B-ENT, 2016, 12, 235-240
Nasopharyngeal thyroid-like low-grade papillary adenocarcinoma D. Borsetto1, D. Cazzador1, V. Prosenikliev1, A. Zanon1, T. Volo1, F. Marino2 and E. Emanuelli1 1 Department of Neuroscience, Operative Unit of Otorhinolaryngology, University of Padua, Via Giustiniani, 2, 35125, Padua, Italy, 2Department of Pathology, University of Padua, via Giustiniani 2, 35125, Padua, Italy
Key-words. Papillary adenocarcinoma; nasopharynx; endoscopic endonasal surgery; nasopharyngeal adenocarcinoma; epistaxis Abstract. Objective: Epistaxis is extremely common in children. Although rare, the presence of an intranasal mass as a cause of bleeding should be ruled out in patients with recurrent or massive epistaxis. We present a patient whose recurrent nose-bleeding had been due to a nasopharyngeal mass. Methods: Case report with relevant literature review. Results: A 15-year-old girl with a history of sudden posterior nasal bleeding was diagnosed with thyroid-like low-grade nasopharyngeal papillary adenocarcinoma of the nasopharynx. A type II nasopharyngeal endoscopic resection was performed with an excellent outcome at 30-months follow-up. The literature review on the topic disclosed only five other paediatric cases, none of which presented with epistaxis. Conclusions: Recurrent epistaxis may infer the presence of nasopharyngeal malignant neoplasms, even in children. To our knowledge, this represents the sixth case in the literature of a paediatric low-grade nasopharyngeal adenocarcinoma and the first presenting with massive epistaxis. The possibility of such a finding should be kept in mind when evaluating children with massive epistaxis.
Introduction Though rare prior to the age of two, epistaxis is extremely common among children up to the age of 10. Thirty per cent of all children aged ≤ 5 years, 56% of those aged 6-10 years and 64% of those aged 11-15 years have had at least one episode of epistaxis in their lifetime.1 In young males, severe unilateral nose bleeding and nasal obstruction are common features, suggestive of juvenile angiofibroma.1 Referral to the ENT is mandatory for endoscopic examination, radiological imaging and when indicated, a biopsy if a tumour is suspected. Among all malignancies, nasopharyngeal cancer is relatively uncommon in Western countries,2 while its incidence is higher in South-East Asia. Undifferentiated carcinoma is the most common malignant epithelial nasopharyngeal tumour and it has been associated with Epstein-Barr virus (EBV) infection.3 Primary nasopharyngeal adenocarcinomas account for only 0.7% of all nasopharyngeal carcinomas.4 They are classified as salivary-gland type adenocarcinoma and lowgrade papillary adenocarcinoma. The so-called thyroid-like type represents a distinctive subtype of the latter.5 Even in endemic areas, nasopharyngeal
borsetto.indd 235
papillary adenocarcinoma (NPA) is extremely rare and its association with EBV remains unclear. The prognosis is excellent after complete surgical resection.6 This is partly because of its rarity; little is known about the aetiopathogenesis of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLGNPPA). In this paper we describe the clinical case of a 15-year-old girl treated for primary TLLGNPPA with copious epistaxis as a presenting symptom. A relevant review of the paediatric literature was conducted. Case report A 15-year-old girl was referred to our institution due to the sudden onset of posterior nose bleeding. Rigid endoscopy identified a pedunculated vegetating nasopharyngeal lesion originating from the bony ridge of the vomer (Figure 1a). After partially successful nasal packing, a contrast-enhanced computed tomography (CT) was performed, with evidence found of a nasopharyngeal obliterating contrast-enhanced mass with no signs of bone erosion (Figure 1b). The patient underwent emergency surgery in order to control the bleeding
6/10/16 12:10
236
D. Borsetto et al local residual tumour. A type II nasopharyngeal endoscopic resection (NER) was performed.7,8 The resection included the anterior wall and the floor of the sphenoid sinus, as well as the posterior third of the nasal septum and the intersphenoidal septum. Histology identified persistent microlocalization of TLLGNPPA, which was resected with free surgical margins. The patient was followed-up with monthly endoscopies during the first year, every two months during the second year and every four months during the third year. Contrast-enhanced MRI was repeated every six months during the first two years. At 30 months of follow-up there was no evidence of local recurrence (Figure 3). The literature concerning low-grade nasopharyngeal papillary adenocarcinoma in the paediatric population was reviewed (Table 2).
