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Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients
Journal of Clinical Neuroscience xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients Janelle Cyprich a,⇑, Daniel A. Donoho b, Andrew Brunswick b, Kyle Hurth c, John D. Carmichael d, Martin H. Weiss b, Gabriel Zada b a
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA d Division of Endocrinology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA b c
a r t i c l e
i n f o
Article history: Received 9 March 2019 Accepted 4 October 2019 Available online xxxx Keywords: Nonfunctional pituitary adenoma Plurihormonal Sella Thyrotropin Transsphenoidal surgery Tumor
a b s t r a c t Silent thyrotropin pituitary adenomas (TSHomas) are defined by absence of hyperthyroidism despite TSH immunopositivity. Data pertaining to clinical and surgical characteristics of silent TSHomas remains limited. We aim to describe the clinical presentation, pathological characteristics, and outcomes in silent TSHoma patients treated at a tertiary pituitary center. We retrospectively identified patients with histologically-proven silent TSHoma who underwent transsphenoidal resection at our center between 2000 and 2016 (n = 1244 total patients). Patients with preoperative hyperthyroidism or thyroidectomy were excluded. Twenty patients with silent TSHomas were included (1.6% of surgically treated PAs), of which 35% were reoperations. Presenting symptoms included vision loss (45%) and headache (40%). Preoperative pituitary dysfunction included hypothyroidism (40%), hypogonadotropic hypogonadism (30%), and panhypopituitarism (15%). Nineteen patients (95%) had macroadenomas (mean diameter 29.9 mm). Extrasellar growth was identified in 17 patients (85%) and 65% had cavernous sinus invasion. Immunostaining for alpha-subunit was positive in 19 patients (95%), and 75% of tumors expressed immunopositivity for hormones other than TSH. Gross total tumor resection was achieved in 9 patients (45%) on follow-up MRI. Major postoperative complications included hydrocephalus (1 patient) and cerebrospinal fluid leak with meningitis (1 patient). Tumor progression and recurrence occurred in 1 patient each (10% total) over the follow-up period (median 18.5 months). Silent TSHomas tend to be large, invasive tumors. In addition to TSH, a majority express immunopositivity for alpha-subunit and gonadotropins, thereby potentially supporting a primitive adenoma lineage and subtype. Despite reoperation in several patients, good overall outcomes with low complication rates were achieved. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Thyrotropin pituitary adenomas (TSHomas) have historically accounted for less than 2% of all pituitary adenomas, making them the least frequent subtype of pituitary adenoma [1,2]. Recent studies have demonstrated a progressive increase in diagnosis of TSHomas over the last several years, likely due to heightened screening and increased awareness among physicians [2–4]. TSHomas are more likely to be macroadenomas compared to other pituitary tumors, and approximately 1 in 3 co-secrete other anterior pituitary hormones, most commonly growth hormone and/or prolactin [5]. TSHomas can be divided into two subtypes: secretory TSHomas and silent TSHomas. ⇑ Corresponding author at: Department of Neurological Surgery, Keck School of Medicine of USC, 1200 North State St, Suite 3300, Los Angeles, CA 90033, USA. E-mail address: [email protected] (J. Cyprich).
Although functional TSHomas classically present with central hyperthyroidism, silent TSHomas are a rare subtype of TSHomas that stain positive for TSH on immunohistochemistry without clinical or biochemical evidence of hyperthyroidism prior to tumor resection [4]. The reason for this is not well understood, though it has been postulated that these tumors may release various isoforms of TSH that are inactive, or the tumor cells may simply not secrete enough TSH to reach a threshold that causes clinical symptoms of hyperthyroidism [6]. These adenomas are most often diagnosed due to symptoms from mass effect, and diagnosis depends on the histopathological staining of the tumor [7,8]. Few studies pertaining to the incidence, management, and treatment outcomes of patients with silent TSHomas have been published. Recent case series of TSHomas demonstrate rates of clinically silent tumors ranging from 7 to 75% [9,4,5]. One study reported similar outcomes between patients with functioning versus silent TSHomas and
https://doi.org/10.1016/j.jocn.2019.10.013 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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found no difference in proportion of plurihormonal adenomas between the two groups [10]. The literature surrounding silent TSHoma is limited and varies according to patient selection based on clinical and biochemical presentation, immunohistochemistry, or both, leading to differences in reported prevalence rates of silent TSHomas. Although from a clinical standpoint they are treated in the same fashion as nonfunctioning pituitary adenomas, the distinction of a silent TSHoma may be clinically and biologically relevant, as these tumors may be associated with more aggressive clinical behavior and worse overall outcomes with regard to recurrence/progression [11]. Our study aims to describe this unique population of patients in terms of incidence, presenting symptoms, tumor pathology, management, and surgical outcomes at a tertiary pituitary center. 2. Methods 2.1. Study design Following IRB approval, a retrospective review was conducted to identify patients whom underwent transsphenoidal surgery at our center between 2000 and 2016. Patients were identified from our electronic pituitary tumor database (RedCap [12]), which includes information about patient demographics, preoperative symptoms and endocrine status, surgical characteristics, pathology, postoperative course, and follow-up details on 1244 patients. We included adults with confirmed histopathologic diagnosis of TSHoma without preoperative hyperthyroidism or history of thyroidectomy. Confirmed histopathologic diagnosis of TSHoma was defined as tumors demonstrating TSH immunopositivity in at least scattered cells. Patients were excluded if they were less than 18 years of age, had less than 3 months of follow up, were hyperthyroid on presentation, had prior history of thyroidectomy, or had biochemical evidence of acromegaly prior to the operation. 