In this comprehensive analysis of the German Pituitary Tumor Registry, we show a prevalence and primary distribution of metastases to the pituitary largely consistent with previously published literature of mostly smaller case series [14]. The identified primary tumor entities clearly point towards a hematogenic rather than lymphogenic mode of metastasis formation for the metastases found in the sellar region. Furthermore, primary tumors known to metastasize to the bone represent a majority of the pituitary lesions identified as metastases.

In comparison to recent meta-analyses [7, 9], our cohort is lacking representation of thyroid primary tumors but shows a higher rate of renal cell carcinoma primary tumors.

This study is limited due to the scarcity of available clinical data. Furthermore, an extensive re-evaluation of historical cases with more recent histopathological methods was not performed and was not the intent of this analysis. However, the size of the case database analyzed here holds significant importance. Given the lack of extensive current studies on metastases to the pituitary gland, our findings highlight the need for further large cohort studies that integrate clinical, pathological and radiological findings.

The 96 metastases represent a total of 0.5% of the cases included in the German Pituitary Tumor Registry (N = 17,896), which is consistent with a previous report from 2007 to 25 cases (0.6%) [1]. This confirms the rarity of metastases and underscores the importance of registries to record such cases.

The finding of breast and lung cancer as the two most prevalent primary tumors in our cohort confirms the most recent meta-analyses [8, 9, 15].

Breast cancer is with 25% of cases the most common primary in our study as well as the literature, representing 24–26% of cases in the meta-analyses of Ng et al. and Javanbakht et al. [7, 9]. This is likely due to the propensity of breast cancer to metastasize to the bone as well as possibly the prolactin-rich environment of the pituitary [7]. While systemic prolactin does not seem to facilitate breast cancer growth, paracrine (as well as autocrine) prolactin stimulation is an important factor in mammary tumor formation [16].

The second most common primary tumor in our study was lung cancer. Considering its general prevalence and predisposition to metastasize to bone and brain [17, 18], lung cancer is the most or second most common primary tumor in pituitary metastases meta-analyses and the most common primary tumor in men [7, 9, 19].

Remarkably, colorectal cancer, which also represents one of the more common malignancies along with lung and breast cancer, rarely presented as pituitary metastases in our study. This is in line with previous reports [7] and underlines that the mechanism of metastatic spread to the pituitary region mostly originates from the vascular system surrounding the primary tumor.

Pituitary metastases have been identified as the initial manifestation of a previously unknown malignant tumor in 20–40% of tumors neurosurgically removed from the sellar region [19,20,21,22], which is well in keeping with our data showing an unknown primary tumor in 22.9% of cases. One of the key challenges of pathological analyses of surgical tissue is the integration of clinical and histopathological findings. If the patient has no previously known neoplastic disease, or one of an entity which is not prone to osseous metastasis, a definitive characterization of the tissue as metastatic is often not possible. It should be noted that due to the historical nature of the registry, a number of cases classified as unknown primary tumor, today might be identified with more modern histopathological diagnostic methods.

Notably, our case series of metastases to the pituitary gland contained a higher number of renal cell carcinomas than most previously described case series, but no case of thyroid carcinoma. This is surprising, as both cancers tend to metastasize to the bone and show similar rates of growth [23, 24]. The suggested work-up and staging guidelines for both renal cell and thyroid carcinoma also do not contain a routine cranial MRI, despite this being proposed for metastatic renal cell carcinoma [25]. Regarding renal cell carcinoma, most of the cases have been diagnosed in the years 2009–2022, possibly representing a higher histological diagnostic certainty based on novel antigen markers. These hypotheses, however, remain speculative, as a comprehensive comparison of available antigen markers and re-analysis of tumor tissue from older samples was not possible.

A recent review did not mention thyroid metastases to the pituitary [8], and it has historically been reported as very rare [26]. However, a meta-analysis from the same year reported a comparatively high rate of thyroid primary tumors in 4.5% [9]. Thyroid cancer might be diagnosed earlier because of the abundant availability of thyroid ultrasound and the comparatively aggressive diagnostic and therapeutic approach in Germany as an endemic iodine deficiency area with a high prevalence of regressive thyroid nodules. This higher surveillance rate in turn may lead to a lower rate of metastatic thyroid cancer compared to other countries [27]. In addition to the possible earlier diagnosis and resection of thyroid cancer, according to German recommendations, a radioiodine therapy is performed in earlier thyroid cancer stages compared to e.g. American guidelines, possibly leading to a lower incidence of pituitary metastases from thyroid cancer [28,29,30].

