Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.

Paraganglioma of the thyroid gland: cytologists' enigma.

Paraganglioma is a neuroendocrine tumour derived from extra-adrenal cells of the neural crest paraganglia of the autonomic nervous system. These rare neoplasms comprise of around 0.012% of head and neck tumours. Paraganglioma arising in the thyroid gland is exceptionally uncommon and can present as a diagnostic challenge on fine-needle aspiration cytology (FNAC). We report a case of primary thyroid paraganglioma in a 19-year-old woman who presented with a solitary thyroid nodule without palpable cervical lymphadenopathy. FNAC from the lesion caused diagnostic dilemma by mimicking follicular neoplasm and C-cell-derived thyroid tumours; final diagnosis was established by histopathology and immunohistochemistry. The main purpose of this case report is to discuss the differential diagnosis and emphasise on the need of immune markers in the diagnosis of thyroid paraganglioma. In view of the uncertain malignant potential of these tumours, a long-term follow-up is recommended.

Paraganglioma of the thyroid: report of a male case with ultrasonographic imagings, cytologic, histologic, and immunohistochemical features.

OBJECTIVE: Thyroid paragangliomas are rare tumors, and both preoperative and postoperative differential diagnosis is difficult. We report the case of a 24-year-old man with a thyroid paraganglioma and the ultrasonographic imaging, histologic, and immunohistochemical findings. DESIGN: The patient presented with an asymptomatic thyroid nodule. An ultrasonogram showed a 3-cm-diameter solid nodule in the upper portion of the right lobe of thyroid, and color Doppler ultrasonography revealed intranodular hypervascular flows. Fine-needle aspiration biopsy yielded single cells and loose clusters of round to oval cells containing ovoid nuclei. A clinical diagnosis of follicular thyroid tumor was made, and right thyroid lobectomy was performed. The tumor was encapsulated and exhibited a prominent lobular pattern. To differentiate between thyroid paraganglioma and other thyroid neoplasms, paraffin sections of the specimen were immunochemically stained with antibodies to calcitonin (CT), carcinoembryonic antigen (CEA), chromogranin A, neuron-specific enolase (NSE), S-100, and thyroglobulin. MAIN OUTCOME: The immunohistochemical staining was positive for chromogranin A and NSE and negative for thyroglobulin, CT, CEA, and S-100. Congo red staining was also negative. Based on these findings, final diagnosis of thyroid paraganglioma was made. CONCLUSIONS: The definitive diagnosis of paraganglioma is made on the basis of the results of immunohistochemical staining. The diagnosis of thyroid paraganglioma is difficult to make both preoperatively and postoperatively.

A functioning-desensitization paraganglioma which caused hemodynamic instability during tumoral resection: report of a case.

Paragangliomas are uncommon tumors arising from the neuroendocrine elements of the paraganglia. Their successful management is associated with many problems. We herein present the findings of a 22-year-old man in whom a paraganglioma was incidentally found and in which the clinical and previous operative behavior was functioning desensitization. As a result, preoperative medication was not performed; however, during the tumor resection the patient demonstrated hemodynamic instability.

Immunohistochemical characterization of a case of duodenal gangliocytic paraganglioma.

A case of duodenal gangliocytic paraganglioma (DGP) arising in the ampulla of Vater of an 84 year old male is reported. The present case shows the typical histological features with a mixture of epitheliold, ganglion-like and spindle cells. Immunohistochemically, the spindle cells were positive with antibodies to neuron specific enorse, S-100 protein and neurofilament (NF), but negative for anti-glial fibrillary acidic protein (GFAP), synaptophysin and myelin basic protein (MBP). Both anti-Leu-7 and -chromogranin A antibodies gave positive reactions with a fine granular pattern in the epithelioid cells. Most ganglion-like cells showed the cytoplasmic immunoreaction with GFAP and a few with NF and synaptophysin. In these three tumor components, no reactivity was detected in the antibodies to the neurohormonal peptides tested. The present data are fundamentally in keeping with those previously reported, but add the immunohistochemical positivity of ganglion-like cells for GFAP, suggesting different neuroglial differentiation.

