part of routine preoperative checkup? PET/CT can reveal
second primary efciently. Incidence of synchronous primary has been reported to be in between
5% and 12% [146, 147]. Second primary is often
small and curable. Detection of synchronous carcinoma is crucial because it may alter the therapeutic approach. Can this replace pan-endoscopy
in early-stage diseases? Opinion differs; PET/CT
may not be as efcient as endoscopy to detect
small supercial lesions [148, 149]. Routine
18-FDG-PET/CT may be considered as an overdoing in nonsmoker HPV-positive patients harboring OPSCC.Reduced rate of second primary
has been reported in such cases [150, 151].
In 10–15% of stage III or IV HNSCC, distant
metastases are likely to be existing at the time of
therapeutic evaluation, which obviously inuences treatment [152]. Competence of 18-FDGPET/CT for discovery of distant metastases is
well recognized, but as the incidence is low in
early-stage HNSCC at presentation, it should be
advised only in advanced N-stage cases.
In cases of carcinoma with unknown primaries
(CUP), the supplementary diagnostic benet of
18-FDG-PET/CT is admiring [153]. PET/CT possesses higher sensitivity compared to CT or MRI
for identifying the occult primary, with additional
benet of its ability to identify distant metastatic
lesion/s and synchronous second primary [154].
PET/CT can also discover non- HNSCC occult
primaries in the thorax or abdomen, responsible
for cervical nodal metastasis [155, 156].
Cartilage invasion is a crucial nding for
proper planning of laryngeal cancer treatment.
This generally beyond clinical access and a
dependable investigative assessment is required.
A meta-analysis of CT scan ndings demonstrates frequency of cartilage invasion from
19% to 27%. False positives are frequent,
whereas false negatives relatively infrequent.
False negativity in negligible cartilage invasion
does not contraindicate nonsurgical policies
like chemoradiation or conservative surgeries,
e.g., partial laryngectomies [157]. But the capability of CT for extralaryngeal extension of
cancer is not as per expectation [158]. MRI for
its unique soft-tissue delineation is the preferred assessment tool for cancer spread beyond
the larynx [159].
19.14.3 Sentinel Lymph Node
Biopsy (SLNB)
One major area of controversy is about the diagnostic value of SLNB in HNSCC.SLNB may be a
valuable diagnostic method to appropriately evaluate cervical lymph node metastases. SLNB could
472
B. H. Siddiquee
avoid morbidity of elective neck dissection (END)
and primary chemoradiation therapy in smaller
oral cavity cancer [160]. Although the diagnostic
value of sentinel node assessment by ne needle
aspiration cytology appears to be promising, it was
later shown as not acceptably fruitful [161].
Authentication of the sentinel lymph node
biopsy technique demands that cases undergoing
SLNB should have identical therapeutic efcacy
as patients treated by END. Therapeutic and
prognostic signicance of tumor-positive sentinel lymph nodes should be judged critically.
Succeeding therapeutic neck dissection should be
deferred until detailed histopathological and
immunohistochemistry reports are available.
Type of neck dissection will depend on the individual merit of the case, but it may cause some
additional morbidity. Otherwise, radiotherapy
could be an option though this may also precipitate morbidity. It would be better if per-operative
sentinel lymph node frozen-section biopsy
enables to take instant decision on whether a formal therapeutic neck dissection has to be carried
out or not to avoid hassle and hazards of second
surgery. Frozen-section biopsy of the sentinel
lymph nodes has been practiced for breast cancer
and malignant melanomas. But sensitivity for
micrometastases is poor and not justiable in
these tumors [162, 163].
Thus, there are still a number of questions yet
to be solved before incorporating SLNB in routine practice. Further clarication is required
whether only sentinel node biopsy is capable
enough to identify early regional metastases. If it
comes true, additional elaborate studies will be
necessary to determine whether regional therapeutic control after SLNB is identical to END.It
is desirable that morbidity for secondary therapeutic neck dissection following SLNB should
not exceed that of primary selective END [164].
