Ectopic pituitary adenoma of the TSH-secreting sphenoidal sinus with excellent response to somatostatin analogs. Theory of the embryogenesis and literature review from a clinical case

Journal Pre-proofs Ectopic pituitary adenoma of the TSH-secreting sphenoidal sinus with excellent response to somatostatin analogs. Theory of the embryogenesis and literature review from a clinical case Eugenia Ortiz, Marcelo Peldoza, Eduardo Monnier, Roger Gejman, Miguel Henriquez, Maria Ines Barra, Roxana Gayoso, Jorge Sapunar, Miguel Villaseca, Pablo Guzmán PII: DOI: Reference:

S0039-128X(19)30225-9 https://doi.org/10.1016/j.steroids.2019.108535 STE 108535

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Steroids

Received Date: Revised Date: Accepted Date:

25 June 2019 24 October 2019 30 October 2019

Please cite this article as: Ortiz, E., Peldoza, M., Monnier, E., Gejman, R., Henriquez, M., Barra, M.I., Gayoso, R., Sapunar, J., Villaseca, M., Guzmán, P., Ectopic pituitary adenoma of the TSH-secreting sphenoidal sinus with excellent response to somatostatin analogs. Theory of the embryogenesis and literature review from a clinical case, Steroids (2019), doi: https://doi.org/10.1016/j.steroids.2019.108535

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Ectopic pituitary adenoma of the TSH-secreting sphenoidal sinus with excellent response to somatostatin analogs. Theory of the embryogenesis and literature review from a clinical case. Authors: Ortiz, Eugenia a,b Peldoza, Marcelo c,d Monnier, Eduardo d Gejman, Roger e Henriquez, Miguel f,g Barra, Maria Ines a,b Gayoso, Roxana a,c Sapunar, Jorge a,b Villaseca, Miguel h,i Guzmán, Pablo h,i a

Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera.

b

Internal Medicine Service, Hospital H. Henríquez de Temuco, Chile.

c

Department of Preclinical Sciences, Faculty of Medicine, Universidad de La Frontera.

d

Neurosurgery Service, Hospital H. Henríquez de Temuco, Chile.

e

Department of Pathological Anatomy, Faculty of Medicine. Universidad Católica de Chile.

f

Department of Medical Specialities, Faculty of Medicine, Universidad de La Frontera.

g

Otolaryngology Service, Hospital H. Henríquez de Temuco, Chile.

h

Department of Pathological Anatomy, Faculty of Medicine. Universidad de La Frontera.

i

Pathological Anatomy Service, Hospital H. Henríquez de Temuco, Chile

Corresponding author: Eugenia Ortiz MD. Manuel Montt 112. Temuco Chile [email protected] Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera.

1

Abstract Ectopic thyrotropin-secreting pituitary adenomas are rare, with only 10 published cases. We report the case of a 52-year-old woman who was referred for primary hypothyroidism, who showed clinical signs of hyperthyroidism and had been under treatment with levothyroxine. Her exams revealed high levels of thyroid stimulating hormone (TSH), at odds with free thyroxin (FT4) and raised triiodothyronine (T3), which remained elevated after medication suspension, suggesting possible central hyperthyroidism. Sellar MRI showed normal pituitary gland, with a mass in the sphenoid sinus of 24 mm. A possible ectopic TSH secreting pituitary tumor of sphenoid sinus was hypothesized. After a single dose of a sustained-release pellet of a somatostatin analog (octreotide)(20 mg), plasma levels of thyroid hormones were normalized and a significant tumor reduction was demonstrated in MRI control at 7-weeks´ follow-up. The tumor was removed by transsphenoidal endoscopy, and the biopsy confirmed an adenoma with positive immunostaining for TSH and GH. Hyperthyroidism recurrence was observed in hormonal controls 4 weeks after surgery. Treatment with sustained-release octreotide was reinitiated, every 60-days for two years, with normalization of the thyroid hormone profile, but with a residual lesion with the appearance of a tumor in the MRI. A second tumor resection was performed, achieving sustained hormonal cure and no residual tumor lesion at 2-years´ follow-up. To our knowledge, this is the first report of an ectopic thyrotropin-secreting pituitary adenoma of the sphenoid sinus. Clinical and laboratory aspects relevant to this entity are reviewed, emphasizing the usefulness of octreotide in the management of the reported case.

