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Double pituitary adenomas: a series of three patients
Pathology (2002 ) 34, pp. 57– 60
ANATOMICAL
PATHOLOGY
DOUBLE PITUITARY ADENOMAS: A SERIES OF THREE PATIENTS PENELOPE A. MC KELVIE *
AND
PETER MC NEILL †
*Department of Anatomical Pathology and †Division of Clinical Neurosciences, St Vincent’s Hospital, Fitzroy, Victoria, Australia
Summary Multiple pituitary adenomas may occur in up to 1.6–3.3% of patients with Cushing’s syndrome. We report three patients with double pituitary adenomas detected at surgery. Two patients had Cushing’s disease, but trans-sphenoida l exploration revealed a small prolactinoma in each. One prolactinoma also contained small numbers of basophils. Reoperation in both patients because of persistent Cushing’s syndrome showed an ACTH-secreting micro-adenoma. The third patient with acromegaly had two macro-adenomas discovered in different parts of the gland at surgery: one plurihormonal and one null cell tumour. Careful evaluation of pre-operative MRI may not always detect more than one pituitary adenoma.
apparently complete removal of that tumour was carried out with residual pituitary tissue remaining on the right side. Histology showed a chromophobe adenoma with scattered basophils within the adenoma showing Crooke’s hyaline change ( Fig. 1) . Immunocytochemical studies demonstrated strong reactivity for prolactin in the majority of adenoma cells ( Fig. 2), with scattered single cells and small clusters reactive for ACTH ( Fig. 3).
Key words: Double pituitary adenoma, prolactinoma, ACTH- and PRLsecreting adenoma, Cushing’s syndrome, Cushing’s disease. Received 19 February, accepted 6 June 2001
INTRODUCTION Multiple pituitary adenomas are rarely reported in the neurosurgical literature. However, a recent surgical series included 13 cases with multiple adenomas, 12 of which had Cushing’s syndrome.1 We report a further three patients with double adenomas. Two of our patients also had Cushing’s disease, but an ACTH-secreting adenoma was detected only after the second trans-sphenoidal surgery.
Fig. 1 Photomicrograph of first adenoma of Case 1 showing predominantly chromophobe cells with scattered basophils, some of which show Crooke’s hyaline change ( arrows ) ( H&E, original magnification, ´200 ).
CASE REPORTS Case 1 This 40-year-old man presented in August 1997, with a 12-month history of tiredness, dizziness, aching in the joints, easy bruising of the skin, and thin, dry hair. He had noticed weight gain particularly around the face, with headaches, polyuria and marked decrease in libido. On examination, he was hypertensive with typical Cushingoid facies and body habitus, with hirsutism and abdominal striae. Investigations showed high urinary free cortisol excretion with high basal cortisol levels and loss of diurnal variation accompanied by very high ACTH levels. Dexamethasone infusion test showed suppression of cortisol and ACTH levels during infusion, but marked rebound on the following day. CT scan suggested a low-density area in the pituitary gland on the left side, but artifact precluded confident diagnosis. The patient was unable to have a magnetic resonance imaging ( MRI) scan due to his size and claustrophobia . At surgery on 21 August 1997, the surgeon identified a soft pituitary adenoma about 4 mm in diameter on the left side of the pituitary gland. An
Fig. 2 Photomicrograph of first adenoma of Case 1 showing predominantly prolactin-secreting cells with scattered basophils which are negative for PRL ( immunoperoxidase stain for prolactin, original magnification, ´400 ).
ISSN 0031–3025 printed/ISSN 1465– 3931 online/02/010057 – 04 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/00313020120105651
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Pathology ( 2002 ), 34, February
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Fig. 3 Photomicrograph of first adenoma of Case 1 showing clusters of ACTH-secreting cells in a background of chromophobe cells ( immunoperoxidase stain for ACTH, original magnification, ´200).