The data presented in this analysis should alert clinicians to consider the possibility of metastasis in patients with any of the listed neoplastic entities and a newly detected sellar mass, particularly if the primary tumor has already metastasized to the bone [31].

In an analysis of the autopsy subgroup, we confirmed the current perspective on the higher prevalence of invasion to the posterior as opposed to the anterior pituitary. There are different hypotheses explaining this phenomenon. The posterior gland is directly connected to systemic circulation, while the hypophyseal portal system may be protecting the anterior gland to a certain degree. A pituitary metastasis might also be secondary to a sellar bone metastasis, which spreads to the pituitary gland tissue via existing vascular contacts. The latter view is supported by an autopsy study showing pituitary and sellar bone metastases, rather than brain metastases, to be syntopic [31]. It is further corroborated by a recent study discussing combinations of pituitary tumors and metastases [11].

As sellar masses are often discovered incidentally, clinical criteria to assess the likelihood of metastasis are required to guide (radio-)surgical decision-making. While PitNET/adenomas are common in the general population, with a prevalence of microadenoma of about 10% in thon MRI imaging, it should be noted that in patients with a known malignant tumor, a pituitary mass is more likely to represent a metastasis (incidence reported around 5%) than a PitNET/adenoma (incidence of 1.8%) [3,4,5, 20]. This information should also be provided to the neuropathologists for consideration in their assessment. As metastases are more likely to affect the posterior pituitary, the defining clinical symptom differentiating pituitary metastasis from PitNET/adenoma is isolated AVP deficiency [7].

In addition to clinical presentation, imaging diagnostics can help to identify pituitary metastases. However, signal characteristics of metastases on MRI are variable. Findings include loss of hyperintensity of the posterior pituitary (pituitary bright spot) on T1 weighted imaging [32, 33] and hyperintensity on T2 [3], although reports are conflicting [32, 33]. Postgadolinium enhancement is also not reported consistently [32]. The European Society of Endocrinology guidelines for the management of aggressive pituitary tumors suggest an initial imaging protocol comprising of 2–3 mm sagittal T1, coronal T1 before and after gadolinium injection, coronal T2 or axial T1-weighted slices to assess a possibly malignant mass in the sellar region [34].

Rapid growth on follow-up MRI can be a warning sign for a metastasis, sometimes with a constriction by the sellar diaphragm leading to a dumbbell-shaped tumor [32, 35]. While cavernous sinus invasion is also common in PitNET/adenomas, a bilateral invasion can point towards malignancy [33]. Furthermore, the presence of visual pathway edema enhances the likelihood of a metastasis over a pituitary macroadenoma [36].

While bony erosion of the sellar floor can also occur in PitNET/adenomas, it may occur more frequently in metastasis [33]. Haemorrhage and apoplexy are uncommon [33]. There are currently no conclusive reports on the utility of molecular imaging in pituitary metastases.

While neurosurgery is an important treatment option, gross total resection of the tumor is often impossible due to infiltration of the surrounding tissue and bone as well as intense vascularization [37]. Although survival rates in cancer patients with pituitary metastasis are known to be poor, clinical case series have shown prolonged survival in patients with certain pathologies due to surgical removal of the pituitary metastasis [36, 38, 39]. However, as the therapy goal in those patients often is of palliative nature, and additionally, when there is no acute cranial nerve compression, radiosurgery can be an effective alternative to neurosurgery in selected cases [40,41,42], and has become the first-line treatment in many centers [36, 43].Importantly, a recent retrospective study by Hong et al. showed reduced overall survival in patients with non-treated pituitary metastases [44]. Their study reported on 48 cases, which is a large cohort considering the rarity of these entities. Still, the limited number of cases, the retrospective nature of this study and possible selection bias do not allow for a clear conclusion on treatment recommendation.

In our center, we generally recommend a combined hybrid procedure of surgery and radiosurgery or conventional radiotherapy in the treatment of metastases to the pituitary, since the required radiation dose differs between PitNET/adenomas and a metastases, and imaging alone is not sufficient to obliviate pathologic evaluation.