Adenoid Cystic Carcinoma of Submandibular Salivary Gland With Late Metastases to Lung and Choroid: A Case Report and Literature Review

Adenoid Cystic Carcinoma of Submandibular Salivary Gland With Late Metastases to Lung and Choroid: A Case Report and Literature Review

Accepted Manuscript Adenoid cystic carcinoma of submandibular salivary gland with late metastases to lung and choroid: a case report and literature re...

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Accepted Manuscript Adenoid cystic carcinoma of submandibular salivary gland with late metastases to lung and choroid: a case report and literature review Qian Cai, MD Ruiguang Zhang, MD, PHD Gang Wu, MD, PHD Xiaorong Dong, MD, PHD PII:

S0278-2391(14)00438-8

DOI:

10.1016/j.joms.2014.04.011

Reference:

YJOMS 56293

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 8 February 2014 Revised Date:

14 April 2014

Accepted Date: 14 April 2014

Please cite this article as: Cai Q, Zhang R, Wu G, Dong X, Adenoid cystic carcinoma of submandibular salivary gland with late metastases to lung and choroid: a case report and literature review, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/j.joms.2014.04.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title page Article title:

Adenoid cystic carcinoma of submandibular salivary gland

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with late metastases to lung and choroid: a case report and literature review

Authers:

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Qian Cai, MD, Cancer Center, Union Hospital, Tong Ji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: [email protected] Tel: +86013476018828 Ruiguang Zhang, MD, PHD, Cancer Center, Union Hospital, Tong Ji Medical College, Huazhong University of Science and Technology, Wuhan, China Email: [email protected] Tel: +86015071116898

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Gang Wu, MD, PHD, Cancer Center, Union Hospital, Tong Ji Medical College, Huazhong University of Science and Technology, Wuhan, China Email: [email protected] Tel: +86013871240042

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*Corresponding author. Xiaorong Dong, MD, PHD.

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Affiliations: Cancer Center, Union Hospital, Tong Ji Medical College, Huazhong University of Science and Technology, Mailing address: Wujiadun 156, Hankou, Wuhan, Hubei, China Post code:430000

Email: [email protected]

Tel: +86013986252286

ACCEPTED MANUSCRIPT Adenoid cystic carcinoma of submandibular salivary gland with late metastases to choroid Qian Cai, Ruiguang Zhang, Gang Wu, Xiaorong Dong1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of

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Science and Technology, Wuhan 430022, China

ABSTRACT: Purpose

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Adenoid cystic carcinoma (ACC) is a rare type of cancer that can exist in many body sites. Distant metastasis (DM) is one of the most common features of ACC, usually occuring several years after the initial diagnosis. Approximately half of ACC patients

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are found to develop DM after initial treatment of the primary tumor. Here we present a case of ACC with late metastasis to the lung and choroid, which is extremely rare.

Materials and Methods

A 43-year old female patient had a history of adenoid cystic carcinoma of

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submandibular salivary gland. Five years after total resection and postoperation radiotherapy, distant metastases were found in the left lung and left choroid by

Result

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immunohistochemistry and imaging examinations.

After radiotherapy for the lesions of the lung and eye, the patient had a partial

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response and remained progression-free at almost 7 months.

Conclusion

Although many metastatic sites have been reported, currently, there are only six cases in the literature about ACC metastasizing to the choroid. For those metastatic ACC patients, although modality treatments including chemotherapy and/or radiotherapy 1

Corresponding author: Xiaorong Dong, Cancer Center, Union Hospital, Tongji

Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 430022. E-mail: [email protected] Tel: +86-13986252286

ACCEPTED MANUSCRIPT were given, most patients have continuous metastasis and fatal outcome.

KEY WORDS: adenoid carcinoma, submandibular salivary gland, lung metastasis, choroidal metastasis, radiotherapy

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INTRODUCTION

Adenoid cystic carcinoma (ACC) is a rare type of cancer that can occur in many body sites. It occurs primarily in the head and neck, and in particular, the salivary glands. ACC is an indolent carcinoma, and grows steadily. Distant metastasis usually

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happen late in the late clinical course. Here we present a 43-year old female patient with a history of adenoid cystic carcinoma of submandibular salivary gland. Five

found, which is extremely rare.

