Review Article
Primary Adenoid Cystic Carcinoma of Lung – An Overview
Muhammad Shahid Iqbal1* and Shahzeena Aslam2
1Department of Clinical Oncology, Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
2Department of Clinical Oncology, Cambridge University Hospitals, UK
*Corresponding author: Muhammad Shahid Iqbal, Department of Clinical Oncology, Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN. UK
Published: 05 Dec, 2016
Cite this article as: Iqbal MS, Aslam S. Primary Adenoid
Cystic Carcinoma of Lung – An
Overview. Clin Oncol. 2016; 1: 1158.
Abstract
Adenoid cystic carcinoma of the lung is a rare salivary gland-type neoplasm. Due to the rarity of the disease, its clinicopathological behaviour and management principles are poorly understood. The main evidence has come from institutional experience and retrospective case series. In this current overview, an attempt is made to search the available literature and to summarise the existing evidence.
Introduction
Adenoid cystic carcinoma (ACC) is a distinctive type of malignant epithelial neoplasm that
most commonly arises from salivary glands of the head and neck and less commonly from lacrimal
glands, breasts, skin, vulva and upper aerodigestive system.Primary ACC of the lung is an extremely
rare neoplasm, accounting for only 0.04-0.2% of all primary lung tumours [1]. In the thorax, most
of these cancers originate from central airways, such as the trachea and main bronchus, and ACC of
the peripheral lung is extremelyrare [2]. Because of their relatively indolent nature, these tumours
used to be referred to as benign glandular neoplasms, but are now regarded as low-grade bronchial
carcinomas [1]. Because of rarity of the disease, randomised control trials are not possible and the
evidence of management is mainly based on institutional experience and retrospective case series/
reports. The aim of this overview is to summarise the pattern of the disease, management options
and their outcomes.
Clinical features
Cough, wheeze, dyspnoea and haemoptysis are the most common presenting symptoms [3,4].
In a study involving 40 patients with ACC, Molina et al. [5], common presenting symptoms were
as follows: cough (70%), dyspnoea (60%), wheezing (42.5%), pneumonia (30%) and haemoptysis
(27.5%) In another study of 38 patients, the frequency of presenting symptoms were as follows;
shortness of breathing 72%, wheeze 39%, cough 23%, stridor 21% and haemoptysis 18%. Many
patients had two or more symptoms [6]. There is often a long interval between the onset of
symptoms and diagnosis. Maziak et al. [6] demonstrated that the mean duration of symptoms
before diagnosis was 15 months with a range of 1-72 months. This is most likely due to the relatively
slow growing nature of the disease and the fact that plain chest radiograph frequently fails to show
any abnormality.
Unlike other bronchogenic carcinomas of the lung, smoking is not thought to be a definite risk
factor for thedevelopment of primary ACC of the lung [3,4]. However, in one series, over half of
the patients with ACC (69.2%) were reported to be current or former smokers. This percentage was
higher than that of reported adult smokers in the UnitedStates, even going back to 1970. This may
raise a question about the actual relationship between smoking andsalivary gland-type tumours [5].
In another study by Gaissert et al. [7] 135 patients with ACC were evaluated and one third
ofpatients were smokers. The presenting symptoms in this group were as follows; dyspnoea 48%,
cough 40%, haemoptysis 21%, wheeze 32%, stridor 15%, hoarseness 7% and dysphagia 5%. The
mean duration of symptoms was 12.2 months.
Histological features
ACC exhibits three predominant histological growth patterns. The most frequent and
predominant pattern is a cribriform pattern (nests of tumour cells containing numerous sharply
outlined luminal spaces, sometimes containing mucinous secretion within their lumens). The
second most common pattern is a tubular pattern (characterised by singly scattered gland-like
spaces with wide-open lumina lined by two to three layers of small cuboidal cells, sometimes containing a pinkish amorphous secretion within the lumen). The
least frequent pattern (and mostaggressive), is a solid pattern (sheets
of cells lacking luminal structures that showvesicular nuclei and open
chromatin; mitotic activity is occasionally identified within these
solid areas) [2,4,8]. Lymphatic or vascular invasion is uncommon
although perineural invasion has been reported in few cases [5].
