Thyrotropin-secreting pituitary adenomas: outcome of pituitary surgery and irradiation.

ORIGINAL

ARTICLE

E n d o c r i n e

C a r e

Thyrotropin-Secreting Pituitary Adenomas: Outcome of Pituitary Surgery and Irradiation Elena Malchiodi, Eriselda Profka, Emanuele Ferrante, Elisa Sala, Elisa Verrua, Irene Campi, Andrea Gerardo Lania, Maura Arosio, Marco Locatelli, Pietro Mortini, Marco Losa, Enrico Motti, Paolo Beck-Peccoz, Anna Spada, and Giovanna Mantovani Departments of Clinical Sciences and Community Health (E.M., E.P., E.F., E.S., E.V., I.C., M.A., P.B.P., A.S., G.M.), Neurological Sciences (E.M.) and BIOMETRA Department (A.G.L.), University of Milan; Endocrinology and Diabetology Unit (E.M., E.P., E.F., E.S., E.V., I.C., P.B.P., A.S., G.M.) and Unit of Neurosurgery (M.L.), Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20112 Milan, Italy; Istituto Clinico Humanitas IRCCS (A.G.L.), 20089 Rozzano, Italy; Unit of Endocrine Diseases and Diabetology (M.A.), San Giuseppe Hospital, Multimedica Group, 20123 Milan, Italy; Pituitary Unit , Department of Neurosurgery (P.M., M.L.), Istituto Scientifico San Raffaele, Università Vita-Salute, 20132 Milan, Italy; and GVM Care and Research, Maria Cecilia Hospital (E.M.), 48010 Cotignola, Italy

Objective: Our objective was to describe the effects of surgery and radiotherapy on hormonal control and tumor mass in short- and long-term follow-up of TSH-secreting pituitary adenomas (TSHomas). Methods: This was a retrospective multicenter study. Results: We collected data of 70 TSHomas (70% macroadenomas). The mean follow-up was 64.4 (range 3–324) months. Overall, 97% of patients were treated with surgery; in 27% of them radiotherapy was associated. After surgery, 75% of patients normalized thyroid function, 58% normalized both pituitary imaging and hormonal profile, 9% developed pituitary deficiencies, and 3% had tumor or hormonal recurrence, all within the first 2 years after surgery. Presurgical medical treatment did not significantly improve surgical outcome (63% vs 57%). Radiotherapy controlled hypersecretion in 37% of patients within 2 years, whereas 32% of patients developed new pituitary deficiencies from 18 to 96 months from treatment. At last follow-up, 80% of patients normalized thyroid function, whereas 20% were currently on medical treatment: 85% with somatostatin analog (SSA) alone and 15% with SSA combined with methimazole. Subjects who achieved disease control had surgery as the only treatment in 80% of cases and surgery combined with irradiation in 20%. Conclusions: Surgery remains the first-choice treatment for TSHoma. If surgery is successful, recurrence is rare. When surgery is unsuccessful or contraindicated, SSA and radiotherapy are effective in controlling hyperthyroidism and tumor growth in the majority of patients. The effects of radiotherapy on TSH secretion and tumor mass are greater within the first years after treatment, whereas pituitary deficiencies may occur several years later. (J Clin Endocrinol Metab 99: 2069 –2076, 2014)

T

hyrotropin-secreting pituitary adenomas (TSHomas) are rare pituitary tumors and represent an even rarer cause of hyperthyroidism. Recent data from the Swedish

register report an incidence of 0.15 per 1 million inhabitants with a prevalence of 2.8 cases per million (1). Since the first case described in 1960 (2), an increase in the num-

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received December 11, 2013. Accepted February 7, 2014. First Published Online February 19, 2014

Abbreviations: CRT, conventional radiotherapy; FT4, free T4; LAR, long acting release; PRL, prolactin; RS, radiosurgery; RTH, resistance to thyroid hormone; SSA, somatostatin analog; TSHoma, TSH-secreting pituitary adenoma.

doi: 10.1210/jc.2013-4376

J Clin Endocrinol Metab, June 2014, 99(6):2069 –2076

jcem.endojournals.org

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 02 September 2014. at 10:32 For personal use only. No other uses without permission. . All rights reserved.