2.2. Preoperative examination Preoperative symptoms were recorded and endocrine status was determined using serum pituitary-based hormonal labs, including serum TSH, free T4, prolactin, and IGF-1. Preoperative tumor imaging was obtained, including contrast-enhanced magnetic resonance imaging (MRI). Tumors with a maximum diameter of greater than one centimeter on MRI were considered macroadenomas. 2.3. Immunostaining Following surgery, immunohistochemistry was performed on all tumor specimens using standard pathology methods, including immunostaining for TSH, alpha subunit, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), prolactin, and adrenocorticotropic hormone (ACTH). Tumor specimens may demonstrate immunopositivity either diffusely, partially, or in scattered cells. Patients whose tumors demonstrated TSH immunopositivity in at least scattered cells were included in this study. Of note, the majority of tumors in our study demonstrated immunopositivity for other hormones in addition to TSH. 3. Results
Table 1 Patient Demographics and Presenting Symptoms. Demographics Age, mean ± SD Female, n (%) Clinical presentation: Vision loss Headache Incidental finding Decreased libido Fatigue Dizziness Oligo/amenorrhea Tumor recurrence or progression on follow-up imaging
51.8 ± 15.9 7 (35) n (%) 9 (45) 8 (40) 2 (10) 6 (30) 7 (35) 1 (5) 2 (10) 7 (35)
Table 1 illustrates baseline patient demographics and preoperative symptoms. Of the 20 patients with silent TSHoma, 7 were female (35%). Thirteen patients (65%) were newly diagnosed at their initial presentation to our service and 7 patients (35%) presented with tumor recurrence, 3 of whom were asymptomatic and showed residual or recurrent tumor based solely on follow-up imaging. Patient age at presentation ranged from 20 to 75 years, with a mean of 51.8 years and standard deviation of 15.9 years. Preoperative symptoms in patients with silent TSHoma included vision loss (45%), headache (40%), fatigue (35%), and dizziness (5%). Decreased libido was reported in 6 out of 13 men (46%) and oligomenorrhea/ amenorrhea was reported in 2 of 7 women (29%). Two patients (10%) presented with an incidental finding of silent TSHoma, one of whom endorsed no accompanying symptoms at the time of presentation. 3.2. Preoperative endocrine status Table 2 illustrates preoperative endocrine status in patients with silent TSHoma. Eight patients (40%) had hypothyroidism prior to surgery, making hypothyroidism the most common preoperative endocrine dysfunction. Other endocrine abnormalities included hypogonadotropic hypogonadism (30%) and panhypopituitarism (15%). Three patients (15%) had evidence of mildly elevated prolactin (
3.1. Patient demographics and clinical presentation 3.4. Surgical characteristics Of the 1244 patients who underwent surgery for resection of pituitary adenomas between 2000 and 2016, 20 patients (1.6%) met inclusion criteria for histologically verified silent TSHoma.
Table 4 describes surgical characteristics of patients with silent TSHoma. Thirteen patients (65%) underwent their first operation,
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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J. Cyprich et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 2 Preoperative Endocrine Status.
Table 5 Immunostaining.
Preoperative endocrine status:
n (%)
Immunopositivity, n (%):
Normal Hypothyroidism Hypogonadotropic hypogonadism Hyperprolactinemia Panhypopituitarism
8 8 6 3 3
TSH Alpha-subunit LH FSH GH ACTH Prolactin Plurihormonal
(40) (40) (30) (15) (15)
Table 3 Preoperative Lab Values. Preoperative lab values, mean ± SD: TSH, mIU/L (n = 12) Free T4, lg/dL (n = 7) Total T4, lg/dL (n = 3)
1.61 ± 0.91 1.15 ± 0.28 6.10 ± 0.36
while 7 patients (35%) underwent reoperation. Intraoperative gross total resection was achieved in 13 cases (65%). Intraoperative CSF leak occurred and was repaired in 7 patients (35%). 3.5. Histopathological characteristics Tumor hormonal immunopositivity is illustrated in Table 5. Fifteen tumors (75%) were plurihormonal and all tumors except one (95%) were immunopositive for alpha-subunit (Fig. 1). Table 6 shows immunohistochemistry results of individual cases. The most common hormones aside from TSH expressing immunopositivity were LH (65%) and FSH (20%). Other pituitary hormones expressing immunopositivity included ACTH (10%), GH (5%), and prolactin (5%), despite any clinical or laboratory evidence of Cushing’s disease, acromegaly, or hyperprolactinemia other than stalk effect. Histology and immunohistochemistry of select cases are demonstrated in Fig. 1. 3.6. Postoperative follow-up and complications Patient follow-up time and outcomes, including postoperative complications, are illustrated in Table 7. Follow-up time ranged from 3 to 184 months, with a median of 18.5 months. Nine patients (45%) had no evidence of residual disease on 3-month follow-up MRI. The most common postoperative complications were delayed hyponatremia (10%) and epistaxis (10%). Other complications included 1 patient with transient diabetes insipidus and 1 patient with a postoperative CSF leak and meningitis. There were no deaths or carotid artery injuries. Early readmission occurred in 3 cases (15%). Early reoperation was necessary in 2 cases (10%), one for postoperative CSF leak repair and the other for postopera-
Table 4 Imaging and Surgical Characteristics. First operation, n (%) Macroadenoma at presentation, n (%) Maximum tumor diameter (mm), mean ± SD Extrasellar tumor growth, n (%): Cavernous sinus invasion Right Left Bilateral Suprasellar extension Infrasellar invasion Sphenoid Sinus Clivus Growth into Ventricle Intraoperative gross total resection, n (%) Intraoperative CSF leak, n (%)
13 (65) 19 (95) 29.9 ± 14.9 17 (85) 13 (65) 7 (35) 4 (20) 2 (10) 16 (80) 4 (20) 3 (15) 1 (5) 1 (5) 13 (65) 7 (35)
20 (100) 19 (95) 13 (65) 4 (20) 1 (5) 2 (10) 1 (5) 15 (75)
tive hydrocephalus requiring ventriculoperitoneal shunt insertion. One patient (5%) had evidence of tumor progression at one year post-operation. Tumor recurrence was observed in another patient (5%) at more than 7 years post-operation. Adjuvant treatments included stereotactic radiosurgery (25%), external beam radiation therapy (5%), and reoperation (5%).