and to perform a subtotal resection of the lesion for diagnostic purposes. The patient’s hospital stay was two days. No intra- or perioperative complications were observed. Macroscopically, the tumour was soft and gritty with an exophytic and papillary appearance. Microscopically, it showed papillary features and the columnar lining or pseudostratified cells contained bland, round-to-oval nuclei, as well as minute nucleoli; mitotic figures were rare and there were foci of necrosis. No EBV was detected in the tumour tissue for the in situ hybridization assay to identify small EBV-encoded RNA, or on PCR amplification, performed for seeking out the EBV LMP-1 oncogene. A polymerase chain reaction assay was performed on genomic DNA to detect HPV, with negative results. As shown in Table 1, the tumour tissue was strongly and diffusely immunoreactive for thyroid transcription factor 1 (TTF-1), pancytokeratin, CK7, CK19 and oestrogen receptors. The Ki67labeling index reached 4% in the most intensively staining tissue area. Based on these histological and immunohistochemical findings, a diagnosis of TLLGNPPA was established. The patient underwent staging with F-18fluorodeoxyglucose positron emission tomography (Figure 2) and contrast-enhanced magnetic resonance (MRI) of the head and neck. The imaging ruled out any thyroid neoplasms, regional or distant metastases, but provided evidence of a
A
Discussion Epistaxis in children is rarely severe and generally does not require nasal packing or hospital admission. In most cases, the bleeding is spontaneous, anterior and self-limiting. A primary cause can only be identified in a small proportion of cases; otherwise, when no underlying cause is recognized, the epistaxis is defined as idiopathic. Blood dyscrasia, blood vessel abnormalities and vestibulitis are rare differential diagnoses in children. In 2014, Patel et al.9 reported that an abnormal coagulation pattern was evident in 4.6%
B
Figure 1 a) Intraoperative endoscopic view of a nasopharyngeal lesion; b) cranial CT with contrast enhancement: the nasopharyngeal mass (asterisk) obliterates the nasopharynx without evidence of bone erosion.
borsetto.indd 236
6/10/16 12:10
237
Thyroid-like adenocarcinoma of the nasopharynx Table 1 Summary of immunohistochemical findings. Antibody
Clone
Source
Dilution
DAKO
1:50
TTF1
4C1/E1/G8
Novocastra
Pan CK
MN116
DAKO
TG
DAK-Tg6
DAKO
1:100
+
DAKO
1:25
-
DAKO
CK 19
RCK108
DAKO
CK 20
Vimentin P63
S100
SMA ER
P53
B-catenin Ki 67 TSH
K20,8
Vim 3b4
DAKO
DAK-p63
DAKO
Polyclonal
DAKO
1:50
1:50
1:50
-
Novocastra
1:100
DAKO
1:50
MIB1
4C1/E1/G8
Novocastra Novocastra
-
1:50
1:2000
DO7
17C2
+
-
DAKO
DAKO
-
RTU
1A4 EP1
-
+
D5/16 B4 OV-TL
+
1:50
CK 5/6 CK 7
1:50
Result
-
RTU
+
1:50
-
1:25
-
+ 4% -
TTF-1: thyroid transcription factor-1; TG: thyroglobulin; ER: oestrogen receptor; TSH: thyroid stimulating hormone receptor; CK: cytokeratin; SMA: smooth muscle actin.
Figure 2 Local residual tumour confirmed by F-18-fluorodeoxyglucose positron emission tomography. The nasopharyngeal residual mass had an average SUV of 3.51 and a volume of 1.29 cm3.
of patients with nasal bleeding in their series. The incidence of coagulation disorders was in the range of 10.6% to 33% in patients with increased activated partial thromboplastin time.9 In addition
borsetto.indd 237
to laboratory tests, the diagnostic workup for children with recurrent epistaxis should include flexible or rigid nasal endoscopy. A biopsy is indicated when a neoplastic aetiology is suspected. In the same patient series as above, when flexible nasal endoscopy was performed, it revealed nasal masses as the primary cause of epistaxis in 3.3% of children, despite only 0.8% of the cases being diagnosed with worrisome masses.9 In our case, epistaxis was the presenting symptom of an extremely rare malignant nasopharyngeal neoplasm in a 15-year-old girl. To date, there have been no reports in the literature of malignant nasopharyngeal masses being the primary cause of nasal bleeding in female adolescents. Our patient was diagnosed with a nasopharyngeal adenocarcinoma in its thyroid-like variant. The literature distinguishes between two types of primary nasopharyngeal adenocarcinomas. The salivary-gland type arises from the submucosal seromucous glands and tends to be aggressive, while the low-grade papillary adenocarcinoma originates from the mucosal surface glands of the nasopharynx and is termed low-grade10 due to its slow and indolent growth. Only small case series of NPA have been described in the English literature,
