Content uploaded by Jong-Ryool Oh
Author content
All content in this area was uploaded by Jong-Ryool Oh on Aug 08, 2015
Content may be subject to copyright.
A preview of the PDF is not available
Ga-68 Somatostatin receptor PET/CT in von Hippel-Lindau disease
Abstract and Figures
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas. Cross-sectional modalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease.
Figures - uploaded by Jong-Ryool Oh
Author content
All figure content in this area was uploaded by Jong-Ryool Oh
Content may be subject to copyright.
... The remaining six case reports included patients who underwent PET-CT with gallium-68 DOTA-conjugated peptides ( 68 Ga-PET). In two cases, the patients underwent 68 Ga-PET for evaluation and staging of a PNET and a pheochromocytoma in the context of known VHL disease (3,4). In two other cases, 68 Ga-PET was performed for staging of a pancreatic tumor in one patient and an adrenal tumor in the other patient; these patients were unaware of the diagnosis of VHL, which was established clinically after the incidental detection of associated hemangioblastomas on 68 Ga-PET imaging (5,6). ...
... In our literature review, we identified 16 patients with hemangioblastomas expressing somatostatin receptors on Octreoscan and 68 Ga-PET imaging (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). It is important to note that, compared with Octreoscan, 68 Ga-PET scans have superior spatial resolution, shorter scanning time, and higher sensitivity and specificity. ...
... Although 68 Ga-DOTATATE PET/CT helps to distinguish intracranial metastases from NETs versus other primary neoplasms, other intracranial lesions expressing somatostatin receptors, particularly meningiomas and hemangioblastomas, can also demonstrate 68 Ga-DOTATATE uptake. Oh et al. reported the case of a 36-y-old woman with von Hippel-Lindau disease in which 68 Ga-DOTATATE PET/CT for pancreatic tumor restaging found new avid cerebellar and spinal hemangioblastomas (9). In cases for which distinguishing between meningioma/hemangioblastoma and NET is necessary, structural brain MRI and the clinical context remain crucial to reaching an accurate diagnosis. ...
Neuroendocrine tumors (NETs) are rare neoplasms with an exceedingly low incidence of intracranial metastasis. We present a 79-year-old female with a biopsy-proven pulmonary neuroendocrine tumor who presented with an intracranial mass in the posterior fossa that was DOTATATE avid on a 68Ga-DOTATATE PET/CT, facilitating the rare diagnosis of intracranial NET metastasis. The case highlights the utility of advanced imaging techniques in differentiating intracranial NET metastasis from other etiologies.
... PET is an important imaging modality in management of patients with RDs, 110111112 such as multiple endocrine neoplasia syndromes (MEN1, MEN2A, MEN2B), 113 tumoral calcinosis, 114 Von-Hippel Lindau (VHL), 115 familial carcinoid syndrome, 116 metastatic pheochromocytoma, and paraganglioma, 117 hemangioendothelioma, and other hereditary cancer syndromes. 118 Appropriately employing the capabilities of AI in conjunction with PET could improve monitoring and management of RDs. ...
Almost 1 in 10 individuals can suffer from one of many rare diseases (RDs). The average time to diagnosis for an RD patient is as high as 7 years. Artificial intelligence (AI)-based positron emission tomography (PET), if implemented appropriately, has tremendous potential to advance the diagnosis of RDs. Patient advocacy groups must be active stakeholders in the AI ecosystem if we are to avoid potential issues related to the implementation of AI into health care. AI medical devices must not only be RD-aware at each stage of their conceptualization and life cycle but also should be trained on diverse and augmented datasets representative of the end-user population including RDs. Inability to do so leads to potential harm and unsustainable deployment of AI-based medical devices (AIMDs) into clinical practice.
... al, showed propranolol activity in in-vitro models of VHL RCC and CNS HB, in addition to retrospective data suggesting that propranolol may slow HB growth in VHL patients [16]. 68 Ga-DOTATATE positron emission tomography (PET) imaging of VHL patients has shown that VHL-HBs have avidity to somatostatin analogues [17][18][19]. Neuroendocrine tumors that express somatostatin receptors (SSTRs) demonstrate a clinical response to somatostatin analogue therapy [20,21] and this has been demonstrated in VHL related pancreatic neuroendocrine tumors as well [22]. Sizdahkhani et. ...
