Pituitary, Adrenal and Thyroid Incidentalomas

Endocrine-Related Cancer (1998) 5 131-150 Pituitary, adrenal and thyroid incidentalomas

H E Turner, N R Moore1, J V Byrne1 and J A H Wass

Departments of Endocrinology and 1Radiology, Radcliffe Infirmary and University of Oxford, Woodstock Road, Oxford OX2 6HE UK (Requests for offprints should be addressed to J A H Wass)

Introduction depends on the method of detection - whether it is based The use of increasingly sophisticated imaging techniques on an autopsy series of patients assumed to be asympto- has produced a new clinical problem; namely the matic, or on a series of patients undergoing imaging of the evaluation and management of the serendipitously head. discovered mass - ‘incidentaloma’. In the last 50 years of endocrinology, these lesions have been described mainly Autopsy studies in the adrenal and pituitary glands by pathologists on the basis of autopsy studies of patients assumed to have been In 1936, Costello published the results of an examination asymptomatic. The current challenge is the investigation of 100 pituitary glands at post-mortem, in which small of these lesions, which are now more frequently detected adenomas were found in 22.5% of cases using sections of during life, to allow not only the correct identification and up to 1.5 mm in size (Costello 1936). Costello called these investigation of those with a hypersecretory syndrome, tumours ‘subclinical adenomas’ and found them to be whether it be clinically apparent or subclinical, but also the equally distributed between the sexes. They become more correct identification of those masses which are malignant common with increasing age (Parent et al. 1981). Other and which may therefore produce significant problems in autopsy studies have shown that between 1.5 and 26.7% the future. As more experience is gained on the natural of pituitaries examined in subjects not suspected of having history of the true incidentaloma, appropriate follow-up pituitary disease harbour adenomas (Molitch & Russell and treatment can be instigated as necessary. The rationale 1990). The reason for this wide variation in frequency may of investigations therefore should be to evaluate most partly be due to different slice thickness used to examine accurately and cost-effectively which patients do not have the pituitary. The majority of studies suggest a frequency an incidentaloma, but a lesion that requires further active of between 10 and 20%. A recent study of 1000 pituitary treatment. glands using the same section thickness as Costello found Terminology may be confusing, as ‘incidentaloma’ incidental lesions in 178 (18%) glands, and in one-third and ‘incidentally discovered’, and ‘subclinical’ have these were >2 mm in diameter (Teramoto et al. 1994). The been used, often interchangeably in this context. While a lower prevalence of incidental findings in this study pituitary macroadenoma or adrenal carcinoma may be compared with the Costello data may in part be due to incidentally discovered, we believe that they should not be classification of areas of hyperplasia as adenomas in the described as incidentalomas. This term should be reserved original paper. An analysis of 12 autopsy studies reported for those lesions which are incidentally discovered, that that there were only three incidental macroadenomas have no associated hormonal hyper- or hyposecretion, and detected (all <15 mm), out of a total of 9737 pituitaries that have a benign natural history. The incidental radio- examined (Molitch & Russell 1990). Interestingly two of logical discovery of a mass may be one of clinical these larger tumours were found in the series of patients relevance in a patient for example subsequently found to aged over 80 at post-mortem (Kovacs et al. 1980). This be hyperprolactinaemic, although hitherto asymptomatic - series showed a frequency of pituitary adenomas of 13%, perhaps a better term for these lesions is ‘subclinical’ to and 9 out of the 17 adenomas examined (53%) immuno- differentiate them from the true incidentaloma. stained for prolactin (PRL).

Pituitary Therefore, pituitary microadenomas are a common finding at autopsy, and appear to become commoner with Epidemiology increasing age. Incidental macroadenomas are in contrast The vast majority of pituitary incidentalomas are micro- uncommon, and also appear to be commoner in older age- adenomas (<1 cm in diameter). Their reported prevalence groups.

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Imaging studies had mesoadenomas (tumour diameter 11-20 mm) and The detection of incidental pituitary lesions on imaging showed no increase in tumour size during follow-up. All depends on the technique, use of contrast agents, and the the patients with microadenomas that had been detected slice thickness used. The true prevalence of asymptomatic incidentally on imaging for reasons such as vertigo, adenomas is probably higher than detected in many concussion and syncope, were asymptomatic with normal imaging studies, because of the limited sensitivity of pituitary function, and no visual field abnormalities. magnetic resonance imaging (MRI) for small tumours, Thus after detailed endocrine and visual examination, and this may explain why the reported prevalence is higher macroadenomas, even if they present serendipitously, in an autopsy population. This is illustrated by a recent have usually produced significant effects, mesoadenomas autopsy study of 1000 pituitary glands, where 178 (18%) may do so and microadenomas have rarely done so. glands harboured incidental tumours, but only 61 (6%) were >2 mm in size and thus likely to be visible on Pathology computed tomography (CT) or MRI (Teramoto et al. Positive immunostaining for PRL was shown in 34/81 1994). MRI with gadolinium-diethylenetriamine penta- adenomas (42%) in an analysis of pituitary adenomas acetic acid (Gd-DTPA) administration demonstrated detected at autopsy (Molitch & Russell 1990). McComb et asymptomatic pituitary adenomas in 10% of normal al. (1983) compared the pattern of immunostaining of the volunteers aged 18-60 years (Hall et al. 1994). A study tumours found at autopsy with those removed surgically, using CT scans with contrast enhancement identified and showed that there was a marked difference (Table 1). probable adenomas in 12/107 (11.2%) normal women The majority in the subclinical/autopsy series were (Wolpert et al. 1984). Chong et al. (1994) found focal negative (54%) or PRL staining (42%) whereas only 25% pituitary hypointensities in 40% of healthy volunteers on of the surgical series were null cell adenomas and 29% T1-weighted spin echo MRI, but found that in the majority PRL staining. There was a higher number of growth they could be differentiated from pituitary microadenomas hormone (GH) positive, adrenocorticotrophin (ACTH) by their smaller size and less marked degree of signal and mixed GH/PRL staining adenomas in the surgical difference relative to the pituitary gland. series (McComb et al. 1983). This difference is obviously Incidental pituitary macroadenomas have occasionally in part due to the fact that prolactinomas often do not been reported, where a tumour >1 cm in diameter has been require surgery, and also because the secretory tumours detected when imaging for non-endocrine indications, for are likely to present with clinical effects during life. example a head injury or seizures (Chacko & Chandy It is not uncommon for multiple adenomas to be 1992). However, these are not true incidentalomas, as detected in the pituitaries found to harbour incidentalomas illustrated by a series of five cases, where three patients - 3/42 subjects in one study (Parent et al. 1981), 2/20 in had hypopituitarism and four of the patients underwent another (Kovacs et al. 1980) and 7/100 subjects in another surgery (Chacko & Chandy 1992). Reincke et al. (1990) (McComb et al. 1983). The significance of this is unclear, report 18 patients with ‘incidentalomas’ of the pituitary. but the tumours do not necessarily have the same immuno- Four patients in this series required neurosurgery - two staining characteristics. because of visual field defects, one because of displace- ment of the chiasm by the tumour, and one who had biochemical evidence of acromegaly. Three of the cases Natural history not requiring neurosurgery were luteinising hormone/ Follow-up data of incidentally detected microadenomas follicle-stimulating hormone deficient. It is therefore show that they very rarely show significant enlargement, incorrect in our view to describe all these tumours as true whereas larger incidentalomas are more likely to enlarge incidentalomas. Four of the truly asymptomatic patients (Table 2). The data from Reincke et al. (1990) show that

Table 1 Pattern of immunostaining of pituitary tumours found at autopsy and removed surgically.