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Key words: Ectopic, Pituitary adenoma, Thyrotropinoma, Sphenoid sinus. Abbreviations: CT: Computed tomography EPAs: Ectopic pituitary adenomas FT4: Free thyroxin FT3: Free triiodothyronine IHC: Immunohistochemical study MRI: Magnetic resonance imaging PRL: Prolactin RTH: Resistance to thyroid hormone syndrome TSH: Thyroid-stimulating hormone T3: Triiodothyronine Author statement and acknowledgements: Conceptualization, Writing - original draft: EO. Writing - reviewing and editing: MP, PG. Investigation: EO, MP, PG, EM, MH, RG. Formal analysis: EO, MP, PG. Declarations of interest: None Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Case report A 52-year-old female patient was referred to the endocrinology departament for the assessment of primary hypothyroidism diagnosed in November 2013 with an associated treatment of levothyroxine for 12 months. The medical history showed a weight loss of 12 kilograms in the previous 6 months with conserved appetite, frequent bowel movements, muscle weakness and nervousness. Physical examination determined a heart rate of 104/minute, blood pressure was 150/90 mmHg, the patient showed fine tremor and thin skin with an increase in temperature and dermatographism. There were no signs of thyroid orbitopathy. The thyroid gland was diffuse and slightly enlarged, with no palpable nodules. No myxedema was found in the lower extremities. Hormone values showed a TSH of 4.73 uUI/ml (reference range: 0.27-4.2) and FT4 3.88 ng/dl (reference range: 0.7-1.48). The hormone levels prior to beginning levothyroxine treatment were (July 2013): TSH 7.86 uUI/mL, total T4 19.8 ug/dl (reference range: 4.5-12.5) and T3 365.2 ng/dl (reference range: 84.6 -201.8). The thyroid ultrasound identified a solid, hypoechogenic lesion in the left thyroid lobe, 5x4x4mm, with no capsule or calcifications, with an associated mixed Doppler flow. Based on the latter findings the decision was to suspend the levothyroxine and check on hormone levels in 30 days. At the checkup, the patient referred to a reduction in symptoms; however, both hormones remained high: TSH 8.12 uUI/mL and FT4 5.53. For this reason, central hyperthyroidism was suspected. Propranolol was indicated to manage heart rate. The study of the remaining pituitary hormones was normal. Sex hormone binding globulin levels were found to be high. An MRI of the sella turcica with dynamic sequence showed a mass of 24 x 13 x 23 mm (anteroposterior, transversal, craniocaudal axis) in the sphenoid sinus, discretely hyperintense in T1-weighet image (T1WI) and T2-weighet image (T2WI), with heterogeneous contrast enhanced with septations, that protrude towards the nasopharynx, with local bone erosion in CT scan but normal floor of the sella turcica. The stalk and the pituitary glands were of normal size, as observed in all MRI sequences (Figure 1A). The nasopharyngolaryngoscopy concluded that there was no visible mass in the nasopharynx. Therefore the diagnosis was a probable ectopic TSH-secreting tumor in the sphenoid sinus, and a suppression test was done with a sustained-release pellet of the somatostatin analog octreotide (one-time dose of 20mg IM) on June 18, 2015. Subsequent controls on thyroid hormones levels showed a gradual reduction until

