Primary Pituitary Adenoid Cystic Carcinoma: A Rare Salivary Gland-Like Tumor in the Sella

Abstract

Adenoid cystic carcinoma (ACC) is a tumor of the exocrine glands that originates primarily from the minor and major salivary glands, nasopharynx, and lacrimal glands. ACC grows slowly but is locally aggressive and prone to recurrence. It is uncommon for ACCs to develop in the pituitary gland as a primary tumor. We present a case of primary pituitary ACC extending to the sphenoid sinus resembling an invasive adenoma in a 71-year-old woman with a history of nasal epistaxis. We reviewed other reported cases of pituitary ACCs with retrospective validation of whether the tumor was primary or not. The intrasellar tumor exhibited MYB rearrangement with enlargement and destruction of the sella turcica and dural tears toward the sphenoid sinus, which would be consistent for a tumor originating from the pituitary gland. Including our case, only four intrasellar and one suprasellar ACC have been confirmed as primary tumors. All intrasellar ACCs had the characteristic of some form of invasion of neighboring structures with evidence of hyperprolactinemia. ACC could develop in the pituitary gland as a form of salivary gland-like tumor derived from the ectopic salivary gland rests. ACCs rarely arise from the pituitary gland; however, the accurate determination of primary occurrence is difficult because of the invasive nature of these tumors, and the anatomical relationship with the sphenoid sinus and the cavernous sinus. Excessive bleeding from the tumor or unexpected internal carotid artery injury should be avoided during surgery for primary and secondary pituitary ACC.

Introduction

Adenoid cystic carcinoma (ACC) is a malignant epithelial tumor of the exocrine glands accounting for approximately 10% of all epithelial salivary neoplasms. They originate not only from the minor salivary glands but also the lacrimal glands, nasopharynx, bronchus, breast, and intestinal as well as genitourinary tracts [1–3]. Sinonasal ACCs account for 5% to 15% of all malignant sinonasal tumors [3], representing approximately 13% of all ACCs of the head and neck [4]. ACCs are typically slow-growing but locally aggressive tumors that are prone to recurrence. They often invade the cranial base not only directly but also indirectly, where sinonasal or lacrimal ACCs spread through the cranial nerves (referred to as “perineural spreading”) in particular, with rates of cranial base invasion between 4 and 22% [5]. Although primary ACCs of the sphenoid sinus represent only 3–4% of all sinonasal ACCs [3, 6, 7], they can potentially invade the surrounding region, including the sellar turcica.

Recent studies have indicated that a recurrent t(6;9)(q22–23:p23–24) chromosomal translocation in ACC results in a MYB proto-oncogene transcription factor-nuclear factor I/B (MYB-NFIB) gene fusion, which is detected in 59.1% of head and neck ACCs [8], but has not been observed in any non-ACC malignant tumors of the head and neck [9]. Therefore, the clinical and differential diagnoses of ACC may be aided by the detection of molecular biomarkers, including assessment of MYB-NFIB gene fusion or MYB activation by fluorescence in situ hybridization (FISH) or immunohistochemical staining of MYB proteins. In addition, fusions of MYBL1-NFIB and NOTCH1 mutations have also been reported as common alterations in ACC, being detected in up to 10% of cases [10].

We report an extreme rare case of primary pituitary ACC diagnosed through a combination of radiological, pathological, and intraoperative findings. Although a few cases of pituitary ACC have been reported as a primary tumor to date, the underlying molecular biological findings, including MYB rearrangement and pituitary transcription factors, have not been elucidated yet. We also review the literature for cases of primary, secondary invasive, and metastatic ACCs of the pituitary gland.

