In literature very few authors have evaluated submandibular
gland, sublingual and minor salivary glands tumors
together as one entity. However in 1979, Batsakis[
2] called this group as minor and lesser major salivary
glands tumor. In our study we have followed the same nomenclature.
The submandibular and sublingual glands are
collectively called lesser major glands and rest of tumors
are enumerated under minor salivary gland tumors. Our
study confirms that clinically the main presenting symptom
is painless mass and is quite consistent with the literature[
3]. Adenoid cystic was the most frequent histology
in our patient population and is also a consistent finding in the literature[
4]. Early stage salivary gland tumors are
usually curable by adequate surgical resection alone. The
prognosis is more favorable when the tumor is in a major
salivary gland; the parotid gland is most favorable, then
the submandibular gland; the least favorable primary sites
are the sublingual and minor salivary glands[
5]. Large
bulky tumors or high-grade tumors in parotid cancers carry
a poorer prognosis and may best be treated by surgical
resection combined with postoperative radiation therapy
while as in minor salivary gland neoplasms it depends
mainly on site and histological grade[
6]. For high-grade
or larger (¡İ4 cm) tumors, a more extensive resection may
be necessary along with neck dissection[
7]. Surgical resection
usually includes an adequate cuff of normal tissue
around the tumor. Involvement of bone (mandible or
maxilla) requires an appropriate palatectomy or mandibulectomy[
8].
In Spiro's[9] review of previously untreated minor
salivary gland neoplasm's, the 5 year survival for malignant
neoplasms was 73%, 10 year survival was 56%, 15
year survival was 46% and the 20 year survival was 35%
for patients treated with surgery. This data was compared
to a similar cohort of patients with major salivary gland
neoplasms and no difference in survival was found. Patients
with sinus primaries had a significantly lower overall
survival rate compared to patients with oral lesions at
10 years. Spiro also divided minor salivary gland malignancies
into two groups: low-grade neoplasms including
low-grade mucoepidermoid carcinoma, low grade adenocarcinoma,
and acinic cell carcinoma; and high-grade malignancies
including malignant mixed tumor, high grade
mucoepidermoid tumors, high grade adenocarcinoma and
adenoid cystic carcinoma. Patients with low-grade histologies
had a significantly better survival rate over twenty years. Low grade lesions had a 93% survival at 10 years
compared to high grade tumors with a 42-58% survival at
10 years[10].
In our data the 5 year overall survival probability was
better in well differentiated tumors as compared to poorly
differentiated tumors but it did not reach the statistical
significance. However the differentiation in our data
is purely as per pathology report which is different from
what Dr. Spiro has used.
Minor salivary gland cancers tend to have a worse
outcome than those involving the major salivary glands,
particularly adenoid cystic cancers. In a 20-year review of
21 patients treated for minor salivary gland malignancy
in a single institution, it was found that mucoepidermoid
tumors were more common in the oral cavity and adenoid
cystic carcinomas in the sinonasal tract (p=0.002).
Outcome was variable with sinonasal and adenoid cystic
carcinoma having a poorer outcome. Kaplan-Meier
curves showed that oral tumors had a higher probability
of long term survival. Radical surgery with reconstruction
and post-operative adjuvant radiotherapy was effective
in achieving loco-regional control. There were no local
recurrences within 5 years and three after 5 years. Five
patients developed metastatic disease within 10 years and
a further two after 10 years. Late recurrences occurred
and survival was mainly determined by the presence of
systemic disease[11]. A benefit for adjuvant radiation in
high-risk cases was suggested in another series of 128 patients
with malignant intraoral minor salivary gland tumors
who were treated with either surgery alone (n=59)
or surgery followed by postoperative radiation (n=32);
the remainder were either unresectable or refused surgical
treatment. Radiation was administered to patients with
close or positive surgical margins or metastatic cervical
lymphadenopathy. Although local recurrence rates were
the same or slightly higher in the radiated patients, the
fact that this group was selected for radiation based upon
poor prognostic features led the authors to postulate a
beneficial effect of radiation. The five year survival rates
were similar in the two groups (86 versus 88 percent, respectively)[12]. The effect of radiation therapy on minor
salivary gland neoplasms was retrospectively studied in
a group of 160 patients at MD Anderson Cancer Center in 1994 by Garden et al.[13]. The group recommends
the use of radiation in patients with perineural invasion,
positive margins, high-grade histology, recurrence, and
in patients with neck disease. Microinvasion of small unnamed
nerves is not an indication for radiotherapy. They
recommend a dose of 60 gray in 2 gray per fraction over
6 weeks. Treatment should commence as soon as possible
after surgery. In the mid 1980's when high-grade lesions
were treated only by surgery recurrence rates were reported
to be as high as 50%. In this series only 12% had a
local recurrence, while 36% of patients relapsed with distant
metastasis. External beam radiation has been shown
to increase local control in unresectable and inoperable
lesions.
