Discussion
Pituitary tumors are very common, and most are benign. The World Health Organization (WHO) classification of tumors of the central nervous system (2000) categorizes pituitary tumors into three grades: benign, intermediate or atypical, and malignant [
7]. It is worth noting that the pathological classification assigned should be closely associated with clinical biological behaviors. Therefore, the WHO standards state that, even if pathological analyses reveal that the primary or metastatic lesion of pituitary tumor that has metastasized to subarachnoid space or extracranial sites is benign, it still belongs to the malignant pituitary tumor classification for its aggressive biological behavior [
7‐
12]. Pituitary carcinoma, the most common form of malignant pituitary tumors, is also defined by the presence of a pituitary tumor that either is not contiguous with the primary sellar tumor and/or is not a pituitary tumor that has metastasized to sites distant from the pituitary [
2,
4,
13]. This terminology is commonly used for describing the malignant pituitary adenoma. Currently, there is still controversy regarding the initiation and progression of pituitary carcinoma, the focus of which is whether it develops from benign adenomas or occurs
de novo and whether the hormonal subtype does affect tumor aggressiveness, treatment outcome and prognosis [
1]. Although the progression from benign pituitary adenomas to carcinomas has often been considered [
1,
6,
14,
15], the detailed mechanisms underlying this phenomenon are still unclear and may involve multiple molecular events.
A literature review revealed that pituitary carcinoma is very uncommon and accounts for only approximately 0.1% to 0.2% of all pituitary tumors [
2,
3,
15‐
17]. According to a recent study, most of the reported pituitary carcinomas are functional (83%), with 35% of the lesions producing ACTH, 33% PRL, 9% growth hormone (GH), 4% luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH), and only 1% TSH [
1]. Nonfunctioning tumors represent 19% of all cases, also including silent ACTH, FSH, LH and rare null-cell pituitary carcinomas [
1]. Similar results were reported in another study, with the majority (36%) of the hormonally active tumors producing PRL; 30% secreting ACTH; 5% producing GH; 2% producing TSH, gonadotropin-releasing hormone or LH; and 23% not secreting any hormones [
18]. The endocrine parameters (hormone in blood serum) in the case of our patient were clinically normal. However, the immunopathological examination revealed positive ACTH staining. Hence, the possibility of an ACTH adenoma that did not affect endocrine function could not be ruled out clinically. As reported previously, corticotrophic carcinomas develop in the setting of “silent” corticotrophic tumors in approximately 25% cases [
2]. Similarly, it remains unclear whether a metastatic functional pituitary adenoma can possess endocrine function.
The spread pathway of tumor cells from a pituitary carcinoma has not been determined, but has been proposed to be varied, including cerebrospinal fluid circulation and lymphatic or hematogenous metastasis to extracranial sites [
19,
20]. The metastasis of pituitary carcinomas might be related to the biological properties of tumors, such as invasion, as well as to the surgical procedures used. According to the existing literature, the metastases of pituitary tumors mostly occur after surgery, in particular after craniotomy. As reported by Tanaka
et al., the development of metastases followed surgery performed for primary pituitary tumors in 21 (70%) of 30 cases [
21]. Therefore, it was suggested that surgery may precipitate postoperative metastasis of pituitary adenomas. From a neurosurgeon’s point of view, this may be due to several reasons. First, neurosurgery, especially a craniotomy, not only can rupture the tumor capsule but also can injure the normal arachnoid membrane, creating favorable conditions for the spread of tumor cells along the subarachnoid space. Second, the vessels of or around the tumor are destroyed, which may enhance hematogenous metastasis. Third, tumor cells may be disseminated by the surgical instruments or flush water. Moreover, we noticed that most patients with postoperative metastases of pituitary tumors reported in the literature underwent craniotomies before 2000 [
5,
9‐
12,
22‐
27]. After 2000, because of the progress made with the use of the endonasal transsphenoidal surgical technique, this approach has been applied in more than 90% of pituitary tumor surgeries. The endonasal transsphenoidal approach rarely causes a massive cerebrospinal fluid leakage or tumor cell dissemination to the subarachnoid space, and, as a result, the possibility of surgery-associated postoperative tumor metastasis in the subarachnoid space is significantly reduced. On the basis of this analysis, it is indicated that postoperative metastasis of pituitary tumors may be closely related to the surgical methods employed. However, the discussion above lacks the support of randomized controlled studies with large sample sizes. Moreover, the case sample with postoperative pituitary tumor metastasis is relatively low. Therefore, the analyses above are clinical inferences that require further verification.
