Clinical Pathologic Conference Case 4: An adult male patient with a sellar mass

Abstract

Clinical Presentation

A 62-year-old Black male patient presented to the emergency department in August of 2021 with muscle weakness and macroglossia. The patient's medical history included hypertension, osteoporosis, femoral and pubic bone fractures, muscle wasting, and generalized pain. He reported an unintentional loss of 100 pounds within the preceding 6-month period. Upon further questioning, the patient revealed that his muscle weakness began several years prior, in 2015. He also stated that a prior evaluation by a neurologist at an outside facility had been done, and that there was no concern for a neuropathic process. A physical examination and laboratory work-up were undertaken in the emergency department.

The patient demonstrated vocal changes including hoarseness and dysphagia, and examination revealed unilateral macroglossia with immobility (Fig. 1), and fullness of the base of tongue area. He exhibited extreme muscle weakness and spasmodic episodes and was unable to lift his legs off of the hospital bed. The patient had hypophosphatemia and hyperparathyroidism, indicative of electrolyte and endocrine derangement. Otolaryngology was consulted, and initial imaging studies were performed.

A computed tomography (CT) scan of the brain completed upon admission showed a 6.5-cm mass centered in the sellar region, which was eroding the left mastoid, clivus, and bilateral sphenoid sinuses (Fig. 2A, 2B). A mass effect was noted upon the posterior left orbit and medial rectus muscle. Magnetic resonance imaging (MRI) with and without contrast was then performed the next day, and this redemonstrated the heterogeneously enhancing mass extending anteriorly to the ethmoid sinus, abutting the bilateral optic nerves, and indenting the frontal lobes of the brain superiorly (Fig. 3A, 3B, 3C). The mass also encroached upon the posterior nasal cavity and nasopharynx. It was seen to displace the pituitary gland superiorly. The cavernous sinus was invaded by the mass, and the bilateral internal carotid artery cavernous segments were encased.

Based on these findings, the patient was taken to the operative room for bilateral nasal endoscopy and biopsy. At surgery, the mass was noted to be at least partially encapsulated. Several biopsies were taken, and intraoperative consultation was performed.

Differential Diagnosis

Considering the clinical presentation and the patient's medical history, a bone neoplasm associated with a systemic condition is postulated; furthermore, the differential diagnosis should include other sinonasal tumors, such as benign tumors of the base of the skull (pituitary adenoma or craniopharyngioma), or endocrine lesions involving bones (hyperparathyroidism-related bone tumor). In this particular case, the initial discussion also includes a quite broad number of lesions such as suprasellar teratoma, Rathke cleft cyst, multiple myeloma with bone involvement, nasopharyngeal angiofibroma, and meningioma.

The CT scan revealed an extensive osseous neoplasm located at the base of the skull, affecting both the sphenoid and ethmoid bones, with involvement of the nasal cavity and brain, exhibiting various calcific deposits. The imaging findings are consistent with a well-circumscribed solid neoplasm containing several calcified foci.

Meningiomas are typically slow-growing tumors of the meninges that account for more than one-third of all primary central nervous system tumors, most are of benign nature (grade I). They are frequently attached to the dura mater. Meningiomas are more prevalent in women in middle age, and can cause symptoms like headaches, seizures, or focal neurological deficits, depending on their location and size. They can occasionally be atypical or malignant, requiring more aggressive treatment (Ogasawara et al., 2021). Upon histological examination, meningiomas are classified into various subtypes, such as meningothelial, fibrous and transitional. Psammoma bodies are often present. The fibroblastic variant of meningioma can closely resemble a number of spindle cell tumors, but immunohistochemistry is crucial for differentiation. Meningiomas typically express EMA (epithelial membrane antigen), vimentin (Toland et al., 2021) and SSTR2.

Nasopharyngeal angiofibromas are rare, benign tumors that occur almost exclusively in adolescent male patients, in contrast to the present case. They originate in the nasopharynx and are characterized by a spindle cell neoplasm with rich vascularity. These tumors often present with symptoms like nasal obstruction, epistaxis, and facial swelling. Due to their vascular nature, they can be challenging to manage surgically and may require pre-operative embolization to reduce bleeding risk (Gemmete et al., 2012; Baba et al., 2023). Histologically, nasopharyngeal angiofibromas have a prominent vascular component with numerous dilated blood vessels. The neoplastic cells are typically stellate or spindle-shaped and are embedded in a fibrous or myxoid matrix. The characteristic vascular pattern and location in the nasopharynx usually point toward the correct diagnosis (Sánchez-Romero et al., 2017).