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Treatment Outcome in 70 Patients With TSHoma


nosis. Some clinical (age at diagnosis) and radiological (pituitary imaging at diagnosis) parameters were compared in the 2 groups to study their prognostic effect.

ber of TSHomas diagnosed in the last 3 decades has been observed, this finding probably due to both practitioner awareness and the introduction of ultrasensitive TSH immunometric assays. The presence of elevated free thyroid hormones and detectable TSH are features shared with resistance to thyroid hormone (RTH), a rare disease with completely different etiopathology and treatment. Consequently, failure to diagnose these different disorders may result in improper thyroid ablation in patients with TSHomas or unnecessary pituitary surgery in patients with RTH. The primary aim of treatment in patients with TSHomas is to restore a euthyroid state and to correct symptoms related to pituitary mass. The first therapeutic approach is pituitary neurosurgery. If surgery is unsuccessful or contraindicated, pituitary radiotherapy and/or medical treatment should be considered (3). Even if recorded reports increased, many questions are still open. The main limitations are due to the rarity of the disease and the heterogeneity of published series. In particular, in the literature, there are few data on treatment outcome and long-term follow-up (2, 4 –7). The aim of this study is to analyze the clinical presentation and the effects of surgery and radiotherapy on hormonal and tumor mass control in a large series of 70 patients with TSHomas in short- and long-term follow-up.

Data are expressed as mean ⫾ SD and/or as the median and interquartile range (25%–75%), as appropriate. Normally distributed variables were compared using Student’s t test, preceded by Levene’s test to check variance equality. Nominal data were analyzed by Fisher’s exact test in 2 ⫻ 2 contingency tables or ␹2 test otherwise, whereas the other non-Gaussian variables were evaluated by Mann-Whitney U test. Statistical analysis was carried out by SPSS version 17.0. Values of P ⬍ .05 were considered statistically significant.

Patients and Methods

Results

Patients

Population at diagnosis The mean age at diagnosis was 44.1 ⫾ 12.0 years (41.8 ⫾ 13.8 years in patients diagnosed before 2000 and 45.5 ⫾ 11.4 years since 2000). Neuroradiological imaging revealed a microadenoma in 30% (16 females and 5 males) and a macroadenoma in 70% (20 females and 29 males) with an extrasellar extension in 77.5% of cases. Only 2 microadenomas (9%) presented with extrasellar extension. When comparing patients diagnosed before 2000 with those after 2000, no significant differences were found in the percentage of microadenomas vs that of macroadenomas (32% vs 28%). Concomitant hypersecretory syndromes were diagnosed in 24% of patients (17 of 70, 88% macroadenomas) were characterized by a concomitant hypersecretory state with this distribution: 76% GH, 12% prolactin (PRL), 6% gonadotropins, and 6% GH and gonadotropins. Pituitary deficiencies were observed in 12.8% of patients (9 of 70), all with macroadenomas: 11% hypoadrenalism, 55% hypogonadism, and 34% both. Because most patients were not tested for GH deficiency (66%), it is likely that this deficit was underdiagnosed.

We retrospectively collected data of 70 consecutive patients (34 males and 36 females) with TSHoma diagnosed from 1982 to February 2012 by 2 tertiary referral centers in Milan (Endocrinology and Diabetology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda, Ospedale Maggiore Policlinico and Pituitary Unit, Department of Neurosurgery, San Raffaele Scientific Institute). Seventeen patients were previously described (4, 8). The diagnosis of TSHoma was based on clinical, radiological, and biochemical findings. In particular, the presence of elevated free thyroid hormones (FT4, FT3) with normal/high serum TSH concentrations and abnormal response of TSH to at least 1 dynamic test (ie, incomplete inhibition of TSH secretion after T3 suppression test (80 –100 ␮g 3 times daily orally for 8 –10 days) and absent or impaired TSH response during 200 ␮g iv, TRH stimulation test). Contrary to RTH, most patients with TSHoma display a clear reduction in FT4 and FT3 levels after chronic somatostatin analog (SSA) administration (octreotide long acting release [LAR] 30 mg every 28 days for 2–3 months) (8). This test represents a useful method in differential diagnosis with RTH. Further diagnostic investigations, such as measurement of SHBG and glycoprotein hormone ␣-subunit as well as sequencing of exons 7 to 10 of the thyroid receptor-␤ gene, should be considered in doubtful cases. We arbitrarily selected a cutoff point in the middle of our observational period (year 2000) and divided our series into 2 groups according to the year of diag-

