pituitary

Pituitary apoplexy

Pituitary apoplexy

Definition

Pituitary apoplexy (PA) is a clinical condition characterized by a sudden increase in pituitary gland volume secondary to ischemia and/or necrosis.

Key concepts

● due to the expansion of a pituitary neuroendocrine tumor from hemorrhage or necrosis

● typical presentation: paroxysmal H/A with endocrinologic and/or neurologic deficit (usually ophthalmoplegia or visual loss)

● management: immediate administration of glucocorticoids, and transsphenoidal decompression within 7 days in most cases.

Epidemiology

Pituitary apoplexy epidemiology.

Classification

It is important to note that pituitary apoplexy may be divided into hemorrhagic or ischemic, each with unique neuroimaging findings.

Etiology

Pituitary apoplexy etiology.

Pathophysiology

Some postulate that a gradual enlarging pituitary tumor becomes impacted at the diaphragmatic notch, compressing and distorting the hypophyseal stalk and its vascular supply. This deprives the anterior pituitary gland and the tumor itself of its vascular supply, apoplectically causing ischemia and subsequent necrosis.

Another theory stipulates that rapid expansion of the tumor outstrips its vascular supply, resulting in ischemia and necrosis. This explanation is doubtful, since most tumors that undergo apoplexy are slow growing.

Cerebral ischemia due to pituitary apoplexy is very rare. It may be caused by vasospasm or direct compression of cerebral vessels by the tumor.

Clinical features

Pituitary apoplexy clinical features.

Diagnosis

Pituitary apoplexy diagnosis.

Differential diagnosis

Seung et al., present an unusual case of bitemporal hemianopsia caused by a large anterior communicating artery aneurysm.

A 41-year-old woman was admitted to our neurosurgical department with a sudden-onset bursting headache and visual impairment. On admission, her vision was decreased to finger counting at 30 cm in the left eye and 50 cm in the right eye, and a severe bitemporal hemianopsia was demonstrated on visual field testing. A brain computed tomography scan revealed a subarachnoid hemorrhage at the basal cistern, and conventional cerebral catheter angiography of the left internal carotid artery demonstrated an 18×8 mm dumbbell-shaped aneurysm at the ACoA. Microscopic aneurysmal clipping was performed. An ACoA aneurysm can produce visual field defects by compressing the optic chiasm or nerves.

Seung et al., emphasize that it is important to diagnose an aneurysm through cerebrovascular study to prevent confusing it with pituitary apoplexy 1).

A 52-year-old woman, previously diagnosed with asymptomatic Rathke cleft cyst (RCC), came with a severe headache, along with visual dysfunction and symptoms of pituitary insufficiency. Fluid-attenuated inversion recovery magnetic resonance imaging demonstrated diffuse hyperintensity in the cerebral cisterns, whereas watery clear cerebrospinal fluid was obtained by lumbar puncture. Surgery performed 1 month after onset revealed a nonhemorrhagic lesion, with a final diagnosis of nonhemorrhagic RCC rupture.

Yokota et al., conclude that nonhemorrhagic RCC rupture and subsequent leakage of the contents into subarachnoid space were the underlying pathogenesis in the present case of RCC resembling apoplexy 2).

Treatment

Pituitary apoplexy treatment.

Outcome

see Pituitary apoplexy outcome.

Case series

Pituitary apoplexy case series.

Case reports

Pituitary apoplexy case reports.

Pituitary apoplexy in Dogs

Nineteen cases of suspected Pituitary apoplexy were included. The majority of dogs showed behavioural abnormalities (11/19). Neurological signs more frequently identified were obtundation (7/19), vestibular signs (7/19) and epileptic seizures (6/19). The onset of neurological signs was per-acute in 14 out of 19 cases. Data regarding CT and MRI were available in 18 and 9 cases, respectively. Neurological signs resolved in less than 24 h in seven patients. The short-term prognosis was defined as favourable in the majority of the study population. The median survival time was of 7 months from the time of PA diagnosis. This is the first description of neurological signs, imaging findings and outcome in a large group of dogs with PA 3).

References

1)

Seung WB, Kim DY, Park YS. A Large Ruptured Anterior Communicating Artery Aneurysm Presenting with Bitemporal Hemianopsia. J Korean Neurosurg Soc. 2015 Sep;58(3):291-3. doi: 10.3340/jkns.2015.58.3.291. Epub 2015 Sep 30. PubMed PMID: 26539276; PubMed Central PMCID: PMC4630364.
2)

Yokota H, Ida Y, Wajima D, Nishimura F, Nakase H. Rathke Cleft Cyst with Evidence of Rupture into Subarachnoid Space. World Neurosurg. 2016 Oct 21. pii: S1878-8750(16)31061-0. doi: 10.1016/j.wneu.2016.10.072. [Epub ahead of print] PubMed PMID: 27777166.
3)

Galli G, Bertolini G, Dalla Serra G, Menchetti M. Suspected Pituitary Apoplexy: Clinical Presentation, Diagnostic Imaging Findings and Outcome in 19 Dogs. Vet Sci. 2022 Apr 15;9(4):191. doi: 10.3390/vetsci9040191. PMID: 35448689.

Pituitary adenoma recurrence

Pituitary adenoma recurrence

Tumor recurrence or residual regrowth are poor prognosis for pituitary adenoma.

A comprehensive review of the literature quantified the pituitary adenoma recurrence rates for commonly observed pituitary adenomas after transsphenoidal surgical resection with curative intent. Findings suggest that surveillance within 1 year may be of low yield. Further, clinical trials and cohort studies investigating the cost-effectiveness of surveillance schedules and their impact on the quality of life of patients under surveillance will provide further insight to optimize follow-up 1).

The old 2004 World Health Organization classification introduced atypical adenoma, which was equivocally defined as an invasion with increased mitotic activity that had a Ki67 labeling index (LI) greater than 3%, and extensive p53 immunoreactivity. However, aPAs that exhibit all of these features are rare and the predictive value for recurrent pituitary adenomas (PAs) remains uncertain.

Remission is lowest in patients with nonfunctioning adenomas, and recurrence is highest in patients with a prolactinoma. The remission rate has not improved over 3 decades of publication, but there is a modest decrease in recurrences with time. The highest incidence of tumor recurrence is between 1 and 5 years after surgery. Surgery-related hypopituitarism was highest in Cushing’s disease. The most important predictor for recurrence is the postoperative basal (non-stimulated) hormone level in functioning adenomas, while in nonfunctioning adenomas no single convincing factor could be identified 2).

With a high rate of recurrence, Nonfunctioning pituitary adenomas (NFPA) should be closely followed-up over a long-term period. Improvement of surgical techniques with advanced surgical equipment and adjuvant radiosurgery would lead to reduce the recurrence rate and improve patients’ outcome 3).

Pituitary adenoma recurrence risk

Postoperative residue, age, immunohistological subtypes, invasion, tumor size, hormone levels, and postoperative radiotherapy can predict the risk of recurrence in patients with PAs. Additionally, biomarkers such as Ki-67, p53, cadherin, pituitary tumor transforming gene, matrix metalloproteinase-9, epidermal growth factor receptor, fascin actin-bundling protein 1, cyclooxygenase-2, and some miRNAs and lncRNAs may be utilized as valuable tools for predicting PA recurrence. As no single marker can independently predict PA recurrence, we introduce an array of comprehensive models and grading methods, including multiple prognostic factors, to predict the prognosis of PAs, which have shown good effectiveness and would be beneficial for predicting PA recurrence 4).