4

normalization two weeks after administration (Table 1). This fact confirmed the ectopic secretion of TSH by the tumor. An MRI checkup of the sella turcica at two months post-dose showed a remarkable reduction in tumor size (15.8 mm craniocaudal) (Figure 1C). An endoscopic trans-sphenoidal surgery was performed nine weeks after administration of the octreotide. A tumor was removed, the macrocospic aspect of which was described as an irregular fragment of brownish tissue, 1.5 x 0.7 x 0.3 cm, with a finely regular and shiny surface. The floor of the sella turcica was undamaged. Microscopy revealed a proliferation of fused and cuboidal cells, eosinophilic and slightly granular cytoplasm, medium to large nuclei, with moderate anisokaryosis and pleomorphism, that tended to be arranged in nodules and cords, without mitosis (Figure 2A). The immunohistochemical study showed: intense positivity for TSH (90%) (Figure 2B), and GH (30%), focal positivity for FSH, chromogranin and positive Ki-67 staining less than 1%. The cells did not react for cytokeratin 8, ACTH, P53, prolactin or LH. The conclusion was a TSH-producing adenoma. Postoperative evolution was satisfactory. At the four-week checkup there was evidence of a rise in FT4 and T3 with an inappropriately normal TSH. A control MRI showed postoperative inflammatory changes with no evidence of recurrence. It was decided to maintain the octreotide treatment with a 60-day- 20 mg sustained-release pellet together with imaging and hormone levels follow-up. The control MRI images at 2 years post-surgery showed persistence of a lesion located between the posterior wall of the sphenoid sinus and the vomer, 20 mm, hyperintense in T2WI . Octreotide was suspended in April 2017 and a rise in FT4 and T3 was observed. Thus it was decided to re-operate on the patient using the endoscopic transsphenoidal approach, finding friable tissue, which was compatible in the histology with an ectopic pituitary adenoma. Treatment with somatostatin analogs was not required again, with TSH, FT4 and T3 remaining normal.

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Discussion: Ectopic pituitary adenomas Ectopic pituitary adenomas (EPAs) are rare intracranial tumors found exclusively outside the sella turcica, and they have no sellar component (1). Shuman et al. recently published a literature review of 85 cases, of which 72 (85%) secreted 1 or more hormones. The adrenocorticotropic hormone (ACTH) was the most commonly secreted (36%), then prolactin, (28%), GH (22%) and TSH (16%) (2). It is considered that they arise from remnant of pituitary tissue in the faringeal region and in other region in the migration path of Rathke´s pouch. The primordium of the anterior lobe of the pituitary gland appears in the fourth week of gestation from an ectodermal invagination of the oropharynx, known as Rathke’s pouch. Then, the pituitary tissue migrates through the craniopharyngeal canal to the sphenoid sinus or nasopharynx and ascends to bond to the neurohypophysis. It is suggested that these remnants are embryonic cells that become an adenoma with or without hormonal production in adult life (3). Another subtype of ectopic pituitary adenoma, suprasellar or subdiaphragmatic, would come from the cells of the anterior lobe of the hypophysis that remain bonded to the supradiaphragmatic portion of the pituitary stalk (4) From an anatomopathological point of view, EPAs are characterized as being located under the respiratory epithelium and frequently having bone involvement. Optical microscopy reveals a variety of growth patterns. Immunohistochemistry (IHC) shows a 80% positive reaction to cytokeratin and a negative reaction with the S100 protein. EPAs are positive for neuroendocrine markers, being CD56 and synaptophysin the most sensitive markers while chromogranin and neuron specific enolase (NSE) may also be detected (1). Thompson classified the IHC for pituitary hormones from these tumors in the GH-PRL-TSH family: Functioning Lactotroph or NonFunctioning Silent Lactotroph, ACTH family: Functioning Corticotroph or Non-Functioning Corticotroph, Gonadotropin family: Non-Functioning Silent Gonadotroph, Non-Classified Adenoma: Plurihormonal Adenoma, and Silent Hormone (1).

6

Ectopic TSH-secreting pituitary adenomas Ectopic TSH-secreting pituitary adenomas are pituitary tumors located outside the sella turcica associated with an undamaged hypophysis. The literature review identified only 10 previously reported cases, which are summarized in Table 2. The average age at diagnosis was 40 years, the size was between 10 and 24 mm, 8 of them were in the nasopharynx, 2 suprasellar and our case in the right sphenoidal. Most were misdiagnosed as Basedow Graves disease, treated initially with antithyroid drugs and one with iodine-131 on two occasions. Our case received levothyroxine due to the misdiagnosis of primary hypothyroidism based on the elevation of TSH. Ectopic TSH-secreting tumors are clinically and biochemically the same as intrasellar tumors; however, they present nasal obstruction symptoms in 8/11 (72%) and in suprasellar tumors a decrease in visual acuity and visual field involvement 2/11 (18%), left temporal hemianopia (5) or bitemporal hemianopia (6). Our patient did not have nasal or visual obstruction symptoms; the imaging study showed a sphenoid mass with an associated undamaged hypophysis, which aided in the diagnosis. The immunohistochemistry of the 11 reviewed cases was positive for TSH, GH and PRL 18%, TSH and GH 27%, TSH and PRL 9%, and TSH alone 45%. Immunohistochemical staining is not always correlated with secretion in vivo (hormone levels in blood) nor with the clinic, as in this case, where the IGF-1 was normal without acromegaly. It is not clear how this phenomenon occurs, and it has been suggested that the release of GH would be very low to be detected in blood or that it would have reduced biological activity (7). The differential diagnosis must be made with a thyroid hormone resistance syndromes (RTH) (8), and in our case with sphenoid tumor lesions of another origin. RTH includes those defects that interfere with the biological activity of a structurally intact hormone and secreted in normal amounts. The first alterations associated with RTH described in literature were mutations in the gene that encodes the thyroid hormone receptor ß (TRß). Also, defects in the membrane transporter and the metabolism of thyroid hormones have been described. TRß mutations show an autosomal dominant inheritance, which is why family history can be found. The type of resistance is called central or pituitary, since it is predominantly in the pituitary rather than in peripheral tissue. Clinically, there is evidence of both hypo- and hyperthyroidism. The laboratory