Follow-up and criteria of remission All patients were investigated using basal and dynamic tests of pituitary function and by pituitary imaging before treatment, shortly after treatment (1–3 months) and then annually if there was no other specific indication. After surgery or radiotherapy, patients were considered cured when basal TSH, basal free thyroid hormone levels, and dynamic response of TSH to evocative test were normalized. Patients were considered in partial remission when FT4 and FT3 normalized but an altered response to dynamic tests remained. Patients were considered controlled when FT4 and FT3 were normalized under medical therapy. All patients gave their informed consent to the collection of their data.

Statistical analysis


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Figure 1. Treatment approaches and outcomes. *, Eleven patients were treated for central hyperthyroidism, 6 patients were treated for both central hyperthyroidism and residual acromegaly, and 1 patient normalized TSH but was treated with dopamine agonist for residual hyperprolactinemia. ˆ, One patient had relapsing hyperthyroidism on surgical rest after a 2-year period of euthyroidism, 1 patient was irradiated 1 year after surgery for relapsing adenoma with no biochemical evidence of associated hyperthyroidism, and 4 euthyroid patients were irradiated for enlargement of surgical rest. °, Twenty patients maintained an altered response to at least 1 provocative TSH test (either TRH stimulation test and/ or T3 suppression test), 1 patient with mixed TSH/GH/FSH adenoma normalized GH and TSH secretion but maintained an incomplete inhibition of FSH after a 1-mg ethinyl estradiol suppression test.

Treatments The first-line treatment was surgery in 53% of cases and pharmacotherapy in 47% (Figure 1). In particular, 57% of macroadenomas (28 of 49) and 43% of microadenomas (9 of 21) were first treated with surgery. Medical treatments were used as first-line therapy to restore euthyroidism before surgery. None of the patients had surgical contraindication. Medical treatments used as firstline therapy were SSAs in 38% of cases (12 of 33), thyrostatic drugs in 23.5% (8 of 33), dopamine agonists in 7% (2 of 33), a combination of SSAs and dopamine agonists in 7% (2 of 33), and SSAs in combination with antithyroid drugs in 24.5% (9 of 33) of cases. Surgery was proposed as a second-line approach to all patients who had been initially medically treated, but 2 refused: 1 with a large tumor with suprasellar mass underwent radiosurgery and SSAs, and 1 with a microadenoma refused both surgery and radiotherapy and thus started chronic SSA therapy (Figure 1). Radiation therapy on the surgical residue was performed in 26% of patients. After surgery or irradiation, 13 of 69 patients (20%) needed medical treatment: 11 were treated with SSAs for pure TSHoma, 1 was treated with SSAs for mixed GH/ TSH adenoma and 1 with dopamine agonists for persistence of hyperprolactinemia.

