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Pituitary gland metastasis from primary tumours is uncommon on its own. Rarely, some of these primary tumours may be of unknown origin. This metastasis to the pituitary gland could manifest as diabetes insipidus, cranial nerve palsies, headaches, fatigue and other symptoms. In rare cases, it could present as loss of libido. We describe here this rare presentation, loss of libido, examine the diagnosis and management undertaken, and provide a systematic review of the literature for similar cases.
It is a rare case with a rare presentation that shows the importance of a good clinical examination and tests that help us reach a final diagnosis in order to provide the definitive treatment for it.
A 37-year-old man originally presented in June 2007 with left axillary lymphadenopathy. He went on to have axillary clearance. The pathology report only revealed reactive lymphadenopathy. The tumour marker profile before radical axillary dissection was unremarkable. Physical examination, including breast examination, apart from the lymphadenopathy, was otherwise unremarkable. Testicular ultrasound examination showed an abnormal small right testicle with a diffuse pathology. He subsequently had a right orchidectomy in July 2007; however, his testes only showed atrophic changes. Following the orchidectomy, a positron emission tomography scan in July 2007 failed to identify a primary site of the adenocarcinoma.
In September 2008, this patient had left axillary and skin recurrence in the same area and block dissection for residual ER/PR/HER2 negative adenocarcinoma. He was later also treated with six cycles of Mitomycin C, Cisplatin, 5-Fluorouracil (MCF) chemotherapy for an unknown primary tumour starting in February 2009, and received radiotherapy to the nodal region and tumour bed. He was subsequently well and placed in follow-up. The MCF protocol consisted of a combination of mitomycin C (7 mg/m2 on day 1 of cycles 1, 3 and 5), cisplatin (50 mg/m2 on day 1) and 5-fluorouracil (600 mg/m2 on day 1), delivered as a 21-day cycle.
He was regularly followed up with CT scans which showed that, apart from a stable plaque of thickening in his left axillary scar, there was no evidence of recurrence until January 2014. In January 2014, he presented to his general practitioner with loss of libido and impotence. He was investigated with a hormone profile, which showed low testosterone 1.2 ng/mL (2.8–8.0 ng/mL), low T3 1.5 pg/mL (2.3–4.2 pg/mL), low free T4 0.5 ng/L (0.8–1.8 ng/L), normal thyroid-stimulating hormone TSH 3.3 U/mL (0.3–5.0 U/mL), low morning cortisol 4.2 µg/dL (4.3–22.4 µg/dL), normal afternoon cortisol 3.5 µg/dL (3.1–16.7 µg/dL), low follicle stimulating hormone (FSH) 1.0 mIU/mL (1.6–8.0 mIU/mL), low luteinising hormone (LH) 1.1 mIU/mL (1.5–9.3 mIU/mL) and low prolactin 0.7 ng/mL (2.0–18.0 ng/mL), consistent with pituitary failure. The patient was not checked for diabetes insipidus.
He was started on hormone replacement therapy and further investigated. His treatment was comprised of levothyroxine, 75 mg orally once daily, and hydrocortisone, 20 mg orally two times a day, both continuously. On February 2014, a CT scan of his chest, abdomen and pelvis showed no recurrent disease, while his MRI scan showed a 19 mm pituitary tumour extending superiorly into the suprasellar cistern (figure 1). An endoscopic resection of pituitary of pituitary fossa tumour was performed in June 2014, with the biopsy showing a morphology that was the same as his original presentation of adenocarcinoma. However, it now slightly had a changed profile in that it was now very mildly estrogen receptor/progesterone receptor positive and defInitely HER2 positive. MRI scans were performed presurgery and postsurgery (figures 2 and and33).
Further investigation did not reveal any primary pathology and he is currently on adjuvant transtuzumab for a year and Hormonal manipulation for 5 years. After completion of transtuzumab, he will be under regular surveillance.
Literature searches were performed for articles looking at the metastatic involvement of the pituitary gland in different cancers and the types of symptoms that manifest when metastasis to the pituitary gland is present. The literature reviewed included the years 1975–2011. The literature included reports of cases or case-series involving metastatic disease of the pituitary gland, with specific emphasis on presentation, disease progression, treatment and prognosis.
Metastasis of the pituitary gland is uncommon with signs and symptoms being detected at a much later time in the disease progression.1 Pituitary gland metastasis has been reported from almost every tissue type,2 3 however, breast and lung cancer are the commonest sites of the primary tumour and account for two-thirds of the cases, but metastasis from lymphoma, leukaemia, melanoma, kidney, colon and prostate cancer are also reported. In approximately 3% of cases, the primary tumour remains undetected despite intensive investigations (figure 4).2–34 In cancers with unknown primaries, the median survival is 4–12 months, with about 50% survival at 1-year and about 10% survival at 5 years from diagnosis.35 The incidence of metastatic cancers of unknown origins is not known.
