Primary papillary epithelial tumour of the sella: expanding the spectrum of TTF-1-positive sellar lesions.

AIM: To describe four novel primary epithelial tumours of the sella with papillary architecture and Thyroid Transcription Factor 1 (TTF-1) expression. METHODS: Paraffin-embedded tissue from the four cases and recurrence of patient 1 was investigated with haematoxylin-eosin, special histochemical stains, immunohistochemistry with a broad panel of antibodies and next-generation sequencing. The ultrastructure of one tumour was studied in tissue retrieved from paraffin. RESULTS: The lesions occurred in three females aged 20, 26 and 42 years and a male aged 49 years. They presented with signs and symptoms secondary to pituitary stalk compression. Preoperative neuroimaging documented mixed solid and cystic, enhancing sellar masses with suprasellar extension. Histologically, the tumours showed thin papillae lined by a single layer of cytokeratin and TTF-1-positive cuboidal and cylindrical cells with mildly atypical nucleus. Next-generation sequencing performed in three cases did not identify any mutations. The main differential diagnosis included metastasis from lung or thyroid carcinoma, extraventricular choroid plexus papilloma and sellar ependymoma. CONCLUSION: We suggest the descriptive term of primary papillary epithelial tumour of the sella (PPETS) for this entity and propose that it could represent the intracranial equivalent of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma. The cell of origin of PPETS remains undetermined although the intense and ubiquitous expression of TTF-1 may suggest a derivation from the infundibulum or ventricular recess. Our study expands the spectrum of sellar TTF-1-positive tumour and challenges the view that they all derive from pituicytes.

A nonmyeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma.

AIMS: Resident and peripherally derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion and attenuating host immune responses. Differentiating these cells' origins is challenging and current preclinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel nonmyeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation. METHODS: NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25 mg/kg to 125 mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immunocompetent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using immunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64. RESULTS: NMT achieves >80% haematopoietic chimerism by 12 weeks without BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice. CONCLUSION: NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases.

Cortical Lewy bodies and Aß burden are associated with prevalence and timing of dementia in Lewy body diseases.

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aß plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aß plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aß plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

Characterization of MENX-associated pituitary tumours.

AIMS: The aim of this study is to evaluate the pathological features, serum hormone levels and ex vivo cultures of pituitary adenomas that occur in rats affected by MENX syndrome. MENX is multiple endocrine neoplasia syndrome caused by a germline mutation in the cell cycle inhibitor p27. Characterization of MENX adenomas is a prerequisite to exploit this animal model for molecular and translational studies of pituitary adenomas. METHODS: We investigated MENX pituitary adenomas with immunohistochemistry, double immunofluorescence, electron microscopy, reverse transcription polymerase chain reaction (RT-PCR), measurement of serum hormone levels and ex vivo cultures. RESULTS: Adenomas in MENX rats belong to the gonadotroph lineage. They start from 4 months of age as multiple neoplastic nodules and progress to become large lesions that efface the gland. Adenomas are composed of chromophobic cells predominantly expressing the glycoprotein alpha-subunit (αGSU). They show mitotic activity and high Ki67 labelling. A few neoplastic cells co-express gonadotropins and the transcription factor steroidogenic factor 1, together with growth hormone or prolactin and Pit-1, suggesting that they are not fully committed to one cell lineage. Ex vivo cultures show features similar to the primary tumour. CONCLUSIONS: Our results suggest that p27 function is critical to regulate gonadotroph cells growth. The MENX syndrome represents a unique model to elucidate the physiological and molecular mechanisms mediating the pathogenesis of gonadotroph adenomas.

A challenging case of sporadic melanocytoma of the jugular foramen.

BACKGROUND: The jugular foramen (JF) can be the site of several tumours. Paragangliomas, schwannomas and meningiomas are the most commonly reported. We describe a case of melanocytoma originating from the JF and presenting with an accessory nerve palsy. ILLUSTRATIVE CASE: A 48-year-old woman presented with a 6-month history of cervical and left shoulder pain with wasting and weakness of the left trapezius. A Magnetic Resonance Imaging (MRI) showed a T1-hyperintense, T2-isointense, heterogeneously enhancing lesion involving the left JF and extending into the cerebello-medullary and cerebello-pontine cisterns. A retrosigmoid craniotomy was performed and a near-total removal achieved. The accessory nerve was involved by tumour and could not be preserved. Given the diagnostic uncertainty between melanotic schwannoma, metastatic melanoma and meningeal melanocytoma, next generation sequencing and genome-wide DNA methylation arrays were performed, documenting a mutation in GNA11 (c.6226A>T, p. Gln209Leu) and a methylation profile consistent with melanocytoma. The patient underwent adjuvant fractionated radiotherapy of the tumour remnant. A follow-up MRI 4 years after surgery did not show any tumour recurrence. CONCLUSIONS: The differential diagnosis of skull base pigmented tumours can be challenging, particularly when they occur in unusual locations such as the JF. They can be misdiagnosed given their similar clinical, neuroradiological and pathological features if anatomy of the site of origin is not carefully considered and molecular tests are not performed, leading to erroneous treatment and follow-up planning.