CASE REPORT

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years after initial treatment, distant metastasis in the left choroid of the eyeball was

A 43-year old female was subjected to the total resection of a tumor in the left submandibular gland in 2009. Pathological examination confirmed the diagnosis of

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adenoid cystic carcinoma with perineural invasion (fig. 1A and 1B). In the local hospital, postoperative radiotherapy was then given: 32 Gy by 16 fractions in photon therapy followed by 30 Gy by 15 fractions in electronic therapy. The radiation field

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included the tumor bed and the entire left neck. The patient was admitted to our hospital in November 2012 because of painless but progressive deterioration of vision of her left eye for one month. Ultrasonography

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revealed a space-occupying lesion in the globe. A whole body PET-CT scan was then performed to identify the primary tumor, that displayed a hypermetabolic mass in the left lower lobe of the lung (fig. 2A), with enlarged subcarinal and left hilar lymph nodes (fig. 2B). Additionally, the rear of her left globe showed increased isotope uptake (fig. 2C). Physical examination showed the left and right vision acuity was 20/80 and 20/20, respectively. CT-guided biopsy of the mass in the lung was performed. Immunohistochemistry showed strong reactivity for CK5/6 (fig. 3A), CK7 (fig. 3B), CK8/18 (fig. 3C), CD117 (fig. 3D), calponin (fig. 3E), and smooth muscle actin (SMA) (fig. 3F), while the tumor was negative for CK20, P63, S-100,

ACCEPTED MANUSCRIPT synaptophysin (Syn) and thyroid transcription factor-1 (TTF-1). Pathologically, the diagnosis of metastatic tubular adenoid cystic carcinoma was made. Differential diagnoses included primary and metastatic ACC of the lung. The possibility of primary ACC could not be ruled out by the above systemic evaluation. However, a clinical diagnosis of metastatic ACC was established based on her

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previous history of adenoid cystic carcinoma of the submandibular gland.

The patient then received chemotherapy of docetaxol (75 mg/m2, Day 1) plus cisplatin (75 mg/m2, Day 1) for four cycles. The partial response (PR) was obtained.

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Radiotherapy was given by standard 3-dimensional conformal radiotherapy (3DCRT). The gross target volume (GTV) included left lower lung tumor and the enlarged mediastinal and hilar lymph nodes with a total dose of 66 Gy/33 fractions. The

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clinical target volume (CTV) was defined from GTV plus 6 mm a three dimensional margin. Planning target volume (PTV) was defined from CTV plus 10mm three dimensional margin with 50Gy/25 fractions. During the radiotherapy, she complained painful swelling and excessive tearing of her left eye. A magnetic resonance imaging (MRI) showed a tumor in her left globe. Transverse T1-weighted MRI of the left eye

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showed normal signal in the upper part of the tumor, whereas slight hyperintense signal in the lower part. Transverse T2-weighted MRI showed slight hypointense signal. The upper part of tumor mass showed inhomogeneous enhancement in enhanced T1-weighted MR image (fig. 4). A funduscopy (fig. 5) confirmed the

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location of the mass in the choroid of the eyeball. Based on her previous history, these features suggested a metastasis to the left

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choroid with bleeding. After the radiotherapy for lung metastasis, radiotherapy for the metastatic disease in the left choroid and retrobulbar tissue was given intensitymodulated radiation therapy (IMRT), because of her refusal of resection of her left eye mass. The left eye mass and soft tissue behind the globe received radiotherapy, with 50 Gy/25 fractions and then tumor inside the eye was boosted to 10 Gy/5 fractions. During the radiotherapy of choroid metastasis, the clinical symptoms were relieved. One month later, a second MRI examination showed the volume of the mass in her choroid shrunk by almost 50% (fig. 6). The lesion in her left lung also reached partial response (fig. 7). Since then, the patient remained progression-free at almost 7 months.

ACCEPTED MANUSCRIPT DISCUSSION ACC, first described by Billroth in 18561, is a rare type of cancer that can occur in many body sites. It is seen primarily in the head and neck, and in particular, the salivary glands. It has also been reported that ACC can occur in the external

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auditory canal, nasopharynx, lacrimal glands, breast, vulva, esophagus, cervix, and Cowper glands2-5. The palate is the most common site involved intraoral6. Besides, ACC can also locate in minor salivary glands and tongue7, 8. It accounts for less than 1% of all malignancies that arise from head and neck, and about 10% of all salivary 10

. ACC is defined as a “basaloid tumor consisting of epithelial and

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tumors9,

myoepithelial cells in various morphological configurations, including tubular, cribriform and solid patterns. It has a relentless clinical course and usually fatal

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outcome”9. ACC is recognized as an indolent, but persistently growing carcinoma. It has a prolonged clinical course, but often develops distant metastasis (DM) late in the clinical course11-13.