Craniopharyngiomas are slow-growing, benign tumors that arise from remnants of Rathke pouch. However, unlike cysts, they are solid tumors, often containing calcifications. They account for 1% to 5% of all primary intracranial neoplasms and can be diagnosed in children, adolescents, or adults above the age of 50 years. This tumor is usually located in the suprasellar region and may cause a number of symptoms, such as headaches, visual disturbances, hormonal disturbances, and growth retardation among children. Hypopituitarism and hypothyroidism are common endocrine symptoms of craniopharyngioma (Apps et al., 2023). Craniopharyngiomas are histologically classified in two main types: adamantinomatous and papillary. Adamantinomatous craniopharyngiomas show nests of squamous epithelium with peripheral palisading and “wet keratin.” Papillary craniopharyngiomas have a papillary architecture lined by cuboidal or columnar epithelium. Craniopharyngiomas are generally not misidentified as spindle cell tumors due to their epithelial component (Wu et al., 2022).

Rathke cleft cysts are benign, fluid-filled cysts that arise from remnants of Rathke pouch, an embryonic structure that gives rise to the anterior pituitary gland between the third and fourth week of development. These cysts are usually located in the sella turcica. Most Rathke cleft cysts are asymptomatic and discovered incidentally, but larger cysts can cause headaches, visual disturbances, or pituitary dysfunction. Computed tomography imaging generally shows evidence of a fluid-dense mass without calcifications, that does not enhance with contrast (Lu et al., 2020; Petersson et al., 2022). Histologically, the Rathke cyst lining can vary from simple cuboidal epithelium to ciliated columnar epithelium with goblet cells. The cyst contents may include mucin, extravasated serum protein, and/or cellular debris, and they are unlikely to be mistaken for spindle cell tumors (Lu et al., 2020; Petersson et al., 2022).

In addition, suprasellar teratomas are quite rare. They are characteristically constituted of diverse tissues, often including hair, teeth, bone, and cartilage. These tumors can present in childhood or adulthood, causing symptoms like headaches, visual disturbances, hormonal imbalances, or hydrocephalus (Kürner at al., 2024). Histologically, teratomas are characterized by the presence of tissues derived from all three germ layers (ectoderm, mesoderm, and endoderm). Identification of this tissue usually makes the diagnosis clear (Kang et al., 2024).

Pituitary adenomas are benign tumors that arise from the pituitary gland and account for 15% of all intracranial tumors. They are usually either functional (hormone-secreting) or non-functional (not hormone-secreting). Functional adenomas can cause a variety of symptoms depending on the hormone they produce, such as Cushing disease (excess cortisol), acromegaly (excess growth hormone), or prolactinoma (excess prolactin). Non-functional adenomas can cause symptoms due to their size and mass effect, such as headaches, visual disturbances, or pituitary dysfunction. Giant pituitary adenomas represent 8% of all pituitary adenomas and occur predominantly in male patients in their 30s or 40s, and cavernous sinus invasion is a common finding (Gaillar et al., 2022). Histologically, pituitary adenomas are composed of relatively uniform neuroendocrine tumor cells arranged in sheets or cords. The cells have round nuclei and may contain secretory granules. Pituitary adenomas have generally a distinct endocrine appearance (Lu et al., 2022).

Hyperparathyroidism is characterized by the production of excessive amounts of parathyroid hormone, which leads to an increase in blood calcium. This can cause a variety of bone abnormalities, including fractures, and brown tumors. Brown tumors are benign lesions that result from the abnormal bone remodeling process in hyperparathyroidism. Any bone can be affected, including the skull (Xie et al., 2019). The patient who suffers from hyperparathyroidism may develop symptoms of muscle weakness, pain in the joints or bones, and fatigue (Loya-Solis et al., 2014). Histologically, brown tumors consist of fibrous tissue with numerous multinucleated giant cells and areas of hemorrhage. The presence of giant cells and the clinical context of hyperparathyroidism help differentiate this lesion from other giant cell tumors (Bennett et al., 2020).

