throughout the world , especially in developing countries , the incidence of lung cancer is on the rise . in the united states ,
the last decade has seen an increased availability of techniques to aid screening , early diagnosis and targeted treatment of all forms of lung cancer , despite which the incidence continues to rise .
however other systemic manifestations as well as signs and symptoms related to metastatic spread and paraneoplastic syndromes should be kept in mind . through this case presentation and review of the literature
, we aim to discuss one such scenario , where a patient presented with central diabetes insipidus ( di ) related to pituitary metastasis , even though there was no identifiable primary lung lesion at the time of presentation .
metastatic lesions account for about 1% of all sellar and parasellar pituitary tumors and have to be borne in mind when evaluating patients .
a 47-year - old female with a 20-pack year smoking history presented to an outside hospital after she overdosed on acetaminophen for relief of her headache .
she had been presenting to various hospitals with complaints of headache , nausea and intermittent episodes of vomiting for 18 months .
she had previously been evaluated at our institution a year before for headache and had a computed tomography scan done , which was reported negative for any intracranial lesions .
her review of systems was positive for polyuria and polydipsia , which had started about 2 weeks prior to presentation .
her initial laboratory studies at the outside hospital revealed serum sodium of 157 meq / l ( nl : 135 - 146 meq / l ) in addition to abnormal liver function studies ; the latter attributed to acetaminophen overdose .
she was treated with high dose desmopressin ( ddavp ) for presumed di and transferred to our facility , which is a tertiary level referral hospital .
a magnetic resonance imaging ( mri ) study of her brain done at the outside hospital had revealed a lesion , 2.5  1.5 cm in size , in - homogeneously enhancing in the sellar with some extension into the suprasellar cistern and erosion of the posterior wall of the sphenoid sinus .
no other brain lesions were noted on this scan . on admission to our institute , she continued to have headache , polyuria and polydipsia .
her cbc revealed anemia , with hemoglobin of 9.5 g ( nl : 11.7 - 15.5 g ) , normocytic and normochromic in nature . based on her hormonal assay , namely low tsh of 0.3
lh < 0.1 miu / l , normal prolactin and cortisol levels , she was thought to have a non - functioning pituitary mass .
she was presumed to have a diagnosis of central di and was given a dose of ddavp again .
an mri of her brain was repeated in our institution with contrast this time , which revealed a large , invasive suprasellar mass with heterogeneous enhancement and extension into the adjacent sphenoid sinus .
the mass was associated with mild suprasellar extension and compression of the optic chiasm [ figure 1a ] .
another ring - enhancing centrally cystic lesion was identified in the right superficial frontal lobe with mild surrounding edema [ figure 1b ] .
although the sellar mass could represent an invasive pituitary macroadenoma with preferential inferior growth , given the relatively rapid growth of the sellar lesion and the concomitant presence of additional frontal lobe lesion , the possibility of a metastatic disease needed to be considered at this time .
( a ) sagittal view of the brain demonstrating an invasive suprasellar mass with heterogeneous enhancement and extension into the adjacent sphenoid sinus , ( b ) ring - enhancing centrally cystic / necrotic lesion in the right superficia l fronta l lobe with mild surrounding edema she underwent a trans - sphenoidal pituitary biopsy subsequently and had to be transferred to the intensive care unit after the biopsy due to acute hypoxic respiratory failure .
the pathological examination of the mass in pituitary revealed the typical features of an adenocarcinoma : solid nests and glands formed by tumor cells that have abundant cytoplasm containing intracellular mucin and pleomorphic nuclei [ figure 2a ] .
the cells were positive for thyroid transcription factor-1 ( ttf-1 ) [ figure 2b ] , which is a sensitive and specific marker of lung adenocarcinoma .
the tumor cells demonstrated a cytokeratin profile typical of lung adenocarcinoma ( ck-7 and cam 5.2-positive , ck-20-negative ) and were negative for the neuroendocrine markers ( cd-56 , chromogranin , and synaptophysin ) .
an identical immunophenotype can be found in thyroid carcinomas , which have a distinctly different histologic appearance , and some primary adenocarcinomas of the head and neck , including sinonasal carcinoma , which can express ttf-1 in rare cases .
solid nests of cells with abundant clear cytoplasm and focal formation of gland - like structures with eosinophilic cytoplasm ( h and e , magnification  60 ) , ( b ) trans - sphenoidal resection of pituitary mass .
immunohistochemistry stain highlights the expression and nuclear localization of ttf-1 in the neoplastic cells , which supports the diagnosis of metastatic lung adenocarcinoma ( ttf-1 ihc , magnification  20 ) to evaluate further for a primary lesion , a ct scan of the chest was obtained which revealed multiple pulmonary emboli , mediastinal lymphadenopathy , and patchy ground - glass opacity within the lateral aspect of the right lower lobe with no distinctly visible mass .
endobronchoscopy with ultrasound - guided fine needle aspiration of the right hilar lymph nodes yielded malignant cells that had the cytological appearance of lung adenocarcinoma [ figure 3 ] .