The treatment for pituitary carcinoma should be comprehensive, including neurosurgery, radiotherapy, chemotherapy and medical therapy [
1‐
3,
15‐
17]. Neurosurgery has been considered to be the first line treatment for pituitary carcinoma, for it not only can relieve the clinical symptoms by removing the lesions but also can aid in the diagnosis by providing pathological samples [
1,
2,
15]. Although it is considered that surgery alone is rarely curative, especially for patients with multiple intracranial or systemic metastases, it should be pointed out that surgery can notably prolong survival in some cases [
28]. Our patient is a case in point, because he underwent four surgeries in the 16-year follow-up period and had a satisfactory recovery after each surgery. Individualized surgical plans should be developed for the treatment of pituitary carcinoma, including transsphenoidal surgery, transcranial surgery and combined surgeries. Transsphenoidal surgery may be preferable in most cases, except for those with multiple intracranial metastatic lesions or large pituitary carcinomas with invasiveness into parasellar structures, for whom transcranial surgery should be recommended.
In our patient, three intracranial lesions were found in the MRI examination. Because all the lesions were located supratentorially, a one-stage transcranial operation was performed to remove all three lesions simultaneously. Furthermore, although the lesions were intracranial, they were all located at sites outside the brain; therefore, it was feasible to remove the lesions with minimal invasion of the brain tissue. The outcome of the surgery was satisfactory, with no serious postoperative complications. After surgery, radiation therapy, such as fractionated radiation therapy, stereotactic radiosurgery and whole-brain or spinal radiation, should be administered in most cases to prevent tumor relapse [
1,
2,
15,
29]. In patients with tumors subtotally resected or with multiple intracranial metastases, radiation therapy should be performed earlier to slow growth of the tumor and/or metastatic deposits. Clinically, radiation therapy has been suggested to be effective in achieving local control or slowing tumor growth in some cases [
1,
15,
29]. However, because these results lack evidence derived from randomized controlled trials, the usefulness of radiation therapy should be determined in further studies.
Chemotherapy is commonly used in the treatment of many types of carcinomas; however, its application in the treatment of pituitary carcinoma is just now being tested. The most commonly used drugs are temozolomide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in combination with 5-fluorouracil [
2,
30]. Other agents used include cisplatin, etoposide, cyclophosphamide, adriamycin, methotrexate, vinblastine and bleomycin. Although various chemotherapy protocols have been applied in the treatment of pituitary carcinomas, no significant effect on tumor size or secretion and only transient improvement or stabilization have been observed in a minority of patients [
1,
15]. More important, because of the rarity of these lesions, the potential use of chemotherapeutic drugs in the treatment of pituitary carcinoma has not been verified in multicenter randomized controlled trials. Therefore, similarly to radiotherapy, the usefulness of chemotherapy also needs to be validated by future studies. Medical therapy, such as with bromocriptine and cabergoline, has been considered as the first-line treatment for functional pituitary adenomas (benign). In pituitary carcinomas, medical therapy has been used to control excess hormone secretion and/or tumor proliferation. Currently, the most widely used clinical drugs include dopamine agonists, octreotide and lanreotide, which have been used to treat PRL-, GH-, ACTH- and TSH-secreting pituitary carcinomas [
1,
2,
15]. However, the clinical benefit was reported to be minimal. In general, the efficacy of medical therapy for pituitary carcinomas still needs to be determined. Future improvements in targeted molecular therapies (biotherapy or gene therapies) and immunotherapy may provide more effective options for treatment of malignant pituitary tumors.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JW wrote the initial manuscript draft. YW was the neurosurgeon who treated the patient. QB collected the images of the patient. PW and EM performed the pathological examinations. All authors read and approved the final manuscript.