Three histological subtypes of ACC are known, as described above: the cribriform, tubular, and solid subtypes. Among the three subtypes, the solid subtype is 14, 15

. The immunohistochemistry plays an important role in

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the most aggressive9,

identifying the current case. CD117 was strongly expressed in this carcinoma. P63, S100 and SMA are intensely stained in myoepithelial cells16, 17. In contrast, CK5 and CK7 are expressed in luminal cells17. The case presented was supported by these

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features, which is in accordance with other reported cases16, 17. The peak incidence of ACC among people is from 40 to 60 years of age11, 15, which suggests that ACC is predominately a tumor of adulthood. Although a 1:1.3

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male to female ratio was observed11, another report demonstrated ACC with a slight female predominance, 3:2 male to female ratio18. However, there is no apparent predominance by sex within Chinese populations15. The typical clinical symptom involves a slow-growing, firm, unilobular mass in the gland. An important associated symptom is painful swelling. Sometimes clinical symptoms are ignored so the tumor can grow rather large. The initial treatment of ACC is wide resection of primary tumor combined with postoperative radiation therapy. The neck dissection should be oriented or selected in order to identify levels of lymph node encompassed in the dissection19. Postoperative radiotherapy is considered to improve the local control, but not

ACCEPTED MANUSCRIPT necessarily survival20. The recommendation of adjuvant radiotherapy often depends on putative prognostic indicators, which includes stage, tumor site, microscopic or gross disease at the surgical margin, histological type, and perineural or perivascular invasion20. In previous reports, the dose of adjuvant radiotherapy ranged from 44 to 68.4 Gy, with a mean dose of 60 Gy20, 21, 22. Patients who received a dose greater than

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60 Gy after surgery were reported to have significantly higher local control rates than those who received less than 60 Gy23. The total dose should be no less than 66 Gy. In cases with a positive margin, the dose should reach 66 to 70 Gy. It seems that cisplatin, as well as high-dose melphalan, chemotherapy should cause a favorable result, but no statistically significant difference was confirmed in survival compared

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to placebo24, 25.

DM is one of the most common features of ACC, and usually occurs as a

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sign of the late course of disease26. Sung et al12 reported that the median DM interval was 48 months after the initial treatment in 46 ACC patients. The most common site of metastasis is lung15. However, ACC can also metastasize to other organs including bone, cerebrum, liver, thyroid, and spleen.27 Lung metastases usually progress slowly. On the contrary, bone metastases indicate a rapid progression28, 29. In our case, the

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patient developed lung failure five years after the initial treatment, which indicated a mild progression. DM may still develop even if local control has been achieved.

There are some factors associated with DM in ACC patients. Perineural invasion

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has been concerned to be an unfavorable prognostic factor, associated with DM and adverse final outcome11, 30. In addition, previous studies have demonstrated a higher rate of DM with positive surgical margin in Chinese, Italian, and American

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populations11, 31,32. Solid subtype, primary tumor larger than 3 cm, primary tumor located in the minor glands of oral cavity and pharynx, local recurrence, and cervical lymph node involved were also demonstrated9, 33. Compared with DM, local lymph node metastases are rare, but it is also a predictor of negative outcome34. So far, there are only six literature reports of DM to the choroid35-40 (table 1). Among these cases, the tumor in 5 cases arose from submandibular gland35, 374-40, and one was located in palate40. There is a significant female predominance, with a 1:5 male to female ratio. Our case also aligns to the above observation. One case reported a choroid metastasis synchronous with the initial diagnosis of palatal ACC36. In the other cases, the interval from initial treatment of the primary tumor to choroid

ACCEPTED MANUSCRIPT metastasis ranges from 10 months to 5 years35,

37-40

. Three of the patients who

developed choroidal metastasis received external beam radiotherapy35, 37, 39, with total doses ranging from 30 to 65 Gy. Three patients refused to receive any treatment36, 38, 40

. Unfortunately, most of the reported cases were lost follow-up. As a result, the

authors cannot be certain whether there is any relation between treatment and

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prognosis. 1/3 to 1/2 of ACC patients were found to develop DM while the primary tumor was under complete control9, 33. The median time to distant failure after initial treatment of primary tumor is 47.7 months9. For those metastatic ACC patients, although modality treatments including chemotherapy and/or radiotherapy were given,

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most patients develop metastases9.