There is no validated and well-accepted prognostic classification of PAs to predict the clinical outcome and guide clinical practice. Tumor recurrence or residual regrowth identified by MRI scans and endocrine studies and associated clinical and pathological characteristics were analyzed for patients who underwent surgery in the years 2008-2016 at West China Hospital. Thereby, a new clinicopathological classification was proposed and applied.

After a median follow-up of 44.0 months, tumor recurrence and residual progression were identified in 48 (25.0%) and 29 (37.2%) cases, respectively. Proliferative potential (HR=2.188, p=0.002), invasiveness (HR=1.698, p=0.029), larger tumor size (HR=1.029, p=0.004), high-risk PA subtype (HR=2.151, p=0.004) and postoperative residual (HR=1.941, p=0.007) were risk factors for recurrence/progression in the early stage after surgery. With respect to clinicopathological classification, compared with Grade 1a tumors, Grade 1b, 2a and 2b adenomas had poorer prognoses with an increased probability of tumor recurrence/progression of 5.133-, 4.467- and 20.1-fold, respectively.

The proposed clinicopathological classification of PAs showed significant value in predicting prognosis and succeeded in identifying cases with more clinically aggressive lesions with recurrence or residual regrowth. This prognostic classification may be helpful when identifying aggressive PAs and deciding the appropriate therapeutic strategy for patients with PAs 5).

1)

Caulley L, Whelan J, Khoury M, Mavedatnia D, Sahlollbey N, Amrani L, Eid A, Doyle MA, Malcolm J, Alkherayf F, Ramsay T, Moher D, Johnson-Obaseki S, Schramm D, Hunink MGM, Kilty SJ. Post-operative surveillance for somatotroph, lactotroph and non-functional pituitary adenomas after curative resection: a systematic review. Pituitary. 2022 Nov 23. doi: 10.1007/s11102-022-01289-x. Epub ahead of print. PMID: 36422846.
2)

Roelfsema F, Biermasz NR, Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary. 2012 Mar;15(1):71-83. doi: 10.1007/s11102-011-0347-7. Review. PubMed PMID: 21918830; PubMed Central PMCID: PMC3296023.
3)

Lee MH, Lee JH, Seol HJ, Lee JI, Kim JH, Kong DS, Nam DH. Clinical Concerns about Recurrence of Non-Functioning Pituitary Adenoma. Brain Tumor Res Treat. 2016 Apr;4(1):1-7. doi: 10.14791/btrt.2016.4.1.1. Epub 2016 Apr 29. PubMed PMID: 27195254; PubMed Central PMCID: PMC4868810.
4)

Lu L, Wan X, Xu Y, Chen J, Shu K, Lei T. Prognostic Factors for Recurrence in Pituitary Adenomas: Recent Progress and Future Directions. Diagnostics (Basel). 2022 Apr 13;12(4):977. doi: 10.3390/diagnostics12040977. PMID: 35454025; PMCID: PMC9024548.
5)

Lv L, Yin S, Zhou P, Hu Y, Chen C, Ma W, Jiang Y, Wang Z, Jiang S. Clinical and pathological characteristics predicted the postoperative recurrence and progression of pituitary adenoma: a retrospective study with 10 years follow-up. World Neurosurg. 2018 Jul 4. pii: S1878-8750(18)31426-8. doi: 10.1016/j.wneu.2018.06.210. [Epub ahead of print] PubMed PMID: 29981466.

Pituitary adenoma

Pituitary adenoma

Pituitary adenoma (PA) is a common pituitary tumor that arises from the adenohypophysis, in the pituitary gland.

Epidemiology

Pituitary adenoma epidemiology.

Classification

see Pituitary adenoma classification.

Risk factors

Pituitary tumors have very few known risk factors, and these are related to genetics. There are no known environmental or lifestyle-related risk factors for pituitary tumors. Though science has suggested that people who are overweight or obese might be at increased risk.

Youn et al. discovered that a 3’untranslated region (3’UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA.

Although further studies are needed to verify the impact of this variant on pituitary adenoma susceptibility, the results may help to understand CDKN2B polymorphism and the risk of pituitary adenoma 1).

Genetic syndromes

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 4

McCune-Albright syndrome

Carney complex

Pathogenesis

Pituitary adenoma pathogenesis

Natural History

see Pituitary adenoma Natural History.

Clinical features

see Pituitary adenoma clinical features.

Diagnosis

Pituitary Adenoma Diagnosis.

Treatment

see Pituitary adenoma treatment.

Outcome

Pituitary Adenoma Outcome.

Recurrence

see Pituitary adenoma recurrence.

Case series

see Pituitary adenoma case series.

1)

Youn BJ, Cheong HS, Namgoong S, Kim LH, Baek IK, Kim JH, Yoon SJ, Kim EH, Kim SH, Chang JH, Kim SH, Shin HD. Asian-specific 3’UTR variant in CDKN2B associated with risk of pituitary adenoma. Mol Biol Rep. 2022 Sep 12. doi: 10.1007/s11033-022-07796-1. Epub ahead of print. PMID: 36097105.

Clinically non-functioning pituitary adenoma

Clinically non-functioning pituitary adenoma

Clinically non-functioning pituitary adenoma (CNFPA) is currently the preferred term for designing all the pituitary adenomas which are not hormonally active (in other words, not associated with clinical syndromes such as amenorrhea–galactorrhea in the context of Lactotroph adenomas, acromegaly, Cushing’s disease or hyperthyroidism secondary to TSH secreting pituitary adenoma).

Epidemiology

see Clinically non-functioning pituitary adenoma epidemiology.

Natural history

Clinically non-functioning pituitary adenoma natural history.

Classification

Clinically non-functioning pituitary adenoma classification.

Pathogenesis

Clinically non-functioning pituitary adenoma pathogenesis.

Clinical features

Clinically non-functioning pituitary adenoma clinical features.

Scores

Knosp Grade

Diagnosis

Clinically non-functioning pituitary adenoma diagnosis.

Differential diagnosis

Clinically non-functioning pituitary adenoma differential diagnosis

Treatment

see Clinically non-functioning pituitary adenoma treatment.

Outcome

see Clinically Non-functioning Pituitary Adenoma Outcome.

Case series

see Clinically non-functioning pituitary adenoma case series.

Case reports

Clinically non-functioning pituitary adenoma case reports

German Pituitary Tumor Registry

German Pituitary Tumor Registry

In 1996, the German Registry of Pituitary Tumors was founded by the Pituitary Section of the German Society of Endocrinology as a reference center for collection and consultant pathohistological studies of pituitary tumors.

The collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with H&E stain and PAS. Monoclonal (prolactin, TSH, FSH, LH, and alpha subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factors Pit-1, T-Pit, and SF-1 has been used in difficult cases. The criteria of the The 2017 World Health Organization classification of tumors of the pituitary gland have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H&E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed.

Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions.

From the studies, Schöning et al. concluded that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended 1).

Inflammatory pituitary lesions account for 1.8% of all specimens from the German Pituitary Tumor Registry. They occur in 0.5% of the autoptical specimens and in 2.2% of the surgical cases. Women are significantly more often affected than men and are often younger when first diagnosed. In general, primary and secondary inflammation can be distinguished, with secondary types occurring more frequently (75.1%) than idiopathic inflammatory lesions (15.4%). In primary inflammation, the lymphocytic type is more common (88.5%) than the granulomatous type of hypophysitis (11.5%). The most common causes of secondary inflammation are Rathke’s cleft cysts (48.6%), followed by tumors (17.4%) such as craniopharyngioma (9.1%), and adenoma (5.5%) or germinoma (2.0%). More causes are tumor-like lesions (7.1%) such as xanthogranuloma (3.5%) or Langerhans histiocytosis (3.5%), abscesses (5.5%), generalized infections (5.1%), spread inflammations (4.7%) and previous surgeries (4.0%). In 1.6% of all specimens, the reason for the inflammation remains unclear. The described classification of hypophysitis is important for specific treatment planning after surgery 2).

Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for the expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA).

In accordance with the literature, combinations of GH/prolactin/TSH-FSH/LH adenoma (4/12), GH/prolactin/TSH-ACTH adenoma (3/12), and ACTH-FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression patterns of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analyzed in 4 patients displayed distinct copy number changes and global methylation patterns.

The data confirm and extend the knowledge on multiple PAs and suggest that such lesions may originate from distinct cell types 3).

Between 1996 and 2020, 12,565 cases were enrolled in the German Registry of Pituitary Tumors including 10,084 PitNETs (10,067 adenomas and 19 carcinomas obtained surgically and 193 adenomas diagnosed at autopsy) as well as 69 spindle cell tumors of the neurohypophysis (64 surgical specimens and 5 autopsies). In six patients (1 post-mortem and 5 surgical specimens), PitNETs, as well as posterior lobe tumors, were found in the specimens. Two of the PitNETs were sparsely granulated prolactin-producing tumors, combined in one case with a granular cell tumor and in one case with a pituicytoma. One of the PitNETs revealed that the autopsy was a sparsely granulated GH tumor combined with a neurohypophyseal granular cell tumor. Two PitNETs were null cell adenomas combined with a pituicytoma and a spindle cell oncocytoma, respectively. Further, one Crooke cell tumor was combined with a spindle cell oncocytoma. In five cases, the PitNETs were larger than the posterior lobe tumors and accounted for the clinical symptoms. Previously, four cases of co-existing pituitary anterior and posterior lobe tumors were described in the literature, comprising two ACTH PitNETs, one gonadotrophic PitNET and one null cell PitNET, each in combination with a pituicytoma. PitNETs and concomitant granular cell tumor or spindle cell oncocytoma, as observed in our cohort, have not been reported before 4).

The first 10 years of this registry based on 4122 cases were reported by Saeger et al. The data supplement former collections of the years 1970-1995 with 3480 surgically removed tumors or lesions of the pituitary region. The cases were studied using histology, immunostainings, and in some cases also molecular pathology or electron microscopy. The adenomas were classified according to the current World Health Organization classification in the version of 2004. From 1996 on 3489 adenomas (84.6%), 5 pituitary carcinomas (0.12%), 133 craniopharyngiomas (3.2%), 39 meningiomas (0.94%), 25 metastases (0.6%), 22 chordomas (0.5%), 115 cystic non-neoplastic lesions (2.8%), and 46 inflammatory lesions (1.1%, 248 other lesions or normal tissue (6.0%)) were collected by us. The adenomas (100%) were classified into densely granulated GH cell adenomas (9.2%), sparsely granulated GH cell adenomas (6.3%), sparsely granulated prolactin (PRL) cell adenomas (8.9%), densely granulated PRL cell adenomas (0.3%), mixed GH/PRL cell adenomas (5.2%), mammosomatotropic adenomas (1.1%), acidophilic stem cell adenomas (0.2%), densely granulated ACTH cell adenomas (7.2%), sparsely granulated ACTH cell adenomas (7.9%), Crooke cell adenomas (0.03%), TSH cell adenomas (1.5%), FSH/LH cell adenomas (24.8%), null cell adenomas (19.3%), null cell adenoma, oncocytic variant (5.8%), and plurihormonal adenomas (1.3%). Following the WHO classification of 2004, the new entity ‘atypical adenoma’ was found in 12 cases in 2005. Various prognostic parameters and clinical implications are discussed 5)

1)

Schöning JV, Flitsch J, Lüdecke DK, Fahlbusch R, Buchfelder M, Buslei R, Knappe UJ, Bergmann M, Schulz-Schaeffer WJ, Herms J, Glatzel M, Saeger W. Multiple tumorous lesions of the pituitary gland. Hormones (Athens). 2022 Aug 10. doi: 10.1007/s42000-022-00392-9. Epub ahead of print. PMID: 35947342.
2)

Warmbier J, Lüdecke DK, Flitsch J, Buchfelder M, Fahlbusch R, Knappe UJ, Kreutzer J, Buslei R, Bergmann M, Heppner F, Glatzel M, Saeger W. Typing of inflammatory lesions of the pituitary. Pituitary. 2022 Feb;25(1):131-142. doi: 10.1007/s11102-021-01180-1. Epub 2021 Aug 31. PMID: 34463941; PMCID: PMC8821060.
3)

Hagel C, Schüller U, Flitsch J, Knappe UJ, Kellner U, Bergmann M, Buslei R, Buchfelder M, Rüdiger T, Herms J, Saeger W. Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles. Pituitary. 2021 Dec;24(6):904-913. doi: 10.1007/s11102-021-01164-1. Epub 2021 Sep 3. PMID: 34478014; PMCID: PMC8550269.
4)

Saeger W, von Schöning J, Flitsch J, Jautzke G, Bergmann M, Hagel C, Knappe UJ. Co-occurrence of Pituitary Neuroendocrine Tumors (PitNETs) and Tumors of the Neurohypophysis. Endocr Pathol. 2021 Dec;32(4):473-479. doi: 10.1007/s12022-021-09677-y. Epub 2021 Jun 15. PMID: 34129177.
5)

Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007 Feb;156(2):203-16. doi: 10.1530/eje.1.02326. PMID: 17287410.

Invasive pituitary adenoma

Invasive pituitary adenoma

Invasive pituitary adenomas are benign pituitary tumors that infiltrate the dura mater, cranial bone, or sphenoid sinus. Gross invasion at the time of operation is observed in up to 35 % of pituitary adenomas 1) 2) 3).

Clinically nonfunctioning pituitary adenoma (NFPA) is a very common type of intracranial tumor, which can be locally invasive and can have a high recurrence rate.

Atypical or aggressive pituitary adenomas are tumors that rapidly increase in size and may invade into the suprasellar or parasellar regions. They are characterized by a Ki-67 nuclear labeling index greater than 10 %.

Molecular markers

Invasive pituitary adenoma molecular markers.

