1. Background

In general, pituitary tumors range in incidence from 0.038% to 0.12% with pituitary adenomas being the most common [1]. In neurosurgical series, tumors of the pituitary, meaning pituitary adenoma or carcinoma, represent 16.5% of all neoplasms, with only a small minority of these neoplasms representing pituitary carcinoma [2]. Metastases to the pituitary gland have been reported to occur in approximately 2% of patients with diagnosed pituitary masses [3]. In autopsy series, pituitary metastases have been reported to be as high as 27% among patients with malignant tumors [4]. As reported in the autopsy series, only 7% of pituitary metastases are reported as symptomatic, which leads to clinical diagnosis, with reported symptoms of diabetes insipidus, ophthalmoplegia, headache, visual field defects, and anterior pituitary dysfunction. Primary malignant tumors of the breast and lung are the most common metastatic lesions found in the pituitary [5].

While metastatic lesions to the pituitary gland or sella turcica have been well described in the literature, a lesser known entity is a composite tumor involving metastases and pituitary adenomas. Only 34 cases have been reported in the literature to date. We aim to better characterize these rare lesions by reviewing reported cases and describing a recently observed case, which includes next-generation sequencing, at our institution.

2. Case Report

A 74-year-old man was referred to our institution’s neurosurgery and otolaryngology department after an outside ophthalmologist ordered an MRI revealing a sellar mass. The patient had a history of left vision loss for the past 3 months prior to his visit. He had a distant history of colon cancer treated with colectomy and was diagnosed 4 years ago with clear cell renal carcinoma that was subsequently treated with left nephrectomy. He was found to have a secondary lung lesion two years prior but did not pursue treatment. An MRI of the brain performed one month previously at an outside hospital displayed a sellar mass with suprasellar extension (4.6 × 3.4 cm) into the orbital apex and cavernous sinus on the left side (Figure 1).

The left eye had lost vision except for a preserved small portion of the upper nasal field. Serum values of prolactin were marginally elevated at 17.86. Given these findings, an endoscopic endonasal transsphenoidal resection of the lesion was recommended.

A preoperative MRI with and without contrast demonstrated growth to a 5.7 × 3.1 × 3.0 cm peripherally enhancing, centrally necrotic mass with sellar expansion (Figure 2). The patient underwent surgery one month later after referral. Tumor volume decreased from 22.70 mL preoperatively to 4.59 mL postoperatively (Figure 3). During postoperative imaging, a new intracranial lesion was noticed in the left occipital lobe (Figure 2(d)).

Microscopic examination showed two neoplasms that were present in separate fragments, as well as juxtaposed or intimately admixed in some others. One component was a pituitary adenoma with no unusual or atypical features. It had a low Ki-67 proliferation index and was immunohistochemically positive for cytokeratins (AE1/AE3 and CK 8/18) and synaptophysin. Prolactin was weakly positive in some areas, along with scattered, luteinizing hormone- (LH-) positive cells. Growth hormone, adrenocorticotrophic hormone, follicle-stimulating hormone, and luteinizing hormone stains were negative. The other neoplastic component was composed of large, atypical cells with clear cytoplasms and prominent nucleoli. Areas of necrosis were associated with this component. It was also positive for cytokeratins (AE1/AE3 and CK 8/18), PAX-8, and renal cell carcinoma marker (RCC-Ma), coexpressed vimentin. It was negative for synaptophysin, pituitary hormones, CK7 and CK20, prostate-specific antigen, and thyroid transcription factor-1. The microscopic findings and immunophenotype indicated a metastatic clear cell renal cell carcinoma to a pituitary adenoma (Figures 4 and 5). On a digital pathology analysis, the pituitary adenoma to renal cell carcinoma ratio was 2.70.

Genetic analysis of the pituitary adenoma component revealed VHL p.P86S missensense variant with a loss of function (variant allele frequency (VAF) of 4.8%) with additional FAT1, HNF1A, and NOTCH2 copy number loss. Gene analysis of the renal cell carcinoma component revealed PBRM1 p.K651 ^∗ stop gain (VAF 25.1%), VHL p.P86S missense variant with a loss of function (VAF 24.7%), NF1 p.N510Y splice region variant (VAF 5.7%), STAG2 p.R216 ^∗ stop gain with loss of function (VAF 3.9%), and NOTCH2 copy number loss. Therefore, overlapping mutations in VHL and NOTCH2 were present in both components of the tumor. Unfortunately, next-generation sequencing was done on archival specimens after the patient expired and germ cell tissue was not available to affirm whether the patient had Von Hippel Lindau disease.

Following surgery, the patient had an uncomplicated postoperative course and reported visual improvement.

The patient returned to the hospital on postoperative day 10 for stereotactic radiosurgery to the newly diagnosed L occipital metastatic lesion. Stereotactic radiosurgery was not able to be performed on the suprasellar tumor as there was not enough separation from the optic nerves.

On the initial postoperative clinic visit, the patient stated that he experienced an improvement in vision; however, the patient was found to have systemic metastatic cancer including significant tumor burden on his lungs. The patient refused further care for the systemic metastatic cancer. The patient died two months later.

3. Methods

After obtaining consent from our institutional review board (IRB #239292), we reviewed one observed case of metastatic disease and pituitary adenoma coexisting in the sella turcica and suprasellar space and performed next-generation sequencing on the composite tumor.