Multiple myeloma is a malignant neoplasm of plasma cells that often affects multiple bones throughout the body, causing bone pain, fractures, and hypercalcemia. Myeloma cells can also interfere with the production of normal blood cells, leading to anemia, infections, and bleeding problems. In the skull, myeloma can present as lytic lesions (Ugga et al., 2018). The solitary involvement of bone by plasmacytoma, or the pure soft tissue plasmacytoma (known as extramedullary plasmacytoma) are both rare. Solitary plasmacytoma has been reported as a lobulated mass in the sphenoid sinus, clivus, and the cavernous sinus (Kariki et al., 2014). Bone imaging shows lytic lesions with destruction of bone trabeculae (Firsova et al., 2020). Myeloma involves the infiltration of tissues by atypical plasma cells that have eccentric nuclei, prominent nucleoli, and a “clock-face” chromatin pattern, which have a distinct morphology, avoiding the confusion with spindle cell tumors (Firsova et al., 2020).

Diagnosis

During the biopsy procedure, tissue was sent from the operating room for frozen section analysis. Sections demonstrated a neoplastic proliferation with no high-grade features identified. The intraoperative diagnosis was “neoplasm with low-grade features, defer to permanent sections for further classification.” Additional tissue was submitted for permanent histology and was received the following day.

Histologic examination of the tumor revealed a moderately cellular and monotonous proliferation of bland cells. There was abundant hemorrhage and vascularity in the specimen (Fig. 4A). The neoplasm had a pink and hyalinized background matrix, and focally, chondromyxoid change was identified (Fig. 4B). Tumor cells were hyperchromatic and had round to elongated nuclei, with finely-dispersed chromatin and inconspicuous nucleoli. They did not seem to be arranged in any particular pattern. Marked pleomorphism, necrosis, and mitoses were not identified (Fig. 4C, 4D). The differential diagnosis comprised a laundry list of bone and soft tissue tumors, which required thorough investigation, and so a large panel of ancillary studies was ordered.

By immunohistochemistry, the tumor cells were positive for SSTR2 (Fig. 4E), and they were weakly and focally positive for synaptophysin and CD99. An MIB-1 proliferative index was estimated at 2%. SMARCB1 expression was partially lost within the tumor. Negative studies included AE1/AE3, CK7, EMA, chromogranin, S100, SOX10, desmin, CD31, CD34, β-catenin, STAT6, NKX3.1, Congo red, PAX8, hep-par 1, ETV4, SS18-SSX, WT-1, and brachyury immunohistochemistry; and a fluorescence in situ hybridization study for HEY1::NCOA2 fusion was negative. The diagnosis was clinched when an in situ hybridization study for FGF23 demonstrated significant overexpression in tumor cells (Fig. 4F). The final diagnosis was phosphaturic mesenchymal tumor.

Management

The patient was admitted to the hospital for management of his several systemic symptoms. He was treated by endocrinology and internal medicine specialists for electrolyte imbalance, vitamin D deficiency, and kidney injury. The patient had further imaging, and was found to have an anterior mediastinal mass, a renal mass, small pulmonary nodules, several small scattered hepatic lesions, and evidence of multiple rib and vertebral fractures. The patient was cachectic because of eating issues due to nausea, tongue swelling, esophageal dysmotility, and inability to swallow, and he required a percutaneous endoscopic gastroscopy (PEG) tube from gastroenterology for increased caloric intake.

The patient's infiltrative sinonasal/skull base tumor was determined to be unresectable after extensive discussion at an internal multidisciplinary tumor conference. He was referred to medical oncology, and one cycle of chemotherapy was given during the patient's admission. He was also referred to radiation oncology for evaluation. He was discharged after he stabilized and stated that he wished to transfer his care elsewhere, but eventually returned to our institution after 6 weeks to re-establish care. Two weeks later, he presented to the emergency department for whole body pain and urinary symptoms and was admitted for deep vein thrombosis of the lower extremity, sepsis secondary to a urinary tract infection, and pancytopenia secondary to chemotherapy. It was determined that the patient was no longer an appropriate candidate for chemotherapy, and upon discussion with palliative medicine, he expressed goals of pursuing comfort care and going home to be with his family. He chose to transition to hospice care, and biopsy of his additional lesions was not undertaken. He was discharged but returned to the emergency department a few days later for dehydration, pain, and a malfunctioning gastric feeding tube. After these issues were addressed, the patient returned to hospice care and was lost to follow-up.