19.14.4 Strategy forAdvanced Neck
Carcinomas
Chemoradiation (CRT) has become the favored
approach for treating oropharyngeal, hypopharyngeal [165], and laryngeal [166] primary carcinomas
in many settings. Advanced carcinomas are generally having large primary or lymph node metastasis
in several levels (N2b/c, N3), and the ideal policy to
address these neck metastases is still debatable.
Options are (1) neck dissection prior to CRT and (2)
primarily planned neck dissection after CRT.
Those practicing neck dissection before
chemoradiation do not nd any logic to shift
from their dogma [167]. Is the neck dissection
following CRT based on primary planning only is
justied or should require further scrutinization
by 18 FDG PET-CT after CRT to sort out patients
demanding surgical clearence? This is the main
controversy, but this issue has been settled by a
randomized controlled trial revealing that an
18-FDG-PET/CT scan, 10–12 weeks after CRT,
is efcient enough to nd out which patients
require neck dissection [168].
One of the main purposes of neck dissection,
whether therapeutic (cN+) or elective (cN0), is to
select patients requiring adjuvant therapy. Precise
information about the involved metastatic lymph
node groups is important to the radiation oncologist to irradiate neck by intensity-modulated
radiotherapy (IMRT). The neck specimen should
be separated into levels and sublevels just after the
operation, and each level should be put into a separate container with appropriate labeling [169].
Locating negative margins in big metastatic nodes
may not be possible sometimes, which makes it
difcult to separate adjacent levels.
19.14.5 Optimal Resection Margins
The Royal College of Pathologists, UK, has
dened 5mm clear margin in histopathology specimen as the safe resection margin in T1–2 oral cavity tumor [170]. Opinion varies from 5to 10mm.
A “sufcient” histopathological clear margin signies lesser risk for tumor recurrence. Necessity
for adjuvant treatment in these cases requires further justication by other ndings. Bad prognostic
features other than close or positive margins
demanding adjuvant CRT subsequent to surgical
resection include metastatic lymph nodes with
extranodal extension. Reports assessing oral cavity N0 patients with margins smaller than 5mm,
19 Updates andControversies intheManagement ofHead andNeck Malignancy
473
treated only surgically, have shown that these were
not associated with inferior local control, while
depth of invasion and perineural invasion were
predictive of local recurrence [171].
19.15 Controversies inOral Cavity
Carcinoma (OCSCC)
19.15.1 Nonsurgical Treatment
Surgery is the primary choice for large T2, T3,
and T4 OCSCC.Achievement in laryngeal cancer
and OPSCC with nonsurgical treatment modalities has encouraged researchers to see their role in
OCSCC.Several studies have assessed the effectiveness of denitive CRT for advanced HNSCC,
demonstrating improved survival. However,
OCSCC-based studies in this regard are rare
[172]. So far, no prospective study is available in
the literature comparing surgery with CRT.
Induction chemotherapy prior to surgery has
been advocated to reduce the chance for distant
metastasis. But this is yet to be proved authentically that any signicant difference occurs in
overall survival between the two groups, those
who have induction chemotherapy prior to surgery and the group where surgical treatment is
followed by chemoradiation [173].
19.15.2 HPV inOCSCC
of the tumor and functional aspect of the
organ. Targeting the preservation of vital
functions concerned, concurrent chemoradiotherapy (CRT) is usually preferred over surgery plus adjuvant radiotherapy. Controversies
exist regarding whether to include induction
chemotherapy prior to chemoradiation and
what is the best way to manage the neck.
Moreover, HPV is now an established risk
factor mainly for OPSCC.Prognosis is much
better than that of patients with non-HPV
tumors. Considering the distinct differences
between these HPV-positive and HPVnegative cancers, controversy is going on
regarding the management. The burning question is that are the HPV- positive cases undergoing overtreatment.
