11.1.1 Metastatic disease in endocrine organs

The term metastasis of a neoplasm refers to the spread of a previously localized, cohesive malignant tumour to a site distant from its site of origin with no contiguity with the primary site. The concept of metastases of lymphoma is a difficult one; a deposit in an organ of lymphoma is usually considered to be a component of generalized involvement by lymphoma rather than of metastatic spread. This chapter will focus on metastases in endocrine organs from carcinomas and sarcomas other than lymphoma.

Some writers refer to primary and secondary endocrine organs. This seems to be on the basis of whether a hormone-secreting organ synthesizes the relevant hormone or hormones as a primary function or not. This has led to the neurohypophysis being classified as a secondary endocrine organ, presumably as it does not synthesize hormones but receives them and secretes from the descending axonal system. The adrenal medulla has been relegated to the secondary category, but the reason for this is unclear. It is a moot point whether the principal function of the testis is its exocrine function (which is episodic) or its endocrine function (which fades gradually over a lifetime but is otherwise constant).

We prefer not to use this classification here but to use the more straightforward classification into major endocrine organs and other organs with an endocrine function. The first set comprises the adrenals, pituitary, thyroid, and parathyroid glands. The second includes the ovary, testis, hypothalamus, pineal, thymus, and placenta.

There are, of course, other systems that have an endocrine function but these would not usually be considered major. Some organs that are common recipients of metastases have an endocrine function in their repertoire but would not generally be considered to be endocrine organs. The liver, skin, and lung have important endocrine functions and are certainly recipients of metastases from many primary malignancies, but in terms of metastases to endocrine organs will not be considered here. Other organs that secrete hormones, such as the kidneys and pancreas, can also be the sites of metastases but there is no indication from published works that the juxtaglomerular apparatus or the islets of Langerhans are specific targets for them. The rare amphocrine tumour of the pancreas (1), which has exocrine and endocrine characteristics, may be mistaken for metastasis until special stains and sometimes electron microscopy have been used to demonstrate that it is a primary tumour.

The prevalence of metastatic malignancy varies among:

Prevalence of metastatic malignancy is summarized in Table 11.1.1.1.

Recognition of metastatic disease as a cause of symptoms and signs referable to endocrine organs is important for several reasons. Examples are given in parentheses.

Metastases might:

It is now standard practice for patients with solid organ malignancy to undergo surveillance imaging in order to stage their disease. This imaging has led to greater identification of asymptomatic adrenal masses and as a consequence confusion among clinicians regarding the evaluation and treatment of such ‘incidentalomas’. The adrenal glands are a common site for metastatic deposits. The commonest primary neoplasms that spread to one or both adrenals are of bronchial, renal, and colorectal origin (2, 3). Adrenal metastasis from follicular thyroid carcinoma has been reported. Bilateral metastases are common; 41% of patients with metastases from all primary sites with adrenal involvement have been reported as having bilateral disease.

Incidentally discovered adrenal masses are being detected at an increasing rate. This trend is expected to continue based on the incidence of adrenal masses in autopsy series and the increasing use of high-resolution abdominal imaging techniques. CT and MRI are able definitely to characterize only a minority of these lesions. Biochemical screening for hormone excess is essential regardless of a lack of signs and symptoms. A large, unilateral adrenal metastasis can mimic an adrenal cortical carcinoma, and histologically it can be difficult to differentiate between them. Electron microscopy may be used to confirm the presence of smooth endoplasmic reticulum in adrenal cortical cells or mucin-secreting vacuoles in metastatic adenocarcinoma. Adrenalectomy for incidentally discovered adrenal metastases can be efficacious.

The terms anterior and posterior pituitary gland are now considered to be obsolete and insufficiently precise. The adenohypophysis comprises the pars anterior, the zona intermedia, and the pars tuberalis, which surrounds the infundibular stem of the neurohypophysis. The zona intermedia in human beings is a rudimentary anatomical component, proportionately smaller than the pars intermedia found in animals; the intermedia may be attributed to the adenohypophysis or the neurohypophysis. The neurohypophysis comprises the pars posterior, the infundibular stem, and the median eminence. In this chapter we discuss data according to the classification used by the authors of the cited papers.