scan showed a lesion on the right side of the pituitary gland consistent with a micro-adenoma . Surgery on 30 April 1997 revealed a 5-mm tumour in the right pituitary gland. Histology showed a chromophobe adenoma strongly reactive for prolactin only. Crooke’s hyaline change was not seen in basophils in normal anterior pituitary tissue. Postoperatively, hypercortisolism and high urinary free cortisol excretion persisted. Petrosal sinus sampling indicated a continuing source of ACTH from the pituitary with a high central to peripheral gradient. Further surgery on 30 May 1997 showed tumour tissue measuring 5 mm on the left side of the pituitary gland close to the cavernous sinus. Total hypophysectomy was performed. Histology revealed an ACTH-secreting adenoma with no immunocytochemical evidence of secretion of prolactin or other anterior pituitary hormones. Electron microscopy was not performed. Postoperative urinary free cortisol excretion on low dose dexamethasone fell to 34 nmol/24 h ( normal range < 150 nmol), indicating remission of Cushing’s disease. Full pituitary replacement therapy was instituted. Subsequent clinical examinations showed weight loss and marked improvement in blood pressure control.
Case 3
Postoperative urinary free cortisol on low dose dexamethasone remained high at 1191 nmol/24 h ( normal range < 150 nmol/l). Because of the ongoing evidence of Cushing’s disease and the histological findings, the possibility of a second adenoma was considered. Imaging performed in a larger MRI scanner did not show any obvious abnormality. On 8 October 1997, a further exploration of the remaining pituitary was undertaken with a horizontal incision. On the left side of the gland, the surgeon found a 2-mm diameter lesion consistent with an adenoma. This mass and surrounding apparently normal pituitary tissue were removed. Histology showed a basophil adenoma with moderate reactivity for ACTH ( Fig. 4). Electron microscopy was not performed. Postoperative urinary free cortisol on low dose dexamethasone was undetectable. Serum LH and FSH levels and thyroid function tests were normal. Postoperatively, his blood pressure improved and weight loss progressed steadily.
This 50-year-old man presented in August 2000 with a number of symptoms of acromegaly, including increase in size of hands and feet, prominent frontal bossing, joint soreness and lethargy, sleep apnoea for 5 years, clicking of his jaw and separation of his teeth. For the previous 18 months, systemic hypertension that was increasingly refractory to treatment had been noted. Examination showed obvious features of acromegal y and hypertension. Investigations revealed elevated fasting serum glucose, normal thyroid function tests and normal cortisol secretion. Serum testosterone level was low and serum prolactin was marginally elevated. Growth hormone levels averaged 40 mIU/l ( normal range > 0–5 mIU/l). MRI showed a mass measuring 23 mm in the pituitary fossa with an area of low signal in the left side of the gland ( Fig. 5). At trans-sphenoida l operation, the surgeon found two tumours of different consistency. On the left, a soft white tumour measuring 15 mm in diameter was identified, whereas on the right, a much firmer greyish tumour measuring 20 mm diameter was identified. Histology of the soft tumour showed a predominantly acidophil adenoma with scattered chromophobe cells in diffuse sheets with little connective tissue stroma and numbers of psammoma bodies. Immunocytochemica l
Fig. 4 Photomicrograph of second adenoma of Case 1 showing strong reactivity for ACTH ( immunoperoxidase stain for ACTH, original magnification, ´400 ).
Case 2 This 46-year-old woman presented in April 1997 with severe hypertension , weight gain and proximal muscle weakness. Investigations showed high urinary free cortisol, and elevated serum prolactin levels of 3000 mIU/l ( normal range 65–455 mIU/l). Clinical examination showed systemic hypertension, Cushingoid facies with a buffalo hump and hirsutism. MRI
Fig. 5 MRI scan of Case 3 showing a large pituitary tumour with signal heterogeneity ( arrow and star).
DOUBLE PITUITARY ADENOMAS
studies indicated strong reactivity of most cells for all anterior pituitary hormones except ACTH. Histology of the firm tumour showed an adenoma composed of lobules of chromophobe cells separated by fibrous septa. Immunocytochemical studies showed that only a small percentage of cells were weakly reactive for TSH, FSH and LH.