Type of study Negative PRL positive GH positive ACTH positive Reference

Autopsy 42% (34/81) Molitch & Russell (1990) Autopsy 41% (7/17) 55% (9/17) 1 GH and PRL 0 Kovacs et al. (1980) Autopsy 50% (54/107) 42% (45/107) McComb et al. (1983) Surgical 25.1% (152/606) 29% (176/606) 16.2% (98/606) 8.4% (51/606) McComb et al .(1983) PRL and Silent 6% (36) GH 9.2% (56)

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Endocrine-Related Cancer (1998) 5 131-150 during a mean follow-up of 30 months (range 12-96), only useful to know more about the natural history of pituitary one of seven patients with incidentally detected micro- microincidentalomas, particularly whether there is a adenomas showed tumour enlargement from 5 to 9 mm significant rate of spontaneous resolution, as the autopsy (Reincke et al. 1990) (Table 2). One of the four patients studies show that at least one-third of these tumours are with a larger (11-20 mm in diameter) incidentaloma, with prolactinomas. normal visual fields, showed tumour enlargement from 14 to 20 mm during mean follow-up of 26 months (range 17- Differential diagnosis 48). Neither of these patients required any intervention. It is clearly important that the incidentally detected Thirty-one patients with incidentally discovered pituitary pituitary lesion is evaluated appropriately and masses (15 microadenomas and 16 larger ones of 11- differential diagnoses considered such as cranio- 20 mm diameter), with no significant endocrinopathy or pharyngioma, metastasis or an inflammatory process reduction in visual fields, were followed up for a mean of (Soule & Jacobs 1996). 6.4 years (range 3-11 years). Only 1/16 patients with macroadenomas developed tumour enlargement (15 mm increasing to 20 mm) which required surgery because of Features visual field change; 4 others showed enlargement in the By definition, a patient with a true incidentaloma should diameter of the tumour by 1-2 mm (Donovan & be asymptomatic. Headache is a symptom for which MRI/ Corenblum 1995). One patient with a macroadenoma of CT scanning is performed and incidental pituitary diameter 17 mm developed apoplexy while heparinised adenomas are sometimes detected in these patients. Does for a coronary angiogram. Of the 15 patients with this mean that these patients are symptomatic of the incidentally detected microadenomas, only one tumour tumour? Unless the adenoma is large and causing visual enlarged and only by 1 mm (from 4 to 5 mm) during a symptoms, headache is not a usual feature of these 5 year follow-up. tumours as an isolated finding and is therefore not More data are required to confirm the natural history attributable to pituitary microadenomas (Reincke et al. of these tumours, but, from these small studies, it is likely 1990). that microincidentalomas follow a benign course and there In the series of incidentalomas detected using MRI in are no data to suggest that these will lead to any form of normal volunteers, there was no evidence of endocrin- endocrinopathy. On the other hand incidentally detected opathy in any of the patients with adenomas (Hall et al. macroadenomas may enlarge in size and require surgery - 1994). The difference in prevalence of null cell adenomas and therefore the term incidentaloma should only be and prolactinomas when incidentalomas are compared cautiously applied to macroadenomas. Perhaps incidental- with clinical series is likely to be due to the relatively early oma should only be used for those tumours over 10 mm in detection of adenomas secreting GH or ACTH due to the diameter that remain intra-sellar, often referred to as associated clinical syndromes. Clearly, tumours leading to mesoadenomas. acromegaly or Cushing’s syndrome, even if detected There are data showing that hyperprolactinaemia will incidentally, cannot be defined as incidentalomas. be self-limiting in up to one-third of women affected and It is possible that an incidentaloma may masquerade as that pregnancy may be one feature that will trigger a return the cause of a patient’s disease. At our institution we have to normal function (Jeffcoate et al. 1996). It would be seen two patients in the last year with pituitary

Table 2 Follow-up data for incidentally detected pituitary adenomas.

Number of Number which Tumour size Reference patients Follow-up enlarged

Microadenoma Reincke et al. 7 30 months (12-96) 1 (5 → 9 mm) (<11 mm) (1990) Microadenoma Donovan & 15 6.4 years (3-11) 1 (4 → 5 mm) (<11 mm) Corenblum (1995) Macroadenoma Reincke et al. 4 26 months (17-48) 1 (14 → 20 mm) (11-20 mm) (1990) Macroadenoma Donovan & 16 6.4 years (3-11) 5 (by 1-5 mm) (11-20 mm) Corenblum (1995)

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Turner et al.: Pituitary, adrenal and thyroid incidentalomas microadenomas initially thought to be the cause of their acromegaly or Cushing’s syndrome. No syndromes of Cushing’s syndrome, who actually turned out to have hormone excess developed during a mean follow-up of 6.4 ectopic and adrenal origins of their disease (Fig. 1). years. Similar conclusions were reached in a recent cost- effectiveness analysis where four different management Investigation strategies were compared for a patient with an incidentally Investigation must be directed towards determining detected asymptomatic pituitary adenoma (King et al. whether the pituitary lesion is functioning and producing 1997). Most endocrinologists, in view of the limited long- hormone, and secondly whether there is any evidence of term data in this condition, will consider excluding all hyposecretion of hormones from the remainder of the hypersecretory syndromes, and we subscribe to this view. pituitary gland. Hypopituitarism is very unusual with Patients with incidentally detected macroadenomas microadenomas. However, microadenomas may secrete need to be investigated in the same way; both for hormonal PRL, GH, ACTH or thyroid-stimulating hormone (TSH), hypersecretion, when definitive treatment is indicated and be associated with a typical clinical syndrome. anyway, and also for hypopituitarism, which is commoner These conditions therefore need screening and treating with these larger tumours. Visual field assessment should appropriately with medication or surgery. The most cost- be carefully performed as these will need to be monitored effective means of investigation for hormonal hyper- as the tumour has already demonstrated its capability to secretion have been advocated to include two or three PRL grow (Molitch & Russell 1990). measurements for prolactinoma (Molitch 1995); insulin- like growth factor-I may act as a screen for acromegaly, Management although if the diagnosis is suspected a formal oral glucose The major issues in the management approach to these tolerance test should be performed; 24 h urinary free incidentally detected masses are first to determine whether cortisol and overnight dexamethasone suppression testing there is compression of surrounding structures, or the are useful screening tests for the diagnosis of Cushing’s potential for this as might be expected with macro- disease; and an unsuppressed TSH in the presence of adenomas, and secondly whether there is evidence of elevated free thyroid hormone levels is the marker of the hormone secretion from the tumour. rare TSH secreting tumour. Others suggest that although some form of biochemical screening for acromegaly and Those patients with evidence of hormone excess Cushing’s disease is usually performed in these cases, this should be treated by surgery or with drugs. By our approach may be over cautious (Soule & Jacobs 1996). In definition, the presence of excess hormonal secretion the series reported by Donovan & Corenblum (1995), the indicates an incidentally detected, but clinically relevant, patient evaluation included a clinical assessment and tumour that requires definitive management rather than an serum PRL, but no formal biochemical assessment for incidentaloma. Those with a microadenoma and no hormonal abnormalities (true incidentalomas) should have a follow-up scan performed. There is very little evidence on which to suggest guidelines - Reincke suggests re- scanning at 1 year with no further studies necessary if there has been no change (Reincke et al. 1990) while Molitch suggests a reasonable approach is to repeat the scan at yearly intervals for 2 years, and if there is no increase in the size of the lesion, to lengthen the interval between scans (Molitch 1995). More data are required, but while the natural history is still unclear, repeat scanning for at least 2 years is preferable. For non-functioning mesoadenomas and intra-sellar macroadenomas, we suggest MRI, at 6 months and then annually for 2 years in those with no hypopituitarism or visual problems; the data that there are confirm that patients with mesoadenomas and normal pituitary function show no propensity to progress (Reincke et al. 1990). It is uncertain at present for how long this should be continued and more data are clearly needed. Definitive treatment, usually by surgery, should be recommended for Figure 1 T1 weighted coronal MRI following Gd-DTPA those macroadenomas with increased hormone secretion, administration showing pituitary microadenoma. evidence of hypopituitarism or those with extra-sellar