The commonest primary neoplasms that result in metastatic disease to the pituitary are breast and lung (4). Melanoma and hepatic metastases have also been described. As with the adrenal gland, the prevalence of metastasis in the pituitary or hypophysis cerebri is not clear, though post mortem studies suggest a high prevalence.

The difference in prevalence between the parts of the pituitary gland might be accounted for partly by the size of the recipient parts of the tissue but otherwise is unexplained. Most reported cases of metastatic disease to the pituitary are confined to the posterior lobe, probably related to the richer blood supply as compared to the anterior counterpart (4). Posterior lobe involvement would explain why patients with pituitary metastases frequently present with diabetes insipidus. The detection of pituitary metastasis is further complicated by the lack of specific associated symptomatology or definite radiological diagnostic findings.

Most pituitary metastases are asymptomatic (5). Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain, and ophthalmoplegia are the most commonly reported symptoms. Diabetes insipidus has been reported to occur in 29–71% of symptomatic patients. Differentiation of pituitary metastasis from other pituitary tumours based on neuroimaging alone can be difficult, although certain features, such as thickening of the pituitary stalk, invasion of the cavernous sinus, and sclerosis of the surrounding sella turcica, can indicate metastasis to the pituitary gland. Overall, neurohypophysial involvement seems to be most prevalent, but breast metastases appear to have an affinity for the adenohypophysis. Differentiating metastasis to the pituitary gland from bone metastasis to the skull base, which invades the sella turcica, can also be difficult.

At post mortem examination and clinical examination, thyroid metastases varies from 1.25% to 25% (6). The commonest primary sites are carcinomas of the lung and kidney, and melanoma. Most metastases are microscopic and diagnosis in life is rare. In life, the commonest primary site of a thyroid metastasis is renal cell carcinoma. Histological diagnosis can be very difficult; clear cell follicular adenoma and carcinoma have very similar appearances to renal cell carcinoma and the characteristics on special stains overlap. Immunostains for thyroglobulin can be helpful but in follicular clear cell tumours is often weak and patchy, and uptake of thyroglobulin by the tumour cells of the metastasis can give false-positive immunostaining. Other reported metastases include lung (7) and colon. Fine-needle aspiration cytology can be used to diagnose metastatic involvement as well as nonfollicular primary thyroid neoplasms.

Metastases can induce severe hyperthyroidism and be mistaken for a functioning primary thyroid neoplasm (7). Indeed, a collision tumour can occur in which a primary lung carcinoma metastasizes to a papillary carcinoma of thyroid.

Metastasis to the parathyroid glands are rare. They are most commonly from breast carcinoma, though reported numbers even so are small. They present clinically only when there is diffuse destructive infiltration of all four glands resulting in hypocalcaemia (8). Other metastases are discovered accidentally in life and at post mortem examination.

Adenocarcinoma metastatic from a primary lung carcinoma was associated with hyperparathyroidism in one report (9). The metastasis involved only one gland—the authors considered that the association was coincidental, given the relatively common prevalence of primary hyperparathyroidism.

Neoplasms, especially carcinomas, metastasize to the ovary relatively late in the natural history of the primary disease. As with metastasis to the testis, ovarian metastases can present before the primary tumour has become apparent. Women with ovarian metastases are usually younger than women with primary malignancy of the ovary, possibly because breast and gastric cancer occur at a younger age; women with typical Krukenberg tumours are on average 45 years old. Routes of spread of metastases to the ovary include: local transcoelomic spread from colorectal carcinoma, endometrial carcinoma (via the Fallopian tubes), and Fallopian tube carcinoma; distant transcoelomic spread from stomach and pancreatic primaries; and lymphovascular spread from other primary sites.