DISCUSSION Multiple adenomas of the pituitary gland are not uncommon at postmortem examination, occurring in up to 0.9% of autopsies.2 However, from a clinical standpoint, multiple adenomas are considered rare. A recent series from a surgical database of 660 patients showed 12 cases with double adenomas, including 11 with Cushing’s disease ( ACTH-secreting adenoma), or an incidence of 1.6% of patients with Cushing’s disease.1 Similarly, the Cushing’s database of one of the authors ( PMcN) from 1986 to 2000 contained 60 patients with a 3.3% incidence of double adenoma. Prior to Ratcliff and Oldfield’s series published in 2000, 1 only eight patients had been reported with multiple adenomas confirmed at pituitary surgery.3– 10 Ratcliff and Oldfield highlight their strict definition of multiple adenomas as two or more adenomas with distinct light microscopic and immunohistochemical features in clearly separate locations in a single gland.1 Collision or conjoined tumours and ectopic pituitary tumours were not included in their study, unlike other authors in their series of so-called double adenomas.11 Lesions with variable histological and immunohistochemical patterns may indeed be multiple tumours. However, such collision or conjoint tumours may also represent plurihormonal tumours or may arise from transformation of one tumour. Demonstration of clonality within such lesions by genetic analysis is required to establish the presence of two discrete tumours. The incidental adenomas in our two patients with Cushing’s disease were prolactinomas. Similarly, Ratcliff and Oldfield found that eight of 11 (73%) of their patients with Cushing’s disease had an incidental prolactinoma.1 These prolactinomas may, however, not be easy to detect pre-operatively. Between 23 and 90% of patients with Cushing’s disease have elevated serum prolactin levels before surgery, with normalisation of the levels after removal of the ACTH-secreting tumour of the pituitary.12,13 Conversely, serum prolactin levels may be normal in incidental prolactinomas. Ratcliff and Oldfield found normal pre-operative serum prolactin levels in two of their five patients with Cushing’s disease and incidental prolactinomas, where levels had been measured.1 Therefore, elevation of pre-operative serum prolactin levels, unless markedly elevated, may not be an accurate marker of an incidental prolactinoma. In one of our two patients, pre-operative serum prolactin levels were markedly elevated, while preoperative PRL levels were not measured in the second. The unusual combination of both prolactin and ACTH in a single adenoma, which we noted in case 2, has only previously been described in two patients.14,15 Both of those patients suffered from Cushing’s disease and marked symptomatic hyperprolactinaemia and were cured after trans-sphenoidal removal of a single adenoma.14,15 Histology in each case showed a mixed tumour with both PRL and ACTH secretion on immunohistochemistry, albeit by a separate population of approximately 5–20% basophils within a predominantly chromophobe adenoma.14,15
59
However, in our patient, features of Cushing’s disease persisted after removal of the first adenoma and only remitted after removal of the second pure ACTH-secreting adenoma. Incidental adenomas in patients with two or more pituitary adenomas are usually small, about 2–3 mm diameter.1 In our series, the ACTH-secreting adenomas measured 2 and 5 mm and the incidental prolactinomas 5 and 4 mm. Only in the third case with acromegaly and a GH-secreting adenoma and an incidental null cell adenoma, were both tumours macro-adenomas. Incidental pituitary adenomas in patients with multiple adenomas are often subclinical but, if undetected or not recognised on pre-operative MRI, may be discovered during trans-sphenoidal surgery, as in our Case 3 and in four cases of Ratcliff and Oldfield.1 If not detected either by imaging or during exploration of the gland, such adenomas are discovered only when patients present with a syndrome of hormone excess ( Cushing’s syndrome) that does not remit after removal of a pituitary adenoma. The first tumour may be either a null cell adenoma or prolactinoma. Our second patient had biochemical evidence of dual hypersecretion of ACTH and PRL, though no symptoms related to the hyperprolactinaemia. Although pituitary stalk effect may produce modest elevation of PRL, the level in this patient exceeded generally accepted levels for that effect. The first patient suffered reduced libido, but serum prolactin levels were not recorded. In our first case, the presence of Crooke’s hyaline change indicative of hypercortisolism in some basophils in the prolactinoma was a clue to the presence of a second ACTH-secreting tumour. Although multiple endocrine neoplasia ( MEN) type 1 syndrome is associated with adenomas of the pituitary gland, pancreas and parathyroid, most of the reported cases of double pituitary adenomas do not have this syndrome. The single patient of Ratcliff and Oldfield’s series of 13 cases who did not have Cushing’s syndrome had known MEN type 1 with a 20-mm TSH-secreting adenoma and incidental 4-mm prolactinoma. Kannuki et al. reported another patient with MEN1 and two pituitary adenomas removed at one operation: a GH-secreting adenoma and null cell adenoma.16 Double pituitary adenomas are uncommon, but appear to occur at increased frequency in patients with Cushing’s disease. Double pathology should be suspected if biochemical remission fails to occur after pituitary surgery and the histology does not show an ACTH-secreting adenoma. Signal heterogeneity on MRI may also suggest the presence of more than one tumour. All four cases where two or more adenomas were demonstrated pre-operatively have been reported in the past 2 years.1,7– 9 As magnetic resonance imaging resolution improves, pre-operative detection of multiple tumours will undoubtedly increase. Address for correspondence: Dr P. McKelvie, Anatomical Pathology, St Vincent’s Hospital, 41 Victoria Parade, Fitzroy, Vic 3065, Australia. E-mail: [email protected] .