4. Discussion

Over the last 38 years, 34 cases of pituitary adenomas colliding with pituitary metastatic lesions have been reported (Table 1). Similar to our case report, in most of these cases, patients were radiographically diagnosed initially with pituitary adenomas only for pathologic studies to diagnose a mixture of pituitary adenoma and metastases. In the literature, the median patient age was 65.5 with 56.3% being females. The most common metastatic lesions originated from the lung and kidney with 10 and 6 cases, respectively. Regarding the pituitary tumor, 13 cases reported a nonfunctioning pituitary adenoma while 7 cases reported a prolactinoma.

Clinically, 22 patients presented with vision loss or ophthalmoplegia as the initial indication for surgery. Six cases involved hormonal abnormalities including Cushing’s disease, acromegaly, and hypopituitarism. 27 patients reported undergoing surgery for the pituitary lesion. Of the 16 cases that reported postoperative mortality, the survival ranged from 0 to 24 months with a median of 3.5 months and a mean of 4.7 months. Of the 27 cases that commented on radiation therapy, 13 patients underwent radiation treatment.

Although rarely reported, autopsy evidence demonstrates that the sella hosts metastases in up to 27% of patients diagnosed with metastatic malignancy [35]. Meta-analysis studies described pituitary adenomas occurring in about 17% of the general population [36]. If there is no correlation or association with the tumors, then the probability of a patient who perishes from metastatic malignancy has a 5% chance of possessing a composite tumor consisting of a pituitary adenoma and metastases. However, with only 34 cases known the literature, the data does not align well. It remains unknown if pituitary adenomas influence metastases to the sella either positively, negatively, or not at all. One possible explanation is that the rich vascular network found in pituitary adenomas exposes the tumor to metastatic cells. Future clinicians should be weary that sellar masses in patients with history of metastatic cancer may appear similar to benign pituitary lesion but must be followed aggressively.

Regarding our patient’s case, a few differential diagnostic possibilities should be considered based on microscopic findings. Pituitary adenomas and, in general, endocrine neoplasms can have extensive atypia and can undergo infarct, creating a malignant appearance, although these changes do not correlate with the biologic behavior or indicate pituitary carcinoma. Metastatic carcinomas from other sites, such as breast and lung, should also be considered in the differential diagnosis of the carcinoma component. Together with the characteristic cytohistomorphologic findings, immunohistochemical markers make this differential relatively straightforward. In our case, the patient’s previously established diagnosis of renal cell carcinoma was also very helpful, even though the slides of the previous nephrectomy specimen, which was performed long ago at an outside institution, were not available for review. The presence of a lung lesion could also represent a second primary; however, microscopic and immunohistochemical findings did not support a lung origin. Meningioma may also be a consideration as part of a sellar collision tumor with pituitary adenoma [19, 37], and a clear cell meningioma may resemble clear cell renal cell carcinoma. Again, immunohistochemical findings strongly supported a renal cell carcinoma.

Genetic analysis revealed that the pituitary adenoma and the renal clear cell carcinoma shared a common VHL variant. Both the pituitary adenoma and the identified clear cell renal carcinoma expressed VHL P86S missense mutation leading to a loss of function. While the pituitary adenoma had a VAF of 4.8%, the identified clear cell renal carcinoma had a VAF of 24.4%. Similar mutations have been documented in cases of renal cell carcinoma [38, 39]; however, recent studies have reported VHL inactivation alone is insufficient to cause tumor formation [40]. We do not have germ cell data to ascertain if our patient had VHL disease; however, the presence of VHL and NOTCH2 in both tissue samples and the history or renal clear cell carcinoma suggest an abnormality that points towards germ-line mutation. Our patient’s tumor had a stop mutation in the PBRM1 gene which is the second most commonly mutated gene in RCC and is associated with normal cell proliferation. Additional mutations of relevance were NOTCH2 copy number loss in both the renal cell carcinoma and pituitary adenoma which could lead to impaired regulation [41], an NF1 splice variant in the RCC which could affect normal cell proliferation [42]. While there was an apparent STAG2 stop mutation in the RCC that could lead to impaired division, most STAG2 mutations are associated with bladder cancer [43], but there is little genetic analysis on the association of STAG2 to RCC. This is distinct from the most common genetic deficiencies found for pituitary adenomas, the most common genetic mutations being loss of function of MEN1 [44], Gs-alpha protein activation [45], and AIP gene in familial isolated pituitary adenoma [4]. While the genotypic analysis had little effect on the diagnosis and prognosis of the patient, it is the first instance of tpdelmolecular analysis of composite tumors; further sequencing can improve our understanding of tumor metastasis mechanisms.

In conclusion, composite tumors of the pituitary region are more morbid than pituitary adenomas. Treatment should be guided based on the most aggressive tumor, and adjuvant radiation should be used most often. Next-generation sequencing data can be successfully carried out on each component of tumor and be used as an avenue to identify potential targets as well as potentially understand pathogenesis [46]. We hope other clinicians in the future will consider genomic analysis to better understand the genetic cause of composite tumors and improve treatment modalities.

Conflicts of Interest

The authors of this paper have no conflict of interest.