4. Discussion To date, this is one of the largest case series of patients with silent TSHomas at a single institution. We report the demographics, preoperative presentation, immunostaining patterns, and outcomes following surgical resection of silent TSHomas, which tend to be large and invasive tumors at the time of diagnosis. All but one patient in our study presented with a macroadenoma based on preoperative MRI, which is congruent with our findings of frequently-reported headaches and vision loss at time of presentation. These findings are consistent with previous studies reporting high rates of macroadenomas and symptoms of mass effect in patients with silent TSHoma [4,5]. Rates of headache and vision loss were also much higher in our silent TSHoma cohort compared to our entire database that includes all patients with pituitary adenomas [13]. Seventeen of 20 patients (85%) in our series had evidence of extrasellar tumor growth based on preoperative imaging. In addition, 13 patients (65%) had evidence of cavernous sinus invasion, which differs substantially from prior literature where reported rates range from 17% in a series of patients with silent TSHoma [4] to 23% in a series of combined silent and active TSHoma cases [3]. What’s more, the rate of cavernous sinus invasion is higher in silent TSHomas compared to a cohort including all nonfunctioning pituitary adenomas in our database (65% vs 57%, respectively), suggesting silent TSHomas may in fact be more aggressive than other subtypes of nonfunctioning tumors. This may be attributed to the fact that our hospital is a high-volume tertiary pituitary center that treats a large portion of complex cases, as demonstrated by our reoperation rate in this series. However, it is important to note that the rate of cavernous sinus invasion in all patients with pituitary adenomas at our institution was substantially lower at 36%, supporting the notion that nonfunctioning adenomas and, in particular, silent TSHomas are more aggressive tumors at baseline [13]. The majority of patients in our series included male patients. Previous demographic studies have shown that the majority of pituitary adenomas are diagnosed in women at younger ages (less than 30 years) and in men at older ages [14,15]. Therefore, our mean age of 51.8 years may be a reason for the higher percentage of males observed with silent TSHoma in our series. The most common preoperative symptoms reported among our patients were headache and visual loss, both symptoms of mass effect that have been well described in prior studies of TSHoma [5,7]. Three patients had mild elevation of serum prolactin (mean 38 ng/mL) on presentation which was felt to be a result of pituitary stalk effect. Pituitary stalk effect occurs when mechanical compression
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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Fig. 1. Histology and immunohistochemistry of silent thyrotropin pituitary adenomas H&E shows adenomas with sheeted and lobular growth patterns. Expression of TSH was variable and included diffuse (e.g. cases 16 and 17 in Table 6), patchy (e.g. case 19), and scattered staining patterns (e.g cases 18 and 20). TSH expression ranged from granular and cytoplasmic to membranous (e.g case 16). Expression of alpha-subunit (a-SU) was variable.
of the pituitary stalk decreases dopamine delivery to the anterior pituitary, relieving prolactin-secreting cells from normal dopaminergic inhibition and ultimately resulting in mild hyperprolactinemia [16–18]. The patients in our study presenting with hyperprolactinemia also reported amenorrhea/oligomenorrhea, galactorrhea, and gynecomastia in the absence of positive immunostaining for prolactin. These symptoms have previously been described as features of pituitary stalk effect, particularly in patients with nonfunctioning pituitary adenomas [16]. Additionally, one patient with hyperprolactinemia and hypothyroidism was on thyroid replacement and thus hyperprolactinemia due to hypothyroidism was thought to be excluded in this patient. Hypopituitarism of at least one hormonal axis was common among our patients, including hypogonadotropic hypogonadism and panhypopituitarism. Rates of panhypopituitarism were substantially higher in patients with silent TSHoma compared to a cohort of all patients with pituitary tumors at our institution
(15% vs 4.8%, respectively) [13]. Eight patients had a diagnosis of hypothyroidism prior to surgery, three of whom had panhypopituitarism. All patients with the exception of one were taking levothyroxine at the time of presentation. Of the patients diagnosed with hypothyroidism preoperatively, four were presenting with tumor recurrence based on follow-up imaging and had been diagnosed with hypothyroidism following their first surgical resection many years prior. Interestingly, the other four patients were diagnosed with hypothyroidism within 6 months prior to their operation. To our knowledge, preoperative hypothyroidism in the setting of silent TSHoma has not previously been described. Pituitary hormone testing was available for most but not all patients, and when available was consistent with central hypothyroidism or normal thyroid function. All patients in our series had tumors that stained immunopositive for TSH in at least scattered cells. Nineteen of 20 patients had tumors that stained immunopositive for alpha-subunit, a signifi-
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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J. Cyprich et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 6 Individual patient presentation, immunostaining, and follow-up period. Age
Gender
Clinical presentation
Preoperative endocrine status
Immunostaining (other than TSH)
Follow up time (months)
1
20
F
Hyperprolactinemia (30 ng/mL)
Alpha-subunit, LH, FSH
14
2
46
M
Panhypopituitarism
Alpha-subunit, LH, FSH
184
3
70
M
Hypothyroidism
Alpha-subunit, LH
14
4
68
M
Panhypopituitarism
Alpha-subunit, LH, FSH
3
5 6
73 75
F M
53 5
40
M
Alpha-subunit, LH
118
8
43
F
Hypothyroidism Hypogonadotropic hypogonadism Low GH axis Hypothyroidism Hypogonadotropic hypogonadism Normal
Alpha-subunit, LH Alpha-subunit, LH
7
Visual Loss Headache Amenorrhea Visual Loss Decreased Libido Fatigue Tumor Recurrence Visual Loss Tumor Recurrence Decreased Libido Fatigue Visual Loss Visual Loss Dizziness Decreased Libido
Alpha-subunit, LH
143
9 10 11
47 53 41
M F F
Normal Normal Hypothyroidism Hyperprolactinemia (38 ng/mL)
Alpha-subunit, LH Alpha-subunit, LH, GH Alpha-subunit, LH, ACTH
140 3 44
12
55
M
Normal
Alpha-subunit, LH
30
13 14 15
52 24 57
F F M
Hypothyroidism Normal Normal
ACTH Alpha-subunit Alpha-subunit
6 3 22
16
48
M
Normal
Alpha-subunit
15
17 18
50 30
M M
Hypogonadotropic hypogonadism Hyperprolactinemia (25.1 ng/mL)
Alpha-subunit Alpha-subunit
33 31
19
62
M
Normal
Alpha-subunit, PRL
3