Neurosurgical contribution within a complex NF1 supraregional service.

OBJECTIVES: The goal of this study was to review and present neurosurgical related activity within a multidisciplinary nationally commissioned specialty neurofibromatosis type I (NF1) center. PATIENTS & METHODS: We reviewed all NF1 Neurosurgical MDTs, NF1 Neurosurgical clinics and all neurosurgical procedures carried out in NF1 patients over an 8-year period. RESULTS: Since the inception of the service in 2009, 1505 cases were discussed at our NF-1 multidisciplinary meeting, 171 clinic appointments in complex NF1 patients with neurosurgical pathologies and 43(cranial and spinal) operations were performed. CONCLUSIONS: The formation of a supraregional multidisciplinary team allows for a better understanding of the disease, a comprehensive evaluation of neuroimaging findings and a steep learning curve in the management of NF1 surgical conditions. We provide holistic treatment for these patients via direct care, specialist advice and liaison with local units.

A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal.

The 2017 World Health Organization (WHO) classification proposes to type and subtype primary adenohypophyseal tumours according to their cell lineages with the aim to establish more uniform tumour groups. The definition of atypical adenoma was removed in favour of high-risk adenoma, and the assessment of proliferative activity and invasion was recommended to diagnose aggressive tumours. Recently, the International Pituitary Pathology Club proposed to replace adenoma with the term of pituitary neuroendocrine tumour (PitNET) to better reflect the similarities between adenohypophyseal and neuroendocrine tumours of other organs. The European Pituitary Pathology Group (EPPG) endorses this terminology and develops practical recommendations for standardised reports of PitNETs that are addressed to histo- and neuropathologists. This brief report presents the results of EPPG's consensus for the reporting of PitNETs and proposes a diagnostic algorithm.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Low levels of cobalamin, epidermal growth factor, and normal prions in multiple sclerosis spinal cord.

We have previously demonstrated that multiple sclerosis (MS) patients have abnormal cerebrospinal fluid (CSF) levels of the key myelin-related molecules cobalamin (Cbl), epidermal growth factor (EGF), and normal cellular prions (PrP(C)s), thus confirming that some CSF abnormalities may be co-responsible for remyelination failure. We determined the levels of these three molecules in post-mortem spinal cord (SC) samples taken from MS patients and control patients. The control SC samples, almost all of which came from non-neurological patients, did not show any microscopic lesions of any type. All of the samples were supplied by the U.K. MS Tissue Bank. The Cbl, EGF, and PrP(C) levels were determined using enzyme-linked immunosorbent assays. The SC total homocysteine level was determined using a competitive immunoenzymatic assay. CSF samples, taken from a further group of MS patients, were used for the assay of holo-transcobalamin (holo-TC) levels. The Cbl, EGF, and PrP(C) levels were significantly decreased in MS SCs in comparison with controls and, paradoxically, the decreased Cbl levels were associated with decreased SC levels of homocysteine, a biochemical marker of Cbl deficiency. The trends of EGF and PrP(C) levels paralleled those previously found in CSF, whereas that of Cbl was the opposite. There was no significant difference in CSF holo-TC levels between the MS patients and the controls. Given that we have previously demonstrated that Cbl positively regulates central nervous system EGF levels, it is conceivable that the low EGF levels in the MS SC may be causally related to a local decrease in Cbl levels. Only PrP(C) levels were invariably decreased in both the SC and CSF regardless of the clinical course of the disease. These findings suggest that the simultaneous lack of Cbl, EGF, and PrP(C)s may greatly hamper the remyelination process in MS patients, because they are key molecules of the machinery for remyelination.

An immunoenzyme technique for the identification of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors using digoxigenated-GM-CSF.