Simple involvement of an ovary by metastatic carcinoma does not equate to a Krukenberg tumour. Krukenberg, in 1896, described a primary sarcoma-like condition of the ovary with mucin production; he probably mistook the vigorous fibrous stromal reaction to metastatic mucin-secreting adenocarcinoma cells for fibrosarcoma, as tumour cells have been shown to induce mitoses in ovarian stroma. He did not clearly suggest that the tumour was metastatic and consequently did not indicate a primary site, so there is no ‘true’ Krukenberg tumour that arises in the stomach, large bowel, or anywhere else. The term Krukenberg tumour nowadays is applied to bilateral nodular ovarian involvement by metastatic carcinoma that has signet-ring cells and a reactive proliferation of ovarian stromal cells. Ovarian metastases with these appearances make up 4–8% of carcinomas metastatic to the ovary, and so Krukenberg tumours by these criteria are uncommon. Their prevalence in a population will be determined by the prevalence of gastric and colorectal carcinomas in that population. The prognosis is usually poor (10). Breast cancer rarely produces Krukenberg tumours as defined above. Metastases can stimulate ovarian stromal cells to secrete androgens and oestrogens resulting in virilization or menstrual abnormalities.

Metastases from breast carcinoma to the ovaries is relatively common. In post mortem studies before the introduction of tamoxifen and herceptin the prevalence of ovarian metastasis was 40%. The ovaries are characteristically involved bilaterally but without signet ring cells and so are not Krukenberg tumours as defined. The histological pattern usually mirrors that of the primary tumour. The clinical differential diagnosis is between primary ovarian tumours (which are bilateral in about one-third of cases) and metastases from breast and alimentary tract neoplasms. The histological differential diagnosis includes primary carcinoid tumour, sex cord stromal tumour, poorly differentiated serous adenocarcinoma of ovary, and metastatic carcinoma.

Large bowel adenocarcinoma metastasizes to the ovaries commonly; this depends on the stage of the primary but can be as high as 30% of cases. In patients having oophorectomy at the time of excision of adenocarcinoma of the colorectum, which is an unusual condition in most centres, the prevalence was 10% involvement of the ovaries by metastasis. Ovarian involvement by appendiceal adenocarcinoma and carcinoid tumour are well recognized. As with metastases in the testis and elsewhere, an ovarian mass can be the presenting event, which is later realized to be secondary ovarian involvement. The differential diagnosis of colorectal metastases is among primary endometrioid and mucinous carcinoma of ovary and secondary endometrial and endocervical carcinoma to the ovary.

Primary carcinoid tumour of the ovary is usually unilateral and often associated with a teratomatous neoplasm in which the carcinoid has developed. Metastatic carcinoid tumours are usually bilateral and associated with disseminated peritoneal spread; there is no association with germ cell layers other than epithelium, as there might be in a carcinoid tumour arising in a teratoma. Ovarian metastases of carcinoid tumour usually indicate a poor prognosis. Mucin-secreting carcinoids may have a Krukenberg appearance.

Metastases from the female genital tract to the ovary are relatively uncommonly diagnosed in life. It may be impossible to distinguish metastatic spread from synchronous development of primaries in, say, the endometrium and ovary. In some cases, studies of restriction fragment length polymorphism will demonstrate that there are two primaries but this is not in common clinical use. Metastases from the cervix and Fallopian tube to the ovary are rare (11).

Examples of endocrine-to-endocrine organ spread include metastasis to the ovary from thyroid carcinoma and neuroblastoma of adrenal gland.

Metastatic involvement of the testis is rare but is important to consider clinically in any testicular mass. Not all cases suspected on clinical examination of being metastatic carcinoma are so; testicular actinomycosis can mimic secondary malignancy (12).

The commonest metastases are from the prostate (13) with lung second and then renal parenchymal cell carcinoma, colorectum, and melanoma (melanoma of the testis can also be primary). Metastases except prostatic metastases are usually unilateral, not multinodular, and often lack a distinct border to the testicular mass. Histologically intertubular growth is usual with sparing of the testicular tubules. The deposits are often microscopic and multifocal.