Clinical features

They can be presented as Non-pulsatile exophthalmos.

Infrequently they produce cerebrospinal fluid rhinorrhea.

Differential diagnosis

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable from pituitary adenoma until identification of metastases.

Treatment

Invasive pituitary adenoma treatment.

Outcome

Aggressive pituitary adenomas (APAs) are pituitary tumors that are refractory to standard treatments and carry a poor prognosis.

Case reports

A 57-year-old man presented with visual deterioration and bitemporal hemianopsia. MRI of the brain demonstrated a sellar mass suspected to be pituitary macroadenoma with a displacement of the stalk and optic nerve impingement. The patient underwent stereotactic endoscopic transsphenoidal resection of the mass. Postoperative MRI demonstrated gross total resection. Pathology revealed a sparsely granulated corticotroph adenoma with malignant transformation. Immunohistochemistry showed a loss of expression of MLH1 and PMS2 in the tumor cells. Proton therapy was recommended given an elevated Ki67 index and p53 positivity. Before radiotherapy, there was no radiographic evidence of residual tumor. Temozolomide therapy was initiated after surveillance MRI showed recurrence at 16 months postoperatively. However, MRI demonstrated marked progression after 3 cycles. Next-generation sequencing using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C. Immunotherapy with ipilimumab/nivolumab was initiated, and MRI demonstrated no residual tumor burden 34 months postoperatively.

APA is a tumor with frequent recurrence and a short median expected length of survival. Shah et al. demonstrated the utility of immunotherapy in a single case report of APA, with complete resolution of recurrent APA and improved survival compared with a life expectancy 4).

References

1)

Oruçkaptan HH, Senmevsim O, Ozcan OE, Ozgen T. Pituitary adenomas: results of 684 surgically treated patients and review of the literature. Surg Neurol. 2000;53:211–219.
2)

Scheithauer BW, Kovacs KT, Laws ER, Jr, Randall RV. Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 1986;65:733–744.
3)

Selman WR, Laws ER, Scheithauer BW, et al. The occurrence of dural invasion in pituitary adenomas. J Neurosurg. 1986;64:402–407.
4)

Shah S, Manzoor S, Rothman Y, Hagen M, Pater L, Golnik K, Mahammedi A, Lin AL, Bhabhra R, Forbes JA, Sengupta S. Complete Response of a Patient With a Mismatch Repair Deficient Aggressive Pituitary Adenoma to Immune Checkpoint Inhibitor Therapy: A Case Report. Neurosurgery. 2022 May 13. doi: 10.1227/neu.0000000000002024. Epub ahead of print. PMID: 35544035.

Transsphenoidal approach for pituitary adenoma

Transsphenoidal approach for pituitary adenoma

Cerebrospinal fluid fistula after transsphenoidal surgery for pituitary adenomas may be prevented by skull base reconstruction with fat autograft. However, graft changes may interfere with the interpretation of postoperative images. The aim of Cossu et al. was to describe the radiological evolution of the fat autograft.

A retrospective analysis was performed, including patients undergoing transsphenoidal surgery for pituitary adenomas with a fat autograft for skull base reconstruction. Clinical and radiological data were collected, with an assessment of fat autograft and the extent of resection. Statistical analysis was performed using Kruskal-Wallis and Wilcoxon signed-rank test while Spearman’s Rho was used to analyze the relationship between variables.

Seventy-two patients were included. Macroadenomas was diagnosed in 62 cases (86.1%) and in 21 cases an invasion of the cavernous sinus was described (29%). Gross total resection was achieved in 84.7% of cases. The volume of the fat graft significantly decreased between 3 months and 1 year after surgery (p = 0.01) and between 1 year and the last follow-up (mean 4.63 years, p < 0.01). Fat signal ratio significantly diminished between 3 months and 1 year in unenhanced and enhanced T1-weighted sequences (p = 0.04 and p = 0.02 respectively). Volume reduction was related to the decrease in the signal ratio in unenhanced T1 sequences (p = 0.008).

Fat resorbs with time: almost 50% of the fat volume is lost during the first year after surgery and 60% is resorbed at 4.6 years. T1-signal, before and after gadolinium injection, also decreases during the first year, probably because of the progressive fibrosis of the graft. This information will contribute to the interpretation of postoperative images 1).

The aim of a study of Butenschoen et al. was to analyze the postoperative improvement of visual function after adenoma resection and to identify prognostic factors for the postoperative clinical recovery. They performed a retrospective analysis of all consecutive patients treated via a transsphenoidal approach for pituitary adenomas from April 2006 to December 2019 in a high-volume neurosurgical department. The primary outcome was postoperative visual acuity and visual field impairment; the clinical findings were followed up to 3 months after surgery and correlated with clinical and radiographic findings. In total, 440 surgeries were performed in our department for tumors of the sella region in a time period of 13 years via a transsphenoidal approach, and 191 patients included in the analysis. The mean age was 55 years, and 98% were macroadenomas. Mean preoperative visual acuity in patients with preoperative impairment (n = 133) improved significantly from 0.64/0.65 to 0.72/0.75 and 0.76/0.8 (right eye R/left eye L) postoperatively and at 3 months follow-up (p < 0.001). Visual acuity significantly depended on Knosp classification but not Hardy grading. The strongest predictor for visual function recovery was age. Transsphenoidal pituitary tumor resection remains a safe and effective treatment in patients with preoperative visual impairment. It significantly improves visual acuity and field defects after surgery, and recovery continues at the 3 months follow-up examination 2).

Dai et al. quantitatively synthesized the comparative efficacy and safety of the most common surgical approaches including endoscopic transsphenoidal approach, sublabial transsphenoidal microsurgery (STMS) and endonasal transsphenoidal microsurgery (ETMS) for all kinds of pituitary tumors. This systematic review and network meta-analysis were performed on randomized controlled trials (RCTs) and comparison studies from databases of Pubmed, EMBASE, and the Cochrane Library. They selected the rate of gross complete resection as the primary outcome of efficacy. And the incidence of all complications, cerebrospinal fluid (CSF) leak, diabetes insipidus, nasal septal perforation, death, and bleeding were designed as our primary outcomes of safety. Twenty-seven studies with 2618 patients were included in this network meta-analysis. On efficacy, there was no statistical difference among the three methods including ETES, STMS, and ETMS. As for safety, results indicated that the incidence of total complications of STMS (OR = 4.74; 95% CI 1.03, 40.14) is significantly superior to ETES. And the incidence of diabetes insipidus of ETMS (OR = 2.21; 95% CI 1.31, 3.81) was significantly superior to that of ETES. Besides, there was no statistical difference in the other complications including CSF leak, nasal septal perforation, death, and bleeding. They clarified the overpraise of the efficacy of endoscopy especially the endonasal transsphenoidal approach and verified that all the approaches owned similar efficacy. Moreover, they recommended the endoscopy to be the first choice for pituitary tumors, because it demonstrated the best safety 3).

The transsphenoidal approach is the gold standard for pituitary adenoma resection. However, despite advances in microsurgical and endoscopic techniques, some pituitary adenomas can be challenging to cure.