20
73
M
Panhypopituitarism
Alpha-subunit, LH, FSH
3
Visual Loss Headache Visual Loss Incidental Headache Oligomenorrhea Galactorrhea Fatigue Headache Fatigue Decreased Libido Tumor Recurrence Tumor Recurrence Tumor Recurrence Headache Decreased Libido Fatigue Headache Decreased Libido Fatigue Tumor Recurrence Headache Visual Loss Gynecomastia Incidental Headache Visual Loss Fatigue Tumor Recurrence
Table 7 Postoperative Follow Up and Outcomes. Follow-up time (months), median (range) GTR on 3-month follow-up MRI, n (%) Post-surgical complications, n (%): None Hyponatremia Epistaxis DI (transient) CSF leak Meningitis Hydrocephalus Death Early readmission, n (%) Early reoperation, n (%) Recurrence, n (%) Progression, n (%)
18.5 (3–184) 9 (45) 15 (75) 2 (10) 2 (10) 1 (5) 1 (5) 1 (5) 1 (5) 0 (0) 3 (15) 2 (10) 1 (5) 1 (5)
cantly higher rate than in previous reports [9]. The majority of patients in our series had plurihormonal tumors according to immunostaining. The most common pituitary hormones that stained immunopositive aside from TSH were LH and FSH. The most common combination was positivity for TSH, alpha-subunit, and LH which was seen in 7 out of 20 patients (35%). These findings contradict one recent study of silent TSHomas [4] which reported
the most common immunopositive hormones to be GH and prolactin, however, this is likely due to differences in the way silent TSHomas were classified. Our study excluded patients presenting with acromegaly and, therefore, only had one patient whose tumor stained positive for GH. The high incidence of co-secretion with LH and FSH seen in our study is suggestive of a primitive adenoma lineage and subtype [19]. Patients with silent TSHoma had similar rates of progression and recurrence compared to all patients with nonfunctioning pituitary adenomas at our institution. However, rates of both progression and recurrence were lower for patients with silent TSHomas compared to rates described in other studies of silent TSHoma [10], potentially due to our relatively shorter follow-up time and low number of patients included in this study. Significantly, 35% of our patients initially presented for reoperation due to tumor recurrence, suggesting the rate of recurrence in patients with silent TSHomas is actually quite high compared to other types of pituitary adenomas [20]. The main limitations of the current study are the retrospective nature of our data collection and the low absolute number of patients in our series. However, the diagnosis of silent TSHoma is rare and all prior studies have been limited to retrospective reviews with few cases. Our study is unique in that we excluded
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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patients who exhibited hypersecretion of other anterior pituitary hormones on presentation. Patients with acromegaly were excluded in order to eliminate the inclusion of GH and TSH cosecreting tumors. Co-secretion of ACTH and TSH was not necessary to exclude as this tumor type was not encountered. 5. Conclusion This case series is one of the few studies that describes patients with silent TSHoma separately from patients with functioning TSHomas who present with central hyperthyroidism. Our findings indicate the importance of comprehensive preoperative biochemical workups in addition to more detailed pathologic assessments due to the plurihormonal nature of silent TSHomas. Unlike biochemically active tumors which often present as microadenomas, silent TSHomas have often become large invasive lesions by the time they are diagnosed. Although silent TSHomas are rare, it is important for physicians to consider these lesions particularly in the differential diagnosis of the patient with hypothyroidism, headaches, and visual disturbances. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol 2007;156 (2):203–16. [2] Ónnestam L, Berinder K, Burman P, et al. National incidence and prevalence of TSH-secreting pituitary adenomas in Sweden. J Clin Endocrinol Metab 2013;98 (2):626–35.
[3] Yamada S, Fukuhara N, Horiguchi K, et al. Clinicopathological characteristics and therapeutic outcomes in thyrotropin-secreting pituitary adenomas: a single-center study of 90 cases. J Neurosurg 2014;121(6):1462–73. [4] Azzalin A, Appin CL, Schniederjan MJ, et al. Comprehensive evaluation of thyrotropinomas: single-center 20-year experience. Pituitary 2016;19 (2):183–93. [5] Clarke MJ, Erickson D, Castro MR, Atkinson JL. Thyroid-stimulating hormone pituitary adenomas. J Neurosurg 2008;109(1):17–22. [6] Bertholon-Grégoire M, Trouillas J, Guigard MP, Loras B, Tourniaire J. Mono- and plurihormonal thyrotropic pituitary adenomas: pathological, hormonal and clinical studies in 12 patients. Eur J Endocrinol 1999;140(6):519–27. [7] Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 1999;84(2):476–86. [8] Beck-Peccoz P, Persani L. Medical management of thyrotropin-secreting pituitary adenomas. Pituitary 2002;5(2):83–8. [9] Wang EL, Qian ZR, Yamada S, et al. Clinicopathological characterization of TSHproducing adenomas: special reference to TSH-immunoreactive but clinically non-functioning adenomas. Endocr Pathol 2009;20(4):209–20. [10] Kirkman MA, Jaunmuktane Z, Brandner S, Khan AA, Powell M, Baldeweg SE. Active and silent thyroid-stimulating hormone-expressing pituitary adenomas: presenting symptoms, treatment, outcomes, and recurrence. World Neurosurg 2014;82(6):1224–31. [11] Cooper O, Melmed S. Subclinical hyperfunctioning pituitary adenomas: the silent tumors. Best Pract Res Clin Endocrinol Metab 2012;26(4):447–60. [12] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377–81. [13] Agam MS, Wedemeyer MA, Wrobel B, Weiss MH, Carmichael JD, Zada G. Complications associated with microscopic and endoscopic transsphenoidal pituitary surgery: experience of 1153 consecutive cases treated at a single tertiary care pituitary center. J Neurosurg 2018;1–8. [14] McDowell BD, Wallace RB, Carnahan RM, Chrischilles EA, Lynch CF, Schlechte JA. Demographic differences in incidence for pituitary adenoma. Pituitary 2011;14(1):23–30. [15] Hemminki K, Försti A, Ji J. Incidence and familial risks in pituitary adenoma and associated tumors. Endocr Relat Cancer 2007;14(1):103–9. [16] Zhang F, Huang Y, Ding C, Huang G, Wang S. The prevalence of hyperprolactinemia in non-functioning pituitary macroadenomas. Int J Clin Exp Med 2015;8(10):18990–7. [17] Skinner DC. Rethinking the stalk effect: a new hypothesis explaining suprasellar tumor-induced hyperprolactinemia. Med Hypotheses 2009;72 (3):309–10. [18] Randall RV, Scheithauer BW, Laws ER, Abboud CF. Pseudoprolactinomas. Trans Am Clin Climatol Assoc 1983;94:114–21. [19] Lopes MBS. The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol 2017;134(4):521–35. [20] Roelfsema F, Biermasz NR, Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary 2012;15(1):71–83.
