Lung adenocarcinoma metastasis within a pituitary neuroendocrine tumor: a case report with review of literature

Abstract

Collision tumors involving the metastasis of malignant neoplasms to pituitary neuroendocrine tumors (PitNETs) are extremely rare. We herein report a case involving a patient with lung adenocarcinoma metastasis within a PitNET who exhibited relatively rapid progression of neurological symptoms. A 75-year-old man who underwent tumor resection 36 and 18 years prior to presentation for bladder and colon cancer, respectively, without recurrence presented with bitemporal hemianopsia, ptosis, and diplopia of the right eye. Subsequent magnetic resonance imaging (MRI) revealed a tumor 3.2 cm in diameter that extended from the anterior pituitary gland to the suprasellar region. Gadolinium-enhanced MRI of the tumor showed heterogeneous contrast enhancement. Considering the relatively rapid progression of neurological symptoms, semi-emergency endoscopic endonasal transsphenoidal surgery was performed. Histopathological examination revealed a group of thyroid transcription factor-1- and napsin A-positive papillary proliferating cells intermingled with α-subunit- and steroidogenic factor-1-positive PitNET cells. Thus, the patient was diagnosed with lung adenocarcinoma metastasis within a gonadotroph PitNET. Genetic testing revealed the presence of an EGFR (Ex-19del) mutation, after which chemotherapy was initiated. Additional stereotactic radiotherapy was performed for the residual tumor in the sella turcica. With continued chemotherapy, good control of both the primary and metastatic tumors was noted after 24 months after surgery. Cases of malignant neoplasm metastasis within a PitNET are difficult to diagnose. In the case of a sella turcica tumor with relatively rapid progression of neurological symptoms, early surgical intervention is recommended given the possibility of a highly proliferative tumor and the need to obtain pathologic specimens.

DESPITE the already rare occurrence of malignant neoplasm metastasis to the normal pituitary gland, malignant neoplasms metastasizing to neoplasms in the sella turcica, resulting in collision tumors, occur even more infrequently [1, 2]. Collision tumors are defined as the presence of two or more histologically distinct tumors, benign or malignant, within the same anatomical location. Pituitary neuroendocrine tumors (PitNETs), meningiomas, gliomas, schwannomas, and hemangioblastomas have been reported as recipient tumors in patients with sella turcica collision tumors, whereas breast and lung cancers have been reported as the most common primary tumors [2].

Only 33 reports have been available on collision tumors in which a malignant neoplasm metastasized within a PitNET. Moreover, the clinical symptoms and imaging findings associated with these collision tumors closely resemble those of a solitary PitNET, making preoperative diagnosis difficult. Here, we report a case involving a patient with a PitNET who had a history of colorectal and bladder cancers, a relatively rapid progression of neurological symptoms, and malignant neoplasm metastasis within the PitNET determined following early surgical intervention. Moreover, histopathological evaluation revealed the presence of a new lung adenocarcinoma.

Case Presentation

A 75-year-old male presented with bitemporal hemianopsia that surfaced 4 months prior, along with ptosis and diplopia in his right eye observed 2 months prior. He underwent cystectomy with artificial vesicostomy for bladder cancer 36 years ago and tumor resection for colon cancer 18 years ago; both conditions are in remission with no recurrence signs. On initial presentation, the patient exhibited inadequate oculomotor nerve palsy in the right eye, with visual function assessment revealing decreased visual acuity in both eyes and bilateral hemianopsia. No respiratory symptoms (e.g., cough and sputum), urinary symptoms (e.g., painful urination and hematuria), or gastrointestinal symptoms (e.g., anorexia and bloody stools) were observed.

Magnetic resonance imaging (MRI) of his head revealed a tumor with a maximum diameter of 32 mm extending from the anterior pituitary gland to the suprasellar region. T2-weighted images revealed a high-signal area in the suprasellar region, indicative of a partial cystic component (Fig. 1a–c). The suprasellar portion of the tumor compressed the optic chiasm, whereas the normal pituitary gland compressed upward. Gadolinium-enhanced MRI of the patient’s head showed heterogeneous contrast enhancement of the tumor (Fig. 1d, e).