Materials and Methods

Case Presentation and Pathological and Immunohistochemical Studies

We describe a case of primary intrasellar ACC in a 71-year-old woman. This study was performed in accordance with the Declaration of Helsinki and written informed consent was obtained from the patient. For pathological examination, tissues were fixed in 10% formaldehyde and embedded in paraffin. The 5 µm-thick sections were stained with hematoxylin and eosin. The remaining serial unstained sections were used for immunohistochemistry. Immunohistochemistry was performed using an immunoperoxidase method with an ENVISION FLEX kit (Agilent/Dako, Tokyo, Japan), using horseradish peroxidase and 3,3′-diaminobenzidine tetrahydrochloride. Protein and endogen peroxidase blockage were performed, and we used primary antibodies and dilution rates as follows: pancytokeratin (clone AE1/AE3; Agilent/Dako; 1:300), smooth muscle actin (clone 1A4; Agilent/Dako; 1:400), p63 (clone DAK-p63, Agilent/Dako; 1:100), p40 (clone BC28, Rosch Diagnostic; prediluted), vimentin (clone V9, Agilent/Dako; 1:9), S-100 protein (clone S-100, Agilent/Dako; 1:500), GFAP (clone BSR189; Dianova, Hamburg, Germany; 1:12), CD117/c-kit (clone EP10; Rosch Diagnostic; prediluted), p16 (clone E6H4, Rosch Diagnostic; prediluted), MYB (clone ANA236B, Abcam; 1:100), growth hormone (polyclonal, Agilent/Dako; 1:4), prolactin (polyclonal, Agilent/Dako; prediluted), adrenocorticotropin (clone 02A3, Agilent/Dako; prediluted), thyroid-stimulating hormone (clone 0042, Agilent/Dako; 1:2), luteinizing hormone (clone C93, Agilent/Dako; prediluted), follicle-stimulating hormone (clone C10, Agilent/Dako; prediluted), Pit-1 (clone HPA050624, Sigma-Aldrich; 1:2000), SF-1 (clone EPR19744, Abcam; 1:1000), T-pit (clone AMAB91409, Sigma-Aldrich; 1:1000), GATA-2 (clone AF2046, R&D systems; 1:200), and ER (clone SP1, Ventana; prediluted). P16 expression was considered as positive if strong and diffuse nuclear and cytoplasmic staining was detected in ≥ 70% of the tumor [11].

FISH Analysis of MYB Rearrangement

Unstained 4-μm paraffin-embedded tissue samples underwent deparaffinization and protease pretreatment steps before being denatured and hybridized overnight using the MYB break-apart probe (ZytoLight SPEC MYB Dual Color, Break Apart Probe; ZytoVision, Germany) according to the manufacturer’s instructions. The tissue sections then underwent saline-sodium citrate washes and were mounted in 4′,6-diamidino-2-phenylindole for nuclei counterstaining. The probe is designed to detect translocations involving the chromosomal region 6q23.3 harboring the MYB gene, and has two probes labeled with green and orange fluorochromes that hybridize at the 5′ and 3′ ends of the MYB gene, respectively. Break-apart signals in ≥ 10% of cells were considered indicative of rearrangement [12].

Literature Review Search Strategy

A literature review was conducted by searching the MEDLINE and PubMed databases for related articles published since 1993. The keywords used were: “adenoid cystic carcinoma,” “cylindroma,” “pituitary,” “sellar,” “sphenoid sinus,” “cavernous sinus,” and “intracranial”. Relevant articles in English, Japanese, French, and Chinese were also retrieved and reviewed to identify additional papers not detected using the database search. The identified articles were reviewed with a focus on retrospective validation of whether or not the tumor originated primarily in the pituitary gland.

Case Presentation

A 71-year-old woman with history of repeat epistaxis was found to have a hemorrhagic nasal polyp. She had a medical history of Hashimoto’s thyroiditis and chronic sinusitis that was treated surgically at the age of 17 years. She underwent surgery for the nasal polyp by otolaryngologists at the referring hospital. The intranasal polyp resection surgery was terminated because of excessive bleeding and the intraoperative discovery that the tumor originated from within the sphenoid sinus.

Given that the pathological diagnosis was distinctly ACC, she was referred to our hospital for further treatment. Computed tomography (CT) of the paranasal sinus showed erosive enlargement from the sellar floor to the dorsum sellae and scalloping of the clival bone (Fig. 1a, b). Magnetic resonance imaging (MRI) revealed that the tumor was located inside the sphenoid sinus and continued to the expanded sella turcica. Dynamic pituitary MRI showed displacement of the pituitary stalk to the right side and compression of the thinned pituitary gland supero-laterally. Cavernous sinus invasion was not evident, except for dural thickening along both paraclival internal carotid arteries and the clivus (Fig. 1c, d). The radiological features of the tumor inside both the sellar and the sphenoid sinus were identical on MRI. Whole body positron emission tomography (PET) imaging revealed no accumulation except for in the presenting lesion and diffusely within the thyroid, due to the known Hashimoto’s thyroiditis. Needle aspiration biopsy of the thyroid confirmed only chronic inflammatory cells without malignancy. Clinical examination revealed no signs of neurological dysfunction including visual function. The morning serum prolactin level was high at 86.3 ng/mL, but anterior pituitary provocative testing using four simultaneous hypothalamic hormones (growth hormone-releasing hormone, corticotropin-releasing hormone, thyrotropin-releasing hormone, and gonadotropin-releasing hormone) indicated normal pituitary function except for delayed gonadotropin response that may have been a consequence of advanced age. The results of bromocriptine and thyrotropin-releasing hormone provocative testing for her hyperprolactinemia excluded the possibility of lactotroph adenoma. Endoscopic examination of the nasal cavity showed that the tumor protruded from the nasal ostium of the sphenoid sinus (Fig. 2a).