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients Janelle Cyprich a,⇑, Daniel A. Donoho b, Andrew Brunswick b, Kyle Hurth c, John D. Carmichael d, Martin H. Weiss b, Gabriel Zada b a
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA d Division of Endocrinology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA b c
a r t i c l e
i n f o
Article history: Received 9 March 2019 Accepted 4 October 2019 Available online xxxx Keywords: Nonfunctional pituitary adenoma Plurihormonal Sella Thyrotropin Transsphenoidal surgery Tumor
a b s t r a c t Silent thyrotropin pituitary adenomas (TSHomas) are defined by absence of hyperthyroidism despite TSH immunopositivity. Data pertaining to clinical and surgical characteristics of silent TSHomas remains limited. We aim to describe the clinical presentation, pathological characteristics, and outcomes in silent TSHoma patients treated at a tertiary pituitary center. We retrospectively identified patients with histologically-proven silent TSHoma who underwent transsphenoidal resection at our center between 2000 and 2016 (n = 1244 total patients). Patients with preoperative hyperthyroidism or thyroidectomy were excluded. Twenty patients with silent TSHomas were included (1.6% of surgically treated PAs), of which 35% were reoperations. Presenting symptoms included vision loss (45%) and headache (40%). Preoperative pituitary dysfunction included hypothyroidism (40%), hypogonadotropic hypogonadism (30%), and panhypopituitarism (15%). Nineteen patients (95%) had macroadenomas (mean diameter 29.9 mm). Extrasellar growth was identified in 17 patients (85%) and 65% had cavernous sinus invasion. Immunostaining for alpha-subunit was positive in 19 patients (95%), and 75% of tumors expressed immunopositivity for hormones other than TSH. Gross total tumor resection was achieved in 9 patients (45%) on follow-up MRI. Major postoperative complications included hydrocephalus (1 patient) and cerebrospinal fluid leak with meningitis (1 patient). Tumor progression and recurrence occurred in 1 patient each (10% total) over the follow-up period (median 18.5 months). Silent TSHomas tend to be large, invasive tumors. In addition to TSH, a majority express immunopositivity for alpha-subunit and gonadotropins, thereby potentially supporting a primitive adenoma lineage and subtype. Despite reoperation in several patients, good overall outcomes with low complication rates were achieved. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Thyrotropin pituitary adenomas (TSHomas) have historically accounted for less than 2% of all pituitary adenomas, making them the least frequent subtype of pituitary adenoma [1,2]. Recent studies have demonstrated a progressive increase in diagnosis of TSHomas over the last several years, likely due to heightened screening and increased awareness among physicians [2–4]. TSHomas are more likely to be macroadenomas compared to other pituitary tumors, and approximately 1 in 3 co-secrete other anterior pituitary hormones, most commonly growth hormone and/or prolactin [5]. TSHomas can be divided into two subtypes: secretory TSHomas and silent TSHomas. ⇑ Corresponding author at: Department of Neurological Surgery, Keck School of Medicine of USC, 1200 North State St, Suite 3300, Los Angeles, CA 90033, USA. E-mail address: [email protected] (J. Cyprich).