Prostatic metastases to the testis, on the other hand, grow intratubularly in some cases. On histology, metastatic prostatic carcinoma can be protean and mistaken for a primary testis neoplasm, testicular involvement by lymphoma, and for metastasis to the testis from other primary neoplasms. Spread is usually from a prostatic adenocarcinoma of a similar histological type but it is hardly surprising that metastases with adenosquamous differentiation can also occur. A prostate metastasis can closely mimic a primary testicular Sertoli cell neoplasm (12). Renal cell carcinoma metastatic to the testis may also be mistaken for a Sertoli cell tumour of testis, and also a Sertoli–Leydig cell tumour and a clear cell cystadenoma of epididymis. Any clear cell neoplasm found in the testis should be considered to be metastatic.

The diagnosis of metastatic melanoma or carcinoid to the testis, rather than one of primary testicular origin, will depend on other clinical features and past medical history. It may be impossible to differentiate in some patients whether the testicular mass that is from secondary spread truly represents the pathology present rather than that of a testicular primary tumour (14, 16).

Metastatic melanoma and carcinoid to the testis need careful consideration as both of these tumours can arise as primaries in the testis. Metastatic thyroid carcinoma has been reported in the testis, an example of endocrine-to-endocrine organ spread. Other primary sites contributing to testicular metastases include stomach, pancreas, bladder, skin and specific tumours such as Wilms’ tumour and primary neuroectodermal tumours (15).

Metastasis in the pineal gland or exophysis cerebri are rare. The pineal is a small gland lying between the superior colliculi of the thalamic system. It is roughly conical, hence its name (Latin, pinea, a pine cone). Metastases in the pineal gland are rare, possibly because melatonin is a natural oncostatic agent (17). Primary tumours of the pineal have been reported to be commoner in Japan but the reason is unknown.

Metastatic breast carcinoma might be expected to be found in the pineal as in the pituitary, and this seems to be so. Two cases of oesophageal carcinoma metastatic to the pineal and surrounding structures have been reported and a case of metastatic clear cell carcinoma of kidney (18). Bronchial carcinoma metastatic to the pineal gland can be the presenting feature and the same is true of colorectal carcinoma.

The thymus gland (named from Greek, thymos, a warty excrescence) is considered to be an endocrine organ though some of the thymic hormones are found in many tissues and have a role in wound healing. Nonetheless, the thymus does have a small population of neuroendocrine cells. These cells produce polypeptide and amine hormones that principally act locally in the gland and may be embryologically analogous to the C cells of the thyroid.

Distinction between primary malignant epithelial tumours of the thymus and metastatic carcinoma can be very difficult. Well-differentiated squamous cell carcinoma can arise as a primary thymic tumour or be a metastasis from a bronchial or oesophageal neoplasm; distinction is important as a primary tumour has a much better prognosis than metastatic tumour.

Secondary tumours to the pancreas are relatively common but are almost always asymptomatic. As a consequence they grow to appreciable sizes and it is impossible to determine with confidence whether the initial metastases were to islets of Langerhans or to the exocrine pancreas nearby. Carcinoma of the breast and lung are the commonest primary sites, followed by melanoma of skin and renal cell carcinoma (19). Most patients have metastases in many other organs by the time of pancreatic involvement.

Metastases can be multiple and on imaging techniques resemble islet cell tumours or nesidioblastosis, especially as they are small, well defined and impalpable. There is little destruction of the ductal system apparent on endoscopic retrograde pancreatography. Obstructive jaundice is seldom a feature and diabetes mellitus is likely to be coincidental.

The placenta (from Greek, a flat cake from plaka, a plate) is one of the largest endocrine organs and metastatic malignancy involving the placenta is rare but well recognized. The primary tumour is usually in the mother but occasionally the fetus may develop in utero malignancy, characteristically a blastoma, which spreads widely and involves the fetus’s placenta. Congenital neuroblastoma involving the placenta may be diagnosed on histological examination soon after delivery, and must be distinguished from placental spread from a primitive neuroectodermal tumour or a medulloblastoma arising in the mother (20). These rare tumours can be difficult to diagnose clinically and on imaging: it might not have been apparent that the fetus or the mother had malignancy during the pregnancy.

Maternal primary tumours more commonly result in placental metastases, the commonest being melanoma (21). Lung carcinoma, usually oat cell carcinoma but occasionally squamous cell carcinoma, also arise and occasionally present as placental metastasis.