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Endocrine-Related Cancer (1998) 5 131-150 extension and chiasmal compression (Reincke et al. 1990, causing them to be described recently as a new epidemic Chacko & Chandy 1992). of ‘AIDS’ (adrenal incidentaloma discovered seren- More data are required to determine the most cost- dipitously) (Griffing 1994). It has also become clear with effective means to follow these patients. Since macro- improved biochemical techniques, that there may be adenomas are the incidentally detected tumours most subtle evidence of excess hormone production from these likely to enlarge, it would appear logical to evaluate these masses previously thought to be non-secretory. more frequently than incidental microadenomas, as these Incidentally detected adrenal lesions provide a similar are much less likely to enlarge in a clinically significant dilemma to those found in the pituitary gland, although the manner. It is debatable, however, whether any macro- questions are slightly different - whether the lesion is adenomas should be left and simply monitored, unless malignant and secondly whether there is evidence of they are truly intra-sellar (mesoadenomas). More studies excess hormonal secretion. These adrenal masses include are required before strict guidelines can be produced on cortical adenomas secreting steroids, phaeochromo- duration of follow-up, the frequency of scanning required, cytomas, adrenal carcinomas and metastases, cysts, and and whether predictions can be made, apart from using myelolipomas as well as non-functioning nodules and size, as to which tumours will progress. adenomas.

Summary Epidemiology Pituitary adenomas are being detected more commonly Autopsy studies because of advances in neuroradiology, the more frequent There is wide variation in the reported prevalence of use of imaging and also progress in biochemical analytical adrenal adenomas in autopsy series (Kloos et al. 1995). techniques. The label incidentaloma should only be Adrenal adenomas unassociated with excess hormonal applied after the patient has been assessed for the presence secretion are found in 1-32% of patients in different series of endocrinopathy or mass effects such as visual field (Kloos et al. 1995). This wide range is in part due to the defects. If there is evidence of, for example, hormonal difficulty in distinguishing between cortical nodules, excess, then despite being an incidental finding the tumour focal hyperplasia and true adenomas. However, if small is not an incidentaloma as it is clinically relevant and studies (a total of 50 or less patients) are excluded, the should be treated as any other tumour of that type. True majority of reports show a prevalence of between 1 and incidentalomas should be followed up with sequential 9%, with the two largest studies of 35 000 patients and imaging as discussed above to ensure that they are indeed 9000 patients each reporting a prevalence of 1.97 and benign and clinically irrelevant. 1.45% respectively (Russi & Blumenthal 1945, Russel et al. 1972). Incidentally detected adrenal adenomas occur Suggested management strategy for incidentally with equal frequency in males and females, and become detected pituitary tumours more common with increasing age (Kloos et al. 1995). It 1. Screen for hypo- and hypersecretion of hormones. has been suggested that adrenal nodule formation may be 2. All extra-sellar macroadenomas require definitive part of the ageing process, and may be secondary to treatment. vascular changes (Dobbie 1969). 3. Tumours associated with syndromes of excess hormone secretion need definitive management. Imaging 4. Mass <1 cm diameter - repeat MRI at 1, 2 and 5 years. The incidental detection of adrenal masses by CT 5. Mass >1 cm diameter, and intra-sellar - i.e. meso- scanning usually gives a lower prevalence of incidental- adenoma - repeat MRI at 6 months, 1, 2 and 5 years. oma than the autopsy series, partly due to poor resolution of masses at the smaller end of the spectrum and also because relatively thick scan slices may be used for Adrenal abdominal imaging (Kloos et al. 1995). CT detects The detection of incidental adrenal masses has also incidental adrenal masses in up to 3.5% of cases increased with the improvements in imaging techniques depending on the series (Glazer et al. 1982, Abecassis et such as ultrasound, CT and MRI. There were 178 reports al. 1985, Belldegrun et al. 1986, Herrera et al. 1991). The of adrenal cortical tumours unassociated with excess reason for the higher frequencies detected in some series hormonal secretion as judged by standard biochemical is related to whether patients with malignancy were screening prior to 1974 (Lewinsky et al. 1974), and they included and whether symptomatic adrenal tumours were were described as ‘very rare’ in that paper. In the last two included. or three decades, however, these incidentally detected CT and MRI are commonly used when screening tumours have become a common clinical problem, patients with known malignancy for metastases and the

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Turner et al.: Pituitary, adrenal and thyroid incidentalomas incidental detection of adrenal masses is commoner in this and, if detected, a corticotrophin-releasing hormone test group of patients. Adrenal metastases have been detected are essential in those patients found to have Cushing’s incidentally in 32-73% of cases in various series of syndrome to determine the underlying cause. oncology patients (Kloos et al. 1995). However, it is The terms pre-Cushing’s and subclinical Cushing’s important that in those cases where there are no other signs syndrome have been used to describe the subset of patients of metastasis an accurate assessment of the adrenal mass with apparently ‘silent’ adrenal cortical adenomas that is made, as adrenal lesions in patients with known possess some features of autonomous function. As the malignancy are not necessarily malignant (Glazer et al. natural history is unclear, we suggest that subclinical 1982). rather than pre-Cushing’s is a better term. The cortisol Imaging with CT and MRI cannot differentiate the true secretion can be sufficient to suppress ACTH, leading to adrenal incidentaloma from an incidentally detected reduced uptake in the contralateral gland on adrenal hypersecretory tumour (Karstaedt et al. 1978, Doppman et scintigraphy, and to put the patient at risk of a hypoadrenal al. 1987, Remer et al. 1989, Tsushima 1994). Masses of crisis. There may be loss of the normal diurnal rhythm of the adrenal cortex and medulla in asymptomatic patients cortisol secretion and dexamethasone suppressibility, may subsequently be found to be secretory tumours - despite initially normal cortisol levels (Reincke et al. e.g. cortisol secreting tumours (Herrera et al. 1991, 1992, Osella et al. 1994). In a series of 122 patients with Reincke et al. 1992) or phaeochromocytomas (Prinz et al. incidentally detected adrenal masses, 6 (5%) were 1982, Herrera et al. 1991, Mannelli et al. 1993, Osella et identified with subclinical Cushing’s syndrome with al. 1994). normal baseline cortisol levels, but loss of the diurnal rhythm of cortisol secretion (McCleod et al. 1990). Three Pathology of six patients (50%) had normal 24 h urinary free cortisol but the adrenal scintigraphy showed suppression of the In over half of cases, incidentally detected adrenal nodules contralateral gland in all cases, illustrating the importance are found to be benign adenomas - both functioning and of peri-operative steroid cover to avoid potential non-functioning, whilst metastasis to the adrenal gland is Addisonian crisis if adrenalectomy is performed. Further the second most common diagnosis in approximately one- confirmation of the insensitivity of a 24 h urinary free third of cases (Cook & Loriaux 1996). Adrenal cysts, cortisol measurement comes from a study of subclinical phaeochromocytomas, and primary adrenal cancers are all Cushing’s syndrome found in 12% of patients with much less common (Table 3). incidentalomas, where the low dose dexamethasone suppression test was the most helpful screening test Cushing’s or subclinical Cushing’s syndrome (Reincke et al. 1992). Other reports confirm that lack of It has been clearly demonstrated that Cushing’s syndrome cortisol suppression with dexamethasone was the most may be found in patients with incidentally detected sensitive means of detection of subtle adrenal overactivity adrenal tumours and that biochemical evaluation of these in this group (Rosen & Swartz 1992). Six patients out of a cases is important (Reincke et al. 1992, Osella et al. 1994). series of 45 (14%) with incidentally detected adrenal In addition to the complications of Cushing’s syndrome, masses showed loss of the normal circadian rhythm of unrecognised adenomatous cortisol secretion may lead to cortisol secretion, while only 3 had elevated mean serum a hypoadrenal crisis during surgery to remove the cortisol levels (Terzolo et al. 1995). There may be a adenoma, due to suppression of cortisol secretion from the continuous spectrum from non-secretory adenoma to contralateral adrenal. subclinical Cushing’s and full-blown Cushing’s syndrome Ross & Aron (1990) suggested using the clinical (Fernández-Real et al. 1994) and this may account for parameters of obesity and hypertension to screen for this some of the variation in biochemistry. condition in patients with incidental adrenal masses. Most A large proportion of patients with incidentally endocrinologists use either an overnight 1 mg or a formal detected adrenal tumours have been shown to have low low dose (2 mg/day) dexamethasone suppression test as serum dehydroepiandrosterone sulphate (DHEAS) this is a more accurate screening test (Newell-Price & concentrations (Osella et al. 1994, Terzolo et al. 1996). A Grossman 1996), while others suggest using a high dose comparison of 32 patients with incidentally detected (8 mg) overnight dexamethasone suppression test since adrenal masses and 17 patients with Cushing’s syndrome the diagnosis of pituitary dependent Cushing’s syndrome showed that serum DHEAS levels were lower than normal is not a consideration (Chidiac & Aron 1997) (Table 4). It in 21/24 (87.5%) of the patients with adrenocortical is, however, important to recognise that ACTH dependent masses (Flecchia et al. 1995). The prevalence of low Cushing’s syndrome may lead to asymmetrical adrenal DHEAS was higher than hormonal alterations suggesting enlargement, and give the appearance of a unilateral mass Cushing’s syndrome (17-25% patients) (Flecchia et al. (Cook & Loriaux 1996). Clearly measurement of ACTH 1995). Suppressed levels may be found where cortisol