Surgical outcome Surgery was overall performed in 97% cases (68 of 70) by dedicated neurosurgeons. Sixty-five patients (96%) were operated with a transsphenoidal approach, 1 patient with macroadenoma and extrasellar extension underwent a transcranial approach, and 2 patients had a combined approach. Five patients (7%) required multiple surgery, 4 of whom were reoperated twice and 1 thrice. In these patients, postoperative hormone evaluation refers to the last procedure. At the first control after surgery, pituitary imaging was negative for tumor residue in 41 of 68 subjects (60%). All patients with residual disease had a macroadenoma. Fiftynine percent of patients (16 of 27) with residual adenoma had persistent hyperthyroidism, whereas 41% (11 of 27) showed normalized TSH and free thyroid hormone circulating levels. Patients with negative magnetic resonance imaging were euthyroid in 37 of 41 cases (91%: 57% macroadenomas and 43% microadenomas), 1 patient with microadenoma had persistent hyperthyroidism, 2 patients (1 microadenoma and 1 macroadenoma) had primary hyperthyroidism, and 1 patient with microadenoma had central hypothyroidism. The presence of a macroadenoma significantly reduced the remission rate (44% in macroadenomas vs 80% in microadenomas, P ⫽ .007).


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Overall, hormonal evaluation showed that 17 patients (25%) were still hyperthyroid, 2 (3%) developed primary hyperthyroidism, 1 (1%) developed central hypothyroidism, whereas 48 (71%) were euthyroid. The latter maintained an altered response to at least 1 provocative test in 56% of cases (33% with and 67% without residual rest) (Figure 1). Normalization of both TSH hypersecretion and pituitary imaging was reached in 58% of subjects. Presurgical medical therapies with SSA did not significantly influence the surgical outcome. In particular, a negative postsurgery imaging along with thyroid function normalization were similar in pretreated and non-pretreated patients (63% and 57%, respectively). After surgery, 8 of 17 patients (47%) with mixed adenomas still showed an active disease and residual adenoma. In particular, 6 patients with GH/TSH mixed adenomas had both hyperthyroidism and high serum IGF-I levels, 1 with mixed TSH/PRL-secreting adenoma normalized TSH but not PRL secretion, and 1 patient with mixed TSH/GH/FSH adenoma normalized GH and TSH secretion but not FSH hypersecretion. Cosecretion was normalized in 9 of 17 patients (53%): 7 of 9 (78%) had negative imaging (6 GH-secreting adenomas and 1 gonadotropin-secreting adenoma), 2 of 9 (22%) had tumor residue (1 GH and 1 PRL). Plurihormonal secretion did not significantly change the surgical outcome (47% of mixed adenomas and 31% of TSHomas had persistent disease). After surgery, new pituitary deficiencies were observed in 6 patients (9%: 67% macroadenomas): 2 subjects developed hypogonadism, 2 hypoadrenalism, 1 both hypoadrenalism and hypogonadism, and 1 panhypopituitarism. No patient died or developed major complications (optic nerve and/or carotid injury) in the postoperative period. Radiotherapy Nineteen patients (27%), all with macroadenomas, were treated with radiation therapy. Fractioned conventional radiotherapy (CRT) was used in 32% of patients, whereas 68% of patients underwent radiosurgery (RS). The therapeutic dose varied from 46 to 54 Gy fractionated at 2 Gy per day for CRT and from 12 to 25 Gy in a single dose for RS. Seventeen patients (90%) were irradiated on residual adenoma: 12 were hyperthyroid, 4 were euthyroid but with residual adenoma increased, and 1 had relapsing hyperthyroidism after a 2-year period of euthyroidism. One patient was irradiated 1 year after surgery for relapsing adenoma with no biochemical evidence of associated hyperthyroidism and one because he refused surgery.