Fig. 1

Preoperative magnetic resonance imaging of the brain

Sagittal T1-weighted image (a), coronal T1-weighted image (b), coronal T2-weighted image (c), sagittal T1-weighted post-contrast-enhanced image (d), and coronal T1-weighted post-contrast-enhanced image (e) demonstrating a heterogeneously enhancing intrasellar and suprasellar mass with cystic components and a normal pituitary gland (arrowhead).

Endocrinological evaluation showed a mild increase in PRL (73.1 ng/mL, reference range, 3.0–17.3 ng/mL), a mild decrease in TSH (0.708 ng/dL, reference range, 0.5–5.0 ng/dL), and a decrease in free T3 (1.95 pg/mL, reference range, 2.3–4.0 pg/mL). Moreover, a preoperative GH-releasing peptide-2 loading test showed a peak GH level of 4.58 ng/mL, indicating severe GH deficiency. Additionally, there were no preoperative indications of diabetes insipidus (DI) like polydipsia or polyuria.

We suppose that the high PRL level was caused by the stalk section effect, which is consistent with clinically non-functioning (NF) PitNET. The relatively rapid progression of visual function loss and appearance of oculomotor nerve palsy suggested the possibility of a highly proliferative tumor. Therefore, for diagnostic and therapeutic purposes, we decided on early surgical intervention through semi-emergency endoscopic endonasal transsphenoidal surgery.

The intraoperative findings revealed a dark-red, relatively soft, and suckable tumor with an internal hematoma noted after removal, which were consistent with a PitNET with pituitary apoplexy (Fig. 2). The tumor had extended to the subarachnoid space and was attached to the pituitary stalk.

Fig. 2

Intraoperative visualization

The tumor appears dark-red, relatively soft, and was easily aspirated.

Postoperative visual function evaluation showed improvement in the patient’s bilateral hemianopsia, as well as endocrinological improvement in TSH and GH hyposecretion. Given the lack of postoperative complications, the patient was eventually discharged.

Histopathological examination revealed a PitNET composed mainly of chromophobic cells, which were positive for α-subunit (α-SU) and steroidogenic factor-1 (SF-1), leading to the diagnosis of gonadotroph PitNET. Additionally, a group of poorly differentiated cells with a papillary growth pattern was found to be mixed with the PitNET cells. The site was negative for various anterior pituitary hormones but was positive for epithelial membrane antigen, keratin (AE1/AE3), thyroid transcription factor-1, and napsin A, with Ki-67 levels of 5%–10% of positive nuclei, suggesting lung adenocarcinoma (Fig. 3). Based on these results, a diagnosis of lung adenocarcinoma metastasis within a PitNET (gonadotroph PitNET) was established.

Fig. 3

Pathological findings of the tumor

(a) and (b) Low-power (×40) image showing metastatic adenocarcinoma cells infiltrating the pituitary neuroendocrine tumor (PitNET) cells. Hematoxylin and eosin (HE) staining. (b) TTF-1-positive metastatic adenocarcinoma cells. (c) High power (×400) image showing monomorphous chromophobic PitNET cells in sheets (lower left), intermixed with poorly differentiated cells that proliferate in a papillary pattern (arrow) (HE stain). (d) High power image showing synaptophysin-positive PitNET cells (lower left). (e) and (f) High power image showing PitNET cells expressing α-SU (e) and SF-1 (f). (g) and (h) High power image showing adenocarcinoma cells in a papillary fashion expressing TTF-1 (g) and napsin A (h), whereas PitNET cells were negative (asterisk).