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Table 3 Diagnoses in series of patients with incidentally detected adrenal tumours.

Diagnosis Percentage of series Reference

Cushing’s syndrome 0.6% (2/342) Herrera et al. (1991) 3.3% (7/210) Aso & Homma (1992) 2.2% (1/45) Osella et al. (1994) 5.6% (2/36) Sirén et al. (1993)

Subclinical Cushing’s 4.9% (6/122) McLeod et al. (1990) syndrome 13.3% (6/45) Osella et al. (1994) 12% (8.68) Reincke et al. (1992)

Mineralocorticoid 3.3% (7/210) Aso & Homma (1992) secreting 1.5% (1/68) Reincke et al. (1992)

Phaeochromocytoma 11% (1/9) Prinz et al. (1982) 1.5% (5/342) Herrera et al. (1991) 23% (49/210) Aso & Homma (1992) 4.4% (2/45) Osella et al. (1994) 1.5% (1/68) Reincke et al. (1992) 11.1% (4/36) Sirén et al. (1993)

Carcinoma 1.2% (4/342) Herrera et al. (1991) 4.3% (9/210) Aso & Homma (1992) 8.8% (4/45) Osella et al. (1994) 1.6% (1/63) Bencsik et al. (1995)

Metastases 0.8% (1/122) McLeod et al. (1990) 0.3% (1/342) Herrera et al. (1991) 1.4% (3/210) Aso & Homma (1992) 2.2% (1/45) Osella et al. (1994) 11% (7/63) Bencsik et al. (1995)

Other 22% cysts (2/9) Prinz et al. (1982) 11% lipoma (1/9)

8.6% cyst (18/210) Aso & Homma (1992) 7.1% myelolipoma (15/210)

2.2% myelolipoma (1/45) Osella et al. (1994) 2.2% cyst (1/45)

30.5% (nodular hyperplasia, Sirén et al. (1993) haematomas, lipoma, cyst, myelolipoma, adenoma secreting androgens)

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Table 4 Summary of suggestions for investigation of incidentally detected adrenal masses.

Hypersecretory state Screening test/assessment Reference

Phaeochromocytoma Hypertension Ross & Aron (1990) Symptoms Herrera et al. (1991) Urinary Sirén et al. (1993) catecholamines Kloos et al. (1995) (Serum catecholamines) Newell-Price & Grossman (1996)

Cushing’s or subclinical Hypertension Ross & Aron (1990) Cushing’s syndrome Obesity 1 mg dexamethasone Herrera et al. (1991) suppression test Kloos et al. (1995) Sirén et al. (1993) Low-dose (2 mg/day) dexamethasone Newell-Price & Grossman (1996) suppression test and DHEAS Osella et al. (1994) Terzolo et al. (1995)

Mineralocorticoid hypertension Blood pressure Sirén et al. (1993) Spontaneous hypokalaemia Ross & Aron (1990) Herrera et al. (1991)

In hypertensive patients, upright plasma Kloos et al. (1995) aldosterone and plasma renin activity

Masculinising tumours DHEAS Kloos et al. (1995) Testosterone and CAH evaluation in virilised females or boys with precocious puberty

Feminising tumours Serum oestradiol in feminised men Kloos et al. (1995)

secretion from an autonomous adenoma leads to reduced seem unlikely that these tumours will all progress to overt ACTH secretion. In a group of 45 patients with Cushing’s syndrome as this is a very rare diagnosis, incidentally detected adrenal masses, 42% had DHEAS whereas these mild degrees of adrenal hypersecretion are levels that were significantly lower than those in control common. Secondly, what are the sequelae in terms of risk subjects (Terzolo et al. 1995). This was the commonest of osteoporosis in this group? Is this the population who biochemical abnormality. This suggests that subclinical will become hypertensive and diabetic as suggested in cortisol hypersecretion may be frequently detected in some of the earlier studies based mainly on autopsy patients with incidental adrenal masses. studies? Is there a risk of hypoadrenalism at times of stress Therefore the characteristics of subclinical Cushing’s (McCleod et al. 1990)? Interestingly a recent study has syndrome appear to be normal urinary free cortisol levels, demonstrated enhanced bone metabolism in patients with absence of typical features of Cushing’s syndrome adrenal incidentalomas (Osella et al. 1997). Only when (although diabetes and hypertension may be associated), there is more information on the natural history can these absence of cortisol suppression on overnight or low dose questions be answered and so appropriate management dexamethasone suppression testing, loss of the diurnal advised. Rosen & Swartz (1992) suggested that until these rhythm of cortisol secretion, suppression of ACTH data are available, the insulin tolerance test is the most leading to reduced DHEAS levels and reduced uptake on appropriate test in this group of patients with normal basal adrenal scintigraphy, and risk of hypoadrenalism at times cortisol secretion to ensure there is no impairment of the of stress. ability to respond to stress. Some suggest surgery as the The crucial question regarding subclinical Cushing’s treatment of choice in patients with subclinical Cushing’s syndrome is whether this apparently commonly detected syndrome who have also accelerated hypertension and condition in patients with incidentally detected adrenal obesity (Reincke et al. 1992). A limited follow-up study masses has any long-term clinical significance. It would of a small number of patients showed that in those who