Fig. 1.

Radiological findings; preoperative enhanced computed tomography images showing (a: coronal) expansion of the sella turcica by an intrasellar tumor without cavernous sinus invasion, and (b: sagittal) bone erosion of both the sellar floor and the dorsum sellae (red arrow). Preoperative gadolinium enhanced T1-weighted magnetic resonance imaging (MRI) showing displacement of (c: coronal) the pituitary stalk supero-laterally and (d: sagittal) the pituitary gland superiorly. Note that dural thickening is observed along the paraclival internal carotid artery and the clivus (red arrow). e MRI performed postoperatively and immediately after radiotherapy, showing settling of the pituitary gland and disappearance of the dural thickening along the clivus

Fig. 2.

Intraoperative findings; a preoperative endoscopy via the right nostril revealed a tumor with a clot cap protruding from the natural ostium. b Intraoperative photograph showing that the dura of the sellar floor was fully intact, except for a small fenestration at the lower midline of the floor (arrowhead). c The intrasellar region was occupied by a tumor that was yellow and hard but more mucinous than a typical pituitary adenoma (asterisk). d The pituitary gland was confirmed at the superior part of the sella turcica (star)

Since we were unsure about the diagnosis of pituitary ACC, we performed endoscopic endonasal transsphenoidal surgery (eTSS) for further debulking of the tumor, and confirmation of the anatomical and pathological relationships inside the sella turcica and the sphenoid sinus. After creating a wide opening in the sphenoid sinus, the tumor was carefully removed with control of the bleeding. The surrounding bony structures in the sphenoid sinus, except for the sellar floor, remained but were slightly fragile. Therefore, the tumor inside the sphenoid sinus was removed with special attention to avoid injury to the internal carotid artery (ICA). The dura mater of the sellar floor was fully intact, except for a small fenestration at the lower midline floor, which was covered by destructed bony fragments and thickened sphenoid sinus mucosa suspicious of tumor invasion (Fig. 2b). By debulking the tumor with suction and curettage after dural opening, the pituitary gland descended gradually and was eventually confirmed to be located superiorly inside the sella (Fig. 2c, d). The tumor was yellowish and hard but more mucinous than a typical pituitary adenoma.

The collected tumor specimens were divided into respective areas and examined, and all of them had the typical pathological appearance of ACC. Most regions of the tumor inside the sella consisted of typical cribriform patterns with focal components of solid pattern (< 30%), but the tumor in the sphenoid sinus showed a gradual shading into tubular pattern with abundant interstitium (Fig. 3a, b, f). The tumor cells had invaded along the mucosa of the sphenoid sinus, but dysplasia of the epithelium was not evident (Fig. 3c). Bone specimens obtained from drilling of the clivus also showed interjacent tumor cells within the framework of the bone trabeculae. Immunohistochemical studies showed the tumor to be positive for AE1/AE3, smooth muscle actin, P63, P40, vimentin, and CD117; there was focal positivity for S-100, and the specimen was negative for GFAP, all pituitary hormones, and all pituitary transcription factors (Pit-1, SF-1, T-pit, GATA-2, ER) (Fig. 3d–f). Staining of whole sections for p16 positivity showed positive findings in 30–50% of tumor cells, which is regarded as an overall negative result. In contrast, MYB protein was overexpressed in tumor cells, with FISH using break-apart probes for MYB demonstrating split signals in 68% of tumor cells (Fig. 4). Taking together the pathological together with the radiological and intraoperative findings, a final diagnosis of primary intrasellar ACC extending into the sphenoid sinus was concluded. The postoperative course of the patient was uneventful. Hyperprolactinemia improved to normal range and other pituitary functions were preserved without requiring any replacement therapy. Due to the malignant nature of the pathology, the patient was treated by intensity modulated radiotherapy (IMRT) to the extended tumor bed, including the bilateral cavernous sinuses and the Gasserian ganglion of the trigeminal nerves, with a total dose of 60 Gy per 30 fractions. At 18 months after treatment, the patient remained healthy without symptoms or evidence of tumor recurrence (Fig. 1e).