[Orbital myopathy in metastatic malignant paraganglioma: a paraneoplastic syndrome?]. / Orbitale Myopathie bei metastasiertem malignem Paragangliom: Eine Paraneoplasie?

BACKGROUND: Several disease entities of the orbit are known which display an autoimmunological pathogenesis. Among these disease entities the thyroid-related immune orbitopathy and the idiopathic orbital inflammatory syndrome (orbital pseudotumor). The pathogenesis of these diseases is not well understood; however, an autoimmune inflammatory reaction histologically characterized by a chronic inflammatory cell infiltrate has been suggested. One care of orbital pseudotumor presumably of paraneoplastic origin occurring in a patient with a non-Hodgkin's lymphoma has been reported. We report a patient with a metastatic paraganglioma and a proptosis secondary to enlargement of all extraocular muscles. CASE REPORT: A 52-year-old woman presented with a recent decline in visual clarity of her left eye and diplopia. Two years ago, the diagnosis of a hormonally inactive paraganglioma has been made. Ophthalmologic examination displayed a lagophthalmos caused by a right-sided facial paralysis secondary to a cerebral metastasis and a bilateral enlargement of all extraocular muscles. Curative therapy for the paraganglioma was not available. Palliative therapy as well as a high-dose corticosteroid therapy for the orbitopathy was refused by the patient. The patient died 18 months later. DISCUSSION: Our patient developed orbital changes similar to thyroid-related immune orbitopathy; however, there was no dysfunction of the thyroid. We believe that the orbital changes were a paraneoplastic immune reaction caused by the metastatic paraganglioma. We recommend that in patients who do not conform to the prototypical profile of well-known orbital disease entities should undergo further testing to exclude a remote neoplasm.

Immunohistochemical characterization of HLA-DR-antigen positive dendritic cells in phaeochromocytomas and paragangliomas as a prognostic marker.

Twelve cases of phaeochromocytoma (PCC) and four cases of paraganglioma (PGG) were studied by immunohistochemistry and immunoelectron microscopy in order to demonstrate HLA-DR (Ia)-antigen-positive dendritic cells (IaDCs). Dense infiltration of IaDCs was detected in the majority of PCCs revealing high urinary or serum catecholamine levels, but in aggressively growing PCCs, a familial PCC and all PGGs, few IaDCs were demonstrated. Interestingly, these IaDCs were negative for S-100 protein. Although S-100-protein-positive sustentacular-like cells (SCs), morphologically similar to IaDCs, were also present, these were clearly distinguished from IaDCs by our double immunostaining method. Ultrastructurally, IaDCs had smooth or slightly indented nuclei and contained a moderate amount of endoplasmic reticulum, small mitochondria and vacuoles, extending elongated cytoplasmic processes. These results suggest that determination of the quantity of IaDCs is a highly effective method of assessing the character of PCCs, in particular, their prognosis.

Alveolar soft part sarcoma. Immunohistochemical evidence for muscle cell differentiation.

Seven cases of alveolar soft part sarcomas (ASPSs) were studied immunohistochemically for the presence of a number of differentiation markers in an attempt to define the cellular nature of this tumor. Desmin-positive tumor cells were found in three and muscle actin-positive cells in four cases when studied in formaldehyde-fixed and paraffin-embedded material. In one case studied in frozen sections, focal desmin positivity but no other intermediate filaments were found. Immunostaining for synaptophysin, a general neuroendocrine marker, was negative in all cases. All tumors were positive with a monoclonal antibody NK1C3, which consistently stains melanomas, and three cases showed significant numbers of S-100 protein-positive tumor cells, but immunostaining with HMB-45, a melanoma-specific monoclonal antibody, was negative in all cases. However, several rhabdomyosarcomas studied for NK1C3 and S-100 protein for comparison were also at least focally positive. Electron microscopic examination, performed in three cases, showed uniform paucity of all kinds of filaments in the tumor cells of ASPS, and it specifically failed to reveal any signs of smooth or striated muscle cell differentiation. Thus, the results of the present study do not unequivocally define the nature of ASPS but speak against its paraganglionic character and present evidence for muscle cell differentiation.