a biopsy performed concomitantly revealed tumor cells that resembled those in the pituitary mass . with this evidence of a primary lung adenocarcinoma ,
the pathologist concluded that the pituitary mass most likely represented metastasis from a lung malignancy and not local spread of a sinonasal adenocarcinoma .
cytological examination of the hilar lymph nodes reveals malignant cells with eccentric nuclei and prominent nucleoli on papanicolaou stain thereafter the patient had a rapid decline in her performance status .
pulmonary adenocarcinoma , a subtype of the non - small cell type is the most common type of lung cancer in the united states and also accounts for the most frequent type in non - smokers . while lung cancers rarely metastasize to unusual locations , they do so most commonly to the liver , adrenal glands , bones , and the brain parenchyma .
according to a recent swedish study , small cell lung cancer most commonly metastasizes to liver and central nervous system while adenocarcinoma metastasizes to bone and respiratory system .
rare cases of adenocarcinoma of the lung like ours do metastasize to the pituitary gland .
in addition to metastatic lesions , the differential diagnosis for tumors in the sellar and suprasellar region of the pituitary gland include pituitary adenomas , craniopharyngiomas , optic or hypothalamic gliomas , germ cell tumors , lipomas , and choristomas .
lung cancer is the second most common type of malignancy to metastasize to the pituitary gland ( breast cancer being the leader ) . according to a recent meta - analysis , breast and lung cancer account for 37.2% and 24.2% of the pituitary metastatic lesions , respectively . despite this knowledge , when patients with primary lung cancers present without respiratory symptoms their diagnosis is often delayed due to a delay in making the connection between pituitary symptoms and lung cancer , similar to our patient .
when a patient presents with a pituitary mass , benign lesions like adenomas are difficult to distinguish from metastatic pituitary lesions based on imaging studies .
there are certain clinical characteristics that help discern whether a pituitary lesion is benign vs. whether the lesion needs a more thorough work up to rule out metastasis from a distant primary .
studies , including a recent meta - analysis indicate that di is the most common clinical manifestation in patients who have pituitary metastasis .
reports have indicated that di may be used to distinguish between an adenoma and a metastatic lesion , in that it is more commonly associated with the latter .
this is because metastases target the posterior lobe of the pituitary gland and the infundibulum in preference to the anterior lobe , likely due to a preference of the metastases to follow the pattern of pituitary blood flow in the neurohypophoseal blood vessels .
therefore , if a patient with di is found to have a pituitary mass , the suspicion for a primary lesion elsewhere should increase and aggressive search to look for a primary malignancy should ensue .
several case series have demonstrated how patients have presented with symptoms related to pituitary dysfunction , and have ultimately been diagnosed with other primary malignancies .
however , a study also indicates that only about 50% patients who present with a sellar mass have a known primary malignancy .
thus in a female patient search for primary breast cancer and in a male patient search for primary lung cancer should ensue since these are the most common cancers metastasizing to the pituitary gland .
other clinical characteristics that raise the suspicion for a pituitary lesion to represent a metastatic lesion rather than a benign adenoma include headaches , visual field deficits due to cranial nerve palsies ( especially abducens nerve palsy ) , presence of skull - bone destruction , demonstration of rapid growth on serial scans , and presence of coexisting focal lesions ( metastasis ) . hormonal assay to be most commonly affected is high prolactin levels , which is however the case in both metastatic lesions and macroadenomas ; hence does not help distinguish the two .
our patient had an unusual situation where there was no discernible primary lesion in the lungs , and yet the biopsy histopathology was suggestive of lung - based adenocarcinoma .
clinicians should be aware of malignancies that are well known to metastasize to the posterior pituitary and consider breast and lung as potential sources .
conversely , since not every patient presents with symptoms of metastasis there is a need to recognize the clinical syndromes ( e. g. , di like symptoms or more subtle symptoms like cranial nerve palsies ) associated with potential metastasis to the pituitary .
work up should then include dedicated imaging of the involved region and potential primary malignancies .
early recognition will result in timely institution of therapy for such patients and improved quality of life .
 context : lung cancers are known to metastasize to unusual sites . despite this knowledge often times the diagnosis of a primary lung cancer gets delayed especially when the patient presents without respiratory symptoms.case report : the patient discussed in our review is a 47-year - old female , smoker who had presented to several hospitals with months of headache , nausea and intermittent episodes of vomiting . 
 she was noted to have hypernatremia due to diabetes insipidus and a pituitary lesion on her magnetic resonance images . 
 the pituitary mass on biopsy was found to represent a metastatic focus from a primary lung adenocarcinoma.conclusion:clinicians should be aware of malignancies that are well known to metastasize to the posterior pituitary . 
 conversely , since not every patient presents with symptoms of metastasis , there is a need to recognize the clinical syndromes ( e. g. , diabetes insipidus - like symptoms or more subtle symptoms like cranial nerve palsies ) associated with potential metastasis to the pituitary . 