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Endocrine-Related Cancer (1998) 5 131-150 underwent surgery, there was persistence of abnormal Congenital adrenal hyperplasia biochemistry in some, while in those who were not The diagnosis congenital adrenal hyperplasia (CAH) operated on, the endocrine abnormalities may persist, should be considered in any patient with suggestive appear later or spontaneously remit (Osella et al. clinical features, and appropriate investigations instigated. 1994). On the basis of an incidence of a silent adrenal mass in nearly 82% of patients with homozygous and 45% with Aldosterone secreting tumours heterozygous CAH, it has been suggested that CAH Ross & Aron (1990) suggested that screening for should be excluded in all cases of an incidentally detected spontaneous hypokalaemia is all that is necessary in a adrenal mass (Jaresch et al. 1992). The authors suggest hypertensive patient with an adrenal mass, as this that if a mass >6 cm is detected and the patient found to produces a negative predictive value of 95% for have CAH, then no intervention is necessary as the aldosterone producing adenoma, if the prevalence of combination of CAH and adrenal carcinoma is very rare hypokalaemia in the general population is assumed to be (Jaresch et al. 1992, Ravichandran et al. 1996). A small 10%. study comparing the 17-hydroxyprogesterone response to A low sodium diet may mask subtle hypokalaemia in ACTH in patients with adrenal nodules and controls patients with aldosterone secreting tumours, and if the showed that despite similar baseline values, the 30 and diagnosis is suspected a dietary modification to increase 60 min values were significantly elevated over those of the the sodium intake will reduce the false negative rate of controls (Turton et al. 1992). It is suggested that this may this test. Kloos et al. (1995) suggested that in addition to provide a useful test to establish the benign nature of the measuring a random serum potassium, patients with nodules. Terzolo et al. (1996) showed two distinct groups hypertension should have paired aldosterone and renin of steroid secretion in their series of patients with levels checked, while medications are continued. incidentally detected adrenal masses - one group with Suspicious results are then interpreted in the light of the subclinical Cushing’s and another with an exaggerated drug history and further investigations performed where response of 17-hydroxyprogesterone to ACTH. However, necessary. There are no data, however, to guide practice in Reincke (1996) found that two out of four patients with normokalaemic, hypertensive patients, but in those with subclinical Cushing’s showed an exaggerated 17- hypokalaemia investigation is obviously indicated hydroxyprogesterone response. The reason for these (Table 4). discrepant results is unclear and further work is needed. It is important to recognise that mineralocorticoid The exaggerated 17-hydroxyprogesterone response in hypertension may be due to adrenocortical hyperplasia, patients with incidentally detected adenomas has recently and therefore an adenoma may be misinterpreted as an been shown to be related to impairment of 11β-hydroxy- incidentaloma if there is some evidence of nodularity in lase rather than 21-hydroxylase activity (Reincke et al. the other adrenal gland (Reznek & Armstrong 1994). 1997). A controversy does exist, however, regarding the Clearly careful assessment of the renin and aldosterone value of screening for CAH and many endocrinologists levels should differentiate these diagnoses in the majority suggest that no routine biochemical screening is of patients, but adrenal vein sampling may be necessary necessary, as adrenal scintigraphy will confirm the (Doppman et al. 1992, Sheaves et al. 1996). presence of a benign lesion (Kloos et al. 1995) (Table 4). Aldosterone producing adenomas may show a If biochemical testing is being performed on the premise significantly lower lipid content on chemical shift MRI that an earlier diagnosis is beneficial, then it may be (Tsushima 1994); however, the study population in this difficult to justify screening an asymptomatic patient for report was not one of incidentally detected adrenal this condition. tumours, and biochemical testing would be more accurate. Phaeochromocytoma The frequency of phaeochromocytoma in a 50 year Sex hormone producing adenomas autopsy series of 40 078 patients from the Mayo clinic was The use of testosterone and oestradiol in screening for 0.13% (Sutton et al. 1981). In an analysis of appropriate incidentally detected adrenal tumours is not recommended screening tests for incidentally detected adrenal masses, due to the rarity of these tumours in truly asymptomatic the estimated prevalence of incidentally detected phaeo- patients (Kloos et al. 1995). Testosterone should be chromocytomas was 6.5% (Ross & Aron 1990). Using measured only when indicated, for example in women the frequency of hypertension and other symptoms in the with virilisation or hirsutism. Oestradiol should be general population compared with those with phaeo- measured in those males with feminisation or gynae- chromocytomas, Ross & Aron suggest that the use of comastia (Copeland 1983). hypertension and symptoms will give a negative

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Turner et al.: Pituitary, adrenal and thyroid incidentalomas predictive value of 99.6%. However, because phaeo- Clinical situation chromocytoma is a potentially lethal condition, The clinical situation is rarely helpful when differentiating biochemical screening is required. Urinary vanillyl benign and malignant adrenal masses. There are some mandelic acid gives a positive predictive value of only instances, however, where taking account of the patient’s 71.8% (Ross & Aron 1990) and it is preferable to measure presentation can be helpful. For example, non-secretory 24 h urinary metanephrines or catecholamines, which adrenal masses are likely to be malignant in the presence have sensitivities and specificities of 80 and 93%, and up of an extra-adrenal malignancy but the primary tumour to 100 and 95% respectively (Bouloux & Fakeeh 1995, (e.g. bronchial carcinoma) may still be subclinical when Kloos et al. 1995). Serum catecholamines may be used as the adrenal mass is discovered. a screening test, but this test is most useful during a crisis There is also a suggestion that since adrenal (Bouloux & Fakeeh 1995). It should be noted that there are malignancy in CAH is very rare, these tumours should not reports of totally asymptomatic incidentally detected be removed as they are unlikely to be malignant. There are phaeochromocytomas with normal urinary and plasma some data to support this. In a study of patients with catecholamines and metabolites, and normal stimulation homozygous or heterozygous CAH, 3/42 had adrenal and suppression tests (Mannelli et al. 1993). tumours >6 cm in diameter which were all found to be T2 weighted MRI may be helpful in determining benign (Jaresch et al. 1992). More data are required in this whether an adrenal mass is a phaeochromocytoma, as group. these tumours usually appear hyperintense to the liver The majority of cysts, haemorrhages and myelo- (Boland & Lee 1995), although they may sometimes lipomas have characteristic features on CT scanning, and appear iso- or hypointense. A report of T2 weighted MRI so require no further investigation (Ross & Aron 1990, studies of 81 adrenal masses, showed that this form of Korobkin et al. 1996c), although it should be borne in imaging was able to differentiate phaeochromocytomas in mind that tumours can be partly cystic and may show all cases from other adrenal masses (Doppman et al. haemorrhage. The lack of contrast enhancement of cysts 1987), and therefore MRI is the imaging modality of compared with the enhancement seen in adenomas may choice in this situation. help differentiation in some instances (Reznek & Armstrong 1994). Adrenal carcinoma and metastases Size The possibility of a neoplasm, either a primary adrenal Size is a non-specific and insensitive means of tumour or a secondary deposit from an extra-adrenal differentiating between benign adrenal lesions and neoplasm, should be considered in every case of an metastases from extra-adrenal primary tumours adrenal mass. Primary adrenal carcinomas are often (Abecassis et al. 1985). In a series of 114 adrenal secretory - the prevalence of hormonal secretion carcinomas, 105 (92%) tumours measured >6 cm varying according to the series and investigations (Copeland 1983). Four patients out of a series of 45 with performed. Seventy-five percent of adrenocortical incidental adrenal tumours were found to have a primary carcinomas in one series were secretory - with cortisol the adrenal malignancy - three adrenal carcinomas and one commonest secretory product (Wooten & King 1993). ganglionic neoplasm (Terzolo et al. 1995). A size criterion Endocrinologically active adrenal cancers may also of 6 cm for surgery in this series would not have missed present with evidence of multiple hormone hyper- any adrenal malignancy and included one benign secretion, in contrast to benign adrenal adenomas, diagnosis of a 7 cm myelolipoma, although the authors which are more usually more specialised in their recommend using 4 cm as the size criterion for surgery. manifestations. There is controversy over the value of Using a cut-off of 4 cm, Herrera et al. (1991) reported a measuring DHEAS. Some suggest DHEAS is a useful test ratio of 8:1 benign to malignant, which the authors felt was in screening for adrenal carcinoma as it has been shown to a reasonable size criterion for surgery, in view of the zero be elevated in adrenal carcinoma (Osella et al. 1994); mortality and low morbidity in their operative series. however, in a series of incidentally detected adrenal Malignant tumours <2.5 cm are also found (Lee et al. tumours, another group found low DHEAS levels in half 1991). In a recent survey of 208 patients with incidentally the patients with primary and secondary adrenal detected adrenal masses, the range in size was 3.2-20 cm malignancy as well as those with benign adenomas, and the recommended cut-off for surgery was 4 cm showing that DHEAS was not a useful predictor of (Karsperlik-Zaluska et al. 1997). Using a size of <6 cm in hormonal activity (Bencsik et al. 1996). diameter, and absence of CT characteristics suggestive of Various features and investigations have been cancer (irregular borders and inhomogeneity), the evaluated to assist the accurate distinction between benign negative predictive value for malignancy was calculated and malignant, and these will now be described. to be greater than 99.9% by Ross & Aron (1990). The