19.16.1 Treatment Modality
Options forResectable
Tumor
Sorting of patients for denitive CRT versus primary surgery for locally advanced OPSCC is
complex and controversial, better to be decided
in a multidisciplinary board. In the recent literature, no prospective randomized control trials are
available comparing concurrent CRT with primary surgery plus adjuvant RT. Quality of life
appears to be more or less alike with either
modality [176].
Despite the well-recognized advantages of HPVpositive OPSCC, its impact on OCSCC is yet to be
ascertained. The prevalence of HPV in OCSCC is
low (5.9–21.3%), and p16 expression in OCSCC
does not reveal any survival benet [174, 175].
19.16 Controversies
intheManagement
ofOropharynx Cancer
(OPSCC)
OPSCC generally presents with locally
advanced lesion. Multimodality approach is
required for treatment considering the gravity
19.16.2 Induction Chemotherapy
Induction chemotherapy (IC) followed by CRT
for locally advanced OPSCC may eradicate
early micrometastatic foci and also provide
early symptomatic control. Additionally, radiotherapy disrupts vascular supply to the tumor,
resulting in decreased chemoperfusion. IC can
avoid this issue, allowing greater tissue penetration before denitive chemoradiation.
Despite signicant improvements in locoregional disease control, the issue of development of distant metastases still remains
controversial [177].
474
B. H. Siddiquee
19.17 Controversies inLaryngeal
Carcinoma
19.17.1 Treatment ofPrimaries
inLaryngeal Glottic
Carcinoma
Vocal cord mobility is crucial for treating glottic
cancer. The absence of mobility indicates inltration of the vocalis part of the thyroarytenoid muscle or hardly ever involvement of cricoarytenoid
joint. This is considered as poor prognostic issue.
T1 carcinoma will be converted to T2in case of
impaired mobility, and T3 for immobility. The
inference of impairment mobility of vocal cord is
that the tumor has become considerably larger
and extended laterally. It may require much
extensive endoscopic surgery and thus end up
with voice and swallowing impairment. In case
of T3 lesions, negative resection margin may be
tough to reach endoscopically. This again validates partial laryngectomy by external approach
[178]. If chemoradiation is chosen as the therapeutic option in T2 glottic cancers, impairment of
vocal cord mobility becomes the most signicant
adverse prognostic factor [179].
There are two treatment options for carcinoma
of the anterior commissure of the larynx. The
dilemma to treat it by primary irradiation or by
conservative surgery is yet to be solved. MRI/CT
scan ndings may not be conclusive for staging at
this point.
19.18 Controversies
inNasopharyngeal
Carcinoma (NPC)
Primary treatment for NPC without cervical
lymph node metastasis is by radiotherapy. The
role of systemic therapy is also coming up.
Cisplatin-based concurrent chemoradiation is the
currently used protocol for locally advanced
tumors. The prognosis of NPC has been improving signicantly over the rst two decades of the
twenty-rst century. But still there are some
uncertainties and variations in thinking regarding
the optimal treatment strategy. Distant metastases
appear to be the main sector of treatment failure
despite appreciable local control [180].
In advanced scenario of locoregional NPC,
conventional treatment with radiotherapy is
hopeless, because of local recurrences and development of distant metastases. The neoadjuvant
and adjuvant chemotherapy has been consistently
exhibiting better response, but randomized control trial (RCT)-based evidence is still lacking.
Altered-fractionation radiation techniques could
not demonstrate any improvement in disease-free
or overall survival [181].
19.19 Future Trend ofTherapeutic
Strategies
19.19.1 Targeted Therapy
Advanced HNSCC usually requires multimodal
treatment, which may precipitate signicant toxicity. The promising options for these patients are
molecular targeted therapies. The well-practiced
targeted therapies are epidermal growth factor
receptor (EGFR) monoclonal antibodies (e.g.,
cetuximab, panitumumab), EGFR tyrosine kinase
inhibitors, vascular endothelial growth factor
(VEGF) inhibitors, or vascular endothelial
growth factor receptor (VEGFR) inhibitors.
Some other inhibitors of different pathways and
targets are also promising and require evaluation
by further research [182].