6/10/16 12:10
238
Patient
D. Borsetto et al Table 2 Low-grade papillary nasopharyngeal adenocarcinoma: review among the paediatric population.
1
Wenig et al.10
Author
Age
Sex
2
Wenig et al.10
11
M
3
Carrizo and Luna14
9
M
4
Carrizo and Luna14
13
M
6
Our case
15
F
5
Ozer et al.13
11
17
M
F
Symptoms
Surgical approach
Diagnostic delay
Follow-up
Incidental finding during adenoidectomy
Transpalatal
-
1 year
Nasal fullness, blood in saliva
Transpalatal
3 months
2 years
Nasal obstruction Nasal obstruction
Transpalatal
2 months
15 years
Epistaxis
Endoscopic
Endoscopic
hours
2.5 years
Nasal obstruction
A
Transpalatal
hours
6 months
6 years
1 year
B Figure 3
a) Contrast-enhanced MRI at 30 months is negative for persistent tumour invasion; b) endonasal endoscopy at 30 months shows no sign of macroscopic recurrences.
with a mean overall prevalence of 17.9% cases among all nasopharyngeal adenocarcinomas.4,10,11 No difference in gender distribution has been reported and the mean age at diagnosis was roughly 38 years.4,6 TLLGNPPA represents an extremely rare subset of low-grade NPA5: only 13 cases have been reported in the literature to date. The median age of patients was 34 years (range: 9 to 68 years).12 Only five cases of low-grade papillary nasopharyngeal adenocarcinoma have been reported in the paediatric population13,14 (Table 2) and three of them were diagnosed as TLLGNPPA. Including the present case, the male-to-female ratio is 2:1 in the paediatric population. The roof
borsetto.indd 238
of the nasopharynx was the most common site of origin. Presenting symptoms may be subtle and half of the children diagnosed with TLLGNPPA reported nasal obstruction. None of the patients had epistaxis as a presenting symptom. Including ours, all patients with TLLGNPPA described in the literature underwent surgery with curative intent. Only in recent times has nasopharyngeal lesions become approachable and resectable using a transnasal endoscopic procedure achieving free surgical margins.7 A minimally-invasive endoscopic approach had previously been employed only once in the paediatric population.13 The NER for the treatment of selected primary and locally recurrent nasopharyngeal tumours has proved effective for
6/10/16 12:10
239
Thyroid-like adenocarcinoma of the nasopharynx local disease control and for the quality of life of patients. In experienced hands, this approach appears to be the surgical technique with the lowest rate of complications and can therefore be considered the treatment of choice.7,13 In the reported case, the lesion was confined to the nasopharynx with no involvement of the surrounding structures, lymph nodes or distant metastases, consistent with other cases described in the literature. To the best of our knowledge, an association between EBV and primary TLLGNPPA has rarely been disclosed. Only three published studies tested for EBV in the pathological tissue and found no association.6,14,15 It is of the utmost importance to differentiate TLLGNPPA from other types of nasopharyngeal adenocarcinoma by means of a thorough histopathological examination. NPA generally tends to have an exophytic or infiltrating growth pattern, rather than being submucosal or encapsulated.3 NPA arises from the surface epithelium and comprises arborizing, delicate papillary fronds and crowded glands (Figure 4). The columnar lining or pseudostratified cells have bland, roundto-oval nuclei, fibrovascular cores and miniscule nucleoli. These neoplasms are unencapsulated and infiltrating and mitotic figures are rare. As the term ‘TLLGNPPA’ stems from the close histological resemblance to papillary thyroid carcinoma,13 immunohistochemical studies are also needed to ensure an appropriate differential diagnosis to rule out papillary thyroid carcinoma. Immunostaining for thyroglobulin (TG) is usually negative in TLLGNPPA12; however, Ozer et al. recently reported on a case of TLLGNPPA with focal TG staining.13 Oishi et al. suggested looking for BRAF V600E, the most common mutation found in papillary thyroid carcinoma, in order to rule out the possibility of this neoplasm.12 The most important diagnostic feature of TLLGNPPA, on the other hand, is a positive indication for TTF1, found in all cases described to date. However, abnormal TTF-1 expression in TLLGNPPA remains controversial and further studies, including molecular analyses, are required.12
A
B
C Figure 4 Haematoxylin and eosin stain of the surgical specimen. The morphological picture shows a tumour with papillary features and some cell atypia with progressive microscopic enlargements: a) 100X; b) 200X; c) 400X.
