Pituicytoma and Cushing’s Disease in a 7-Year-Old Girl: A Mere Coincidence?
Pituicytoma is a tumor extremely rare in childhood, with only 4 cases reported in literature. It is thought to arise from the specialized glial elements called “pituicytes.” The association of pituicytoma and Cushing’s disease (CD) has been described only once so far, in an adult patient. A 7-year-old girl was referred for clinical signs of hypercortisolism, and a diagnosis of CD was made. MRI revealed 2 pathologic areas in the pituitary gland. The patient underwent surgery, with microscopic transsphenoidal approach, and a well-circumscribed area of pathologic tissue was identified and removed. Surprisingly, histologic and immunohistochemical study provided unequivocal evidence of pituicytoma. No pituitary adenoma could be identified. For persistent hypercortisolism, the patient necessitated transsphenoidal endoscopic reintervention and 2 other lesions were removed. By immunohistological examination, these lesions were confirmed to be corticotropin-secreting adenoma. Unfortunately, there was no postoperative decrease in corticotropin and cortisol levels, and the patient underwent bilateral laparoscopic adrenalectomy. Considering that we report a second case of association of pituicytoma and corticotropin-secreting adenoma, that CD is infrequent, and pituicytoma is extremely rare in childhood, the coexistence of these 2 tumors should not be considered a mere coincidence. To date, there is no conclusive evidence about the origin of these different subtypes of pituitary tumors. This case supports the hypothesis that these tumors share a common progenitor cell, which could be the folliculostellate cell.
- CD —
- Cushing’s disease
- FSC —
- folliculostellate cell
- GFAP —
- glial fibrillary acidic protein
- SCO —
- spindle cell oncocytoma
To better delineate neoplasm manifesting in the neurohypophysis and pituitary stalk, the World Health Organization, in 2007, proposed to add a new entity, the pituicytoma, to the international classification of human tumors. This extremely rare neoplasm is thought to arise from the specialized glial elements called “pituicytes.” According to the current World Health Organization classification of central nervous system tumors, pituicytoma is considered a rare, low grade, glial neoplasm of adults with low proliferative potential and possibility of cure after surgical resection alone.1 Histologically, it is composed of solid sheets of elongate bipolar spindle cells arranged in fascicles or with storiform pattern. Pituicytomas usually express vimentin and S100 protein, whereas the expression of glial fibrillary acidic protein (GFAP) is variable. Clinical signs and symptoms are related to mass effect, with compression of the optic chiasm and pituitary gland, and consequent headache, visual disturbance, and hypopituitarism. To our knowledge, a total of 75 cases of pituicytoma have been reported and, among them, only 1 occurred in association with Cushing’s disease (CD)2 and 2 with not clearly defined hypercortisolism.3,4 Only 4 pediatric patients5 with pituicytoma have been described so far. We report the first case of a 7-year-old girl with pituicytoma in association with corticotropin secreting adenoma.
A 7-year-old girl was referred to our department for precocious pubarche, reduced growth velocity, increasing weight gain, and progressive muscular weakness. On clinical examination, she showed moon face, central obesity, and generalized hypertrichosis. Her height was 108.7 cm (−2.6 SD), her weight 25.8 kg (0.9 SD), with a BMI of 21.89 (2.5 SD). The resting blood pressure was 90/60 mm Hg. Midnight serum cortisol and corticotropin levels were elevated, respectively, 24.26 μg/dL (669.28 nmol/L) and 33.7 pg/mL (7.41 pmol/L), as well as urinary free cortisol (897.6 μg/24 hours). Overnight 1-mg and low-dose dexamethasone suppression test (30 µg/kg per day for 2 days) were unable to suppress serum cortisol. Three Tesla MRI (MRI 3T) of the pituitary gland, before and after intravenous gadolinium administration, revealed an enlarged pituitary gland associated to a bulged and convex profile of the diaphragma sellae and a shortened pituitary stalk. A small hyperintense (T2-weighted images) area on the mesial and upper portion of the gland and a small hypointense (T1-VIBE dynamic study) area in its median and paramedian left side were also detected (Fig 1 A, B, C, and D). The patient underwent bilateral inferior petrosal sinus blood sampling, before and after corticotropin-releasing hormone administration. The central/peripheral plasma corticotropin gradient after corticotropin-releasing hormone (1.53) was not diagnostic, and intersinus gradient (1.04) was suggestive of a midline lesion. At surgery (microscopic transsphenoidal approach), after dural opening and careful inspection of the gland, no frank adenoma was found; a well-circumscribed area of pathologic tissue on the left side of the pituitary was identified anyway and removed. Histologically, the pathologic tissue revealed a compact architecture consisting of elongate spindle cells arranged in a storiform pattern; immunohistochemical staining of the tumor demonstrated strong positivity for vimentin and S-100 protein; some cells were positive for GFAP. Chromogranin A stained adjacent normal pituitary gland cells, but not pituicytoma cells. Epithelial membrane antigen and synaptophysin were negative too (synaptophysin highlighted residual neurohypophysis parenchyma). No cytoplasmic granularity or vacuolization were found, and only rare mitotic figures were identified (MIB-1 labeling index <1%; Fig 2). These findings provided unequivocal evidence of pituicytoma. No pituitary adenoma could be identified. The postoperative corticotropin and cortisol levels did not return to the normal range, and a second MRI-3T with dynamic study was performed. The study revealed a reduction in the size of adenohypophysis, a hyperintense area in the region of the removed pituicytoma in T2-weighted images (considered a consequence of surgery), and the persistence of the smaller hypointense area previously described (Fig 1 E, F, G, and H). Even if the absence of a significant central/peripheral plasma ratio does not necessarily imply ectopic secretion of corticotropin,6 positron emission tomography was preoperatively performed for additional exclusion of ectopic corticotropin source, without any identification of neoplastic areas. During the following endoscopic reintervention, pathologic whitish tissue, localized in the context of the median/paramedian left side of the pituitary gland, was found and removed, together with an additional pathologic area in the context of the paramedian right side of the pituitary gland. Histologic examination revealed a solid cellular proliferation composed by biphasic population: groups large cells with abundant cytoplasm containing basophilic secretory granules positive for corticotropin and sheets of medium-sized cells containing eosinophilic granules, positive for growth hormone (not shown). Few cells were positive for prolactin. Thyrotropin, luteinizing hormone, and follicle-stimulating hormone resulted negative. As mild nuclear atypia and low proliferative index (0% to 1%) were observed, a grade I pituitary adenoma diagnosis was formulated (Fig 3 A and B). Unfortunately, there was no postoperative decrease in corticotropin and cortisol levels. Considering the young age of the patient and the available therapeutic options, bilateral laparoscopic adrenalectomy was performed. The histologic examination revealed a diffuse adrenocortical hyperplasia secondary to excessive corticotropin production.