References 1. Ratcliff JK, Oldfield EH. Multiple pituitary adenomas in Cushing’s disease. J Neurosurg 2000; 93: 753– 61, 910–1. 2. Kontogeorgos G, Kovacs K, Horvath E, Scheithauer BW. Multiple adenomas of the human pituitary. A retrospective autopsy study with clinical implications. J Neurosurg 1991; 74: 243–7.
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3. Tolis G, Bertrand G, Carpenter S, McKenzie JM. Acromegaly and galactorrhea-amenorrhea with two pituitary adenomas secreting growth hormone or prolactin. A case report. Ann Int Med 1978; 89: 345– 8. 4. Powers SK, Wilson CB. Simultaneously occurring prolactinomas. Case report. J Neurosurg 1981; 55: 124– 6. 5. Woosley RE. Multiple secreting microadenomas as a possible cause of selective trans-sphenoidal adenomectomy failure. J Neurosurg 1981; 58: 267– 9. 6. Blevins LS Jr, Hall GS, Madoff DH, et al. Case report: acromegaly and Cushing’s disease in a patient with synchronous pituitary adenomas. Am J Med Sci 1992; 304: 294–7. 7. Cannavo S, Curo L, Lania A, et al. Unusual MRI findings of multiple adenomas in the pituitary gland: a case report and review of the literature. Magn Res Imaging 1999; 17: 633–6. 8. Salpietri FM, Alafaci C, Grasso G, et al. Transsphenoidal microsurgical selective removal of multiple ( triple) adenomas of the pituitary gland. Acta Neurochir 1999; 141: 425– 8. 9. Tosaka M, Kohga H, Kobayashi S, et al. Double pituitary adenomas detected on preoperative magnetic resonance images. J Neurosurg 2000; 92: 361.
Pathology ( 2002 ), 34, February 10. Wynne AG, Scheithauer BW, Young WF. Coexisting corticotroph and lactotroph adenomas: case report with reference to the relationship of corticotrophin and prolactin excess. Neurosurgery 1992; 30: 919– 23. 11. Kontogeorgos G, Scheithauer BW, Horvath E, et al. Double adenomas of the pituitary: a clinicopathological study of 11 tumors. Neurosurgery 1992; 31: 840– 9. 12. Yamaji T, Ishibashi M, Teramoto A, et al. Hyperprolactinaemia in Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1984; 58: 790–5. 13. Caufriez A, D´esir D, Szyper M, et al. Prolactin secretion in Cushing’s disease. J Clin Endocrinol Metab 1981; 53: 843–6. 14. Sherry SH, Guay AT, Lee AK, et al. Concurrent production of adrenocorticotropin and prolactin from two distinct cell lines in a single pituitary adenoma: a detailed immunohistochemical analysis. J Clin Endocrinol Metab 1982; 55: 947– 55. 15. Mahler C, Verhelst J, Klaes R, et al. Cushing’s disease and hyperprolactinemia due to a mixed ACTH- and prolactin-secreting pituitary macroadenoma. Pathol Res Pract 1991; 187: 598–602. 16. Kannuki S, Matsumoto K, Sano T, et al. Double pituitary adenoma – two case reports. Neurol Med Chir ( Tokyo) 1996; 36: 818– 21.