Fig. 3.

Histopathological features; a Tumor cells obtained from the intrasellar component exhibit a typical cribriform pattern. Cyst-like spaces contain extracellular basophilic mucinous materials (H&E*). b Tumor cells obtained from the sphenoid sinus exhibit shading into a tubular pattern with abundant interstitium from cribriform pattern (H&E*). c Infiltration of the tumor cells underneath of the mucosa of the sphenoid sinus is observed, but squamous dysplasia of the surface epithelium is not evident (H&E*). Immunohistochemical examination of p63 (d, left) and p40 (d, right) shows positivity for abluminal /myoepithelial cells, while CD117 (c-kit) (e) is accentuated around the true lumens. The tumor cells are not positive for any known pituitary transcription factors and hormones including Pit-1 (f). It must be noted that this portion of the specimen obtained from inside the sella showed a rather solid pattern (f). *Hematoxylin and eosin

Fig. 4.

Pathological findings conclusive for adenoid cystic carcinoma; in the immunohistochemical study, only 30–50% of all tumor cells were positive for p16 (a) while showing overexpression of the MYB protein (b). Fluorescence in-situ hybridization (FISH) using a dual-color MYB break-apart probe (c) consisting of a centromeric (green) and a telomeric (red) probe covering the MYB locus and its flanking sequences. The red (arrow) and green (arrowhead) signals are split (d), indicating translocation

Discussion

We have demonstrated that ACC can develop in the pituitary gland as the primary site. The intracranial occurrence of ACC at various skull base regions including the cavernous sinus has been reported, but involvement of the sella turcica is uncommon [13]. However, midline ACCs involving the pituitary gland have been considered to more likely arise from minor salivary glands in the sphenoid sinus [14]. Furthermore, it may be difficult to conclude that the pituitary gland is the primary site because the slow growth and invasive nature of ACCs would delay the diagnosis. Therefore, the literature regarding the pathogenesis of pituitary ACCs should be discussed.

Pathological Differential Diagnosis of ACC Arising in the Sinonasal Tract

Unlike ACCs derived from the salivary gland, care should be taken to identify possible human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) when ACCs occur in the sinonasal tract. HMSC is a recently described distinctive clinicopathologic entity defined by association with high risk HPV, localization to the sinonasal tract, and close histologic resemblance to ACC [15, 16]. While existence of MYB rearrangement is the definitive method of discrimination, whether p16 is negative should be confirmed to exclude the diagnosis of HMSC [17]. Alternatively, most cases of HMSC exhibit severe squamous epithelial atypia of the overlying mucosa [15]. Moreover, polymorphous adenocarcinoma (PAC) is a tumor of the minor salivary glands that exhibits considerable morphologic overlap with ACC and has a good prognosis [18]. Although PAC rarely occurs in the sinonasal tract [19], both tumors share multiple overlapping architectural patterns. PACs do not harbor a myoepithelial component, yet their frequent positivity for p63 (similar to ACC) has made diagnosis challenging. However, p40, another antibody and isotype of p63, has been shown to be a more specific marker of basal and myoepithelial differentiation. Some studies have demonstrated the usefulness of p40 for discrimination of PAC from ACC [20, 21].

Differences Between Primary and Secondary ACC Developing in the Sellar Region

Generally, ACCs presenting as an intracranial mass have been considered to occur through one of three ways: direct extension, hematogenous spread, and perineural spread [22]. In addition, three major routes have also been reported for the intracranial invasion of salivary gland ACCs: the eustachian tube, the mandibular and maxillary nerves, and the ICA [5]. Perineural invasion is found in 52.6–70% of cases on pathological review of specimens from head and neck ACCs [1, 23]. Therefore, the tumor has been considered incurable due to its tendency to recur and metastasize, regardless of its slow and insidious growth.