Pituicytoma is a rare neoplasm of the sellar and suprasellar region, arising from the pituicytes of the neurohypophysis or the infundibulum.1 To date, approximatively only 75 cases have been reported.3,7 The most frequent symptoms of pituicytoma are visual impairment and headache. Patients can also present endocrine disturbances, such as hyperprolactinemia, hypogonadotropic hypogonadism, or hypopituitarism. In just a few patients, pituicytoma was incidentally discovered.8 Uncommon in adults, it is extremely rare in childhood, with just 4 cases described so far, in children of age between 7 and 17 years.3,5 All these children presented with visual impairment and headache, whereas short stature, as a possible sign of endocrine disturbance, was reported only in 1.5
It is well known that pituicytoma is not a secreting tumor and that the endocrine symptoms, related to its presence, are due to the loss of pituitary function, caused by mass effect, rather than to pituitary hyperfunction. However, slightly elevated serum corticotropin levels were found in 1 patient,4 and symptomatic corticotropin hypersecretion, resolved by removing a pituicytoma, has been recently described in another 24-year-old man.3
Differently from these cases, in our patient there was a coexistence of asymptomatic pituicytoma and corticotropin-secreting adenoma. The former should be considered incidentally discovered, because the girl manifested only symptoms of CD obviously persisting after the surgical removal of the pituicytoma. The same tumor association has been recently reported, for the first time, in an adult man. As in our case, the pituicytoma was asymptomatic and incidentally detected during operation for CD.2 The authors wondered whether an association between pituicytomas and endocrine tumors actually exists or whether, in their case, it was coincidental. Considering that we report a second case of this association, that CD is infrequent, and pituicytoma is extremely rare in childhood, the coexistence of these 2 tumors should not be considered a mere coincidence.
It is generally considered that pituicytomas are primary tumors of the neurohypophysis, presumably arising from the pituicytes. Pituicytes are GFAP immunoreactive spindle or stellate cells that are believed to regulate neurohypophysial hormone secretion. However, ultrastructural findings from a single case, revealing transitional features between a pituicytoma and a pituitary adenoma, suggested, for the first time, its possible origin from adenohypophysis folliculostellate cells (FSCs).9 FSCs are S-100-immunoreactive spindle to stellate-shaped cells that are believed to regulate the activity of anterior pituitary endocrine cells through the production of cytokines and growth factors. In the normal pituitary gland, FSCs are concentrated near the center of adenohypophyseal lobules and are the only cells expressing bcl-2, an oncoprotein that inhibits apoptosis and plays a role in the progression of various tumor types. Moreover, some cases of pituicytomas revealing focal expression of bcl-2 have been reported.10,11 Ulm et al10 speculate that, if a potential for multilineage differentiation can be definitively demonstrated for FSCs, neoplastic transformation of such a cell might lead to different subtypes of pituitary tumors, including adenomas, spindle cell oncocytomas (SCOs), and even pituicytomas. More recently, other findings consistent with the idea of a common histogenesis for pituicytomas and SCOs have been reported,7 and SCOs are usually considered as derived from FSCs.
To date, there is no conclusive evidence about the origin of these different subtypes of pituitary tumors. We think that this case can contribute to the debate on the origin of pituicytoma. The association of corticotropin-secreting adenoma and the pituicytoma in both our case and the case in Schmalisch et al,2 supports the hypothesis that these tumors share a common progenitor cell, which could be FSC.
- Accepted August 24, 2015.
- Address correspondence to Donato Amodio, Immune and Infectious Diseases Unit, University Department of Pediatrics, University of Rome Tor Vergata, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio, 4 00165 Rome, Italy. E-mail:
Drs Cambiaso and Amodio took care of patient and drafted the initial manuscript; Dr Procaccini took care of patient, and critically reviewed the manuscript; Drs Longo, Galassi, and Diomedi Camassei critically reviewed the manuscript; Dr Cappa reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Copyright © 2015 by the American Academy of Pediatrics