Although functional TSHomas classically present with central hyperthyroidism, silent TSHomas are a rare subtype of TSHomas that stain positive for TSH on immunohistochemistry without clinical or biochemical evidence of hyperthyroidism prior to tumor resection [4]. The reason for this is not well understood, though it has been postulated that these tumors may release various isoforms of TSH that are inactive, or the tumor cells may simply not secrete enough TSH to reach a threshold that causes clinical symptoms of hyperthyroidism [6]. These adenomas are most often diagnosed due to symptoms from mass effect, and diagnosis depends on the histopathological staining of the tumor [7,8]. Few studies pertaining to the incidence, management, and treatment outcomes of patients with silent TSHomas have been published. Recent case series of TSHomas demonstrate rates of clinically silent tumors ranging from 7 to 75% [9,4,5]. One study reported similar outcomes between patients with functioning versus silent TSHomas and
https://doi.org/10.1016/j.jocn.2019.10.013 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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found no difference in proportion of plurihormonal adenomas between the two groups [10]. The literature surrounding silent TSHoma is limited and varies according to patient selection based on clinical and biochemical presentation, immunohistochemistry, or both, leading to differences in reported prevalence rates of silent TSHomas. Although from a clinical standpoint they are treated in the same fashion as nonfunctioning pituitary adenomas, the distinction of a silent TSHoma may be clinically and biologically relevant, as these tumors may be associated with more aggressive clinical behavior and worse overall outcomes with regard to recurrence/progression [11]. Our study aims to describe this unique population of patients in terms of incidence, presenting symptoms, tumor pathology, management, and surgical outcomes at a tertiary pituitary center. 2. Methods 2.1. Study design Following IRB approval, a retrospective review was conducted to identify patients whom underwent transsphenoidal surgery at our center between 2000 and 2016. Patients were identified from our electronic pituitary tumor database (RedCap [12]), which includes information about patient demographics, preoperative symptoms and endocrine status, surgical characteristics, pathology, postoperative course, and follow-up details on 1244 patients. We included adults with confirmed histopathologic diagnosis of TSHoma without preoperative hyperthyroidism or history of thyroidectomy. Confirmed histopathologic diagnosis of TSHoma was defined as tumors demonstrating TSH immunopositivity in at least scattered cells. Patients were excluded if they were less than 18 years of age, had less than 3 months of follow up, were hyperthyroid on presentation, had prior history of thyroidectomy, or had biochemical evidence of acromegaly prior to the operation. 2.2. Preoperative examination Preoperative symptoms were recorded and endocrine status was determined using serum pituitary-based hormonal labs, including serum TSH, free T4, prolactin, and IGF-1. Preoperative tumor imaging was obtained, including contrast-enhanced magnetic resonance imaging (MRI). Tumors with a maximum diameter of greater than one centimeter on MRI were considered macroadenomas. 2.3. Immunostaining Following surgery, immunohistochemistry was performed on all tumor specimens using standard pathology methods, including immunostaining for TSH, alpha subunit, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), prolactin, and adrenocorticotropic hormone (ACTH). Tumor specimens may demonstrate immunopositivity either diffusely, partially, or in scattered cells. Patients whose tumors demonstrated TSH immunopositivity in at least scattered cells were included in this study. Of note, the majority of tumors in our study demonstrated immunopositivity for other hormones in addition to TSH. 3. Results
Table 1 Patient Demographics and Presenting Symptoms. Demographics Age, mean ± SD Female, n (%) Clinical presentation: Vision loss Headache Incidental finding Decreased libido Fatigue Dizziness Oligo/amenorrhea Tumor recurrence or progression on follow-up imaging
51.8 ± 15.9 7 (35) n (%) 9 (45) 8 (40) 2 (10) 6 (30) 7 (35) 1 (5) 2 (10) 7 (35)
Table 1 illustrates baseline patient demographics and preoperative symptoms. Of the 20 patients with silent TSHoma, 7 were female (35%). Thirteen patients (65%) were newly diagnosed at their initial presentation to our service and 7 patients (35%) presented with tumor recurrence, 3 of whom were asymptomatic and showed residual or recurrent tumor based solely on follow-up imaging. Patient age at presentation ranged from 20 to 75 years, with a mean of 51.8 years and standard deviation of 15.9 years. Preoperative symptoms in patients with silent TSHoma included vision loss (45%), headache (40%), fatigue (35%), and dizziness (5%). Decreased libido was reported in 6 out of 13 men (46%) and oligomenorrhea/ amenorrhea was reported in 2 of 7 women (29%). Two patients (10%) presented with an incidental finding of silent TSHoma, one of whom endorsed no accompanying symptoms at the time of presentation. 3.2. Preoperative endocrine status Table 2 illustrates preoperative endocrine status in patients with silent TSHoma. Eight patients (40%) had hypothyroidism prior to surgery, making hypothyroidism the most common preoperative endocrine dysfunction. Other endocrine abnormalities included hypogonadotropic hypogonadism (30%) and panhypopituitarism (15%). Three patients (15%) had evidence of mildly elevated prolactin (
3.1. Patient demographics and clinical presentation 3.4. Surgical characteristics Of the 1244 patients who underwent surgery for resection of pituitary adenomas between 2000 and 2016, 20 patients (1.6%) met inclusion criteria for histologically verified silent TSHoma.
Table 4 describes surgical characteristics of patients with silent TSHoma. Thirteen patients (65%) underwent their first operation,
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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J. Cyprich et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 2 Preoperative Endocrine Status.
Table 5 Immunostaining.