ANATOMICAL
PATHOLOGY
DOUBLE PITUITARY ADENOMAS: A SERIES OF THREE PATIENTS PENELOPE A. MC KELVIE *
AND
PETER MC NEILL †
*Department of Anatomical Pathology and †Division of Clinical Neurosciences, St Vincent’s Hospital, Fitzroy, Victoria, Australia
Summary Multiple pituitary adenomas may occur in up to 1.6–3.3% of patients with Cushing’s syndrome. We report three patients with double pituitary adenomas detected at surgery. Two patients had Cushing’s disease, but trans-sphenoida l exploration revealed a small prolactinoma in each. One prolactinoma also contained small numbers of basophils. Reoperation in both patients because of persistent Cushing’s syndrome showed an ACTH-secreting micro-adenoma. The third patient with acromegaly had two macro-adenomas discovered in different parts of the gland at surgery: one plurihormonal and one null cell tumour. Careful evaluation of pre-operative MRI may not always detect more than one pituitary adenoma.
apparently complete removal of that tumour was carried out with residual pituitary tissue remaining on the right side. Histology showed a chromophobe adenoma with scattered basophils within the adenoma showing Crooke’s hyaline change ( Fig. 1) . Immunocytochemical studies demonstrated strong reactivity for prolactin in the majority of adenoma cells ( Fig. 2), with scattered single cells and small clusters reactive for ACTH ( Fig. 3).
Key words: Double pituitary adenoma, prolactinoma, ACTH- and PRLsecreting adenoma, Cushing’s syndrome, Cushing’s disease. Received 19 February, accepted 6 June 2001
INTRODUCTION Multiple pituitary adenomas are rarely reported in the neurosurgical literature. However, a recent surgical series included 13 cases with multiple adenomas, 12 of which had Cushing’s syndrome.1 We report a further three patients with double adenomas. Two of our patients also had Cushing’s disease, but an ACTH-secreting adenoma was detected only after the second trans-sphenoidal surgery.
Fig. 1 Photomicrograph of first adenoma of Case 1 showing predominantly chromophobe cells with scattered basophils, some of which show Crooke’s hyaline change ( arrows ) ( H&E, original magnification, ´200 ).
CASE REPORTS Case 1 This 40-year-old man presented in August 1997, with a 12-month history of tiredness, dizziness, aching in the joints, easy bruising of the skin, and thin, dry hair. He had noticed weight gain particularly around the face, with headaches, polyuria and marked decrease in libido. On examination, he was hypertensive with typical Cushingoid facies and body habitus, with hirsutism and abdominal striae. Investigations showed high urinary free cortisol excretion with high basal cortisol levels and loss of diurnal variation accompanied by very high ACTH levels. Dexamethasone infusion test showed suppression of cortisol and ACTH levels during infusion, but marked rebound on the following day. CT scan suggested a low-density area in the pituitary gland on the left side, but artifact precluded confident diagnosis. The patient was unable to have a magnetic resonance imaging ( MRI) scan due to his size and claustrophobia . At surgery on 21 August 1997, the surgeon identified a soft pituitary adenoma about 4 mm in diameter on the left side of the pituitary gland. An
Fig. 2 Photomicrograph of first adenoma of Case 1 showing predominantly prolactin-secreting cells with scattered basophils which are negative for PRL ( immunoperoxidase stain for prolactin, original magnification, ´400 ).
ISSN 0031–3025 printed/ISSN 1465– 3931 online/02/010057 – 04 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/00313020120105651
58
Pathology ( 2002 ), 34, February
MCKELVIE AND MCNEILL
Fig. 3 Photomicrograph of first adenoma of Case 1 showing clusters of ACTH-secreting cells in a background of chromophobe cells ( immunoperoxidase stain for ACTH, original magnification, ´200).