Traditionally performed with a microscope and a sublabial incision, the implementation of the endoscopic visualization and endonasal access has rendered the transsphenoidal approach less invasive and provided improved visualization into and around the sella.

see Endoscopic transsphenoidal approach

The standard endonasal approach has been expanded to provide access to other, parasellar lesions. With the addition of the endoscope, this expansion carries significant potential for the resection of skull base lesions.

see Extended endoscopic transsphenoidal approach

Although there is limited and low quality evidence available, the use of intraoperative ultrasound appears to be a safe and effective technological adjunct to transsphenoidal surgery for pituitary adenoma. Advances in ultrasound technology may allow for more widespread use of such devices 4).

Suprasellar extension is regarded a drawback for complete removal of these tumors through this approach.

Is very important to evaluate the correlation between the preoperative radiologic craniocaudal extension on MRI of pituitary adenomas and the extent of tumor removal. A retrospective study. Tertiary care hospital. 560 patients underwent transsphenoidal removal of pituitary adenomas. The degree of removal of pituitary tumor in the follow-up imaging of the patients was correlated with the preoperative extension in mid-Coronal T1 W Gd. Tumors with suprasellar extension can be classified into: Type I tumors with extension confined to the sellar boundaries, resulted in complete removal in all cases (100%), type II tumors with suprasellar extension reaching the floor of the 3rd ventricle, resulted in complete removal in 70.2% of the cases, type III tumors with suprasellar extension above the 3rd ventricle, had only 13.5% of complete removal. Integration of radiologic findings into a scheme for the preoperative determination of possibility of total removal of the tumor through transsphenoidal approach, can give better correlation to the surgical outcome of pituitary tumors 5).

Costs

Geographic variations in healthcare costs have been reported for many surgical specialties.

In a study, Asemota et al. sought to describe national and regional costs associated with transsphenoidal pituitary surgery (TPS).

Data from the Truven-MarketScan 2010-2014 was analyzed. We examined overall total, hospital/facility, physician, and out-of-pocket payments in patients undergoing TPS including technique-specific costs. Mean payments were obtained after risk-adjustment for the patient- and system-level confounders and estimated differences across regions.

The estimated overall annual burden was $43 million/year in our cohort. The average overall total payment associated with TPS was $35,602.30, hospital/facility payment was $26,980.45, physician payment was $4,685.95, and out-of-pocket payment was $2,330.78. Overall total and hospital/facility costs were highest in the West and lowest in the South (both P<0.001), while physician reimbursements were highest in the North-east and lowest in the South (P<0.001). There were no differences in out-of-pocket expenses across regions. On a national level, there were significantly higher overall total and hospital/facility payments associated with endoscopic compared to microscopic procedures (both P<0.001); there were no significant differences in physician payments nor out-of-pocket expenses between techniques. There were also significant within-region cost differences in the overall total, hospital/facility, and physician payments in both techniques as well as in out-of-pocket expenses associated with microsurgery. There were no significant regional differences in out-of-pocket expenses associated with endoscopic surgery.

These results demonstrate significant geographical cost disparities associated with TPS. Understanding the factors behind disparate costs is important for developing cost containment strategies 6).

References

1)

Cossu G, Turin-Huet V, Garvayo Navarro M, Papadakis G, Daniel RT, Dunet V, Messerer M. Radiological evolution of autograft fat used for skull base reconstruction after transsphenoidal surgery for pituitary adenomas. Pituitary. 2022 Feb 22. doi: 10.1007/s11102-022-01210-6. Epub ahead of print. PMID: 35194708.
2)

Butenschoen VM, Schwendinger N, von Werder A, Bette S, Wienke M, Meyer B, Gempt J. Visual acuity and its postoperative outcome after transsphenoidal adenoma resection. Neurosurg Rev. 2020 Oct 10. doi: 10.1007/s10143-020-01408-x. Epub ahead of print. PMID: 33040306.
3)

Dai W, Zhuang Z, Ling H, Yang Y, Hang C. Systematic review and network meta-analysis assess the comparative efficacy and safety of transsphenoidal surgery for pituitary tumor. Neurosurg Rev. 2020 Feb 8. doi: 10.1007/s10143-020-01240-3. [Epub ahead of print] PubMed PMID: 32036504.
4)

Marcus HJ, Vercauteren T, Ourselin S, Dorward NL. Intraoperative Ultrasound in Patients Undergoing Transsphoidal Surgery for Pituitary Adenoma: A Systematic Review. World Neurosurg. 2017 Jul 20. pii: S1878-8750(17)31154-3. doi: 10.1016/j.wneu.2017.07.054. [Epub ahead of print] Review. PubMed PMID: 28736351.
5)

Hamid O, El Hakim A, El Husseiny H, El Fiky L, Kamel S. Craniocaudal extension as an indication of surgical outcome in transsphenoidal surgery for pituitary adenomas. Indian J Otolaryngol Head Neck Surg. 2013 Aug;65(Suppl 2):231-5. doi: 10.1007/s12070-011-0350-3. Epub 2011 Nov 27. PubMed PMID: 24427652.
6)

Asemota AO, Ishii M, Brem H, Gallia GL. Geographic Variation in Costs of Transsphenoidal Pituitary Surgery in the United States. World Neurosurg. 2020 Mar 4. pii: S1878-8750(20)30420-4. doi: 10.1016/j.wneu.2020.02.145. [Epub ahead of print] PubMed PMID: 321454

Covid-19 and pituitary apoplexy

Covid-19 and pituitary apoplexy

Kamel et al. reported a case of pituitary apoplexy associated with COVID-19 infection. Based on a patient’s clinical findings, review of the other reported cases, as well as the available literature, they put forth a multitude of pathophysiological mechanisms induced by COVID-19 that can possibly lead to the development of pituitary apoplexy. In their opinion, the association between both conditions is not just a mere coincidence. Although the histopathological features of pituitary apoplexy associated with COVID-19 are similar to pituitary apoplexy induced by other etiologies, future research may disclose unique pathological fingerprints of COVID-19 virus that explains its capability of inducing pituitary apoplexy 1).

A 75-year-old man who presented with a headache and was later diagnosed with hypopituitarism secondary to pituitary apoplexy. This occurred 1 month following a mild-to-moderate COVID-19 infection with no other risk factors commonly associated with pituitary apoplexy. This case, therefore, supplements an emerging evidence base supporting a link between COVID-19 and pituitary apoplexy 2).

Martinez-Perez et al. identified 3 consecutive cases of PA and concomitant COVID-19 infection. The most common symptoms at presentation were headache and vision changes. The included patients were successfully treated with surgical decompression and medical management of the associated endocrinopathy, ultimately experiencing improvement in their visual symptoms at the latest follow-up examination. COVID-19 infection in the perioperative period was corroborated by polymerase chain reaction test results in all the patients.

With the addition of our series to the literature, 10 cases of PA in the setting of COVID-19 infection have been confirmed. The present series was limited in its ability to draw conclusions about the relationship between these 2 entities. However, COVID-19 infection might represent a risk factor for the development of PA. Further studies are required. 3).