Preoperative endocrine status:
n (%)
Immunopositivity, n (%):
Normal Hypothyroidism Hypogonadotropic hypogonadism Hyperprolactinemia Panhypopituitarism
8 8 6 3 3
TSH Alpha-subunit LH FSH GH ACTH Prolactin Plurihormonal
(40) (40) (30) (15) (15)
Table 3 Preoperative Lab Values. Preoperative lab values, mean ± SD: TSH, mIU/L (n = 12) Free T4, lg/dL (n = 7) Total T4, lg/dL (n = 3)
1.61 ± 0.91 1.15 ± 0.28 6.10 ± 0.36
while 7 patients (35%) underwent reoperation. Intraoperative gross total resection was achieved in 13 cases (65%). Intraoperative CSF leak occurred and was repaired in 7 patients (35%). 3.5. Histopathological characteristics Tumor hormonal immunopositivity is illustrated in Table 5. Fifteen tumors (75%) were plurihormonal and all tumors except one (95%) were immunopositive for alpha-subunit (Fig. 1). Table 6 shows immunohistochemistry results of individual cases. The most common hormones aside from TSH expressing immunopositivity were LH (65%) and FSH (20%). Other pituitary hormones expressing immunopositivity included ACTH (10%), GH (5%), and prolactin (5%), despite any clinical or laboratory evidence of Cushing’s disease, acromegaly, or hyperprolactinemia other than stalk effect. Histology and immunohistochemistry of select cases are demonstrated in Fig. 1. 3.6. Postoperative follow-up and complications Patient follow-up time and outcomes, including postoperative complications, are illustrated in Table 7. Follow-up time ranged from 3 to 184 months, with a median of 18.5 months. Nine patients (45%) had no evidence of residual disease on 3-month follow-up MRI. The most common postoperative complications were delayed hyponatremia (10%) and epistaxis (10%). Other complications included 1 patient with transient diabetes insipidus and 1 patient with a postoperative CSF leak and meningitis. There were no deaths or carotid artery injuries. Early readmission occurred in 3 cases (15%). Early reoperation was necessary in 2 cases (10%), one for postoperative CSF leak repair and the other for postopera-
Table 4 Imaging and Surgical Characteristics. First operation, n (%) Macroadenoma at presentation, n (%) Maximum tumor diameter (mm), mean ± SD Extrasellar tumor growth, n (%): Cavernous sinus invasion Right Left Bilateral Suprasellar extension Infrasellar invasion Sphenoid Sinus Clivus Growth into Ventricle Intraoperative gross total resection, n (%) Intraoperative CSF leak, n (%)
13 (65) 19 (95) 29.9 ± 14.9 17 (85) 13 (65) 7 (35) 4 (20) 2 (10) 16 (80) 4 (20) 3 (15) 1 (5) 1 (5) 13 (65) 7 (35)
20 (100) 19 (95) 13 (65) 4 (20) 1 (5) 2 (10) 1 (5) 15 (75)
tive hydrocephalus requiring ventriculoperitoneal shunt insertion. One patient (5%) had evidence of tumor progression at one year post-operation. Tumor recurrence was observed in another patient (5%) at more than 7 years post-operation. Adjuvant treatments included stereotactic radiosurgery (25%), external beam radiation therapy (5%), and reoperation (5%).
4. Discussion To date, this is one of the largest case series of patients with silent TSHomas at a single institution. We report the demographics, preoperative presentation, immunostaining patterns, and outcomes following surgical resection of silent TSHomas, which tend to be large and invasive tumors at the time of diagnosis. All but one patient in our study presented with a macroadenoma based on preoperative MRI, which is congruent with our findings of frequently-reported headaches and vision loss at time of presentation. These findings are consistent with previous studies reporting high rates of macroadenomas and symptoms of mass effect in patients with silent TSHoma [4,5]. Rates of headache and vision loss were also much higher in our silent TSHoma cohort compared to our entire database that includes all patients with pituitary adenomas [13]. Seventeen of 20 patients (85%) in our series had evidence of extrasellar tumor growth based on preoperative imaging. In addition, 13 patients (65%) had evidence of cavernous sinus invasion, which differs substantially from prior literature where reported rates range from 17% in a series of patients with silent TSHoma [4] to 23% in a series of combined silent and active TSHoma cases [3]. What’s more, the rate of cavernous sinus invasion is higher in silent TSHomas compared to a cohort including all nonfunctioning pituitary adenomas in our database (65% vs 57%, respectively), suggesting silent TSHomas may in fact be more aggressive than other subtypes of nonfunctioning tumors. This may be attributed to the fact that our hospital is a high-volume tertiary pituitary center that treats a large portion of complex cases, as demonstrated by our reoperation rate in this series. However, it is important to note that the rate of cavernous sinus invasion in all patients with pituitary adenomas at our institution was substantially lower at 36%, supporting the notion that nonfunctioning adenomas and, in particular, silent TSHomas are more aggressive tumors at baseline [13]. The majority of patients in our series included male patients. Previous demographic studies have shown that the majority of pituitary adenomas are diagnosed in women at younger ages (less than 30 years) and in men at older ages [14,15]. Therefore, our mean age of 51.8 years may be a reason for the higher percentage of males observed with silent TSHoma in our series. The most common preoperative symptoms reported among our patients were headache and visual loss, both symptoms of mass effect that have been well described in prior studies of TSHoma [5,7]. Three patients had mild elevation of serum prolactin (mean 38 ng/mL) on presentation which was felt to be a result of pituitary stalk effect. Pituitary stalk effect occurs when mechanical compression
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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Fig. 1. Histology and immunohistochemistry of silent thyrotropin pituitary adenomas H&E shows adenomas with sheeted and lobular growth patterns. Expression of TSH was variable and included diffuse (e.g. cases 16 and 17 in Table 6), patchy (e.g. case 19), and scattered staining patterns (e.g cases 18 and 20). TSH expression ranged from granular and cytoplasmic to membranous (e.g case 16). Expression of alpha-subunit (a-SU) was variable.