The cells show positive staining for actin and myosin but tend to
be negative for neuroendocrine markers CD56, chromogranin and
carcinoembryonic antigen [3]. In a detailed immunohistochemical
examination on 17 out of a total of 34 patients, Hu et al. [1]
demonstrated the following pattern of positive immunostaining;
wide-spectrum keratin in 17/17 patients, p63 in 11/12 patients, SMA
in 6/9 patients, S-100 in 7/8 patients, vimentin in 10/12 patients, CK7
in 11/11 patients, GFAP in 1/3 patients and CEA in 2/9 patients.
Staining was absent for Syn in 7 patients, CD56 in 7 patients, CK20 in
4 patients, CgA in 4 patients and TTF-1 in 14 patients.
Management
Primary ACC of the lung is a rare entity and most of the available
data on these tumours come from retrospective case series. As ACC
are primarily salivary gland tumours, the management principles
have mainly been extrapolated from the clinical management of
salivary gland ACC.
Surgery is the mainstay of the treatment. Sleeve resection,
lobectomy or pneumonectomyare common surgical procedures
depending on the site and extent of disease. In a large retrospective
institutional experience from the Mayo clinic (1972 – 2002 study),
the most common procedures for patients with ACC (n = 40) were
tracheal resection (33.3%), lobectomy (29.2%), and pneumonectomy
(29.2%) [5].
Kang et al. [9] examined a total of 48 patients with primary salivary
gland-type lung cancers. Twenty patients had ACC (7 in the trachea,
5 in the main bronchus and the remaining 8 in peripheral lungs). One
patient received neoadjuvant chemotherapy and one neoadjuvant
radiotherapy. Tracheal resection was performed in 5 patients, carinal
sleeve resection in 4 patients, sleeve lobectomy in 6 patients and
pneumonectomy in 5 patients. No nodal involvement was found in
11 patients, N1 in 3 and N2 in 3 patients. In the remaining 3 patients,
nodal involvement was not mentioned. R1 (positive margin) resection
was found in 8 (40%) patients. Nine patients required no adjuvant
treatment. Adjuvant radiotherapy was employed in ten patients and
one patient required adjuvant chemotherapy. Six of the R1 resection
patients received adjuvant radiotherapy, 3 of these showed disease
recurrence during the follow-up period (range 15.2 – 137 months).
Two patients developed distant metastases and one developed local
recurrence. The remaining two patients refused to have adjuvant
therapy and they were alive without disease recurrence at the time of
publication. Although some studies [5,7,8] have proposed that nodal
staging and surgical excision determine the prognosis, in this study,
there was no statistically significant difference in survival (p =0.5) and
recurrence (p=0.23) rates between lymph node positive and negative
patients respectively.The authors also concluded that although it was
impossible to evaluate the role of adjuvant radiotherapy in the case of
imcomplete surgical resection, R1 resection did not appear to have an
adverse effect on recurrence regardless of post operative radiotherapy
[9].
Maziak et al. [10] in a clinical study of managing ACC at Toronto
hospital (32-year experience) reported outcomes on 38 patients.
Thirty two patients underwent primary surgical resection and six
received primary radiotherapy for unresectable disease. Primary
resection and anastomosis was performed in 29 patients and
prosthetic reconstruction (Marlex mesh) in 3 patients. Three patients
(9%) died within 30 days of the operation. Nine patients developed
recurrent nerve palsy, 8 were found to have airway granulation and
5 developed wound infection. Dysphagia was present in 4 patients
and stenosis in 3 patients. In half of the patients (50%), the surgical
margin was incomplete i.e. R1 resection. The median survival for 16
patients with complete resection was 93 months and for 16 patients
with incomplete resection margins median survival was 61 months
(mean 118 and 90 months respectively). Although there was no
statistically significant difference in these two subgroups, there was
a trend for increased survival in the group who underwent complete
resection particularly at 10 years; complete resection 69% vs.
incomplete resection 30%. The median survival for 6 patients treated
with primary radiotherapy was 87 months [6].