7

exams show raised FT4 and T3 with non-suppressed TSH, generally in the normal or slightly elevated range (3) To differentiate an RTH from a thyrotropinoma, the SHBG measurement was used as a marker of thyroid hormone action (8), which was found to be elevated if it was the case of a TSH-secreting tumor. It is also possible to perform a genetic test to identify mutations in TRß (4). Thyrotropinomas have raised levels of the glycoprotein alpha subunit, as well as a high alphaGSU/TSH ratio. Another criterion used is the response to somatostatin analogs (octreotide or lanreotide), with an expected reduction in peripheral hormones and TSH when dealing with thyrotropinoma, since these tumors mainly have somatostatin receptor subtype 2 (7). The response to the initial test dose of sustained-released octreotide supported the neuroendocrine origin of the sphenoid tumor and the normalization of the thyroid hormones confirmed the TSHsecreting origin. Thirty percent of TSH-secreting intrasellar adenomas co-secrete GH and prolactin, 16 % GH and 11% prolactin. Therefore the rest of pituitary hormones (GH, PRL, IGF-1, gonadal and cortisol axis), must be measured at diagnosis. (7) If an ectopic TSH-secreting EPA is suspected, the first location examination is an exploration with nasolaryngoscopy

given

the

preferred

nasopharyngeal

location.

PET/CT

with

18

fluorodeoxyglucose and Octreoscan detection have been used either to complement the functional imaging study or where computer axial tomography or MRI were not to detect the lesion (4,7,9). Recently, the use of Gallium Dotatate PET was described, which could improve the detection of the location of these tumors (10)

Treatment of Ectopic TSH-secreting Pituitary Adenomas Given the sphenoid location of this tumor and that there were no anatomical difficulties for the transsphenoidal access, surgical removal of the lesion was proposed, requiring a second surgery to remove a portion that invaded the clivus. In the previous cases located in nasopharynx, the treatment of choice was endoscopic transnasal resection, while the transpterional transsphenoidal suprasellar cases were cured in the first surgery. With the use of a dose of sustained-release octreotide, euthyroidism was achieved in 15 days. Accordingly , at 6 weeks a significant reduction in tumor size was found by MRI analysis. This excellent response has been described in intrasellar thyrotropinomas, with an associated treatment of short-acting analogs (of less to 14 days), in which high expression of the somatostatin

8

receptor subtype 2 and low expression of somatostatin receptor subtype 5 in the tumor tissue have been found by immunohistochemistry or mRNA determination. This suggests that receptor subtype 5 has a modulating effect on the reduction of the tumor mass (11). The rapid response to analogs permits its use in the preoperative setting thus reducing the risk of thyroid storm (11,12). The use of sustained-release somatostatin analogs has been described as the primary treatment in intrasellar thyrotropinomas, with a reduction in tumor volume in most of the cases and a reduction of FT4 and FT3 close to 50%, as well as of TSH levels in 30% after 3 months of treatment, lasting over time (13). These features allow its use in patients with invasive tumors or contraindicated for surgery. The time interval of administration of the analog has not been reported in previous works; in the current case, the administration of the sustained-release analog was longer interval than for patients with acromegaly, requiring a dose every 60 days. This could be consistent with the excellent preoperative response. If hormonal secretion persists after surgery, radiation therapy could be used (not reported in previous cases) or somatostatin analogs continued, as it was done in the current case, for two years.