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Endocrine-Related Cancer (1998) 5 131-150 positive predictive value of masses 6 cm and larger signal intensity, and metastases with intermediate depends on the actual size and ranges from 35 to 98%, and intensity, in 20% of cases differentiation was not possible. in view of this Ross & Aron suggest removal of all The tumour/fat signal intensity was found to perform the tumours of >6 cm in diameter. There are many different best of all MRI parameters examined to discriminate recommendations on the optimum size cut-off for surgery adenomas from non-adenomas, although in this study the on suspected adrenal carcinoma - from 3 cm (Thompson attenuation values on unenhanced CT was still the best & Cheung 1987, Bencsik et al. 1995), to 6 cm (Copeland method (Van Erkel et al. 1994). An attempt to improve 1983, Ross & Aron 1990, Sirén et al. 1993). Size can only the accuracy of MRI with an eight echo T2 assessment led be used for guidance, and the most widely accepted to a slight improvement in diagnostic efficacy, but criterion currently for differentiation between benign and considerable overlap remained (Gruss & Newhouse malignant is a diameter >4 cm, with close observation of 1996). Chemical shift MRI has shown promise as a means tumours between 2 and 4 cm in diameter. of differentiating between benign adrenal masses, which typically have a relatively high lipid content, and adrenal Radiological features metastases (Boland & Lee 1995), with a reported accuracy Certain features on imaging are very suggestive of a of 96-100%. More data are needed with this new technique sinister lesion - for example increased size, lack of a (Fig. 3), particularly as it may not prove to be so promising clearly circumscribed margin and evidence of vascular in the differentiation of primary adrenal carcinoma or invasion. phaeochromocytoma from benign lesions (Reinig et al. The CT characteristics of adrenal masses that are 1994). suggestive of malignancy have been examined, and the measurement of attenuation (as a measure of fat content - Fine needle aspiration higher in benign adenomas) on an unenhanced scan may Fine needle aspiration (FNA) has a limited role, enabling be better than size criteria in determining malignancy, a distinction to be made between cystic and solid masses, although there remains a significant overlap (Lee et al. but usually not allowing differentiation of benign and 1991). Different threshold values have been reported from malignant tumours, as although an increased number of 0 to 18 Hounsfield Units (HU) below which the likely mitoses is suspicious, the diagnosis requires evidence of diagnosis is of a benign adenoma (Lee et al. 1991, Van capsular or vascular invasion (Copeland 1983). Aspiration Erkel et al. 1994, Korobkin et al. 1996b). A threshold biopsy should allow the differentiation of metastases from value of 0 HU had a specificity of 100% for primary adrenal tumours. In a series of 13 patients with an characterisation of benign adrenal masses, with a incidentally detected adrenal mass, FNA was performed in sensitivity of 47%, whilst a threshold of 10 HU had a 8, and this allowed surgical exploration for diagnostic sensitivity of 79% and specificity of 96% for benign reasons to be avoided in each case (Gaboardi et al. 1991). adrenal tumours (Lee et al. 1991). Korobkin et al. (1996b) The aspiration biopsies showed that two patients with 3 reported a significant overlap in size criteria between and 4 cm masses had metastatic disease, and that one benign adenomas and non-adenomas, whereas a threshold patient with a 4 cm mass had lymphoma. Silverman et al. of 18 HU on the unenhanced CT scan gave a sensitivity of (1993), in a retrospective review of 97 patients undergoing 85% and specificity of 100%. The reason for the 101 image-guided adrenal biopsies, reported the discrepancy in thresholds is not entirely clear. A study sensitivity of aspiration biopsy as 93% and a negative examining delayed adrenal CT scan 1 h after routine predictive value (i.e. likelihood that benign histology is enhanced abdominal CT scan demonstrated that the mean accurate) of 100% in masses >3 cm in diameter, whereas CT scan attenuation value of 41 adrenal adenomas was in smaller tumours the negative predictive value was only significantly lower (P<0.001) than 10 adrenal metastases 91% as seven patients with benign FNA had malignancy. on delayed enhanced CT scan, with very little overlap This shows that benign histology on biopsy is highly between the two groups (Korobkin et al. 1996a). Further predictive of a benign diagnosis, even in those with known studies are required to confirm the utility of this technique. malignancy elsewhere. The complications of the Colour flow Doppler ultrasound does not appear to be procedure include pneumothorax most commonly (3% in helpful in differentiating benign and malignant adrenal the Silverman series), haemorrhage, bacteraemia and masses (Ghiatas et al. 1996). pancreatitis. The use of MRI (Fig. 2) does not require exposure to radiation, but again there is significant overlap between Serial scanning benign and malignant tumour appearance (Reinig et al. The optimal scanning frequency to detect any tumour 1986, Van Erkel et al. 1994). Doppman et al. (1987) enlargement in this group of patients is unknown and showed that although T2 weighted MRI scans produce reflected in the differing protocols suggested - from differences between non-functioning adenomas with low 3 monthly scans for 1 year and then annually for 2 years

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Figure 2 MRI (T2 weighted fast spin echo) showing left adrenal incidentaloma.

Figure 3 MRI in and out of phase gradient echo images demonstrating high fat content of adrenal incidentaloma.

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(Abecassis et al. 1985), or repeat scans at 3, 9 and 18 Management is not possible with just one diagnostic months (Sirén et al. 1993) or serial imaging at 3-6 monthly test, but a combined effort utilising an endocrinological intervals (Newell-Price & Grossman 1996). The exposure screening approach, radiological evaluation and to radiation involved in CT scanning should not be radionuclide imaging is required to fully assess these forgotten, and follow-up with MRI is preferable for this lesions so as not to miss masses with significant reason. A protocol of MRI scanning at 3 months, 6 months pathological potential, but also to avoid unnecessary and 1 year, with removal of any enlarging mass would adrenalectomies. seem advisable, with a further scan at 2 years if no enlargement has been detected. Suggested algorithm for diagnosis of incidentally detected adrenal masses Adrenal scintigraphy 131 1. Clinical assessment for symptoms and signs of Uptake and accumulation of radiotracers such as [ I]- syndromes of excess hormone secretion, and signs of 6β-iodomethyl norcholesterol, [131I]19-iodocholesterol, 75 extra-adrenal primary carcinoma. and [ Se]selenomethylnorcholesterol allow localisation 2. Short Synacthen test for 17-hydroxyprogesterone (to of the adrenal gland and of adrenal tumours. Thus diagnose CAH) and cortisol (for adrenal insufficiency). functioning tumours such as adenomas causing 3. If 2 is normal: urinary free cortisol collection and glucocorticoid, mineralocorticoid, or androgen excess, overnight dexamethasone suppression tests; urinary and non-hypersecretory adenomas, demonstrate uptake of catecholamines; potassium (aldosterone and renin if radioisotope, whilst primary and secondary malignancies hypertensive and hypokalaemic) - on 120 mmol/day will not and appear as ‘cold’ nodules. However, small sodium diet; surgery if syndrome of hormonal excess. differentiated malignancies may take up tracer and some 4. If 2 and 3 are normal: surgery if diameter of mass cysts or areas of haemorrhage may appear ‘cold’ (Reschini >4 cm, and above results inconclusive of malignancy; if & Peracchi 1984, Pasieka et al. 1992). Negative size <4 cm and no evidence of hormonal excess or extra- scintigraphy is unfortunately not so reliable when smaller adrenal malignancy, repeat MRI scan at 3, 6, 12 and 24 adrenal masses (i.e. <2 cm in diameter) are examined months. (Gross et al. 1994). Adrenal scintigraphy may be useful in It is important to recognise that clinical judgement and patients with bilateral adrenal lesions, where absent or experience is also required when managing these patients, reduced uptake compared with the contralateral gland may and in particular which cases should undergo adrenal- be considered compatible with a malignancy or ectomy. The availability of laparoscopic adrenalectomy destructive lesion (Gross et al. 1995). The significance of reduces surgical morbidity (Jacobs et al. 1997). a unilateral nodule associated with radioisotope uptake but suppressed contralateral adrenal uptake is likely to be due to suppression of the contralateral gland by hypersecretion Thyroid from the nodule, although the overnight dexamethasone The increasing sensitivity of imaging techniques has led to suppression test and urinary free cortisol may be normal the incidental detection of thyroid nodules in patients (Kloos et al. 1995). Thus the scintigraphic scan may be a under investigation for other conditions. In a manner valuable tool in screening for autonomously functioning similar to incidentally detected pituitary and adrenal adenomas (Bardet et al. 1996) but in practice is not widely masses this has led to a clinical dilemma regarding their used and biochemical means are more useful. There are no clinical relevance and the appropriate management data to suggest that adrenal scintigraphy should be used to strategy. follow patients, for example to detect when a non- secretory adrenal mass becomes functional. Epidemiology The proportion of the general population found to have Summary asymptomatic thyroid nodules depends on the The optimal management of patients with incidentally investigation method used - whether it is histological detected adrenal masses requires the definition of whether examination of specimens from autopsy or surgical this is purely a fortuitous discovery of significant specimens, palpation of asymptomatic patient’s necks or pathology, or whether the lesion is a true incidentaloma. by radiological examination using different imaging Clearly this may be difficult in the case of conditions such techniques (Table 5). as subclinical Cushing’s syndrome. Careful follow-up data are required in such cases to allow further elucidation Histopathological series of their natural history. It will also be important to evaluate A post-mortem study of 821 thyroid glands from patients the benefit of diagnosing these subclinical syndromes who had clinically normal thyroid glands at routine earlier and to consider the potential for lead-time bias. general examination in life showed that 49.5% of the