Discussion

Phosphaturic mesenchymal tumor (PMT) is a rare and curious neoplasm that represents less than 0.01% of all soft tissue tumors, according to the World Health Organization's Classification of Soft Tissue and Bone Tumors (5th edition; Folpe, AL, 2020). PMT is of unknown etiology and usually occurs in middle-aged adult patients of either sex. It may occur at any soft tissue location in the body, and a subset of tumors are known to involve bone. Radiographic findings are those of a mass lesion, with or without internal fleck-like calcifications. The majority of PMTs present when they are quite small, and radionuclide positron emission tomography-computed tomography (PET-CT) scans are frequently needed to localize these tumors.

By producing excess fibroblast growth factor 23 (FGF23), PMT classically causes tumor-induced osteomalacia (TIO) in affected patients, even in those with very small tumors. Other causes of osteomalacia, including vitamin D deficiency and renal tubular acidosis, also need to be considered in the differential diagnosis because they can also secrete FGF23 (Deep et al., 2014; Romero et al., 2021; Zhang et al., 2024). FGF23 is a hormone that acts upon the kidneys and parathyroid glands to regulate phosphate levels in the body. Specifically, it inhibits phosphate reuptake in the renal proximal tubules of the kidneys. Excess serum levels of FGF23 therefore induce phosphaturia and put the patient in a hypophosphatemic state. Chronic hypophosphatemia has several possible systemic consequences, such as muscle weakness, difficulty breathing, loss of appetite, weak bones and bone fractures, bone pain, seizures, coma, and death.

Histologically, PMT is composed of a moderately cellular proliferation of bland rounded to spindled tumor cells within a hyalinized and vascular stroma (Folpe AL, 2020; Qari H. et al., 2016). Intratumoral blood vessels may vary in size and peripheral hyalinization may be seen. The tumor cells have finely distributed chromatin, inconspicuous nucleoli, and minimal cytoplasm. Cytologic atypia, increased mitoses, and necrosis are not common features. The background matrix typically calcifies over time, forming so-called “grungy” or disorganized hard tissue. Additionally, the matrix may show attempts at organization into immature chondroid or osteoid material. PMTs contain mature adipose connective tissue, osteoclast-like giant cells, peripheral ossification, cystic change, and metaplastic bone with some frequency. They can mimic other mesenchymal tumors, so immunohistochemistry and correlation with clinical and laboratory findings (low phosphate levels) are essential for accurate diagnosis (Chatterjee et al, 2021). The majority of PMTs are positive for CD56, ERG, FGFR1, SATB2, and SSTR2A by immunohistochemistry, but these markers are somewhat nonspecific. Overexpression of FGF23 by in situ hybridization is more diagnostically helpful, as is demonstration of a FN1::FGFR1 or FN1::FGF1 fusion, identified in the majority of PMTs.

Most PMTs act in a benign manner and are adequately treated with complete surgical excision (Folpe AL, 2020). Patients’ symptoms related to hypophosphatemia significantly improve when FGF23 overproduction by the tumor ceases. However, some PMTs exhibit significant cytologic atypia, increased cellularity, necrosis, and elevated mitotic activity. These lesions are termed malignant PMT, and they have the potential to recur and metastasize. Although no formal staging system exists, careful assessment of histologic features of each PMT case may help to assess the patient's risk of these adverse events.

Funding

This research was not supported by any funding from agencies in the public, commercial, or not-for-profit sectors.

Authorship Contribution Statement

WAGA acted as the Case Discussant at IAOP 2024 and conceived of and wrote the differential diagnosis section. ACM acted as the Case Contributor at IAOP 2024 and conceived of and wrote all other sections and provided clinical and histologic images. Both authors contributed to the references.