Pituitary carcinoma cannot be diagnosed before it develops metastatic spread. The metastasis usually takes place within the CNS to the cerebral cortex, cerebellum or cerebellopontine angle, brainstem, and spinal cord, or outside the CNS to the liver, lymph nodes, bone, lung, and other tissues [1
]. In the absence of metastasis, it seems necessary to attempt screening for those pituitary tumors that might have an aggressive potential to transform into carcinomas, although there is no practical clinical guideline for their screening at present.
In 1997, Pemicone et al. classified adenohypophysial tumors with respect to their aggressive potential and described seven tumor characteristics required for pituitary carcinoma [27
]. The present case fulfilled all of the characteristics that they described except for the presence of mitosis: high Ki-67 immunoreactivity (15%), positive p53 immunoreactivity, macroadenoma tumor size (2 cm), gross invasion (proven by surgery), metastasis (liver), and high blood hormone levels (ACTH and cortisol). In 2004, the WHO introduced for pituitary tumors a new adenoma entity termed atypical adenoma, which was designated as an invasive tumor that exhibits an elevated mitotic index, a Ki-67 labeling index greater than >3%, and extensive nuclear staining for p53 immunoreactivity [48
]. This definition denotes an aggressive potential for atypical adenoma and the possibility of its future malignant transformation. Atypical adenoma differs from carcinoma only in the lack of metastasis. In keeping with the WHO classification in 2004, Kaltsas et al. proposed in 2005 that atypical tumors and those with a Ki-67 labeling index greater than 10%, regardless of p53 immunostaining, should be followed for early recurrence and/or development of metastases [2
]. The pituitary tumor of the present patient fulfills the definition of the atypical adenoma introduced by the WHO, except for the presence of mitosis, and is consistent with the adenomas with a very high Ki-67 labeling index described by Kaltsas. Although there was no mitosis in either the primary or metastasized tumor in the present patient, it has been reported that mitoses were not demonstrated in all pituitary tumors, i.e., positive in 21.4% of invasive pituitary adenomas and 66.7% of pituitary carcinomas [50
]. Nonetheless, this cannot explain why the primary adenoma cells did not show mitosis despite expressing Ki-67 immunoreactivity in a very high proportion. The cell cycle-specific Ki-67 antigen may not always reflect all of the proliferating abilities of individual adenomas that are turning over at different rates. Otherwise, mitoses might have been obscured, though present, by tissue processing or technical artifacts.
The latency period from the diagnosis of pituitary tumor to the demonstration of metastasis varied considerably among patients with corticotroph carcinomas [5
], which probably reflects the difference in the speed at which individual pituitary adenomas transform into carcinoma. In the 53 reported patients with corticotroph carcinomas [5
], the mean (±SE) latency period that we calculated was 93
10 months (range, 3–360 months). The latency period of the present patient was 24 months, which in the order of latency length, was ranked as the fourth shortest. No doubt, the latency period would have shortened if abdominal CT, which detected hepatic metastases, had been performed at an earlier stage. Such clinically rapid progression of the disease, together with twice-repeated early recurrence within the cavernous sinus, is highly suggestive of an aggressive nature of the primary tumor from the beginning of its clinical manifestation.
The aggressive, even malignant, nature of the tumor might be supported by its high radiosensitivity, as evidenced by rapid resolution of cranial nerve palsies within 1–3 months after GKR. Three additional, unique behaviors of the present tumor became evident on neurological and radiological examinations. The first was a transient cystic enlargement of the irradiated residual tumor that was incidentally recognized on MRI 1 month after the first GKR. The second was the occurrence of the lower cranial nerve palsies that caused swallowing difficulty and a husky voice, and the third was destructive bone invasion involving the unilateral whole petrosal bone, which was detected on bone CT at the time of the lower cranial nerve palsies. We have never observed any of these findings in a series of several hundreds of pituitary adenoma patients whom we treated with GKR. There is no description on clinical features of atypical adenoma because it was defined as a pathological, but not clinical, entity intermediate between adenoma and carcinoma. The present tumor pathologically accords well with atypical adenoma except absence of mitosis, and hence its unusual behaviors associated with repeated local recurrence within the cavernous sinus could represent some clinical features of atypical adenoma. It is likely that the patient's tumor, which initially manifested as a clinically invasive macroadenoma or pathologically as an atypical adenoma, subsequently underwent malignant transformation presumably triggered by the surgery and/or irradiation, a main mechanism currently postulated to underlie the development of pituitary carcinoma (1–4).