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CONCLUSION

ACC is a rare type of cancer, which has been reported to exist in many body sites. Almost half of ACC patients develop late DM. Among those metastatic sites, lung is the most common one. There are six cases of DM to the choroid. Among those cases, a significant female predominance is revealed. Four patients, including the present case, received external beam radiotherapy of choroid metastases. However,

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the authors cannot recommend the best treatment modality of ACC with choroid DM.

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2001;96:149-158.

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34. Conley J, Dingman DL. Adenoid cystic carcinoma in the head and neck

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36. Gutmann SM, Weiss JS, Albert DM. Choroidal metastasis of adenocystic

carcinoma of the salivary gland. Br J Ophthalmol 1986;70:100-103. 37. Jenrette JM, Fitzgerald RH Jr. Metastasis to the choroid complicating adenoid

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carcinoma of the submandibular gland. India J Ophthalmol 2008;56(1):75-6.

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39. Demirci H, Vine AK, Elner VM. Choroidal metastasis from submandibular

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Table 1 Previous cases of ACC of salivary gland metastasized to choroid:

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No.

report (ref.)

Age (years) /Sex

Location of

Surg.

Chemo

RT

Time to

Treatment

Time to

primary

the

after the

progression

tumors

choroid

choroid

after the

DM

DM

choroid DM

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Series/case

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Case

1

Shields JA

51/F

(35) 2

Gutmann

Submandibular

Hard palate

N

Y

14

RT

ND

ND

N

N

N

12

Surg

With liver

ND

(37) 4

John SS (38)

Submandibular gland

56/F

simultaneously

ND

ND

ND

11

RT

ND

ND

Y

Y

10

N

ND

Six weeks

Submandibular gland

metastasis

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57 /F

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Jenrette JM

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SM (36)

3

(Month)

Y

gland 88/M

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(Month)

OS

Y

(Carboplatin

after the

and 5-

choroid DM

fluorouracil)

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50/F

6

Sautter H (40)

Y

N

Y

60

gland

ND

Submandibular

ND

ND

gland

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ND: not described; RT: radiotherapy; OS: overall survival

RT

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(39)

Submandibular

ND

ND

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Demirci H

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5

ND

3

Four months after the choroid DM

ND

ND

ACCEPTED MANUSCRIPT Figure legends: Fig. 1 Histopathologic features of submandibular gland ACC A: Tumor cells with hematoxylin & eosin (HE) stain (original magnification ×100), which consists of ductal cells and myoepithelial cells. The myoepithelial cells are predominant and have scant cytoplasm. ACC was

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diagnosed pathologically; B: Hematoxylin & eosin stain for tumor cells (original magnification ×200)

Fig. 2 A hypermetabolic mass in the left lower lobe (A), with enlarged subcarinal and

left eyeball showed increased density (C).

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left hilar lymph nodes (B) under PET-CT scan. Additionally, the rear of the

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Fig. 3 Immunohistochemistry of metastatic ACC in the left lower lobe Strong reactivity for CK5/6 (A), CK7 (B), CK8/18 (C), CD117 (D), Calponin (E), and smooth muscle actin (SMA) (F) Fig. 4 A metastasis in the left eye under MRI

A: Transverse T1-weighted MRI of left eye showing normal signal in the upper part

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of the tumor; B: Transverse T2-weighted MRI showing slight hypointense signal; C: The upper part of tumor mass showing inhomogeneous enhancement in enhanced T1-weighted MRI

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Fig. 5 A metastasis in the choroid of the left eye under fundoscopy

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Fig. 6 MRI preformed one month after radiotherapy of the metastasis of choroid, showing the mass shrunk significantly

A: T1-weighted MRI one month after radiotherapy; B: T2-weighted MRI one month after radiotherapy

Fig. 7 CT scan re-examination one month after the radiotherapy of the lesion in the left lung, showing a partial response A: The metastatic lung lesion after radiotherapy in the lung window; B: The metastatic lung lesion after radiotherapy in the mediastinal window

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