scan showed a lesion on the right side of the pituitary gland consistent with a micro-adenoma . Surgery on 30 April 1997 revealed a 5-mm tumour in the right pituitary gland. Histology showed a chromophobe adenoma strongly reactive for prolactin only. Crooke’s hyaline change was not seen in basophils in normal anterior pituitary tissue. Postoperatively, hypercortisolism and high urinary free cortisol excretion persisted. Petrosal sinus sampling indicated a continuing source of ACTH from the pituitary with a high central to peripheral gradient. Further surgery on 30 May 1997 showed tumour tissue measuring 5 mm on the left side of the pituitary gland close to the cavernous sinus. Total hypophysectomy was performed. Histology revealed an ACTH-secreting adenoma with no immunocytochemical evidence of secretion of prolactin or other anterior pituitary hormones. Electron microscopy was not performed. Postoperative urinary free cortisol excretion on low dose dexamethasone fell to 34 nmol/24 h ( normal range < 150 nmol), indicating remission of Cushing’s disease. Full pituitary replacement therapy was instituted. Subsequent clinical examinations showed weight loss and marked improvement in blood pressure control.
Case 3
Postoperative urinary free cortisol on low dose dexamethasone remained high at 1191 nmol/24 h ( normal range < 150 nmol/l). Because of the ongoing evidence of Cushing’s disease and the histological findings, the possibility of a second adenoma was considered. Imaging performed in a larger MRI scanner did not show any obvious abnormality. On 8 October 1997, a further exploration of the remaining pituitary was undertaken with a horizontal incision. On the left side of the gland, the surgeon found a 2-mm diameter lesion consistent with an adenoma. This mass and surrounding apparently normal pituitary tissue were removed. Histology showed a basophil adenoma with moderate reactivity for ACTH ( Fig. 4). Electron microscopy was not performed. Postoperative urinary free cortisol on low dose dexamethasone was undetectable. Serum LH and FSH levels and thyroid function tests were normal. Postoperatively, his blood pressure improved and weight loss progressed steadily.
This 50-year-old man presented in August 2000 with a number of symptoms of acromegaly, including increase in size of hands and feet, prominent frontal bossing, joint soreness and lethargy, sleep apnoea for 5 years, clicking of his jaw and separation of his teeth. For the previous 18 months, systemic hypertension that was increasingly refractory to treatment had been noted. Examination showed obvious features of acromegal y and hypertension. Investigations revealed elevated fasting serum glucose, normal thyroid function tests and normal cortisol secretion. Serum testosterone level was low and serum prolactin was marginally elevated. Growth hormone levels averaged 40 mIU/l ( normal range > 0–5 mIU/l). MRI showed a mass measuring 23 mm in the pituitary fossa with an area of low signal in the left side of the gland ( Fig. 5). At trans-sphenoida l operation, the surgeon found two tumours of different consistency. On the left, a soft white tumour measuring 15 mm in diameter was identified, whereas on the right, a much firmer greyish tumour measuring 20 mm diameter was identified. Histology of the soft tumour showed a predominantly acidophil adenoma with scattered chromophobe cells in diffuse sheets with little connective tissue stroma and numbers of psammoma bodies. Immunocytochemica l
Fig. 4 Photomicrograph of second adenoma of Case 1 showing strong reactivity for ACTH ( immunoperoxidase stain for ACTH, original magnification, ´400 ).
Case 2 This 46-year-old woman presented in April 1997 with severe hypertension , weight gain and proximal muscle weakness. Investigations showed high urinary free cortisol, and elevated serum prolactin levels of 3000 mIU/l ( normal range 65–455 mIU/l). Clinical examination showed systemic hypertension, Cushingoid facies with a buffalo hump and hirsutism. MRI
Fig. 5 MRI scan of Case 3 showing a large pituitary tumour with signal heterogeneity ( arrow and star).
DOUBLE PITUITARY ADENOMAS
studies indicated strong reactivity of most cells for all anterior pituitary hormones except ACTH. Histology of the firm tumour showed an adenoma composed of lobules of chromophobe cells separated by fibrous septa. Immunocytochemical studies showed that only a small percentage of cells were weakly reactive for TSH, FSH and LH.