of the pituitary stalk decreases dopamine delivery to the anterior pituitary, relieving prolactin-secreting cells from normal dopaminergic inhibition and ultimately resulting in mild hyperprolactinemia [16–18]. The patients in our study presenting with hyperprolactinemia also reported amenorrhea/oligomenorrhea, galactorrhea, and gynecomastia in the absence of positive immunostaining for prolactin. These symptoms have previously been described as features of pituitary stalk effect, particularly in patients with nonfunctioning pituitary adenomas [16]. Additionally, one patient with hyperprolactinemia and hypothyroidism was on thyroid replacement and thus hyperprolactinemia due to hypothyroidism was thought to be excluded in this patient. Hypopituitarism of at least one hormonal axis was common among our patients, including hypogonadotropic hypogonadism and panhypopituitarism. Rates of panhypopituitarism were substantially higher in patients with silent TSHoma compared to a cohort of all patients with pituitary tumors at our institution
(15% vs 4.8%, respectively) [13]. Eight patients had a diagnosis of hypothyroidism prior to surgery, three of whom had panhypopituitarism. All patients with the exception of one were taking levothyroxine at the time of presentation. Of the patients diagnosed with hypothyroidism preoperatively, four were presenting with tumor recurrence based on follow-up imaging and had been diagnosed with hypothyroidism following their first surgical resection many years prior. Interestingly, the other four patients were diagnosed with hypothyroidism within 6 months prior to their operation. To our knowledge, preoperative hypothyroidism in the setting of silent TSHoma has not previously been described. Pituitary hormone testing was available for most but not all patients, and when available was consistent with central hypothyroidism or normal thyroid function. All patients in our series had tumors that stained immunopositive for TSH in at least scattered cells. Nineteen of 20 patients had tumors that stained immunopositive for alpha-subunit, a signifi-
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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J. Cyprich et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 6 Individual patient presentation, immunostaining, and follow-up period. Age
Gender
Clinical presentation
Preoperative endocrine status
Immunostaining (other than TSH)
Follow up time (months)
1
20
F
Hyperprolactinemia (30 ng/mL)
Alpha-subunit, LH, FSH
14
2
46
M
Panhypopituitarism
Alpha-subunit, LH, FSH
184
3
70
M
Hypothyroidism
Alpha-subunit, LH
14
4
68
M
Panhypopituitarism
Alpha-subunit, LH, FSH
3
5 6
73 75
F M
53 5
40
M
Alpha-subunit, LH
118
8
43
F
Hypothyroidism Hypogonadotropic hypogonadism Low GH axis Hypothyroidism Hypogonadotropic hypogonadism Normal
Alpha-subunit, LH Alpha-subunit, LH
7
Visual Loss Headache Amenorrhea Visual Loss Decreased Libido Fatigue Tumor Recurrence Visual Loss Tumor Recurrence Decreased Libido Fatigue Visual Loss Visual Loss Dizziness Decreased Libido
Alpha-subunit, LH
143
9 10 11
47 53 41
M F F
Normal Normal Hypothyroidism Hyperprolactinemia (38 ng/mL)
Alpha-subunit, LH Alpha-subunit, LH, GH Alpha-subunit, LH, ACTH
140 3 44
12
55
M
Normal
Alpha-subunit, LH
30
13 14 15
52 24 57
F F M
Hypothyroidism Normal Normal
ACTH Alpha-subunit Alpha-subunit
6 3 22
16
48
M
Normal
Alpha-subunit
15
17 18
50 30
M M
Hypogonadotropic hypogonadism Hyperprolactinemia (25.1 ng/mL)
Alpha-subunit Alpha-subunit
33 31
19
62
M
Normal
Alpha-subunit, PRL
3
20
73
M
Panhypopituitarism
Alpha-subunit, LH, FSH
3
Visual Loss Headache Visual Loss Incidental Headache Oligomenorrhea Galactorrhea Fatigue Headache Fatigue Decreased Libido Tumor Recurrence Tumor Recurrence Tumor Recurrence Headache Decreased Libido Fatigue Headache Decreased Libido Fatigue Tumor Recurrence Headache Visual Loss Gynecomastia Incidental Headache Visual Loss Fatigue Tumor Recurrence
Table 7 Postoperative Follow Up and Outcomes. Follow-up time (months), median (range) GTR on 3-month follow-up MRI, n (%) Post-surgical complications, n (%): None Hyponatremia Epistaxis DI (transient) CSF leak Meningitis Hydrocephalus Death Early readmission, n (%) Early reoperation, n (%) Recurrence, n (%) Progression, n (%)
18.5 (3–184) 9 (45) 15 (75) 2 (10) 2 (10) 1 (5) 1 (5) 1 (5) 1 (5) 0 (0) 3 (15) 2 (10) 1 (5) 1 (5)
cantly higher rate than in previous reports [9]. The majority of patients in our series had plurihormonal tumors according to immunostaining. The most common pituitary hormones that stained immunopositive aside from TSH were LH and FSH. The most common combination was positivity for TSH, alpha-subunit, and LH which was seen in 7 out of 20 patients (35%). These findings contradict one recent study of silent TSHomas [4] which reported
the most common immunopositive hormones to be GH and prolactin, however, this is likely due to differences in the way silent TSHomas were classified. Our study excluded patients presenting with acromegaly and, therefore, only had one patient whose tumor stained positive for GH. The high incidence of co-secretion with LH and FSH seen in our study is suggestive of a primitive adenoma lineage and subtype [19]. Patients with silent TSHoma had similar rates of progression and recurrence compared to all patients with nonfunctioning pituitary adenomas at our institution. However, rates of both progression and recurrence were lower for patients with silent TSHomas compared to rates described in other studies of silent TSHoma [10], potentially due to our relatively shorter follow-up time and low number of patients included in this study. Significantly, 35% of our patients initially presented for reoperation due to tumor recurrence, suggesting the rate of recurrence in patients with silent TSHomas is actually quite high compared to other types of pituitary adenomas [20]. The main limitations of the current study are the retrospective nature of our data collection and the low absolute number of patients in our series. However, the diagnosis of silent TSHoma is rare and all prior studies have been limited to retrospective reviews with few cases. Our study is unique in that we excluded
Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013
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patients who exhibited hypersecretion of other anterior pituitary hormones on presentation. Patients with acromegaly were excluded in order to eliminate the inclusion of GH and TSH cosecreting tumors. Co-secretion of ACTH and TSH was not necessary to exclude as this tumor type was not encountered. 5. Conclusion This case series is one of the few studies that describes patients with silent TSHoma separately from patients with functioning TSHomas who present with central hyperthyroidism. Our findings indicate the importance of comprehensive preoperative biochemical workups in addition to more detailed pathologic assessments due to the plurihormonal nature of silent TSHomas. Unlike biochemically active tumors which often present as microadenomas, silent TSHomas have often become large invasive lesions by the time they are diagnosed. Although silent TSHomas are rare, it is important for physicians to consider these lesions particularly in the differential diagnosis of the patient with hypothyroidism, headaches, and visual disturbances. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol 2007;156 (2):203–16. [2] Ónnestam L, Berinder K, Burman P, et al. National incidence and prevalence of TSH-secreting pituitary adenomas in Sweden. J Clin Endocrinol Metab 2013;98 (2):626–35.
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Please cite this article as: J. Cyprich, D. A. Donoho, A. Brunswick et al., Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.10.013