The mean follow-up was 5.8 ⫾ 4.5 (1–19) years: 7.8 years after CRT and 4.7 years after RS. Clinical and biochemical characteristics of these patients at the time of the last evaluation are shown in Table 1. After radiotherapy, radiological evaluation revealed the complete disappearance of the pituitary lesion in 1 patient and a significant reduction of the tumor size in 5 patients (26%), whereas in 10 patients (52%), tumor size remained unchanged. No postradiotherapy imaging was available for the remaining 3 patients. At last follow-up, 7 of 19 patients (37%) were still on medical treatment, 6 due to the persistence of hyperthyroidism and 1 for both hyperthyroidism and active acromegaly. Four of 19 patients (21%) normalized TSH and free thyroid hormone levels between 12 and 24 months after radiation, 3 of 19 (16%) developed hypothyroidism (Figure 2), and 5 of 19 (26%) maintained normal free thyroid hormones before and after radiation treatment. Among the euthyroid patients, 8 of 9 (90%) maintained an abnormal response to at least 1 provocative test (Figure 1). New pituitary deficiencies occurred in 6 patients (32%) between 1 and 8 years after treatment: 2 patients developed hypogonadism; 1 combined hypoadrenalism and hypogonadism; 1 combined hypothyroidism, hypoadrenalism, and hypogonadism; 1 combined hypothyroidism and GH deficiency; and 1 panhypopituitarism. Because only 11 patients had a follow-up longer than 4 years, pituitary defects were probably underestimated as shown in Figure 3. No other complications were reported. Comparing RS with CRT, there were no differences on hormonal control and onset of new pituitary deficiencies. Interestingly, all significant tumor shrinkage was observed in the RS group (Table 2). Overall disease-specific outcome The mean follow-up was 64.4 ⫾ 66.4 (from 3–324) months. During this follow-up period, 2 patients (3%) had disease recurrence: 1 had relapsing hyperthyroidism on surgical rest 2 years after surgery, and 1 had relapsing adenoma without biochemical evidence of hyperthyroidism 1 year after surgery. At the last visit, 53 patients (74%) displayed normal TSH and free thyroid hormone levels out of medical therapy: of these, 29 (45% with and 55% without residual adenoma) maintained an abnormal response to at least 1 provocative test. Despite a pathological response to a dynamic test, these patients maintained normal TSH secretion: 68% of these patients had a follow-up longer than 2 years and 39% longer than 5 years. In 1 euthyroid patient, cosecretion of other hormones persisted. Fourteen patients (20%) were well controlled on medical treatment: 10 patients were treated with SSA and 2 with SSA com-


doi: 10.1210/jc.2013-4376

Table 1.


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Patients Treated With Radiotherapy

Pituitary Deficiency Before Age at Radiological Patients Gender Diagnosis Imaging Cosecretion Radiotherapy Treatments 1

M

36

Macro/E

TNS ⫹ RS ⫹ SSA

2

F

47

Macro/E

3

F

20

Macro/E

4

M

57

Macro/E

5

M

68

Macro/E

MMI ⫹ TNS ⫹ CRT ⫹ SSA SSA ⫹ TNS ⫹ RS ⫹ SSA SSA ⫹ RS ⫹ SSA ⫹ MMI TNS ⫹ RS

6

F

31

Macro/E

TNS ⫹ RS

7

M

53

Macro/E

GH

MMI ⫹ TNS ⫹ RS

8

F

29

Macro/E

GH

9

M

47

Macro/E

GH

10

M

22

Macro/E

11

M

39

Macro/E

12

M

38

Macro/E

13

M

21

Macro/E

SSA ⫹ TNS/TC ⫹ CRT ⫹ SSA MMI ⫹ SSA ⫹ TNS ⫹ RS ⫹ SSA MMI ⫹ TC ⫹ RS ⫹ SSA 2TNS ⫹ CRT ⫹ RS ⫹ SSA 3TNS ⫹ CRT ⫹ SSA TNS ⫹ RS

14

M

53

Macro/E

15

M

52

Macro/E

16

M

36

Macro/E

17

M

40

Macro/I

18

F

26

Macro/E

TNS ⫹ RS

19

F

34

Macro/E

TNS ⫹ RS ⫹ SSA

G GH

G, A

G GH

SSA ⫹ TNS ⫹ CRT ⫹ SSA TNS ⫹ CRT ⫹ SSA 2TNS ⫹ CRT ⫹ SSA TNS ⫹ RS ⫹ SSA

Surgical Outcome Relapsing hyperthyroidism on surgical rest 2 y after Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism

Surgical rest and euthyroidism Surgical rest and euthyroidism Surgical rest and euthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Relapsing adenoma and euthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Surgical rest and hyperthyroidism Surgical rest and euthyroidism Surgical rest and hyperthyroidism