[Significance of neuronal acetylcholine receptors as differentiation antigens in neuroblastomas and paragangliomas]. / Die Bedeutung neuronaler Acetylcholinrezeptoren als Differenzierungsantigene in Neuroblastomen und Paragangliomen.

Using a panel of monoclonal antibodies to various epitopes of the alpha-, beta- and gamma-subunit of the muscle acetylcholine receptor (AchR), two different immunohistochemical reactivity patterns--corresponding to different neuronal AchRs--were identified in ganglia of the peripheral and central nervous system. The immunoreactivity pattern of neuroblastomas and paragangliomas was identical to the pattern found in the peripheral nervous system and has not been encountered in any other tumor type. Both the intensity of neuronal AchR immunoreactivity and the transcription of the neuronal AchR alpha-gene seem to correlated with a higher degree of neuroblastoma differentiation.

Urinary bladder paragangliomas. An immunohistochemical study.

The immunohistochemical characteristics of three cases of urinary bladder paragangliomas are presented. These are compared with similar studies on paragangliomas from other anatomic sites and the clinical and pathologic implications are discussed.

Cell-mediated amplification and down regulation of cytotoxic immune response against autologous human cancer.

The cytotoxic host immune response toward autologous human cancer may be regulated by the immunoregulatory network. Here we show that helper T cells, cloned from peripheral blood lymphocytes that were sensitized in vitro against an autologous human malignant paraganglioma, proliferated against and made interleukin 2 when cocultured with the tumor-associated antigen in the presence of autologous accessory cells. Furthermore, the helper cell clones amplified cytotoxic immune response by peripheral blood lymphocytes against the paraganglioma cells in coculture with the blood lymphocytes and the paraganglioma cells. An autologous T cell line bearing suppressor phenotype, established from a lymph node that had been infiltrated with the paraganglioma tumor cells, in contrast to the helper cells, selectively suppressed the cytotoxic immune response by the blood lymphocytes against the paraganglioma cells in identical coculture. These results, therefore, demonstrate the existence of cell-mediated immunologic regulations of the cytotoxic immune response (concurrent amplification and suppression in the same host) against an autologous human tumor.

Duodenal gangliocytic paraganglioma. Clinicopathologic and immunocytochemical study of 11 cases.

The clinicopathologic features of 11 cases (8 in men) of duodenal gangliocytic paraganglioma are presented. The patients averaged 56 years of age; none showed evidence of phakomatosis. Ten tumors occurred in the second portion of the duodenum, and one arose in the third portion. All tumors were polypoid, and half presented with gastrointestinal bleeding. The neoplasms were composed of paraganglioma and carcinoid-like elements, neurons, and Schwann as well as sustentacular cells. All tumors behaved in a benign fashion after local resection or snare polypectomy; long-term follow-up (1-25 years; mean, 8.3 years) showed no recurrence in any case. Immunocytochemical examination demonstrated the presence of somatostatin, serotonin, and human pancreatic polypeptide within endocrine cells and neurons.

Paraganglioma of the cauda equina. A histologic, immunohistochemical, and ultrastructural study and review of the literature.

We report a case of paraganglioma of the cauda equina and filum terminale. Diagnosis was established by the histologic organoid pattern, immunohistochemical staining for neuron-specific enolase and ultrastructural dense-core neurosecretory granules. A survey of the literature yielded 16 previously reported cases, five of which were described in 1983. This suggests that heightened awareness of this entity will result in a corresponding increase in the reported incidence.

Laryngeal paraganglioma. Report of two tumors with immunohistochemical and ultrastructural analysis.

Paraganglionic tumors of the larynx are uncommon neoplasms and their secretory products have rarely been elucidated. We saw two patients whose laryngeal paragangliomas were examined with an electron microscope and by the use of immunocytochemical techniques. Both tumors manifested positive immunoreactivity against calcitonin and vasoactive intestinal polypeptide. One of the paragangliomas was immunoreactive against carcinoembryonic antigen and pursued a biologically malignant course. Our observations suggest the coexistence of amines and hormonal polypeptides in cells of paraganglionic tumors and demonstrate the multihormonal nature of these tumors.