A method for detecting granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors has been devised using human macrophages and a GM-CSF/IL-3-dependent human megakaryoblastic leukemia cell line (M-07e). Recognition of the factor-binding site was accomplished by linking recombinant human (rh) unglycosylated GM-CSF previously labeled with digoxigenated compounds. Digoxigenates were able to link amino and sulphydryl groups of the soluble factor and an immunoperoxidase technique using monoclonal anti-digoxigenin antibody was employed to demonstrate the interaction. To support morphological data cross-linking analysis was performed with M-07e cells using digoxigenated-rh-GM-CSF. Macrophages and M-07e cells incubated with digoxigenated-rh-GM-CSF showed intense positivity by the immunoperoxidase technique. In cross-linking, M07e cells showed a 96 kDa band corresponding to receptor plus bound factor. This technique permits a high degree of specificity in the detection of GM-CSF receptors with good morphological preservation of cellular detail.

Sarcomatoid carcinoma of the anorectal junction with neuroendocrine and rhabdomyoblastic features.

A case of sarcomatoid carcinoma of the anorectal junction in a 71-year-old woman showing neuroendocrine and rhabdomyoblastic features is described. The tumor was diffusely infiltrative and metastases to regional lymph nodes were found at laparotomy. The patient died 6 months after surgery with widespread metastases.

Lipomatous meningioma: a clinicopathologic study of 18 cases with special reference to the issue of metaplasia.

We report 18 cases of lipomatous meningioma occurring in patients aged 14 to 79, most being females (72%). Sixteen were supratentorial and 2 involved the spinal meninges. Follow-up ranged from 1 to 120 months. Fifteen patients were cured with surgery alone and 3 (17%) experienced a recurrence at 7, 8 and 24 months. Of these, one died with disease 4 years after resection of the primary lesion. Histologically, 12 tumors were meningothelial, 3 transitional, 2 showed myxoid stromal changes and 1 was microcystic. The 2 spinal tumors were atypical. The proportion of fatty cells ranged from 10 to 90%. These resembled mature adipocytes or less commonly lipoblasts. Xanthomatous meningothelial cells were also noted in 6 tumors (30%). Both conventional meningothelial as well as lipid-laden cells exhibited epithelial membrane antigen immunoreactivity. In addition, occasional cells resembling mature adipocytes showed reactivity for S-100 protein. Ultrastructurally, lipidization of neoplastic cells varied from intracytoplasmic lipid droplets to a single massive globule. Moreover, lipid-laden meningothelial cells featured interdigitating cell membranes and well-formed desmosomes. Lipid droplets were not membrane-bound. In that metaplasia denotes differentiation of one mature cell type to another, lipid accumulation in meningiomas cannot be considered true metaplasia since their lipid-laden cells retain the immunophenotype and ultrastructural features of meningothelium. We suggest that this distinctive subset of meningiomas be termed "lipidized meningiomas" rather than being included in the metaplastic category.

Medullocytoma (lipidized medulloblastoma). A cerebellar neoplasm of adults with favorable prognosis.

This study describes three cases of neuroectodermal cerebellar neoplasms occurring in adults, characterized by a monomorphic population of round cells with scanty cytoplasm and focal areas of lipid accumulation. Astrocytic and neuronal differentiation was confirmed in these cells by glial fibrillary acidic protein and synaptophysin immunoreactivity. Electron microscopy performed in two cases showed neuritic processes, synapses, and dense-core granules. Patients included two men and one woman, and the age at diagnosis was 36, 37, and 57 years, respectively. Two patients refused any postoperative treatment. One of these had two surgically removed recurrences after 10 and 11 years and died postoperatively from intracranial hemorrhage. The second had two recurrences after 10 and 15 years and is alive and in good health at the last follow-up. The third patient received postoperative radiotherapy and is alive and well after 2 years. Review of the literature revealed seven cases of cerebellar neoplasms with histological features similar to those observed in our series. These lesions have been considered a variant of medulloblastomas. The age of patients ranged from 42 to 77 years (mean age, 51 years); four were women, 3 men. Follow-up information available in two cases indicates a 5-year survival with surgery alone. These data indicate that these cerebellar neuroectodermal neoplasms have morphologically unique features and indolent biologic behavior that distinguish them from the highly aggressive medulloblastoma; the term medullocytoma for this form is suggested.

Oncocytic meningioma.