In a study by Hu et al. [11] 26 of 34 patients were operable (10
patients had R1 resection). Three, 5 and 10-year overall survival
in operable patients was 92%, 91% and 70% respectively. Nine of
10 patients with R1 resection received adjuvant radiotherapy and
the survival was similar to that of R0 resection. Four patients with
R0 resection also underwent postoperative radiotherapy but no
additional benefit was yielded.
Gaissert et al. [7] compared thoracic ACC with that of squamous
cell carcinoma (SCC) of the trachea/carina (135 patients in each
group). 59% of patients with ACC had positive margins in contrast
to only 18% with SCC. 74.8% patients with ACC underwent primary
resection. Reasons for contraindications to surgery were as follows;
extent of airway involvement in 68%, extent of regional disease in
23%, distant disease in 6% and patient choice in 3%. Postoperative
radiation was given in 70% of ACC patients as compared to 46%
patients with SCC. Mean survival period was 69 months with resected
ACC and 41 months with unresected ACC (38 and 8.8 months
respectively with SCC). Overall 5-year survival was 52% for resected
and 33% for unresected ACC and 10-year survival was 29% and 10%
respectively. Complete resection was of prognostic importance but
lymph nodal positivity was not found to be of prognostic value.
Radiotherapy
The role of radiotherapy is not well defined in the literature.
However; in general, this option is kept in reserve for patients with
either incomplete resection margins or in patients with unresectable
disease.
Maziak et al. [6] reported that six of a total of 38 patients were
found to have unresectable disease at the time of presentation and
they received primary radiotherapy. The radiation dose varied from
50 to 75 Gy. Of these 6 patients, one patient could not complete the
radiotherapy and two developed local recurrence after 7 and 8 years
and went on to have palliative surgery with residual tumour present
after the procedure. The survival for these two patients was 33 and 25
months respectively. The median survival for 6 patients treated with
primary radiotherapy was 87 months, which was comparable to surgery
(93 months for 16 patients with complete excision and 61 months
for the remaining 16 patients with incomplete excision). However,
five of these six patients ultimately had a fatal local recurrence. In
this study, 25 out of 32 patients who underwent primary resection
also received pre or post-operative radiotherapy (9 preoperative and 16 post-operatives). In this subgroup treated with dual modality, the
median survival in 23 patients (excluding two operative deaths) was
88 months (range 11 – 263 months) and in the remaining six patients
(excluding one patient with operative death) who did not receive
adjuvant radiotherapy, the median survival was 131 months (5 – 352
months). The difference was not significant, however it is logical to
assume that adjuvant radiotherapy was reserved for high risk patients
and is likely to delay or reduce the incidence of local recurrence [6].
Chopra et al. [10] reported three cases of Lung ACC treated with
surgery followed by postoperative radiotherapy. In two patients, the
disease was in the central bronchus/trachea and in one patient; the
lesion was in the peripheral lung. In the patients with central tumours,
there was an R1 resection, one was treated with 72 Gy in 60 fractions
and the second patient received 50.4 Gy in 28 fractions followed
by a brachytherapy boost of 12 Gy in 2 fractions. The patient with
peripheral lesion required external beam radiotherapy (EBRT) 45 Gy
in 25 fractions and a further boost of 20 Gy in 10 fractions after R2
resection. There were no local recurrences found (follow up range: 14
months to 10 years) although one patient developed a benign tracheal
stenosis one year after the treatment. The authors concluded that
postoperative radiotherapy can effectively eradicate residual disease
after incomplete resection and it may improve the probability of cure.
In the palliative setting, radiotherapy can provide satisfactory
palliation of symptoms. A case report described fast and good symptomatic response to bony metastases in a patient with
aggressive metastatic lung ACC who was resistant to several systemic
chemotherapeutic agents [12].