A review underlines that there could be a specific involvement of the pituitary gland which fits into a progressively shaping endocrine phenotype of COVID-19. Moreover, the care for pituitary diseases need to continue despite the restrictions due to the emergency. Several pituitary diseases, such as hypopituitarism and Cushing disease, or due to frequent comorbidities such as diabetes may be a risk factor for severe COVID-19 in affected patients. There is the urgent need to collect in international multicentric efforts data on all these aspects of the pituitary involvement in the pandemic in order to issue evidence driven recommendations for the management of pituitary patients in the persistent COVID-19 emergency. 4).

Pituitary apoplexy attributed solely to COVID-19 in the absence of other identifiable causes. While much remains to be discovered and understood regarding COVID-19, they discuss the potential pathophysiology of COVID-19-associated pituitary apoplexy and raise awareness of this clinical complication 5)

A neuro-ophthalmic presentation of pituitary apoplexy under the setting of COVID-19 infection in a middle-aged man who presented to ophthalmic emergency with sudden bilateral loss of vision along with a history of fever past 10 days. There was sluggishly reacting pupils and RT-PCR for COVID was positive. Imaging pointed the diagnosis as pituitary macroadenoma with apopexy. In view of pandemic situation, patient was given symptomatic treatment as per the protocols and stabilized. Vision also showed improvement to some extent and the patient is awaiting neurosurgery 6).

A case of a previously healthy woman with severe acute respiratory syndrome coronavirus 2 infection associated with pituitary apoplexy. The plausible pathophysiological mechanisms of pituitary apoplexy in infectious coronavirus disease 2019 are discussed. 7).

A 27-year-old male patient case with progressive decrease in visual acuity, associated with respiratory symptoms and intense headache. Multilobar infiltrate with a reticulonodular pattern is evident on chest CT scan. Brain CT scan with pituitary macroadenoma apoplexy was shown. SARS-Cov2 was confirmed, and respiratory support initiated. However, the patient died shortly afterward, secondary to pulmonary complications.

The angiotensin-converting enzyme (ACE) II receptor is expressed in circumventricular organs and in cerebrovascular endothelial cells, which play a role in vascular autoregulation and cerebral blood flow. For this reason, is rational the hypothesize that brain ACE II could be involved in COVID-19 infection. Underlying mechanisms require further elucidation in the future 8).

A 28-year-old G5P1 38w1d female presented with 4 days of blurry vision, left dilated pupil, and headache. She tested positive for SARS-CoV-2 on routine nasal swab testing but denied cough or fever. Endocrine testing demonstrated an elevated serum prolactin level, and central hypothyroidism. MRI showed a cystic-solid lesion with a fluid level in the pituitary fossa and expansion of the sella consistent with pituitary apoplexy. Her visual symptoms improved with corticosteroid administration and surgery was delayed to two weeks after her initial COVID-19 infection and to allow for safe delivery of the child. A vaginal delivery under epidural anesthetic occurred at 39 weeks. Two days later, transsphenoidal resection of the mass was performed under strict COVID-19 precautions including use of Powered Air Purifying Respirators (PAPRs) and limited OR personnel given high risk of infection during endonasal procedures. Pathology demonstrated a liquefied hemorrhagic mass suggestive of pituitary apoplexy. She made a full recovery and was discharged home two days after surgery.

They demonstrate the first known case of successful elective induction of vaginal delivery and transsphenoidal intervention in a near full term gravid patient presenting with pituitary apoplexy and acute SARS-CoV-2 infection. Further reports may help determine if there is a causal relationship or if these events are unrelated. Close adherence to guidelines for caregivers can greatly reduce risk of infection. 9).

A 25 year old male presented with dyspnoea, cough and high fevers for 4 days. He was commenced on broad-spectrum antimicrobials and oxygen therapy. His respiratory function deteriorated in spite of these measures and he required mechanical ventilation. CT showed left upper lobe consolidation as well as multifocal ground-glass opacification. Case 2: A 43 year-old male presented with headache and was found incidentally to have pneumonia. He was recently diagnosed with pituitary apoplexy secondary to an adenoma with resultant pituitary insufficiency but MRI brain was stable. His respiratory function deteriorated in spite of antibiotics and he required mechanical ventilation. CT showed likely atypical infection with resultant ARDS. Outcome Both underwent nasopharyngeal RT-PCR testing for SARS-CoV-2. Patient 2 was positive. Patient 1 was extubated and made a good recovery. Patient 2 was transferred to another centre for ECMO therapy. He died 27 days after transfer. Conclusion Given the atypical presentations in generally otherwise young and healthy individuals, the decision was made outside of national guidance to perform testing for SARS-CoV-2. This diagnosis had far-reaching implications for the SARS-CoV-2 pandemic within Ireland 10).

1)

Kamel WA, Najibullah M, Saleh MS, Azab WA. Coronavirus disease 2019 infection and pituitary apoplexy: A causal relation or just a coincidence? A case report and review of the literature. Surg Neurol Int. 2021 Jun 28;12:317. doi: 10.25259/SNI_401_2021. PMID: 34345458; PMCID: PMC8326077.
2)

Liew SY, Seese R, Shames A, Majumdar K. Apoplexy in a previously undiagnosed pituitary macroadenoma in the setting of recent COVID-19 infection. BMJ Case Rep. 2021 Jul 28;14(7):e243607. doi: 10.1136/bcr-2021-243607. PMID: 34321266; PMCID: PMC8319972.
3)

Martinez-Perez R, Kortz MW, Carroll BW, Duran D, Neill JS, Luzardo GD, Zachariah MA. Coronavirus Disease 2019 and Pituitary Apoplexy: A Single-Center Case Series and Review of the Literature. World Neurosurg. 2021 Aug;152:e678-e687. doi: 10.1016/j.wneu.2021.06.004. Epub 2021 Jun 12. PMID: 34129968; PMCID: PMC8196470.
4)

Frara S, Allora A, Castellino L, di Filippo L, Loli P, Giustina A. COVID-19 and the pituitary. Pituitary. 2021 Jun;24(3):465-481. doi: 10.1007/s11102-021-01148-1. Epub 2021 May 3. PMID: 33939057; PMCID: PMC8089131.
5)

Bordes SJ, Phang-Lyn S, Najera E, Borghei-Razavi H, Adada B. Pituitary Apoplexy Attributed to COVID-19 Infection in the Absence of an Underlying Macroadenoma or Other Identifiable Cause. Cureus. 2021 Feb 12;13(2):e13315. doi: 10.7759/cureus.13315. PMID: 33732566; PMCID: PMC7956048.
6)

Katti V, Ramamurthy LB, Kanakpur S, Shet SD, Dhoot M. Neuro-ophthalmic presentation of COVID-19 disease: A case report. Indian J Ophthalmol. 2021 Apr;69(4):992-994. doi: 10.4103/ijo.IJO_3321_20. PMID: 33727476; PMCID: PMC8012961.
7)

Ghosh R, Roy D, Roy D, Mandal A, Dutta A, Naga D, Benito-León J. A Rare Case of SARS-CoV-2 Infection Associated With Pituitary Apoplexy Without Comorbidities. J Endocr Soc. 2021 Jan 2;5(3):bvaa203. doi: 10.1210/jendso/bvaa203. PMID: 33501401; PMCID: PMC7798947.
8)