The reason for initial lack of glucocorticoid excess symptoms may require some explanation. It might in part be due to partial cortisol resistance of unknown etiology, because the patient did not develop such hypercortisolemic signs/symptoms as systemic pigmentation and hypertension with hypokalemia until the last few months before death, at which time serum cortisol increased to an extraordinarily high level in parallel with ACTH. It is unlikely that the patient's adenoma secreted a biologically inactive, C-terminally extended, “big” ACTH [51
]. First, the IRMA used for our ACTH measurements does not recognize this high-molecular-weight form of ACTH-related peptide. Second, a closely parallel change in ACTH and cortisol throughout almost the entire clinical course favors the view of tumor-secreted ACTH as a biologically active peptide.
Consistent with the present patient, a substantial proportion of previously reported patients with corticotroph carcinoma did not present initially with Cushing's disease. Of the 53 reported patients, including 34 women and 19 men, only 32 subjects were diagnosed as having Cushing' syndrome or disease at initial presentation [5
]. The remaining 21 cases were endocrinologically asymptomatic, except for one case of galactorrhea–amenorrhea syndrome [25
], and presented with the pituitary mass compressing the adjacent tissues [10
]: visual disturbance in 13 cases, headache in one case, and visual impairment plus headache in five cases (symptoms not described in one case [39
]). These 21 hormonally asymptomatic tumors, which were initially diagnosed as non-functioning adenomas, can be divided into two subgroups on the basis of the subsequent clinical course. One subgroup consisted of 15 adenomas that developed characteristic features of Cushing's disease 73
12 months (range, 6–144 months) after initial diagnosis [10
]. Of these 15 adenomas, only five tumors underwent initial immunohistochemical examination, and all were positive for ACTH, indicating that these 5 adenomas were silent corticotroph adenomas at the initial presentation. Notably, 12 of the 15 adenomas metastasized within 1–2 years after manifesting as Cushing's disease, which suggests the possibility that these metastasized adenomas had already undergone malignant transformation at the time of their clinical manifestation as Cushing's disease. The other subgroup consisted of the remaining six of the 21 adenomas that were all initially diagnosed as silent corticotroph adenoma with ACTH immunostaining and continued to be clinically silent until they caused systemic or craniospinal metastasis [27
It is likely that marginally hypercortisolemic or even eucortisolemic but endocrinologically abnormal subjects have been mixed in with these initially asymptomatic patients, because subjects with Cushing's disease often have upper normal levels of baseline ACTH and/or cortisol in blood. This is in contrast with prolactinomas, in which blood prolactin levels increase proportionally with the size of tumors, and macroadenomas usually have prolactin values more than ten times higher than the normal upper limit, thereby not requiring any dynamic test for diagnosis [1
]. In clinically asymptomatic or subclinical Cushing's disease, however, it is often difficult to make an accurate diagnosis only with baseline cortisol and/or ACTH levels without measuring 24-h urinary free cortisol output or performing appropriate diagnostic tests, such as an overnight dexamethasone suppression test to demonstrate the abnormal glucocorticoid feedback regulation or determination of the morning and midnight cortisol levels to identify the abnormal diurnal rhythm of the ACTH-cortisol axis. The use of such diagnostic tests in patients with invasive macroadenoma will decrease the chance of misdiagnosing asymptomatic patients with Cushing's disease as having a non-functioning pituitary adenoma.
In conclusion, this is the first case of pituitary carcinoma in our university hospital over the last 30 years, which is in accordance with the rarity of this clinical entity. The patient's tumor differed from common invasive macroadenomas, clinically with repeated early recurrence and immunohistochemically with an extraordinarily high Ki-67 labeling index. Rapid aggressive progression of the disease from initial presentation suggests that the patient's pituitary tumor might have emerged de novo as a corticotropinoma with high potential for malignant transformation. In our clinical experience, non-functioning adenomas, the majority of which is represented by gonadotropin-producing adenomas, rarely exhibit a high degree of cavernous sinus invasion, while often showing prominent suprasellar extension. “Non-functioning” adenomas, if they exhibit marked parasellar invasion, should be screened for adenomas of non-gonadotroph lineage. It is important to emphasize that all patients with invasive macroadenoma should be screened for Cushing's disease with an appropriate diagnostic test even if they are hormonally asymptomatic or eucortisolemic, and if they indeed represent Cushing's macroadenoma, they should be carefully followed for the future development of corticotroph carcinoma.