After histopathological evaluation, postoperative chest computed tomography (CT) showed a 22-mm nodule in the middle lobe of the right lung, right hilar lymphadenopathy, and pleural dissemination (Fig. 4). Genetic testing of the excised tissue returned positive for an EGFR (Ex-19del) mutation, which is an indication for molecular-targeted therapy. Hence, chemotherapy (osimertinib) was started on postoperative day 51. In addition, MRI of the sella turcica tumor immediately after surgery showed a residual contrast-enhancing lesion along the pituitary stalk.

Fig. 4

Computed tomography images of the chest (a: coronal image, b: axial image)

Contrast-enhanced chest computed tomography showing a 22-mm nodule in the middle lobe of the right lung (circle), right hilar lymphadenopathy, and pleural dissemination.

After initiating chemotherapy, the residual lesion temporarily shrank. However, 6 months after surgery, MRI revealed regrowth of the lesion, which prompted additional stereotactic radiotherapy in the same area. With continued chemotherapy, good control of both primary and metastatic tumors was observed 24 months after surgery.

The patient provided informed consent for the publication of this report. We conducted a search on PubMed using terms such as pituitary, pituitary adenoma, pituitary neuroendocrine tumor, and metastasis. Subsequently, we selected articles pertinent to this review.

Discussion

The current report details our experience with a case of PitNET in a patient who had a history of colorectal and bladder cancers, a relatively rapid progression of neurological symptoms, and malignant neoplasm metastasis within the PitNET based on early surgical intervention. Histopathological evaluation revealed the presence of a new lung adenocarcinoma.

A malignant neoplasm metastasizes to a PitNET, have been extremely rare, with only 33 cases having been reported so far (Table 1) [2-29]. Including the present case, the average age of the previously reported patients was 66 years (44–87 years), among whom 16 were men and 17 were women. Optic nerve disorder was the most common initial symptom (66.7%, n = 22/33), followed by headache (39.4%, n = 13/33). Regarding endocrine function, 22 of the 27 patients (81.5%) had some kind of pituitary dysfunction. However, there have been no previous reports on patients presenting with DI as an initial symptom, including the case presented in this study. Usually, DI is clinically more frequent in cases of metastatic pituitary tumor, and according to a previous report, 45.2% of patients presented with DI [30]. This may be related to the fact that metastasis normally targets the posterior lobe of normal pituitary [31]. This distinction might highlight a significant difference between metastatic tumors within the PitNET and those in the normal pituitary.

Table 1

Summary of cases with malignant neoplasm metastasis within pituitary neuroendocrine tumors