Conclusions Ectopic thyrotropinomas are extremely rare, representing a diagnostic challenge. Their origin corresponds to remnants of pituitary tissue in the migration passage towards the sella turcica. We present the first case of location in the sphenoid sinus, which like other cases reported in literature presented symptoms of thyrotoxicosis with no symptoms of nasal obstruction. The present study indicates that a dose of sustained-release somatostatin analog can be used as a therapeutic test for normalization of thyroid hormone levels and tumor size reduction. Said treatment could also be used as adjuvant therapy in cases that are not cured with surgery.

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Table 1 Response of thyroid hormones to a single intramuscular dose of 20 mg-sustained-release somatostatin: Hormone levels

TSH (uUI/mL) NV: 0.27-4.2 T3 (ng/mL) NV:0.58 -1.59 T4L (ng/dL) NV: 0.7-1.48

Pre-Somatostatin

Administration Somatostatin

Days Post-Administration of Somatostatin 7

14

21

45

3.13

2.81

0.29

0.29

0.27

0.07

3.2

3.89

1.3

1.1

1.07

0.97

2.89

3.41

2.26

1.38

1.28

1.03

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Table 2 Characteristics of TSH-secreting EPAs published in the literature Cases

Age/sex

Location

Tumor

Local

size

symptoms

Image

Test

Surgery

IHC

Transfacial

TSH,

Transmaxillary

GH,

Somatostatin Analogs

Cooper(14)

45/F

Nasopharynx

Not

Nasal

indicated

obstruction

CT,MRI

no

PRL, FSH ACTH, LH Pasquini(15) Collie(16)

34/M Unknown/F

Nasopharynx Nasopharynx

Not

Nasal

indicated

obstruction

15 x 20

Nasal

mm

obstruction

MRI

no

Endoscopic

TSH

Endonasal CT

no

Endoscopic

TSH

Endonasal

and GH

No

TSH,

and headache Tong(7)

34/F

Nasopharynx

20 x 20

Nasal

MRI, CT,

and nasal

mm

obstruction

Octreoscan

19x17

No

MRI,CT

yes

GH, PRL

cavity Song(3)

40/M

Nasopharynx

yes

mm Nishiike(4)

36/M

Nasopharynx

14 mm

Headache

MRI,CT,

no

PET-CT Wang(5)

45/M

Suprasellar

MRI

Endoscopic

TSH

Endonasal

and GH

Endoscopic

TSH

Endonasal

15 x 12 x

Decreased

yes

Endoscopic

10 mm

vision and

Transsphenoidal

left

Transtuberculum

TSH

temporal hemianopia Yang(17)

27/F

Nasopharynx

Not

Chronic

indicated

nasal

MRI

no

Endoscopic Endonasal

obstruction

11

TSH

Hanaoka(9) Kim(10)

41/M 48/F

Suprasellar Nasopharynx

Not

Bitemporal

MRI,CT,

indicated

hemianopia

FFDG-PET

9x10 mm

Not

MRI, 68

indicated

DOTA-

no

Transsphenoidal

TSH

Transpterional no

Endoscopic

TSH,PRL

Endonasal

TATE PET/CT Actual case

52/F

Sphenoid

24x23x13

sinus

mm

No

MRI,CT

yes

Endoscopic Transsphenoidal twice

12

TSH,GH

Image 1

A

B

C

13

Sellar MRI showed a mass in the sphenoid sinus, discretely hyperintense in T1 and T2, with heterogeneous contrast enhanced with septations, that protrude towards the nasopharynx, and the talk and the pituitary gland showing normal size. T1 gadolinium-enhanced sagital MRI sequence at the beginning (A), one week (B) and seven weeks (C) after octreotide injection demonstrated a significant reduction in tumor size.

14

Image 2

A

B

15

Microphotographs of neoplastic proliferation composed of epithelioid cells, of slight to moderate nuclear pleomorphism and varying amount of finely granular cytoplasm (A, H&E, 400x). Intense, cytoplasmic immunopositivity for TSH (B, 400x).

16

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