ACCs in the sellar region are usually regarded as secondary to tumor invasion or metastasis as opposed to a primary lesion. Approximately 35% of pituitary adenomas, despite being classified as a benign pathology, show invasion of the cavernous sinus and/or the sphenoid sinus through contiguous structures such as the dura mater and bone [24]. Particularly in cases without suprasellar extension, enlargement of the sella turcica should be considered fundamental proof that the tumor arose from the pituitary gland [25]. Conversely, the pituitary gland could be pushed up or encased diffusely, without enlargement of the sella turcica, by secondary invasive tumors [26], even though 48% of primary malignant tumors of the sphenoid sinus extend to the sella turcica [27]. Furthermore, the fenestration of the dura in our case is evidence of extension from inside the sella to the sphenoid sinus, and midline ACCs in the expanded sella turcica without cavernous sinus invasion are difficult to explain as occurring through perineural spreading. Alternatively, three cases of parotid gland ACCs metastasizing to the pituitary gland have been reported, which were considered to have undergone hematogenous spread [28–30]. In our case, we had ruled out metastatic tumor according to the results of the PET scan and thyroid biopsy. Thus, we believe that the tumor was derived from the pituitary gland.

Primary Pituitary ACC as a Part of “Salivary Gland-Like Tumors of the Sella”

Primary salivary gland-like tumors of the sella (SGLTS) were proposed by Hampton et al. in 1997 and are believed to derive from serous and mucous glands entrapped in the infundibulum during pituitary embryogenesis [31]. Primary SGLTS are unusual and, given their rarity, are not included in the World Health Organization classification of pituitary tumors [32]. Salivary gland rests (SGRs) can be found incidentally in the pars intermedia and posterior pituitary with an incidence of 3.4% to 8.8%, based on large autopsy series of both adults and children [33, 34]. Primary SGLTS are considered to be derived from neoplastic transformation of SGRs in the sella. SGLTS cover a morphologic spectrum more typical of salivary gland neoplasia, including pleomorphic adenoma [31, 35], adenocarcinoma [31, 36], acinic cell carcinoma [37], adenoid cystic carcinoma [36], and epithelial-myoepithelial carcinoma [38]. In 2007, van Furth et al. reviewed 12 previously reported cases of SGLTS [37], and subsequently new cases of pleomorphic adenoma and symptomatic salivary gland rest cysts in the sella have been reported, as part of the benign spectrum of SGLTS [39, 40]. It is interesting that our case’s immunohistochemical results indicated no correlation between specific pituitary transcription factors, such as Pit-1, with the development of ACC from SGRs in the pituitary gland.

On the other hand, several instances of intracranial ACC with an unknown primary site have been reported [13, 41–43] and their pathogenesis is still a matter of debate. These lesions may have resulted from perineural invasion or metastasis of an occult extracranial ACC, or arose from intracranial ectopic salivary glands [44, 45]. However, why primary intrasellar ACCs are extremely rare compared to intracranial ACCs remains unclear, even though intracranial ectopic salivary glands arising from somewhere other than the pituitary are very rare.

Literature Review of Primary Intra- and Supra-sellar ACCs

Including our case, we found only five cases of primary ACC with predominantly intra- or supra-sellar components in the literature (Table 1). The first case, reported by Dickhoff et al., was considered a secondary extension from a sphenoid sinus ACC by the authors; however, complete destruction of not only the sellar floor but also the dorsum sellae, and occupation of the tumor in the sella, indicate that the tumor likely originated from the sella [14]. Another case in the suprasellar region was reported as originating from the pituitary stalk, which was confirmed by intraoperative findings; however, anatomical localization of the SGR in the pars intermedia/nervosa suggests that this case should be categorized as an SGLTS [22]. Meanwhile, we found a further four cases that could be classified as secondary intrasellar masses formed by invasion of the surrounding structures [46–49]. In these cases, there was no description of enlargement of the sella turcica or of intradural tumor, except for infiltrated tumor within the cavernous sinuses; however, the pituitary gland was displaced, and bony destruction around the sphenoid sinus was significant.

Table 1.