DISCUSSION Multiple adenomas of the pituitary gland are not uncommon at postmortem examination, occurring in up to 0.9% of autopsies.2 However, from a clinical standpoint, multiple adenomas are considered rare. A recent series from a surgical database of 660 patients showed 12 cases with double adenomas, including 11 with Cushing’s disease ( ACTH-secreting adenoma), or an incidence of 1.6% of patients with Cushing’s disease.1 Similarly, the Cushing’s database of one of the authors ( PMcN) from 1986 to 2000 contained 60 patients with a 3.3% incidence of double adenoma. Prior to Ratcliff and Oldfield’s series published in 2000, 1 only eight patients had been reported with multiple adenomas confirmed at pituitary surgery.3– 10 Ratcliff and Oldfield highlight their strict definition of multiple adenomas as two or more adenomas with distinct light microscopic and immunohistochemical features in clearly separate locations in a single gland.1 Collision or conjoined tumours and ectopic pituitary tumours were not included in their study, unlike other authors in their series of so-called double adenomas.11 Lesions with variable histological and immunohistochemical patterns may indeed be multiple tumours. However, such collision or conjoint tumours may also represent plurihormonal tumours or may arise from transformation of one tumour. Demonstration of clonality within such lesions by genetic analysis is required to establish the presence of two discrete tumours. The incidental adenomas in our two patients with Cushing’s disease were prolactinomas. Similarly, Ratcliff and Oldfield found that eight of 11 (73%) of their patients with Cushing’s disease had an incidental prolactinoma.1 These prolactinomas may, however, not be easy to detect pre-operatively. Between 23 and 90% of patients with Cushing’s disease have elevated serum prolactin levels before surgery, with normalisation of the levels after removal of the ACTH-secreting tumour of the pituitary.12,13 Conversely, serum prolactin levels may be normal in incidental prolactinomas. Ratcliff and Oldfield found normal pre-operative serum prolactin levels in two of their five patients with Cushing’s disease and incidental prolactinomas, where levels had been measured.1 Therefore, elevation of pre-operative serum prolactin levels, unless markedly elevated, may not be an accurate marker of an incidental prolactinoma. In one of our two patients, pre-operative serum prolactin levels were markedly elevated, while preoperative PRL levels were not measured in the second. The unusual combination of both prolactin and ACTH in a single adenoma, which we noted in case 2, has only previously been described in two patients.14,15 Both of those patients suffered from Cushing’s disease and marked symptomatic hyperprolactinaemia and were cured after trans-sphenoidal removal of a single adenoma.14,15 Histology in each case showed a mixed tumour with both PRL and ACTH secretion on immunohistochemistry, albeit by a separate population of approximately 5–20% basophils within a predominantly chromophobe adenoma.14,15
59
However, in our patient, features of Cushing’s disease persisted after removal of the first adenoma and only remitted after removal of the second pure ACTH-secreting adenoma. Incidental adenomas in patients with two or more pituitary adenomas are usually small, about 2–3 mm diameter.1 In our series, the ACTH-secreting adenomas measured 2 and 5 mm and the incidental prolactinomas 5 and 4 mm. Only in the third case with acromegaly and a GH-secreting adenoma and an incidental null cell adenoma, were both tumours macro-adenomas. Incidental pituitary adenomas in patients with multiple adenomas are often subclinical but, if undetected or not recognised on pre-operative MRI, may be discovered during trans-sphenoidal surgery, as in our Case 3 and in four cases of Ratcliff and Oldfield.1 If not detected either by imaging or during exploration of the gland, such adenomas are discovered only when patients present with a syndrome of hormone excess ( Cushing’s syndrome) that does not remit after removal of a pituitary adenoma. The first tumour may be either a null cell adenoma or prolactinoma. Our second patient had biochemical evidence of dual hypersecretion of ACTH and PRL, though no symptoms related to the hyperprolactinaemia. Although pituitary stalk effect may produce modest elevation of PRL, the level in this patient exceeded generally accepted levels for that effect. The first patient suffered reduced libido, but serum prolactin levels were not recorded. In our first case, the presence of Crooke’s hyaline change indicative of hypercortisolism in some basophils in the prolactinoma was a clue to the presence of a second ACTH-secreting tumour. Although multiple endocrine neoplasia ( MEN) type 1 syndrome is associated with adenomas of the pituitary gland, pancreas and parathyroid, most of the reported cases of double pituitary adenomas do not have this syndrome. The single patient of Ratcliff and Oldfield’s series of 13 cases who did not have Cushing’s syndrome had known MEN type 1 with a 20-mm TSH-secreting adenoma and incidental 4-mm prolactinoma. Kannuki et al. reported another patient with MEN1 and two pituitary adenomas removed at one operation: a GH-secreting adenoma and null cell adenoma.16 Double pituitary adenomas are uncommon, but appear to occur at increased frequency in patients with Cushing’s disease. Double pathology should be suspected if biochemical remission fails to occur after pituitary surgery and the histology does not show an ACTH-secreting adenoma. Signal heterogeneity on MRI may also suggest the presence of more than one tumour. All four cases where two or more adenomas were demonstrated pre-operatively have been reported in the past 2 years.1,7– 9 As magnetic resonance imaging resolution improves, pre-operative detection of multiple tumours will undoubtedly increase. Address for correspondence: Dr P. McKelvie, Anatomical Pathology, St Vincent’s Hospital, 41 Victoria Parade, Fitzroy, Vic 3065, Australia. E-mail: [email protected] .