Table 1
Chemotherapy/Targeted Therapies
The role of palliative chemotherapy is not well described in the
literature. A case report described sensitivity to uracil-tegafur and
cisplatin plus radiotherapy [13]. In another case report, several
chemotherapeutic agents including 7 cycles of weekly paclitaxel
combined with cisplatinum, 2 cycles of docetaxel and subsequently
gefitinb was tried but there was no response [14]. In a clinical study by
Hu et al. [15] only one case showed markedreduction in disease after
two cycles of paclitaxel and cisplatin chemotherapy, but six months
later, the disease progressed. Various other chemotherapy regimens,
including gemcitabine and cis-platinum, navelbine and cis-platinum
and single-drug chemotherapy with pemetrexed were tried with
no benefit. One patient, with anunknown EGFR mutation status,
received an oral epidermal growth factor receptor-tyrosine kinase
inhibitor (EGFR-TKI), erlotinib. The primary tumour was stable
after one month but mediastinal disease progressed three months
later. In this study, EGFR mutation status (exon 18-21) was examined
on 2 patients, including a young female who had never smoked, but
no mutations were detected. One case of TTF-1 positive ACC in
peripheral lung has been described in the literature [16]. A summary
of the studies discussed has been provided in Table 1.
Metastatic disease
Distant metastasis is uncommon, although in some studies
the incidence of metastasis was up to 40.5% [5]. In this study of 40
patients with ACC, 15 developed distant metastases: (the main site
of metastases was lung; in 14 out of 15 patients) [17]. Maziak et al.
[18] reported haematogenous metastatic spread in 17 of the total
38 patients (lung metastases in 13 patients, liver in 4, bone in 3
and brain metastasis in 2 patients). The authors stated that ‘to date,
there is no evidence that chemotherapy is useful in the management
of these metastases’ so it can be assumed that these patients with
haematogenous metastatic spread did not receive any systemic
therapy. However these patients survived for as long as 7 years after
the metastatic spread was established with a mean survival interval of
37 months [19].
Survival/Prognosis
Prognosis depends on staging, histological pattern (solid pattern having the worst prognosis and tubular having the best prognosis) and complete resection [2,4,5,14]. In the Mayo clinic study, the survival for patients with ACC was reported as follows; 85% at 1 year, 73% at 3 years, 57% at 5 years, and 39% at10 years. It was compared to that of non-small cell lung cancer treated at the same centre from 1997-2002 (n = 5024) which showed 58% at 1 year, 31% at 3 years and 21% at 5 years. The outcome of patients with ACC was significantly poorer (5- and 10-year survival rates, 55% and 39%, respectively, compared with 87% at both 5 years and 10 years in patients with mucoepidermoid carcinoma (MEC) yet remained better than the outcome of patients with typical lung carcinoma [20].
Future Directions
Response to chemotherapy remains poor. There has been increasing interest in exploiting the over-expression of c-kit protein in salivary gland ACC (in upto 80-90% of cases), but the clinical outcome remains limited. In a phase II study of cisplatin and imatinib in advanced head and neck salivary gland ACC, 8 out of 28 patients showed partial response and 19 patients had useful stabilisation of disease. The median time to progression and overall survival was 15 months (range 1-43) and 35 months (range 1-75) [21], although in another phase II study of Imatinib for ACC of head and neck salivary glands, it had no major effect on the disease [22].
Conclusion
ACC of the lung, although rare, is an important type of lung
cancer that is encountered. The evidence to date from retrospective
case series, suggests that most ACC of the lung are indolent and slow
growing.
Smoking may be related to the incidence of ACC of the lung.
Further data needs to be collected to establish a more definite
relationship. The main stay of curative treatment is with surgery. The
role of radiotherapy remains unclear and further studies are needed
to establish the need for radiotherapy in the radical treatment setting
and in the palliative setting too. Chemotherapy has not shown any
benefit in the majority of patients. The role of oral targeted therapies
such as TKIs and immunotherapy need to be investigated in this
subset of lung cancer patients.
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