Six cases of meningioma showing oncocytic changes are described. The lesions were composed mostly of sheets, nests, and cords of large polygonal cells with finely granular eosinophilic cytoplasm rich in mitochondria. Neoplastic cells showed nuclear pleomorphism with prominent nucleoli. Necrosis and high mitotic rate were present in the majority of cases. Oncocytic differentiation was demonstrated by conventional histology, immunocytochemistry, electron microscopy, and Western-blot analysis. Oncocytic meningiomas showed an aggressive behavior; recurrences were observed in three cases, and invasion of brain cortex was evident in other two cases.

Chordoid glioma of the third ventricle: an ultrastructural study of three cases with a histogenetic hypothesis.

Chordoid glioma is a rare neoplasm occurring in the third ventricle and, as the name implies, having a chordoid appearance. It is currently considered a glial neoplasm of uncertain histogenesis with distinct clinicopathologic features. We report three cases of chordoid glioma with a focus on the ultrastructural appearance. The patients were two men and one woman aged, respectively, 34, 40, and 43 years. Immunohistochemically, all tumors showed strong and diffuse reactivity for glial fibrillary acidic protein and vimentin, whereas immunoreactivity for epithelial membrane antigen and cytokeratin was focal. Ultrastructurally, they showed features of ependymal differentiation for the presence of an apical pole with microvilli and a basal pole characterized, as in normal ependyma, by many hemidesmosomelike structures connecting cell membranes to the underlying basal lamina. Constant features were a submicroscopic cell body zonation (i.e., perinuclear, intermediate, subapical, and apical regions) and the presence of secretory granules. These findings were similar to those described for the secretory ependymal cells of the subcommissural organ, a small structure located in a dorsocaudal region of the third ventricle that undergoes regression after birth in humans. Our observations suggest that chordoid glioma may represent a subtype of ependymoma whose cells resemble the highly specialized ependyma of the subcommissural organ.

Rhabdomyoblastic differentiation in a leiomyosarcoma of the retroperitoneum.

A case of leiomyosarcoma of the retroperitoneum with rhabdomyoblastic areas which developed in a 59-year-old woman is reported. The tumor was composed mostly of spindle cells immunoreactive with desmin and smooth muscle actin antisera. In the lesion there were no fewer than five patches constituted by large pleomorphic elements which reacted with antidesmin, sarcomeric actin and myoglobin antisera. These dual features were interpreted as the result of a divergent differentiation of neoplastic cells.

Epithelioid leiomyoma of the breast with granular cell change: a case report.

A 42-year-old woman with an epithelioid granular cell leiomyoma of the right breast is reported. The cells were spindle to polygonal and displayed finely granular cytoplasm. The smooth muscle differentiation of this tumor was shown by the immunohistochemical positivity of the neoplastic cells with anti-alpha smooth actin and antidesmin antisera. Microfilaments with focal densities were present in the cytoplasm at an ultrastructural level. The granular cytoplasmic changes are related to a relevant number of lysosomes within the neoplastic cells.

Primary neuroendocrine carcinoma with ganglion cell differentiation in a crural lymph node.

A primary neuroendocrine carcinoma with ganglion cell differentiation is described in a crural lymph node. The patient, a 48-year-old woman, presented a palpable lymph node of the crural region in March 1994. Histologically, the lesion was composed mostly of small cells immunoreactive for cytokeratins, neuron specific enolase and synaptophysin. The small cells merged gradually with areas containing ganglion cells immersed in a fibrillar matrix resembling neuropil. Ganglion cells expressed neuron-specific enolase, synaptophysin, neurofilament proteins and S-100 protein. Moreover, a minority of them featured cytokeratin expression. Electron microscopy was performed in the small cell component. These cells featured attenuated desmosomes and electron dense granules with an average size of 120 nm within bundles of intermediate filaments. Clinically, no tumour was found elsewhere despite extensive work-up over the 76-month follow-up period. Although similarities with previous cases of primary neuroendocrine carcinoma of lymph node, ganglion cell differentiation has never been described.

Acinic cell-like carcinoma of the breast.

A case of infiltrating carcinoma of the breast with features similar to those seen in acinic cell carcinoma of the parotid gland is described in a 42-year-old woman. The neoplastic cells were immunoreactive with anti-lysozyme- and anti-salivary-type amylase antisera and contained electron-dense cytoplasmic globules similar to those seen in acinic cell carcinoma of salivary glands. One lymph node out of 18 was found to contain a metastatic deposit. The patient is alive and well 1 year after mastectomy. This appears to be the first case of carcinoma with acinic cell-like features reported in the breast.