A 54‐Year‐Old Male with Multiple Intracranial and Extracranial Masses

Clinical History

A 54‐year‐old male presented with left vision loss, headache and left‐sided facial pain. On physical examination, medial and inferior displacement of the left eye was noted. He had a remote history of intracranial surgeries 17 and 5 years prior to this admission which included a left frontotemporal craniectomy, partial resection of the left anterior temporal lobe and sinonasal surgeries. Magnetic resonance post‐contrast images showed enhancing lesions on the left side adjacent to the optic nerve, in the anterior temporal lobe, fronto‐ethmoid sinus (Figure 1A), parasellar region, skull base, right dura, nasal cavities and nasopharynx. A body positron emission tomography scan demonstrated evidence of tumor in the left deep cervical lymph nodes. Eight months later, intradural masses were noted in the cauda equina, thoracic paravertebral region and lumbar vertebral bodies. The nasopharyngeal mass was biopsied.

Figure 1.

 

Microscopic Pathology

Multiple, irregular, tan, soft tissue fragments measuring 2.4 × 1.9 × 0.4 cm in aggregate were formalin‐fixed and processed using standard techniques. Sections stained with H&E showed a highly cellular tumor with cells arranged in sheets and indistinct lobules separated by fibrovascular tissue (Figure 1B). Microvascular proliferation was present (Figure 1C). Tumor cells showed nuclear pleomorphism and mitoses (arrowheads, Figure 1B,C) which averaged 4/10 high power fields (HPFs). Few areas of necrosis were also present. Tumor cells did not express cytokeratin (CK8/18) (Figure 1D) but showed strong synaptophysin (Figure 1E) and p53 immunoreactivity (Figure 1F). The Ki‐67 labeling index was high (Figure 1G) being 33%. What is your diagnosis?

Diagnosis

Growth hormone‐secreting pituitary carcinoma.

Discussion

This patient with acromegaly and elevated serum growth hormone (GH) and insulin‐like growth factor‐1 levels had an initial diagnosis of growth hormone‐secreting pituitary adenoma 17 years prior to admission. Subsequent growth characteristics led to a clinical diagnosis of pituitary carcinoma, 5 years prior to the current admission. Growth hormone immunoreactivity in tumor cells was also observed in the current biopsy specimen.

The differential diagnosis includes recurrent pituitary adenoma, atypical pituitary adenoma and pituitary carcinoma. Typical pituitary adenomas are well‐defined and may show expansive growth but do not invade the adjacent structures 2. Though some GH‐secreting adenomas can show pleomorphism 2, significant pleomorphism is absent. Mitoses are infrequent and the Ki‐67 proliferation index is usually <3% 1, 3. Atypical adenomas comprise less than 5% of pituitary adenomas and show aggressive features 4. They may invade the sphenoid or cavernous sinus or clivus, possibly indicating high risk of progression to pituitary carcinoma 1, 3. Other features include a mitotic rate of 2/10 HPFs, Ki‐67 proliferation index of >3% and p53 nuclear positivity in 15% of tumors 1, 2, 3. The presence of non‐contiguous craniospinal and/or systemic metastases is necessary for the diagnosis of pituitary carcinoma, as histological features alone are non‐diagnostic. However, a Ki‐67 index of >10% should raise suspicion of malignant potential 2. Pituitary carcinomas are consistently immunoreactive for p53 1, 2, and mitoses are frequent (>6/10HPFs) 2. In this patient, mitoses were not as frequent in the small sample received. However, in addition to the contiguous spread, the presence of non‐contiguous cranial, spinal and lymph node metastases indicated pituitary carcinoma.

Pituitary carcinomas are extremely rare and represent only 0.2% of pituitary tumors 1. Most of the pituitary carcinomas arise from pre‐existing adenomas 2 with a latency period of 2–10 years 4. Less commonly, pituitary carcinomas arise de novo 1, 2, 3, 4. Symptoms of pituitary carcinoma result from mass effect and hormone secretion, and may be clinically indistinguishable from pituitary adenomas 1, 2. However, patients occasionally present with unusual symptoms such as hearing loss and ataxia 2. Most pituitary carcinomas secrete adreno‐corticotropic hormone or prolactin 2 while only 5% are GH secreting 4. Metastases are typically found in the cerebral cortex, cerebellum, spinal cord, leptomeninges, eyes, cervical lymph nodes, heart, lung, liver, pancreas, kidney, pelvic lymph nodes, and bone 1, 2. There are fewer than 20 reported cases of intraspinal metastases 4, including this case. Patients with metastases outside the central nervous system usually die within 1 year 2.

Vascular endothelial growth factor‐A (VEGF‐A) has been implicated in aggressive tumor behavior 3. Additionally, matrix metalloproteinase activity is increased, promoting degradation of the extracellular matrix, which facilitates angiogenesis and invasion 1, 2. Cytogenetic abnormalities include gains of chromosomes 5, 7p, 14q 2 and chromosome 11p deletions 1. Truncated fibroblast growth factor receptor‐4 has been associated with pituitary tumor invasion in animal models 1. As of yet, there are no convincing molecular markers to predict future aggressive or malignant behavior of pituitary adenomas 3.

Tumor debulking is important for symptomatic relief but is rarely curative due to the aggressive and infiltrative nature of the carcinoma 1, 2. Radiotherapy prevents further tumor growth and may even shrink the size of the tumor. However, hormone elevation can persist for months after treatment 1. There is no standardized chemotherapy protocol as randomized, prospective clinical trials are lacking 1. During his prolonged course, this patient underwent several intranasal, intracranial and gamma knife surgeries, and also received radiation and chemotherapy with temozolomide. Finally, he received bevacizumab, a VEGF‐A inhibitor, and responded well. His case is exceptional due to survival for more than 3 years with cranial, spinal and systemic metastases. Such a case with long‐term follow‐up will further elucidate prognosis in patients with this rare disease.