Years of Irradiation Follow-up Outcome: After Radiotherapy Imaging

Irradiation Outcome: Hormonal

Pituitary Deficiency After Radiotherapya

4

Reduction

1

Unchanged Control

4

Reduction

3

Reduction

Partial remission 2 yr later Control G 3 y after

3

NA

Partial remission

5

Unchanged Partial remission G 5 y after

5

Unchanged Partial remission

5

Unchanged Control

1

NA

Control

5

NA

Partial remission

8

Unchanged Control

11

Unchanged Control

14

Unchanged Partial remission G

1

Unchanged Control

19

5

Unchanged Cure 1 y Panhypopituitarism after 1 y after Unchanged Cure 2 y G ⫹ T ⴙ A 2 y after after Reduction Cure 1.5 y T ⴙ GH 1.5 y after after Reduction Partial remission

6

Resolution

10 1.5

Partial remission 3 yr later

A ⴙ G 8 y after

G, A

Cure 1 y after

Abbreviations: A, adrenal; E, extrasellar; F, female; G, gonad; I, intrasellar; MMI, methimazole; NA, not available; T, thyroid; TC, transcranial surgery; TNS, transsphenoidal surgery. a

New pituitary deficiencies are in bold.

bined with methimazole, 1 was treated with SSA for hyperthyroidism and residual acromegaly, and 1 was treated with dopamine agonist for residual hyperprolactinemia. Four patients (6%) developed central hypothyroidism (Figure 1). Overall, 80% of patients normalized TSH hypersecretion out of medical therapy.

Discussion TSHoma is a rare disease, probably often underdiagnosed. The introduction in clinical practice of ultrasensitive immunometric assay for TSH measurement improved the identification of hyperthyroid states with inappropriate TSH secretion. Despite that, a subset of patients with TSHoma is still diagnosed late, and differential diagnosis

with RTH remains a challenge for endocrinologists. Due to the rarity of the disease, published series are few and often small and heterogeneous. In the present study, we reported data of the largest series so far described. In particular, our series is the one with the highest number of patients treated with radiotherapy (n ⫽ 19). A further strength of our study is the long observational period that allowed us to describe both diagnostic and therapeutic changes over time and, for some patients, long-term outcome. In our series of 70 patients, TSHomas occurred with equal frequency in males and females, as previously reported (9). The mean age at diagnosis was 43.6 ⫾ 12.3 years and did not change in patients diagnosed before and after 2000 (41.8 and 45.5 years), these data being in agreement with those of the literature (4 – 6).


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Table 2.


Comparison Between Fractioned CRT and RS

Reduction of tumor mass Lack of hormonal control Onset of new pituitary deficiencies

CRT

RS

P

0/6 4/6 3/6

5/9 2/12 3/12

.04 NS NS

Abbreviation: NS, not significant.

Figure 2. Cumulative incidence patients cured and in partial remission after radiation treatment. On the second x-axis, the number of patients in active follow-up is reported. Nineteen patients were treated with radiation therapy. One patient in partial remission is not shown in the figure because cure time is not known. Five patients were irradiated for increasing residual/recurrent adenoma despite that they were euthyroid. Four patients normalized TSH and free thyroid hormones levels between 12 and 24 months after radiation, and 3 developed hypothyroidism.

According to recent published series (Table 3) (40% [1] and 28% [10]), we observed a higher percentage of microadenomas at diagnosis when compared with that reported by the older series (30% vs 13% ) (6). This observation is probably the result of improved diagnostic techniques that led to an earlier diagnosis, although the percentage of microadenomas was not statistically different when dividing our patients according to the year of diagnosis (32% before 2000 vs 28% after 2000). Pituitary deficiencies were observed in 12.8% of cases, all macroadenomas, whereas cosecretion was found in 24% of pa-

Figure 3. Cumulative incidence of hypopituitarism in patients treated with radiotherapy. On the second x-axis, the number of patients in active follow-up is reported.