Solorio-Pineda S, Almendárez-Sánchez CA, Tafur-Grandett AA, Ramos-Martínez GA, Huato-Reyes R, Ruiz-Flores MI, Sosa-Najera A. Pituitary macroadenoma apoplexy in a severe acute respiratory syndrome-coronavirus-2-positive testing: Causal or casual? Surg Neurol Int. 2020 Sep 25;11:304. doi: 10.25259/SNI_305_2020. PMID: 33093981; PMCID: PMC7568102.
9)

Chan JL, Gregory KD, Smithson SS, Naqvi M, Mamelak AN. Pituitary apoplexy associated with acute COVID-19 infection and pregnancy. Pituitary. 2020 Dec;23(6):716-720. doi: 10.1007/s11102-020-01080-w. Epub 2020 Sep 11. PMID: 32915365; PMCID: PMC7484495.
10)

Faller E, Lapthorne S, Barry R, Shamile F, Salleh F, Doyle D, O’Halloran D, Prentice M, Sadlier C. The Presentation and Diagnosis of the First Known Community-Transmitted Case of SARS-CoV-2 in the Republic of Ireland. Ir Med J. 2020 May 7;113(5):78. PMID: 32603572.

Pituitary adenoma with gangliocytoma

Pituitary adenoma with gangliocytoma

AKA Mixed Gangliocytoma–Pituitary Adenoma

Gangliocytomas originating in the sellar region are rare; most are tumors composed of gangliocytic and pituitary adenomatous elements, forming the so-called mixed gangliocytoma-pituitary adenoma. The majority of mixed gangliocytoma adenomas are associated with endocrinopathies, mainly acromegaly and less often Cushing disease and hyperprolactinemia.

Differentiating these mixed tumors from conventional pituitary adenomas can be difficult pre-operatively, and careful histological analysis after surgical resection is key to differentiating the two entities. There is little literature addressing the possible mechanisms for the development of mixed pituitary adenoma-gangliocytomas; however, several hypotheses have been proposed. It still remains unclear if these mixed tumors differ from a clinical perspective to pituitary adenomas; however, the additional neural component of the gangliocytoma does not appear to modify the aggressiveness or risk of recurrence after surgical resection. We report a unique case of acromegaly secondary to a mixed GH-secreting pituitary adenoma, co-existing with an intrasellar gangliocytoma.

Acromegaly due to a mixed GH-secreting pituitary adenoma and intrasellar gangliocytoma is rare. These mixed tumors cannot be distinguished easily from ordinary pituitary adenomas on the basis of clinical, endocrine or neuroradiologic findings, and histological analysis is required for a definitive diagnosis. Surgical resection is usually sufficient to provide a cure, without the need for adjuvant therapy. These mixed tumors appear to have a good prognosis although the natural history is not well defined 1).

Pathogenesis

The pathogenesis of these mixed tumors remains debatable, and ongoing research is required 2).

Case series

10 cases of mixed gangliocytoma and somatotroph adenomas were evaluated for patterns of cellular differentiation and expression of lineage-specific transcription factors. The tumors were characterized by immunohistochemistry for pituitary hormones, cytokeratins, Pit-1, and the neuronal markers NeuN, neurofilaments (NFP), and MAP2. Double-labeling immunohistochemistry for Pit-1/GH, Pit-1/NFP, Pit-1/MAP2, and NeuN/GH was performed in 9/10 tumors. The data demonstrate that both adenomatous and ganglionic cells express the acidophilic lineage transcription factor Pit-1. Although mixed gangliocytomas and somatotroph adenomas show histologically distinct cellular populations, there is at least a small population of cells that coexpress the Pit-1 transcription factor and neuronal-associated cytoskeletal proteins favoring the theory of transdifferentiation of neuroendocrine cells into neuronal elements of these mixed tumors 3).

Case reports

Although pituitary macroadenomas often cause mass effects on surrounding structures, it is extremely rare for pituitary lesions to disturb cerebrospinal fluid circulation. Sellar gangliocytoma-pituitary adenomas (SGPAs) (Pituitary adenoma with gangliocytoma) are also extremely rare.

Ryder et al., reported the unique case of a man with the unusual combination of acromegaly from an SGPA, who presented with unilateral hydrocephalus. A 60-year-old man presented with rapid neurological deterioration, bitemporal hemianopsia, and acromegalic features. Neuroimaging revealed a large sellar lesion extending superiorly into the left foramen of Monro, causing acute obstructive unilateral hydrocephalus. External ventricular drain placement improved consciousness immediately. The biochemical assessment confirmed acromegaly. Following transsphenoidal debulking, histology revealed a mixed gangliocytoma/sparsely-granulated somatotrophinoma. Despite the residual disease, his vision recovered remarkably, low-dose cabergoline controlled residual excess growth hormone (GH) secretion, and the residual tumour has remained extremely stable over 2 years. Hydrocephalus is an extremely rare complication of pituitary lesions, and unilateral hydrocephalus has never been reported previously. GH secretion in SGPAs is more common than for pituitary adenomas in general, raising questions regarding the aetiology and therapeutic approach to this rare combination tumour 4).

A 67-year-old woman with a past history of type 2 diabetes mellitus presented with worsening glycemic control. She had some acromegaly symptoms and magnetic resonance imaging demonstrated a pituitary tumor. Endocrinological examination found the resting growth hormone (GH) level within the normal range, but elevated insulin-like growth factor 1 level. A 75 g oral glucose tolerance test showed inadequate suppression of nadir GH levels. Acromegaly due to GH-secreting pituitary tumor was diagnosed. The patient underwent endoscopic transsphenoidal surgery resulting in gross total removal of the tumor and recovered well postoperatively. Histological examination of the tumor showed coexistence of relatively large gangliocytoma cells and pituitary adenoma cells, suggesting mixed gangliocytoma-pituitary adenoma. In addition, colocalization of GH and GH-releasing hormone (GHRH) in pituitary adenoma cells was revealed, so the adenomatous components were more likely to produce GHRH in our mixed gangliocytoma-pituitary adenoma case. Mixed gangliocytoma-pituitary adenoma is very rare, and the present unique case demonstrated only the adenomatous components associated with GHRH production.

Sellar gangliocytoma coexisting with pituitary adenoma is recognized as a mixed gangliocytoma-pituitary adenoma and is very rare. A proposed developmental mechanism of growth hormone (GH)-secreting mixed gangliocytoma-pituitary adenoma involves GH-releasing hormone (GHRH) produced by the gangliocytic components promoting the growth of tumor including GH-secreting adenomatous components. Since the present case indicated that the adenomatous components of mixed gangliocytoma-pituitary adenoma could secrete both GH and GHRH simultaneously, progression of GH-secreting mixed gangliocytoma and pituitary adenoma may involve exposure to spontaneously produced GHRH due to the adenomatous components 5).

Two 47-year-old females who presented with masses in the sellar region following a general examination and radiological imaging. The two patients underwent sellar region tumor resection via the trans-naso-sphenoid approach. The histopathological examination confirmed the diagnosis of a hormone-free pituitary adenoma with gangliocytoma. The two patients were in good condition and experienced no specific discomfort subsequent to the follow-up after surgery. Gangliocytoma is a slowly growing and non-metastasizing tumor. A biopsy is required to differentiate a gangliocytoma from a malignant neuroblastoma, and excision is usually curative 6).