No.	Reference	Age	Sex	Function	Primary tumor site	Initial symptom	Endocrinological state	Other intracranial metastasis	First treatment	Further treatment	Pathological findings	Survival time/Status
1	van der Zwan, 1971	73	F	NF	Breast adenocarcinoma	Hyper blood pressure, II	Panhypopituitarism	No	TCS	No	Hormone negative	POD 28/Dead
2	Richardson JF, 1971	70	F	NF	Breast adenocarcinoma	Headache, Vomiting, Papilledema	Replacement	No	TCS	Radiation	N/A	3 Months/Dead
3	Burns WA, 1973	78	M	NF	Renal pelvis ureter carcinoma	Fever, Nausea, Diarrhea	N/A	No	No	No	Hormone negative	1 Month/Dead
4	James RL, 1984	77	M	NF	Renal carcinoma	II, III	Slight hyper PRL, Hypogonadism	No	TSS	N/A	Hormone negative	N/A
5	van Seters AP, 1985	66	F	PRL tumor	Stomach adenocarcinoma	Headache, II	Hyper PRL (medication)	No	TCS	No	PRL positive	POD 12/Dead
6	Molinatti PA, 1985	71	M	NF	Lung small cell carcinoma	II, III	Hypothyroidism	No	Radiation	TSS	FSH/LH positive	1 Month/Dead
7	Molinatti PA, 1985	67	F	Acromegaly	Stomach adenocartinoma	Headache, Nausea, II	Hyper PRL	No	TCS	No	PRL/GH positive	POD 2/Dead
8	Zager EL, 1987	56	F	NF	Breast adenocarcinoma	Headache, Nausea, VI	N/A	No	Radiation	No	FSH/LH positive	3 Weeks/Dead
9	Post KD, 1988	61	F	NF	N/A	Headache, II	Hypothyroidism	No	TSS	Radiation	ACTH positive	N/A
10	Post KD, 1988	77	M	NF	Lung carcinoma	Headache, III	No	No	TSS	Radiation	N/A	6 Months/Dead
11	Ramsay JA, 1988	67	M	NF	Prostatic carcinoma	Incidental findings at autopsy	No	No	No	No	Hormone negative	N/A
12	Ramsay JA, 1988	50	F	Cushing	Pancreas carcinoma	Exophthalmos, Facial obesity	N/A	No	TSS	Chemotherapy radiation	ACTH positive	7 Months/Dead
13	Hurley TR, 1992	76	M	Acromegaly	N/A	Nausea, Lethargy, II, Acromegalic feature	High GH	No	TSS	No	GH positive	6 Months/Dead
14	Abe T, 1997	46	F	PRL tumor	Malignant carcinoid	Headache, II	Hyper PRL	No	medication	TSS	PRL positive	6 Months/Dead
15	Bret P, 2001	75	F	NF	Breast carcinoma	II	Hyper PRL	No	TSS	No	FSH/LH/α-SU positive	18 Months/Alive
16	Bret P, 2001	87	F	NF	N/A	II	Replacement	No	TSS	No	FSH/LH positive	6 Months/Alive
17	Noga C, 2001	60	M	NF	N/A	II	N/A	No	TCS	No	Hormone negative	Few days/Dead
18	Weber J, 2003	62	F	NF	Renal carcinoma	Headache, II	No	No	TSS	TCS	Hormone negative	8 Months/Dead
19	Nasr C, 2006	44	F	Acromegaly	GHRH producing carcinoid	II	High GH	No	TSS	Radiation	GH positive	N/A
20	Jung SM, 2007	70	M	PRL tumor	Melanoma	II, Loss of consciousness	Hyper PRL, Panhypopituitarism	No	TSS	N/A	Hormone negative	N/A
21	Hoellig A, 2009	71	M	NF	Lung small cell carcinoma	II, III	No	yes	TSS	No	N/A	POD 12/Dead
22	Nassiri F, 2012	55	F	Acromegaly	Neuroendocrine tumor (origin unknown)	Acromegalic feature, Leg pain, II	High GH	No	TSS	Radiation	GH positive	21 Months/Dead
23	Rotondo F, 2013	66	M	PRL tumor	Bronchial non-small cell carcinoma	Headache	Hyper PRL	yes	no	No	PRL/GH positive	POD 1/Dead
24	Thewjitcharoen Y, 2014	65	M	PRL tumor	Colorectal carcinoma	Headache, II, III	Hyper PRL, Panhypopituitarism	No	TSS	Chemotherapy	PRL positive	9 Months/Dead
25	Sogani J, 2014	64	M	NF	Lung adenocarcinoma	II	Slight hyper PRL, Hypogonadism	yes	TSS	Radiation	ACTH/PRL positive	More 1 month/Alive
26	Magnori F, 2014	76	F	NF	Renal carcinoma	II, III	N/A	No	TSS	No	FSH/LH/a-SU positive	24 Months/Dead
27	Fujimori K, 2014	80	M	NF	Lung carcinoma	Headache, Nausea, II, III	Replacement	No	TSS	Radiation	N/A	7 Months/Dead
28	Yang C, 2017	62	M	PRL tumor	Melanoma	Headache, Eye pain, II	Hyper PRL, Hypothyroidism	No	TSS	No	PRL positive	22 Months/Alive
29	Mills MT, 2018	65	F	NF	Breast carcinoma	Headache, II	N/A	yes	TSS	No	FSH positive	POD 12/Dead
30	Andreev DN, 2020	55	F	NF	Breast carcinoma	II, III	No	No	TSS	N/A	FSH/LH positive	POD 14/Alive
31	Donofrio CA, 2020	68	M	NF	Colon adenocarcinoma	II	Slight hyper PRL	No	TSS	Chemotherapy radiation	FSH/LH/SF-1 positive	9 Months/Dead
32	Castle-Kirszbaum, 2020	51	F	NF	Breast adenocarcinoma	Septic shock, II	Panhypopituitarism	yes	TSS	Radiation	N/A	6 Months/Alive
33	our case	75	M	NF	Lung adenocarcinoma	II, III	Hyper PRL, Severe GH deficiency, Hypothyroidism	No	TSS	Chemotherapy radiation	a-SU/SF-1 positive	12 Months/Alive