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Turner et al.: Pituitary, adrenal and thyroid incidentalomas glands were nodular on visual examination; 12.2% incidental thyroid nodules 0.6-4.5 cm in size in 13.4% of contained a single nodule and 37.3% multiple nodules 67 patients undergoing imaging of the carotids (Carroll (Mortensen et al. 1955). Approximately one-third of the 1982). In addition, up to 40% of patients thought clinically patients had nodules >2 cm in diameter. At all ages, to have a solitary nodule actually had multiple nodules nodules were found to be commoner in females, and detected by ultrasonography (Scheible et al. 1979). The the frequency increased with age (Mortensen et al. different frequencies with which nodules are detected in 1955). these studies reflects the different demographics of the populations studied, differences in the underlying Clinical examination pathology, and the frequency of the transducer (Solbiati et Out of a total of 5127 patients recruited from the al. 1985). Framingham cohort, 218 (4.2%) were found to have palpable non-toxic nodules (Vander et al. 1968). The Pathology Whickham survey demonstrated thyroid nodules in Histological examination of thyroid nodules from an 0.8% of males and 5.3% of females (Tunbridge et al. autopsy series in subjects with a clinically normal thyroid 1977). A smaller study found a higher prevalence with gland and mean age of 60 years, showed that the 21 (21%) of 100 asymptomatic patients having palpable commonest finding was a non-neoplastic involutional thyroid nodules - with solitary nodules in 9 and multiple nodule, present in one-third of all glands and two-thirds of nodules in 12 patients (Ezzat et al. 1994). The reason nodular ones (Mortensen et al. 1955). Benign follicular for the discrepancy between the two studies is not adenomas were found in 27.3% of glands and primary entirely clear, although the smaller study had a larger carcinoma in 17/821 (2.1%) thyroid glands. Metastatic proportion of women and there was a higher than carcinoma was detected in 15 (1.8%) glands. expected prevalence of positive thyroid microsomal antibodies. Natural history During follow-up of the Framingham cohort over Imaging 15 years, 67 new nodules were detected in the 4909 Several studies have examined the incidence of nodules persons initially free of disease, representing a 15 year detected on ultrasound examination of the neck for non- incidence rate of 1.7% in females and 0.9% in males, with thyroidal conditions (Table 5). This varies according to the no evidence of malignancy (Vander et al. 1968). Of the population studied, but between 19 and 67% of normal 199 people found to have thyroid nodules at the start of the volunteers (Woestyn et al. 1985, Brander et al. 1991, Ezzat study, nodules were present and unchanged in 148 et al. 1994) have been shown to have small nodules of patients, and none showed any evidence of malignancy. <1 cm in diameter. A study of patients undergoing surgery Forty-five lesions had been surgically removed and all for parathyroid disease demonstrated non-palpable were histologically benign. Further data are required on thyroid nodules in 40% using ultrasound and CT (Stark et the malignant potential of incidentally detected or ‘occult’ al. 1983), and duplex ultrasound imaging revealed thyroid nodules.

Table 5 Epidemiology of incidentally detected thyroid nodules.

Method of detection Prevalence Reference

Histopathological (autopsy) 49.5% Mortensen et al. (1955)

Clinical examination 4.2% Vander et al. (1968) 0.8% males and 5.3% females Tunbridge et al. (1977) 21% Ezzat et al. (1994)

Imaging 40% (US and CT) Stark et al. (1983) 13.4% (duplex imaging) Carroll(1982) 27% (US) Brander et al. (1991) 19% (US) Woestyn et al. (1985) 67% (US) Ezzat et al. (1994)

US, ultrasound.

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Benign or malignant? Investigations The possibility of an incidentally detected nodule causing Thyroid carcinoma is relatively uncommon - accounting thyrotoxicosis should be excluded with thyroid function for approximately 1000 new cases and 300 deaths in tests. Once this has been excluded, however, the main England and Wales per year. The main aim when concern is whether there is a risk that the nodule could be investigating patients with an incidentally detected malignant. solitary nodule is to identify the patient with differentiated thyroid carcinoma who requires treatment, while avoiding Ultrasound unnecessary investigations and treatment in the majority. High resolution ultrasonography is very sensitive for the The evidence from epidemiological studies, e.g. the detection of thyroid nodules and often demonstrates Framingham cohort, suggests that the likelihood of an multiple nodules in people previously thought to have a incidentally detected thyroid nodule being malignant is single nodule (Brander et al. 1992). Some suggest that very low. Furthermore, since occult malignancy may be since focal abnormalities of the thyroid gland are discovered in up to 2% of thyroid glands that are normal common, the term ‘nodule’ should be restricted to lesions to palpation this may be of little clinical relevance >5 mm in diameter (Solbiati et al. 1992). (Mortensen et al. 1955). Others have shown that microcarcinomas may exist in up to 5.7% of adults Ultrasonography has not been shown to reliably allow (Sampson et al. 1974, Fukunaga & Yatani 1975). These differentiation between benign and malignant nodules occult carcinomas are usually small, <0.5 cm in diameter, (Simeone et al. 1982). Malignant nodules have been papillary in type and show benign behaviour. However, reported to be hypoechoic compared with the rest of the tumours <1 cm in diameter can still metastasise, and can gland while benign nodules are hyperechoic with a cause death (Boehm et al. 1976). It is not known whether sonolucent rim or ‘halo’(Solbiati et al. 1985). However, in an occult malignancy is a subclinical stage of thyroid one series 7% of cystic lesions were found to be malignant malignancy or a tumour whose behaviour is different from (Ashcraft & van Herle 1981a) and the ‘halo’ sign may also thyroid cancers that become clinically relevant. In the be found in patients with papillary carcinoma (Simeone et future, the genetic characteristics of these tumours may al. 1982). Incomplete and irregularly thickened peripheral assist with this differentiation. halo and poorly defined margins are suggestive of malignancy. The distribution of calcification in a nodule Certain clinical features should be regarded as highly gives some clue to the diagnosis - as peripheral calci- suspicious of thyroid carcinoma in a patient with an fication is benign, while internal, or punctate calcification incidentally detected thyroid nodule. These include a within a nodule is suggestive of a papillary carcinoma nodule discovered in childhood or adolescence (McHenry (Giuffrida & Gharib 1995). Others have demonstrated et al. 1988), or in a male patient (Psarras et al. 1972), or in calcification and cystic changes do not allow complete those with a history of exposure to radiation or a family differentiation between benign and malignant lesions history of medullary thyroid carcinoma. It has also been (Woestyn et al. 1985). Thus although ultrasound may suggested that patients from an iodine deficient area may accurately define the presence, number and size of be at a higher risk of thyroid malignancy (Belfiore et al. nodules, it is not useful for defining the characteristics of 1987). Hamming et al. (1990) rated various clinical the nodule, in particular whether it is benign or malignant. factors as having high, moderate or low clinical suspicion for thyroid cancer, and showed that patients with one Radioisotope scanning clinical factor with high suspicion for cancer had a 71% Thyroid carcinoma does not usually concentrate incidence of cancer in the nodule, whereas those with a radioisotope and therefore will appear ‘cold’ on imaging. low suspicion had an 11% incidence. Two or more clinical However, only 12.8% of cold nodules were malignant, factors with high suspicion led to a 100% chance of cancer. while 6.6% of ‘warm’ nodules were malignant in one It is interesting that although family history of medullary study using 131I uptake (Psarras et al. 1972). A review of thyroid carcinoma, rapid tumour growth, very firm several studies, which included 4457 patients undergoing nodule, and vocal cord paralysis were all factors shown to radioiodine scans and then undergoing surgery, showed be associated with a high suspicion of thyroid carcinoma, that only 17% of cold nodules were malignant (Ashcraft age less than 20, male sex, and head and neck irradiation & van Herle 1981b). Other causes of cold nodules include were not shown to have predictive value. Thus it is colloid nodules, cysts or haemorrhage. Hot lesions on unlikely that patients with incidentally detected thyroid radionuclide imaging are rarely associated with nodules will have any features that put them in the high malignancy (Freitas et al. 1985), but may represent a hot suspicion group. nodule adjacent to a malignancy.