Three cases of a composite sellar tumor composed of a gangliocytoma and an adenoma are presented. Two patients who showed acromegaly and hyperprolactinemia had a gangliocytoma and a growth hormone (GH)-prolactin cell adenoma in close proximity. The gangliocytoma contained growth hormone-releasing hormone (GHRH) by immunohistochemistry. At the electron microscopical level, the gangliocytoma was characterized by numerous synaptic vesicles. The third patient, a child with Cushing’s disease, presented a corticotropin-releasing hormone (CRH)-positive gangliocytoma in close contact with an adrenocorticotropic hormone (ACTH) secreting adenoma, the latter a typical densely granulated ACTH cell adenoma. Ultrastructurally, the gangliocytoma revealed synaptic vesicles and sparse secretory granules. The results suggest that gangliocytomas may promote the development of pituitary adenomas by hypersecretion of releasing hormones. Whereas 20 cases of sellar GHRH producing gangliocytomas in acromegaly are reported in the literature, the combination of a CRH-positive gangliocytoma and an ACTH cell adenoma in Cushing’s disease is apparently the first case 7).

1) , 2)

Lee MH, McKelvie P, Krishnamurthy B, Wang YY, Caputo C. An intrasellar pituitary adenoma-gangliocytoma presenting as acromegaly. Endocrinol Diabetes Metab Case Rep. 2017 Apr 27;2017:17-0035. doi: 10.1530/EDM-17-0035. PMID: 28469929; PMCID: PMC5409941.
3)

Lopes MB, Sloan E, Polder J. Mixed Gangliocytoma-Pituitary Adenoma: Insights on the Pathogenesis of a Rare Sellar Tumor. Am J Surg Pathol. 2017 May;41(5):586-595. doi: 10.1097/PAS.0000000000000806. PMID: 28079576.
4)

Ryder S, Robusto J, Robertson T, Alexander H, Duncan EL. Unilateral hydrocephalus from a gangliocytoma-somatotrophinoma: first reported case. Endocrinol Diabetes Metab Case Rep. 2021 Jul 1;2021:EDM210037. doi: 10.1530/EDM-21-0037. Epub ahead of print. PMID: 34236040.
5)

Teramoto S, Tange Y, Ishii H, Goto H, Ogino I, Arai H. Mixed gangliocytoma-pituitary adenoma containing GH and GHRH co-secreting adenoma cells. Endocrinol Diabetes Metab Case Rep. 2019 Oct 3;2019:19-0099. doi: 10.1530/EDM-19-0099. Epub ahead of print. PMID: 31581122; PMCID: PMC6790896.
6)

Chen D, Xu J, Zhong P, Huang X, Xu M. Pituitary adenoma with gangliocytoma: Report of two cases. Oncol Lett. 2014 Aug;8(2):781-784. doi: 10.3892/ol.2014.2183. Epub 2014 May 27. PMID: 25013498; PMCID: PMC4081391.
7)

Saeger W, Puchner MJ, Lüdecke DK. Combined sellar gangliocytoma and pituitary adenoma in acromegaly or Cushing’s disease. A report of 3 cases. Virchows Arch. 1994;425(1):93-9. doi: 10.1007/BF00193956. PMID: 7921420.

Pituitary adenoma classification

Pituitary adenoma classification

They are classified based on size or cell of origin. Pituitary adenoma can be described as microadenoma, macroadenoma, and giant tumors based on size. Microadenoma is tumors less than 10 mm, while macroadenoma includes tumors larger than 10mm. Giant pituitary adenomas are more than 40 mm. There are functional pituitary adenomas in which the cell type that composes them causes increased secretion of one or multiple hormones of the anterior pituitary. Alternatively, there are Non-Functioning Pituitary Adenomas that do not secrete hormones, but they can compress the surrounding areas of the anterior pituitary leading to hormonal deficiencies 1).

The 2017 World Health Organization classification of tumors of the pituitary gland

see The 2017 World Health Organization classification of tumors of the pituitary gland.

In the fourth edition of the World Health Organization classification of endocrine tumors, are two critical changes to the classification for pituitary adenomas.

One is that the term “atypical adenoma,” which was characterized based on highly proliferative properties to predict adenomas that carry a poor prognosis, was completely eliminated due to the lack of definitive evidence. The other change is the introduction of more precise cell lineage-based classification of pituitary adenoma that is defined based on lineage-specific transcription factors and hormones produced. Accordingly, null cell adenomas have been re-defined as those that show completely negative immunostaining either for hormones or for adenohypophyseal transcription factors 2).

Somatotroph adenoma.

Lactotroph adenoma.

Tyrotroph adenoma.

Corticotroph adenoma.

Gonadotroph adenoma.

Null cell adenoma

Plurihormonal pituitary adenoma and double adenomas.

The classification is based upon the size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment, and recurrence 3).

Current classification systems for PAs are based primarily on secretory characteristics of the tumor but are also classified on the basis of phenotypical characteristics, including tumor size, degree of invasiveness (e.g., Knosp grade), and immunohistological findings 4).

The anterior WHO classification system for PAs was refined to include designations for benign adenoma, atypical adenoma, and pituitary carcinoma on the basis of p53 immunoreactivity, MIB-1 index, mitotic activity, and the absence/presence of metastases 5) 6).

These tumor types can be microadenomas or macroadenomas and can either be functional or non-functional.

By Size

Pituitary microadenoma

Pituitary macroadenoma

Giant pituitary adenoma

Volume can be calculated using MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2) transverse (TV), antero-posterior (AP) and cranio-caudal (CC).

By Function

Functioning pituitary adenoma

Nonfunctioning pituitary adenoma

Pituitary adenomas with gangliocytic component are rare tumors of the sellar region that are composed of pituitary adenoma cells and a ganglion cell component. Their histogenesis and hence nosology is not yet resolved because of the small number of cases reported and lack of large series in the literature 7).

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until the identification of metastases.

Consistency

Although most authors differentiate easily aspirated (soft) tumors from those that are not (fibrous, might require prior fragmentation), there is no universally accepted PA consistency classification. Fibrous PA tends to be hypointense on T2WI and has lower apparent diffusion coefficient (ADC) values. Fibrous tumors seemed to present higher invasion into neighboring structures, including the cavernous sinus. Several articles suggest that dopamine agonists could increase PA consistency and that prior surgery and radiotherapy also make PA more fibrous. The anatomopathological studies identify collagen as being mainly responsible for fibrous consistency of adenomas.

Conclusions: Preoperative knowledge of PA consistency affords the neurosurgeon substantial benefit, which clearly appears to be relevant to surgical planning, risks, and surgery outcomes. It could also encourage the centralization of these high complexity tumors in reference centers. Further studies may be enhanced by applying standard consistency classification of the PA and analyzing a more extensive and prospective series of fibrous PA. 8).

Knosp Grade

Knosp Grade.

Hardy’s Classification of Pituitary Adenomas

Hardy’s Classification of Pituitary Adenomas.

References

1)

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