M, male; F, female; NF, clinically non-functioning tumor; PRL tumor, PRL producing tumor; Cushing, Cushing’s disease; II, optic nerve disorder; III, oculomotor nerve palsy; VI, abducens nerve palsy; TCS, transcranial surgery; TSS, transsphenoidal surgery; α-SU, α-subunit; SF-1, steroidogenic factor-1; POD, postoperative day; N/A, not available

Surgery was the most common initial treatment (81.8%, n = 27/33), of which, transsphenoidal sinus surgery was the most common (66.7%, n = 22/33). Radiotherapy was performed as supplementary treatment in 33.3% of the patients (n = 11/33). Pathological findings using immunostaining were positive for gonadotropin in 9 of 28 patients (32.1%), but transcription factors were additionally examined in only 2 patients. The prognosis was poor, with 21 of the 28 patients (75.0%) dying within 24 months. The breakdown of the primary malignant neoplasms was as follows: malignant neoplasms of the lung and trachea (21.2%, n = 7/33), breast (21.2%, n = 7/33), digestive organs (15.2%, n = 5/33) and kidneys and urinary organs (15.2%, n = 5/33); neuroendocrine tumors (9.1%, n = 3/33); malignant melanomas (6.0%, n = 2/33); and unknown (12.1%, n = 4/33) (Fig. 5). The aforementioned breakdown of the primary malignant neoplasms was similar to that of pituitary metastases [1]. Meanwhile, the breakdown of recipient PitNETs was as follows: NF PitNET (66.7%, n = 22/33), PRL-producing tumors (18.2%, n = 6/33), acromegaly (12.1%, n = 4/33), and Cushing’s disease (3.0%, n = 1/33). The aforementioned breakdown closely resembles that for PitNETs themselves, suggesting that specific PitNETs have no affinity with malignant neoplasms and that they metastasize through the same mechanisms driving pituitary metastases of malignant neoplasms (Fig. 6). In other words, the malignant neoplasms metastasize to the posterior lobe of the pituitary gland via the arterial blood flow of the neurohypophysis in the same way that they metastasize into tumors of the sella turcica via the abundant arterial blood flow that nourishes the pituitary gland, including branches of the capsular artery, inferior hypophysial artery, and superior hypophysial artery of the internal carotid artery [11].

Fig. 5

Primary site of the malignant neoplasm metastasizing within a pituitary neuroendocrine tumor (PitNET).

Fig. 6

Frequency of pituitary neuroendocrine tumors (PitNETs) with metastatic malignant neoplasms classified according to endocrinological function.

Moreover, previous reports have supported the hypothesis that PitNETs activate the trophic vasculature and increase blood flow to the sella turcica via such trophic vessels [32]. Other possible mechanisms include direct invasion from adjacent bony structures or meninges or through the cerebrospinal fluid surrounding the sella turcica [33]. Among the patients with malignant neoplasm metastasis within a PitNET, only 60.6% (n = 20/33) had a known history of malignant neoplasm prior to definitive diagnosis, whereas only 15.2% (n = 5/33) had other intracranial metastases preoperatively. Although the present case had a history of malignant neoplasms of the bladder and colon, similar to patients described in previous reports, no other intracranial metastases had been observed. Moreover, despite the lack of no respiratory symptoms in the present case, a histopathological examination revealed the presence of a lung adenocarcinoma within the PitNET, indicating a new malignant neoplasm of the lungs and thus triple cancer.