Conclusion Epistaxis is an extremely common condition. More than 60% of children and adolescents up to 15 years of age experience at least one
borsetto.indd 239
episode during their lives. Patients with massive, recurrent epistaxis should be referred to an ENT department to look for a local or systemic cause.
6/10/16 12:10
240 Although nasopharyngeal tumours are rare, they can occur in children, too. Primary thyroid-like nasopharyngeal papillary adenocarcinoma is an extremely uncommon diagnosis; however, even in children, it can be responsible for nose bleeding. Complete endoscopic tumour resection provides good outcomes, no comorbidities and excellent quality of life. Acknowledgements The authors thank Frances Coburn for correcting the English version of this paper. References 1. Qureishi A, Burton MJ. Interventions for recurrent idiopathic epistaxis (nosebleeds) in children. Cochrane Database Syst Rev. 2012;9:1-23. 2. Berkiten G, Kumral TL, Yildirim G, Uyar Y, Atar Y, Salturk Z. Eight years of clinical findings and biopsy results of nasopharyngeal pathologies in 1647 adult patients: a retrospective study. B-ENT. 2014;10(4):279284. 3. Fu CH, Chang KP, Ueng SH, Wu CC, Hao SP. Primary thyroid-like papillary adenocarcinoma of the nasopharynx. Auris Nasus Larynx. 2008;35(4):579-582. 4. Pineda-Daboin K, Neto A, Ochoa-Perez V, Luna MA. Nasopharyngeal adenocarcinomas: a clinicopathologic study of 44 cases including immunohistochemical features of 18 papillary phenotypes. Ann Diagn Pathol. 2006;10(4):215-221. 5. Perez-Ordonez B. Hamartomas, papillomas and adenocarcinomas of the sinonasal tract and nasopharynx. J Clin Pathol. 2009;62(12):1085-1095. 6. Sillings CN, Weathers DR, Delgaudio JM. Thyroid-like papillary adenocarcinoma of the nasopharynx: a case report in a 19-year-old male. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;110(3):e25-28. 7. Castelnuovo P, Dallan I, Bignami M, Battaglia P, Mauri S, Bolzoni Villaret A, Bizzoni A, Tomenzoli D, Nicolai P. Nasopharyngeal endoscopic resection in the management of selected malignancies: ten-year experience. Rhinology. 2010;48(1):84-89.
borsetto.indd 240
D. Borsetto et al 8. Emanuelli E, Albu S, Cazzador D, Pedruzzi B, Babighian G, Martini A. Endoscopic surgery for recurrent undifferentiated nasopharyngeal carcinoma. J Craniofac Surg. 2014;25(3):1003-1008. 9. Patel N, Maddalozzo J, Billings KR. An update on management of pediatric epistaxis. Int J Pediatr Otorhinolaryngol. 2014;78(8):1400-1404. 10. Wenig BM, Hyams VJ, Heffner DK. Nasopharyngeal papillary adenocarcinoma. A clinicopathologic study of a low-grade carcinoma. Am J Surg Pathol. 1988;12(12):946-953. 11. Guo ZM, Liu WW, He JH. A retrospective cohort study of nasopharyngeal adenocarcinoma: a rare histological type of nasopharyngeal cancer. Clin Otolaryngol. 2009;34(4):322-327. 12. Oishi N, Kondo T, Nakazawa T, Mochizuki K, Kasai K, Inoue T, Yamamoto T, Watanabe H, Hatsushika K, Masuyama K, Katoh R. Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: case report and literature review. Pathol Res Pract. 2014;210(12):1142-1145. 13. Ozer S, Kayahan B, Cabbarzade C, Bugdayci M, Kosemehmetoglu K, Yucel OT. Thyroid-like papillary adenocarcinoma of the nasopharynx with focal thyroglobulin expression. Pathology. 2013;45(6):622-624. 14. Carrizo F, Luna MA. Thyroid transcription factor-1 expression in thyroid-like nasopharyngeal papillary adenocarcinoma: report of 2 cases. Ann Diagn Pathol. 2005;9(4):189-192. 15. Ohe C, Sakaida N, Tadokoro C, Fukui H, Asako M, Tomoda K, Uemura Y. Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: report of two cases. Pathol Int. 2010;60(2):107-111.
Diego Cazzador, MD Department of Neuroscience, Operative Unit of Otorhinolaryngology, University of Padua, Italy Via Giustiniani 2 35128 Padua, Italy Tel.: +39 0498218778 Fax: +39 0498211994 Email:
[email protected]
6/10/16 12:10