Reviewing the location of metastases in 201 cases, McCormick et al4 found an involvement of the posterior lobe either alone or in combination with the anterior lobe in 84·6% of cases, whereas the anterior lobe was affected in 15.4% of cases.
The predilection for metastasis to the posterior lobe is mainly attributed to the lack of direct arterial blood supply to the anterior lobe.4–7 36 37 The posterior lobe is supplied by the hypophyseal arteries, whereas the anterior lobe is nourished by the portal vessel system and secondarily by the lower infundibular stem, which partly arises from the posterior lobe. Another contributing factor is that the posterior lobe has a large area of contact with adjacent dura.7 Metastatic deposits in the anterior lobe are usually the result of a contiguous spread from the posterior lobe. The anterior lobe seems to be susceptible to ischaemic infarcts and is associated with a large metastatic lesion of the posterior lobe.7 36
In most of the patients, the signs and symptoms of metastasis to other parts of the body such as lymph node, lung or bone are the first manifestations and metastasis to the pituitary gland occurs later.1 At the time of diagnosis of the pituitary metastasis, many patients have widespread evidence of the disease; however, pituitary dysfunction as the first presentation of the primary breast cancer and infundibular involvement occurs rarely.38
The present case presented with symptoms of feeling unwell, decreased libido and an inability to achieve erection, which implied anterior hyperphysical involvement. A review of the literature suggested that clinical presentation of decreased libido is a rare event, approximately 1%. The patient was not checked for diabetes insipidus, which presents in approximately 45% of pituitary metastasis, not confirming if metastasis was limited to the anterior pituitary lobe (figure 5).2–34
The patient’s hormone profile clearly indicated hypopituitarism with testosterone, T3, free T4, FSH, LH, prolactin and morning cortisol all being low and he was subsequently commenced on levothyroxine and hydrocortisone therapy.
Pituitary MRI of the patient revealed a 19 mm pituitary tumour extending superiorly to the suprasellar cistern (figure 1). The location of tumour in imaging provided a higher possibility of differentiation between malignant and benign disease. Clinical and radiological features of pituitary metastasis can be indistinguishable from benign suprasellar lesions such as pituitary adenoma. Histopathology remains the key to the diagnosis of pituitary metastasis. Luu et al39 reported four patients with sellar lesions presenting with anterior visual pathway compression initially diagnosed as pituitary adenoma who on immunohistochemistry were found to have metastasis to the pituitary. Classification of the cell histology determined the primary site of origin in some patients.
This case underwent endoscopic resection of the pituitary fossa tumour which showed ER/PR reactivity, 3+ HER2 status and appearance consistent with metastatic carcinoma. The previous immunohistochemistry obtained from the left axillary/skin recurrence in 2008 was found to be ER/PR/HER2 negative. In men, 1.7–45% of breast cancers are HER2 positive.40 Sari et al6 reported a comparative study of the immunohistochemical detection of hormone receptor status and HER2 expression in primary and paired recurrent/metastatic lesions of patients with breast cancer. Analysis was made on 78 patients with metastatic breast carcinoma whose ER, PR and/or HER2 status was known both on the tissue samples of primary and recurrent metastatic lesions (RML).
Among the RML sites, 20.5% were locoregional and 70.5% were distant metastatic sites. Among 61 patients with known HER2 expression on both primary and RML, 14.7% (n=9) had discordant results. Among these discordant cases, three had positive primaries and negative RML; six had negative primaries and positive RML. Among 18 patients who had HER2 positive primaries, 16.6% (n=3) had HER2 negative metastasis. Among 43 patients who had HER2 negative primaries, 14% (n=6) had HER2 positive metastasis.
Recent reports suggest that the receptor status of metastatic lesions may occasionally change compared to the primary tumour. The mechanisms underlying these discordant findings between the primary and RML are not very clear. As these discordant results make changes in treatment decision, a biopsy of the metastatic lesion is highly recommended in patients with metastatic breast cancer when feasible.
Treatment of malignant pituitary involvement consists of transcranial and transphenoidal surgeries, chemotherapy and radiotherapy. The regression of metastasis is achieved after each of these treatments.
Competing interests: None.
Patient consent: Not obtained.
Provenance and peer review: Not commissioned; externally peer reviewed.