Our study is the first in literature to demonstrate that
patients with primary neoplasm in submandibular gland
do worse compared to patients with minor salivary gland
tumors. In literature so far the most frequent encounter
has been the opposite. Our data also concurs with the fact
that radiation combined with surgery has a protective effect
on hazard of death as compared to other modalities.
This has been discussed in length in study by Dutch Head
and Neck Oncology Cooperative Group[14]. Although
minor salivary gland neoplasms are infamous for late recurrence,
70% of recurrences appear within 2 years. Paranasal
sinus lesions are particularly prone to recurrence,
as are adenoid cystic carcinomas, adenocarcinoma, and
pleomorphic adenomas excised without an adequate margin.
There are reports of local recurrence developing over
20 years after initial treatment.
With regards to metastasis, in Spiro's[15] series of
378 patients who had carcinomas of the minor salivary
glands, at least 19% developed distant spread with the
likelihood significantly increased if the neck was clinically
positive at presentation. The incidence of distant
metastasis for adenoid cystic carcinoma is reported to be
between 25%-50%; the most frequent sites being the lung
and bone. With adenoid cystic carcinoma, surgical excision
of isolated pulmonary metastasis is indicated due to
its indolent nature.
Prospective trials of adjuvant chemotherapy for resected
minor salivary gland tumors have not been conducted,
and the few small retrospective series do not consistently support benefit. Thus, the routine use of adjuvant
chemotherapy cannot be justified unless in the setting of
a clinical trial. The role of systemic chemotherapy in the
management of salivary gland cancers is limited to disease
that is metastatic or locally advanced and unresectable.
Clinicopathological data have demonstrated correlations
between poor clinical outcomes and the expression
of molecular markers such as mutated p53 protein and vascular
endothelial growth factor (VEGF) in salivary gland
cancers. Recent studies have also evaluated the epidermal
growth factor receptor family including erbB1/EGFR
and erbB2/HER2 as potential therapeutic targets. While
the prognostic significance of EGFR overexpression has
not been well defined, overexpression of the HER2 oncoprotein
has been associated with biological aggressiveness
and poor prognosis in most series. Given the suboptimal
response rates, duration of response, and toxicity
of conventional chemotherapy, a better understanding of
the biology of salivary gland malignancies will lead to
improved prognostication and treatment. With the emergence
of molecular targeted therapy, these tumors become
an optimal candidate for trials of investigational drugs and
established drugs for new indications[16]. Suen and John[17] performed a multicenter review of patients who had
received systemic 5-Flurouracil, cisplatin and or adriamycin
based chemotherapy for advanced salivary gland
tumor. The overall response in the series was only 42%.
Fast neutron beam radiation therapy or accelerated hyper
fractionated photon beam therapy are shown effective
in unresectable tumors. The Radiation Therapy Oncology
Group in United Sates and Medical Research Council of
Great Britain compared the efficacy of neutron therapy
vs. conventional radiation in a randomized, clinical trial.
Disease free and overall survival seems to be favorable
with fast neutron therapy[18]. Clinical trials are appropriate,
and should be considered whenever possible.
Radiotherapy (RT) combined with local hyperthermia
or concomitant chemoradiotherapy may play a role
in the treatment of some locally advanced or recurrent
salivary gland tumors, but experience is limited and thus
are experimental approaches. Combining photons with
carbon ion therapy is promising, but clinical experience
is limited[19]. Other technical improvements in RT delivery such as three-dimensional conformal RT or intensity
modulated RT hold promise for increasing rates of
tumor control while minimizing toxicity[20]. There is
sparse data regarding brachytherapy in salivary gland tumors
of the hard and/or soft palate that had been excised.
In this study all patients had close or involved margins.
Six were treated with a dental applicator alone, two with
an applicator and additional I-125 seeds in tubes and one
with an implant alone. The applicator consists of two layers
of plastic made from a dental impression enclosing a
predetermined number of I-125 seeds, 9-39, glued to one
surface and a layer of ash metal to protect the tongue. It
was inserted 1-3 months post-operatively and delivered
35-62 Gy, median 56 Gy, at 5-7 mm depth over 58-156 h,
median 120 h, at 0.26¨C0.67 Gy/h, median 0.45 Gy/h. With
median follow-up of 50 months there were no recurrences.
So, brachytherapy is an effective way of delivering postoperative
radiotherapy to the hard and soft palate salivary
gland tumors that have been incompletely excised or have
unfavorable histology. Local control is excellent, treatment
time is short and morbidity is minimal[21].
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