tients, 88% of whom had macroadenomas. Our data confirmed a relationship between tumor volume and both anterior pituitary deficiencies and multiple hypersecretion, as previously reported (6). The goal of treatment is to remove the pituitary lesion and restore euthyroidism. The treatment approach changed over time. In particular, SSAs and RS became more frequently used since the 1990s, whereas conventional radiotherapy has been progressively abandoned. However, surgery remains the first choice of treatment, unless contraindicated (11). In our series, the first-line treatment was surgery in 53% of cases and pharmacotherapy in 47%, similar to other series (6, 10). In particular, surgery was the first-line treatment for most of the macroadenomas with extrasellar extension. Overall, 97% of patients underwent surgery, 58% of them showing both normal thyroid function and a neuroradiological imaging negative for residual tumor. If we consider hormonal profile only, 75% of patients were controlled with no need for further medical therapies. Reviewing data on 192 cases demonstrating that, after pituitary surgery, one-third of patients normalized both serum thyroid hormone levels and pituitary imaging, whereas one-third of patients normalized only thyroid hormone levels (9). Conversely, recent series report a complete surgical remission rate of 60% to 70% (1, 6) with the exception of a Dutch series in which only 14% of patients were cured after surgery (10) (Table 3). Presurgical medical treatment and plurihormonal secretion did not significantly change surgical outcome, whereas macroadenomas had a significantly lower rate of remission, as expected (9, 11). After surgery, the recurrence rate was 3% in our study, 10% in a Belgian series, and 50% in a Dutch series. In our series, all tumor and hormonal recurrence occurred within the first 2 years after surgery, regardless of radiological outcome. In line with our data, the Dutch series described all surgical recurrences within 3 years (10), whereas in the Belgian series, relapses have been described up to 7 years after surgery (6). These data suggest that close hormonal and radiological follow-up should be performed in all patients, particularly during the first years after surgery. Our series is the only one with the major number of patients treated with radiotherapy. The four largest series published up to now showed a total of 28 subjects treated


doi: 10.1210/jc.2013-4376

Table 3.


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Published Series

Series

Age, No. y Male

Macroadenomas Cosecretion Surgery Remission

Losa et al, 1996 (4) Brucker-Davis et al, 1999 (5) Socin et al, 2003 (6) Macchia et al, 2009 (7) Ónnestam et al, 2013 (1) Van Varsseveld et al, 2014 (10) Present series

17 25 43 26 28 18 70

14/17 23/25 34/43 11/26 16/28 13/18 49/70

41.8 48 44 45 56 48 44.1

10/17 8/25 23/43 11/26 11/28 12/18 34/70

5/17 5/25 17/43 4/26 13/28 3/18 17/70

8/17a, 12/14b, 4/10c 8/23a,b,c 21/36a,b 12/22a,b 16/22b 2/14a, 6/14b 41/68a, 51/68b, 23/51c

Radiotherapy Remission NE 5/12a,b 5/8b 3/3b 2/5b NE 4/19b, 8/19c

Abbreviation: NE, not evaluable. Eleven patients were described previously in Losa et al (4). a

Negative imaging.

b

Euthyroidism/central hypothyroidism.

c

Normalization of TSH response to dynamic tests.