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Therefore, radionuclide imaging cannot distinguish experience is required, particularly in those with benign from malignant nodules with high specificity. incidentally detected thyroid nodules, before screening for Many feel that the radioisotope scan has no place in the medullary thyroid carcinoma is advised in all with nodular primary distinction between benign and malignant disease including incidentally detected nodules. nodules (Giuffrida & Gharib 1995). Management FNA cytology There are very few data on the natural history of these FNA is the most accurate tool presently available for lesions. Some authors suggest that there is no indication diagnosing malignancy in a thyroid nodule, although it is for intervention in these commonly detected abnormalities operator and experience dependent (Ashcraft & van Herle (Elte et al. 1996). Others feel that those over a certain size 1981b, Giuffrida and Gharib 1995). There are limitations should be evaluated further by FNA (Giuffrida & Gharib to the technique as it does not allow assessment of 1995), while others recommend that those nodules over a invasion of the capsule or vasculature, and it can be certain size should be followed up with clinical difficult to distinguish follicular adenoma from assessments. Based on the population data, it seems carcinoma. Those with suspicious histology should unlikely that these incidentally detected lesions provide a therefore be operated on. A recent review of data pooled significant risk of malignancy, and it might be appropriate from seven series of thyroid FNA showed that 69% of to suggest investigation only in those with risk factors as nodules were diagnosed as benign, 10% suspicious, 4% mentioned above or clinical features that raise suspicion malignant and 17% non-diagnostic (Gharib & Goellner of malignancy. The investigation of choice should be 1993). The false negative rates varied from 1.3 to 11.5%, FNA, which may need to be ultrasound guided where the with an average of 5.2%. Unless all patients undergoing lesion is small, and management should then proceed as FNA have surgery, the true false negative rate will not be for any solitary nodule. It will be impossible to predict best known, although most believe this to be less than 5%. The management, however, until there are more data on the average false positive rate in these studies was 2.9%. It is natural history of these lesions, but it appears that thyroid important to recognise, however, that these are data for nodules are more likely to be true incidentalomas than palpable thyroid nodules which are not incidentalomas. adrenal or pituitary incidental lesions and unlike the Löwhagen et al. (1981) suggested that small occult situation in the adrenal gland, and to a certain extent the carcinomas are not a target for aspiration biopsy cytology pituitary, there is no evidence at present that incidentally since they are not clinically detectable, and inclusion of detecting thyroid lesions is in any way beneficial to the these neoplasms may ‘dilute’ the results of pre-operative patient in terms of the earlier detection of a significant FNA. There are suggestions that proton magnetic disease process. resonance spectroscopy on fine needle aspirates may differentiate benign follicular adenomas from malignant tumours so avoiding the necessity for surgery, but this Suggested algorithm for diagnosis of technique is not widely available (Delbridge et al. 1994). incidentally detected thyroid masses There are few data on the long-term risk of malignancy in Diameter <1.5 cm and no risk factors such as irradiation incidentally detected thyroid nodules; however, some and family history, observe and annual follow-up for suggest that those >1.5 cm diameter should have 2years. ultrasound directed FNA performed and management Diameter <1.5 cm and risk factors for malignancy - FNA. depending on the cytology (Giuffrida & Gharib 1995). Diameter >1.5 cm - FNA.

Calcitonin It has been recently suggested that serum calcitonin should Conclusions be measured in all patients with thyroid nodules (Pacini et It is clear that the term incidentaloma is a misnomer when al. 1994). Eight out of 1385 (0.57%) patients referred with applied in the widest context to serendipitously discovered nodular thyroid disease had elevated calcitonin levels, and lesions in the pituitary, adrenal or thyroid gland. Clearly a had medullary thyroid carcinoma confirmed in all, despite clinically relevant disorder which requires treatment FNA suggestive of medullary thyroid carcinoma in only should not be labelled as an incidentaloma, a term which two of eight patients (Pacini et al. 1994). In a series of should be restricted to the detection of a lesion that is 1167 patients with nodular thyroid disease, 504 of whom associated with no obvious consequence. The pathological had solitary nodules, 3% had elevated basal calcitonin and biological significance of true incidentalomas is levels and medullary thyroid carcinoma was found unknown, but may represent responses to hyperplastic histologically in 41.1% of these cases, which represented stimuli including the local hormonal and growth factor 1.37% of the total series (Niccoli et al. 1997). Further environment. A better understanding of the genetic

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Downloaded from Bioscientifica.com at 09/29/2021 09:23:43AM via free access Endocrine-Related Cancer (1998) 5 131-150 features of incidentally detected lesions may help good predictor of hormonal activity in nonselected patients management in terms of defining which ones may undergo with incidentally detected adrenal tumours. Journal of further growth or a change to a more aggressive behaviour Clinical Endocrinology and Metabolism 81 1726-1729. pattern. It will be useful to gather further information on Bertagna C & Orth DN 1981 Clinical and laboratory findings and conditions such as subclinical Cushing’s syndrome or results of therapy in 58 patients with adrenocortical tumours microscopic carcinoma of the thyroid in order to allow admitted to a single medical centre (1951-1978). American appropriate investigations and management to be Journal of Medicine 71 855-875. Boehm T, Rothouse L & Wartofsky L 1976 Metastatic occult instigated. More data are required on the long-term follicular thyroid carcinoma. Journal of the American Medical follow-up of these patients, before evidence-based Association 235 2420-2421. management protocols can be proposed. Although Boland GW & Lee MJ 1995 Magnetic resonance imaging of the improved imaging techniques have ‘created’ this adrenal gland. Critical Reviews in Diagnostic Imaging 36 115- relatively new dilemma of the ‘incidentaloma’, it is likely 174. that technological developments will help us decide Bouloux PMG & Fakeeh M 1995 Investigation of between a true incidentaloma and a subclinical tumour, phaeochromocytoma. Clinical Endocrinology 43 657-664. and to differentiate benign from malignant tumours. Brander A, Vikinkoski P, Nickels J & Kivisaari L 1991 Thyroid However, it is unlikely that these techniques will ever gland: US screening in a random adult population. 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