Summary of the five cases of primary intra- and supra-sellar adenoid cystic carcinoma

Author	Year	Age/sex	Location	Symptoms	Endocrine	Treatment	Outcome
Dickhoff et al.	1993	41/F	IS, SpS, Rt. CS	Headache, CN VI palsy	hPRL	Op, RT	2 years AWD
Gilcrease et al.	1999	44/F	IS, SS, pES	Hemianopsia	hPRL (GA)	Op	Died on POD 8
Tsuyuguchi et al.	2001	34/F	SS	Lt. VA loss	HP, hPRL	Op (4) RS (10)	3.5 years DOD
Zuo et al.	2012	53/M	IS, SpS, Lt. CS	Headache, Lt. VA loss	N.A	Op, RT	4 years AWOD
Present case	2020	71/F	IS, SpS, NC	Epistaxis	hPRL	Op, RT	1.5 year AWOD

AWD alive with disease, AWOD alive without disease, CN cranial nerve, CS cavernous sinus, DOD dead on disease, GA galactorrhea and amenorrhea, HP hypopituitarism, hPRL hyperprolactinemia, IS intrasellar, N.A. not available, NC nasal cavity, Op operation, pES posterior ethmoid sinus, POD postoperative day, RS radiosurgery, RT radiation therapy, SpS sphenoid sinus, SS suprasellar, VA visual acuity

It is difficult to determine the specific tumor characteristics because of the small number of cases, but ACCs in this region appear to occur often in middle-age women, as is the case for all ACCs in all locations [50]. Furthermore, they are not usually associated with pituitary dysfunction except for hyperprolactinemia, and frequently invade surrounding structures such as the sphenoid sinus and the cavernous sinus, which means that they can resemble invasive pituitary adenomas. However, it should be noted that endoscopic eTSS for ACCs in the sphenoid sinus or in the sella may be challenging and dangerous. Dickhoff et al. had to discontinue surgical resection because of excessive bleeding from the tumor [14], and Zuo et al. encountered an unexpected injury of the C4 segment of the ICA [51]. It is notable that 3 out of the 10 ICA injuries during endoscopic eTSS that were reported in two individual case series involved patients diagnosed with ACC upon pathological review [51, 52]. The cavernous or paraclival ICA may become fragile because of ACC invasion, and we should pay particular care when manipulating tissue around the ICA in such cases.

The prognosis of primary intra- or supra-sellar ACC is unknown, but it is likely to be worse than typical sinonasal ACCs. Amit et al. performed a meta-analysis of 520 cases of nasal/paranasal ACCs, which revealed that those of sphenoid/ethmoid sinus origin had a significantly worse prognosis than those originating from other sites, and only cases where negative resection margins were achieved were associated with a favorable prognosis; moreover, the use of additional radiotherapy or chemotherapy did not contribute to improved survival [6]. One study advocated debulking surgery followed by conformal radiotherapy or chemoradiotherapy over radiotherapy alone for epithelial tumors in the sphenoid sinus [53].

Recent developments in radiotherapy, including IMRT and proton beam radiation therapy, appear to result in good local control rates for paranasal sinus ACCs [54–56]. Indeed, it has been noted that 96% of ACCs respond to radiotherapy; however, recurrence rates after radiotherapy has been reported to be as high as 95% [57]. Therefore, the development of new therapeutic targets for MYB-positive ACCs in regions where achieving negative resection margins is difficult is anticipated.

Conclusions

We have presented the radiological, pathological, and intraoperative findings of an extremely rare case of primary intrasellar ACC. Although the pituitary gland is known to incorporate SGRs developing a variety of SGLTS, the rarity of pituitary ACCs may be attributed to the difficulties in demonstrating that they are a primary malignant tumor. This is because of the invasive nature of these tumors, and the anatomical relationships with the sphenoid sinus and the cavernous sinus. Although their radiological features resemble those of invasive pituitary adenoma, excessive bleeding from the tumor or unexpected ICA injury should be avoided during surgery.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by KS, TO, SK, and JK. KS, MK, and TO were part of the endoscopic surgical team in our neurosurgical and otolaryngological departments and performed all surgical and perioperative treatments described in this study. The first draft of the manuscript was written by KS and all authors commented on the final version of the manuscript. JA and YS were the pathologists assigned to histopathological evaluation of the specimens from this patient. EO was the radiation oncologist assigned to deliver radiation therapy to this patient. HU and MM supervised the drafting of this manuscript. All authors have read and approved the final manuscript.

Funding

No funding obtained.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This study was performed in accordance with the Declaration of Helsinki.

Informed Consent

The patient provided informed consent to publication of this case report.