EGFR overexpression has been detected in
about 90% of HNSCC.It is considered as a negative prognostic factor, which increases the size of
the cancer, decreases its radiosensitivity, and also
increases the risk of recurrence [183].
The heterogeneity of molecular disorders in
HNSCC still makes it difcult to put on estimable strategy for targeted treatment. Few biopharmaceuticals are being tested in clinical and
preclinical settings. The fact is that they could not
bring any revolutionary change in the treatment
of HNSCC, and yet remain to be standard therapeutic options. Identication of molecular markers connected with the treatment response will
help personalize targeted and nontargeted treatment. Ongoing interest of scientists in genetic
19 Updates andControversies intheManagement ofHead andNeck Malignancy
475
and molecular biology may render targeted therapy a fundamental modality of cancer treatment
in the coming years.
19.19.2 Immunotherapy
PD-1 and PD-L1 are immune checkpoint proteins present on the cellular surface. Inhibitors of
immune checkpoints are emerging as a frontline
treatment for several types of cancer [184].
HNSCCs are quite common cancers.
Although many patients with locally advanced
stage enjoy a long period of disease-free survival with combined modality treatment comprising surgery, radiation, and chemotherapy,
lot of cases develop local recurrence and
regional or distant metastasis and are labeled as
incurable. Chemotherapy has limited efcacy
due to signicant toxicity in metastatic HNSCC,
with an average overall survival of less than a
year [185]. Immunotherapy with PD-1 and
PD-L1 inhibitors has dramatically altered the
treatment of multiple cancers [186, 187]. Till
now, the strongest evidence for the application
of immunotherapy in cisplatin- refractory disease is for PD-1-directed antibodies [188].
Research focusing on biomarkers to nd out a
rational combination and more rened method
for patient selection is essential to expand the
benet to suffering people through these emerging inspiring drugs.
19.19.3 Cancer Stem Cells (CSCs)
Cancer stem cells (CSCs) are the subgroup of
cells contained by the cancerous lesion that contribute to resistance to therapies and potential for
recurrence. These have signicant inuence on
the treatment success and disease progression. In
addition to two well-known types of stem cells,
embryonic and adult stem cells, existence of a
third variety, named as cancer stem cells (CSCs),
has been discovered recently [189].
Conventional concept regarding malignant
transformation is that it starts from a randomized
genetic mutation, which can affect any cell. The
mutant cell population, which has gained proliferative properties and resultant genomic instability, ensues further epigenetic and genetic events,
prompting assembly of the new aggressive subclones with consequent tumor development
[190].
In contrary to the ordinary model of clonal
evolution in carcinogenesis, a new theory has
been put forward based on the CSC’s role. This
“CSC hypothesis” can logically illuminate the
reasons for poor response to therapies, high mortality rate, and tendency to develop synchronous
and metachronous primaries in HNSCC patients
[191].
Among the heterogeneous cell population of
HNSCC lesions, the small subpopulation of
CSCs is considered as responsible for resistance
to radio- and chemotherapy, local recurrence of
cancer, and also initiation of metastasis due to
high migration capability [192, 193].
The CSC hypothesis may have major implications on cancer treatment and may lead to development of new therapeutic strategies even
shifting from conventional to a new treatment
paragon.
19.20 Conclusion
Head and neck malignancy is a vast, interesting,
and controversial chapter of medicine, which
involves multiple disciplines for management.
Still, surgery, radiotherapy, and chemotherapy
are the main treatment modalities, although signicant qualitative changes have occurred in
these during the last several decades. The foremost mounting idea is the functional organ preservation without compromising prognosis. In
case of radiotherapy and chemotherapy, research
has been destined to make them more target specic and to reduce toxicity. Future trend of experimentation will be concentrated on detecting
HNSCC in its premanifestation stage and also
anticipating behavioral pattern with the help of
immunological and non-immunological biomarkers. Targeted therapy, immunotherapy, and
cancer stem cell management will get due importance in therapeutic policies.
476
B. H. Siddiquee
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