Previous reports have highlighted the difficultly of distinguishing between a solitary PitNET and a malignant neoplasm metastasizing within a PitNET before surgery based solely on clinical and imaging findings. In many cases, metastatic lesions are too small to cause any clinical or imaging changes. Moreover, emerging symptoms are often similar to those of a solitary PitNET and may include poor visual function due to optic chiasm compression, headache, hypopituitarism, and slight hyperprolactinemia.

Considering the appearance of external ophthalmoplegia, PitNETs associated with pituitary apoplexy may be more naturally considered as a differential diagnosis rather than collision tumors. This is because 27% (n = 9/33) of patients with malignant neoplasm metastases within PitNETs had external ophthalmoplegia, whereas 58.8% (n = 10/17) of those with solitary PitNETs had external ophthalmoplegia in the presence of pituitary apoplexy [34, 35].

Imaging modalities, such as CT and MRI, are helpful in assessing the localization and extension of tumors in the sella turcica; however, distinguishing between a solitary PitNET and a malignant neoplasm metastasizing within a PitNET still remains difficult. Nevertheless, similar to cases involving malignant neoplasm metastasis to the parasellar region, metastatic diseases should be considered in patients exhibiting invasive destruction of bony structures, such as the sella turcica, anterior and posterior floor processes, dorsum sellae, and clivus; those showing rapid lesion growth on routine imaging evaluation; or those displaying other intracranial lesions suggesting metastases [36].

Consequently, histopathological examination is essential for a definitive diagnosis, and it is important that the tumor be removed as much as possible. The entire resected specimen should be immunostained and histologically assessed to ensure that no malignant lesions are missed. En bloc removal poses challenges with intracranial malignant tumors due to potential harm to adjacent healthy tissue. Therefore, the common approach for extracting intracranial tumors, even malignant ones, involves piecemeal removal. During this procedure, we shield the surrounding tissue using cotton and rigorously wash to prevent the spread of tumor cells.

The prognosis of patients with malignant neoplasm metastases within PitNETs is generally poor given that the malignancy is often already intracranially and systemically disseminated. The literature indicates that 56% and 19% of patients present with systemic and intracranial metastases, respectively, with a reported median survival of 4 months [19, 25, 26]. Recently, advances in diagnostic imaging have made early detection possible, and advances in chemotherapy, such as molecular-targeted drugs, have led to reports of good prognosis in cases of malignant neoplasm metastases within PitNETs [2]. With appropriate histopathological evaluation, chemotherapy with molecular-targeted agents, and additional stereotactic radiotherapy, both lung and sella turcica lesions in the present case resolved well with good tumor control and a relatively good outcome.

Endoscopic endonasal transsphenoidal surgery, which is relatively minimally invasive, may be an option for not only immediate decompression of the tumor and improvement of abnormal hormone secretion but also diagnosis. Hence, tumor specimen collection and correct diagnosis of a malignant neoplasm metastasizing to a lesion in the sella turcica, as in the present case, will allow physicians to strategize a detailed treatment plan. Furthermore, our approach can spare patients with advanced-stage malignant neoplasms from invasive tests and unnecessary aggressive treatments.

Conclusion

In cases of sella turcica tumors with a relatively rapid progression of neurological symptoms, early surgical intervention is recommended given the possibility of a highly proliferative tumor, such as a malignant neoplasm. Moreover, obtaining adequate pathology specimens for diagnostic confirmation is imperative.

Disclosure

None of the authors have any potential conflicts of interest associated with this research. This article was previously posted to the Research Square preprint server with (https://doi.org/10.21203/rs.3.rs-1552497/v1) on April 18, 2022.

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