References 1. Ratcliff JK, Oldfield EH. Multiple pituitary adenomas in Cushing’s disease. J Neurosurg 2000; 93: 753– 61, 910–1. 2. Kontogeorgos G, Kovacs K, Horvath E, Scheithauer BW. Multiple adenomas of the human pituitary. A retrospective autopsy study with clinical implications. J Neurosurg 1991; 74: 243–7.
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3. Tolis G, Bertrand G, Carpenter S, McKenzie JM. Acromegaly and galactorrhea-amenorrhea with two pituitary adenomas secreting growth hormone or prolactin. A case report. Ann Int Med 1978; 89: 345– 8. 4. Powers SK, Wilson CB. Simultaneously occurring prolactinomas. Case report. J Neurosurg 1981; 55: 124– 6. 5. Woosley RE. Multiple secreting microadenomas as a possible cause of selective trans-sphenoidal adenomectomy failure. J Neurosurg 1981; 58: 267– 9. 6. Blevins LS Jr, Hall GS, Madoff DH, et al. Case report: acromegaly and Cushing’s disease in a patient with synchronous pituitary adenomas. Am J Med Sci 1992; 304: 294–7. 7. Cannavo S, Curo L, Lania A, et al. Unusual MRI findings of multiple adenomas in the pituitary gland: a case report and review of the literature. Magn Res Imaging 1999; 17: 633–6. 8. Salpietri FM, Alafaci C, Grasso G, et al. Transsphenoidal microsurgical selective removal of multiple ( triple) adenomas of the pituitary gland. Acta Neurochir 1999; 141: 425– 8. 9. Tosaka M, Kohga H, Kobayashi S, et al. Double pituitary adenomas detected on preoperative magnetic resonance images. J Neurosurg 2000; 92: 361.
Pathology ( 2002 ), 34, February 10. Wynne AG, Scheithauer BW, Young WF. Coexisting corticotroph and lactotroph adenomas: case report with reference to the relationship of corticotrophin and prolactin excess. Neurosurgery 1992; 30: 919– 23. 11. Kontogeorgos G, Scheithauer BW, Horvath E, et al. Double adenomas of the pituitary: a clinicopathological study of 11 tumors. Neurosurgery 1992; 31: 840– 9. 12. Yamaji T, Ishibashi M, Teramoto A, et al. Hyperprolactinaemia in Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1984; 58: 790–5. 13. Caufriez A, D´esir D, Szyper M, et al. Prolactin secretion in Cushing’s disease. J Clin Endocrinol Metab 1981; 53: 843–6. 14. Sherry SH, Guay AT, Lee AK, et al. Concurrent production of adrenocorticotropin and prolactin from two distinct cell lines in a single pituitary adenoma: a detailed immunohistochemical analysis. J Clin Endocrinol Metab 1982; 55: 947– 55. 15. Mahler C, Verhelst J, Klaes R, et al. Cushing’s disease and hyperprolactinemia due to a mixed ACTH- and prolactin-secreting pituitary macroadenoma. Pathol Res Pract 1991; 187: 598–602. 16. Kannuki S, Matsumoto K, Sano T, et al. Double pituitary adenoma – two case reports. Neurol Med Chir ( Tokyo) 1996; 36: 818– 21.