with radiotherapy (Table 3) (1, 5–7). In the present report, 19 patients, all bearing a macroadenoma, underwent radiotherapy when surgery was contraindicated or not resolutive. Radiotherapy allowed us to achieve good control of hormone hypersecretion in 37% of patients within 1 or 2 years. Moreover, tumor mass was reduced in 37% of cases and in no cases was tumor regrowth observed. Our results are in accordance with the literature that reports a control rate after radiation ranging between 20% and 50% (1, 5, 6). As previously described for acromegaly, also in TSHomas, CRT and RS appear to be equally effective on hormonal control and hormonal normalization did not correlate with shrinkage of the tumor mass (12, 13). In our series, all significant tumor reduction was observed in the RS group. Nevertheless, the small number of patients does not allow accurate statistical tests to evaluate possible differences among CRT and RS. In our population, postradiotherapy hypopituitarism was demonstrated in 32% of treated patients (without difference in patients treated with CRT or RS), an incidence similar to that observed in nonfunctioning or GH-secreting pituitary adenomas patients after radiation therapy (13–15). A long-term follow-up is necessary because hypopituitarism may occur even several years after treatment. Previous studies reported that normalization of TSH secretion together with complete removal of tumor mass could be obtained in 55% to 70% of patients (68% [1], 55% [6], and 66% [9]). In our series, normal TSH and free thyroid hormone levels were observed in 80% of patients at the last visit, even though the presence of tumor remnant was demonstrated in 30% of them. We also observed that TSHomas treated with surgery or radiotherapy maintained euthyroidism over time despite an altered response to dynamic tests. Subjects who achieved disease control had surgery as the only treatment in 80% of cases and surgery combined with irradiation in 20%.

In patients with persistent disease, the treatment of choice was represented by long-acting SSAs. This is based on the evidence that TSHomas, in particular mixed GH/ TSH adenomas, express a variable number of somatostatin receptors (16), and resistance to analogs is very rare in these patients (3). In the present series, only 1 patient with a large surgical irradiated rest was not controlled by the combination of octreotide LAR 30 mg monthly and methimazole 10 mg daily. TSHomas also express dopamine receptors (17), but TSH responses to dopaminergic agents are heterogeneous (18). One of our patients with mixed TSH/PRL secretion and residual hyperprolactinemia after surgery was well controlled by cabergoline 0.5 mg/wk. In conclusion, our data confirm that early diagnosis is important to provide a greater chance of surgical success. If surgery is successful, recurrence is rare. When surgery is unsuccessful or contraindicated, SSAs and radiotherapy are effective in controlling TSH hypersecretion and tumor growth. The effects of radiotherapy are greater within the first years after treatment even if pituitary deficiencies may occur several years later. Therefore, in these patients, we suggest a regular radiological and hormonal follow-up, which should be closer during the first years after treatment.

Acknowledgments We thank Dr Marcello Filopanti for his help in the revision of the paper. We thank Dr.ssa Laura Montefusco for data provided. Address all correspondence and requests for reprints to: Dr Elena Malchiodi, Endocrinology and Diabetology Unit, Pad. Granelli, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda-Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. E-mail: malchiodi.elena@ gmail.com.


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This work was supported by ricerca corrente funding by Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milan. Disclosure Summary: The authors have nothing to declare.

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Outcome of radiotherapy for pituitary adenomas.

Endoscopic endonasal surgery for pituitary adenomas.

Feasibility and outcome of re-irradiation in the treatment of multiply recurrent pituitary adenomas.

Endoscopic endonasal transsphenoidal surgery for pituitary adenomas.

Visual complications following irradiation for pituitary adenomas and craniopharyngiomas.

Invasiveness of pituitary adenomas.

Pituitary adenomas of adolescents.

Silent pituitary adenomas.

Haemorrhage into pituitary adenomas.

Management of aggressive pituitary adenomas and pituitary carcinomas.

Thyrotropin pituitary adenomas.

Treatment of pituitary carcinomas and atypical pituitary adenomas: a review.

Multihormonal pituitary adenomas.

[Microadenomas and hypersecreting pituitary adenomas].

Ectopic pituitary adenomas.

Gonadotroph-cell pituitary adenomas.

Endoscopic endonasal transsphenoidal surgery of 1,166 pituitary adenomas.

External irradiation of growth hormone producing pituitary adenomas: prolactin as a marker of hypothalamic and pituitary effects.

Nonaneurysmal subarachnoid hemorrhage secondary to transsphenoidal surgery for pituitary adenomas.

Clonal origin of pituitary adenomas.

Clonal origin of pituitary adenomas.

Endoscopic endonasal transsphenoidal surgery in elderly patients with pituitary adenomas.

MicroRNAs in Human Pituitary Adenomas.

progenitor marker GFRα2 in human pituitary adenomas and normal pituitary.