Von Hippel-Lindau disease is an inherited, autosomal dominant tumor predisposition syndrome which leads to susceptibility for developing hemangioblastomas of the central nervous system and retina, as well as other tumor types. No approved systemic therapies exist for this disease. Here, we present a patient diagnosed with Von Hippel-Lindau disease, with central nervous system and retinal hemangioblastomas, treated with propranolol and subsequently with Lanreotide. On both treatments, the patient showed notable symptom improvement. In addition, since starting Lanreotide, the patients hemangioblastoma has remained stable on imaging. Based on the symptom improvement in this patient and other reported findings in the literature, propranolol and somatostatin agonist therapy may have an anti-tumor effect in Von Hippel-Lindau associated hemangioblastomas; however, further investigation is warranted.
Background
Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel‐Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy. Expression of somatostatin receptor 2A (SSTR2A) in VHL‐related hemangioblastomas has been described earlier, but the extent of expression in a larger population has yet to be determined. The authors hypothesize that a substantial subset of VHL‐related hemangioblastomas show SSTR2A expression, which may serve as a potential new treatment target.
Methods
Patients who were surgically treated for a VHL‐related hemangioblastoma from 1990 until 2021 at the UMC Utrecht were included. Clinical data was derived from a clinical database. Tissue samples were histopathologically examined with use of hematoxylin and eosin staining, and immunohistochemical analysis of SSTR2A expression was performed.
Results
Forty‐three tissue samples were obtained from 26 patients. Nine showed strong positivity for SSTR2A expression, whereas 13 showed moderate and 15 sparse expression. Three samples showed no expression of SSTR2A. The distribution showed right‐skewedness favoring a strong expression. SSTR2A expression colocalized with endothelial markers and not with stromal cells. Additionally, within‐patient variability for SSTR2A expression was described in 14 patients.
Conclusion
SSTR2A is expressed in varying degrees in the majority of VHL‐related hemangioblastomas. Future treatment with somatostatin analogues or even peptide receptor radionuclide treatment may be considered for SSTR2A‐positive cases.
Von Hippel–Lindau disease is a rare multisystem disorder that shows autosomal dominant inheritance. It is a cancer syndrome that is characterized by the development of a variety of benign and malignant tumors—CNS hemangioblastomas, retinal angiomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, adrenal pheochromocytomas, and epididymal cystadenomas. Here we present the ⁶⁸ Ga-labeled DOTANOC scans of 2 siblings who show an interesting spectrum of findings consistent with Von Hippel–Lindau disease.
PET/CT and radioisotope therapy are diagnostic and therapeutic arms of Nuclear Medicine, respectively. With the emergence of better technology, PET/CT has become an accessible modality. Diagnostic tracers exploring disease-specific targets has led the clinicians to look beyond FDG PET. Moreover, with the emergence of theranostic pairs of radiopharmaceuticals, radioisotope therapy is gradually making it's way into treatment algorithm of common cancers in India. We therefore would like to discuss in detail the updates in PET/CT imaging and radionuclide therapy and generate a consensus-driven evidence based document which would guide the practitioners of Oncology.
Hemangioblastomas (HBs) are highly vascularized, slow-growing, rare benign tumors (WHO grade I). They account for about 2% of intracranial neoplasms; however, they are the most common primary cerebellar tumors in adults. Another frequent seat is the spinal cord (2-10% of primary spinal cord tumors). HBs are constituted by stromal and capillary vascular cells; macroscopically, HBs appear as nodular tumors, with or without cystic components. Although most of the HBs are sporadic (57-75%), they represent a particular component of von Hippel-Lindau disease (VHL), an autosomal dominant syndrome with high penetrance, due to a germline pathogenic mutation in the VHL gene, which is a tumor suppressor with chromosomal location on the short arm of chromosome three. VHL disease determines a variety of malignant and benign tumors, most frequently HBs, renal cell carcinomas, pheochromocytomas/paragangliomas, pancreatic neuroendocrine tumors, and endolymphatic sac tumors. Up to 20% of cases are due to de novo pathogenic variants without a family history. Many epidemiologic details of these tumors, especially the sporadic forms, are not well known. The median age of patients with sporadic HBS is about 40 years. More than two-third of VHL patients develop one or more central nervous system HBs during their lifetime; in case of VHL, patients at first diagnosis are usually younger than the patients with sporadic tumors. The most common presenting signs and symptoms are related to increased intracranial pressure, cerebellar signs, or spinal cord alterations in case of spinal involvement. Magnetic resonance imaging is the gold standard for the diagnosis, assessment, and follow-up of HBs, both sporadic and syndrome-related; angiography is rarely performed because the diagnosis is easily obtained with magnetic resonance. However, the diagnosis of an asymptomatic lesion does not automatically result in therapeutic actions, as the risks of treatment and the onset of possible neurological deficit need to be balanced, considering that HBs may remain asymptomatic and have a static or slow-growing behavior. In such cases, regular follow-up can represent a valid therapeutic option until the patients remain asymptomatic. There are no actual pharmacological therapies that are demonstrated to be effective for HBs. Surgery represents the primary therapeutic approach for these tumors. Observation or radiotherapy also plays a role in the long-term management of patients harboring HBs, especially in VHL; in few selected cases, endovascular treatment has been suggested before surgical removal. This chapter presents a systematic overview of epidemiology, clinical appearance, histopathological and neuroradiological characteristics of central nervous system HBs. Moreover, the genetic and molecular biology of sporadic and VHL HBS deserves special attention. Furthermore, we will describe all the available therapeutic options, along with the follow-up management. Finally, we will briefly report other vascular originating tumors as hemangioendotheliomas, hemangiomas, or angiosarcomas.
Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that is characterized by the presence of various malignant and benign tumors, including retinal and central nervous system hemangioblastomas. Hemangioblastomas are highly vascular tumors that can occur sporadically or within VHL disease. Herein, we present 68Ga-DOTATATE PET/CT findings of a unique case of suprasellar hemangioblastoma in a 52-year-old man with VHL disease.
Spinal neoplasms encompass a cohort of pathologies affecting the spinal cord, meninges, and vertebrae, including benign neoplasms as well as primary and secondary malignancies. Diagnostic imaging frequently starts with CT to assess osseous involvement and MRI to localize abnormalities within the spinal canal and determine anatomic relationships to the thecal sac and spinal cord, with myelography representing an adjunct modality in select cases. Fluorodeoxyglucose (FDG) PET can be helpful in determining aggressiveness of a neoplasm and in the case of multiple myeloma can distinguish active from inactive lesions. With the rise of novel radiotracers including gallium-68-labeled somatostatin analogs such as DOTATATE and prostate cancer-specific agents such as PSMA and fluciclovine, the role of PET imaging has become more central in the diagnostic workup and treatment response assessment in spinal neoplasms. While PET/CT was historically considered the reference standard for oncological spinal imaging, the multiparametric capabilities of PET/MRI allow for a combination of functional and anatomic information that holds great promise for clinical practice.
A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients and from sporadic renal cell carcinomas. The VHL gene is evolutionarily conserved and encodes two widely expressed transcripts of approximately 6 and 6.5 kilobases. The partial sequence of the inferred gene product shows no homology to other proteins, except for an acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. 17 refs., 4 figs. 1 tab.
Purpose:
(68)Ga-DOTA-Tyr(3)-octreotide positron emission tomography ((68)Ga-DOTA-TOC PET) has proven to be superior to (111)In-DTPA-D-Phe(1)-octreotide ((111)In-octreotide) planar scintigraphy and SPECT imaging in neuroendocrine tumours (NETs). Because of these promising results, we compared the accuracy of (123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging with PET in the diagnosis and staging of metastatic phaeochromocytoma and neuroblastoma, referring to radiological imaging as reference standard.
Methods:
Three male and eight female patients (age range 3 to 68 years) with biochemically and histologically proven disease were included in this study. Three male and three female patients were suffering from phaeochromocytoma, and five female patients from neuroblastoma. Comparative evaluation included morphological imaging with CT or MRI, functional imaging with (68)Ga-DOTA-TOC PET and (123)I-MIBG imaging. Imaging results were analysed on a per-patient and on a per-lesion basis.
Results:
On a per-patient basis, both (68)Ga-DOTA-TOC and (123)I-MIBG showed a sensitivity of 100%, when compared with anatomical imaging. In phaeochromocytoma patients, on a per-lesion basis, the sensitivity of (68)Ga-DOTA-TOC was 91.7% and that of (123)I-MIBG was 63.3%. In neuroblastoma patients, on a per-lesion basis, the sensitivity of (68)Ga-DOTA-TOC was 97.2% and that of (123)I-MIBG was 90.7%. Overall, in this patient cohort, (68)Ga-DOTA-TOC PET identified 257 lesions, anatomical imaging identified 216 lesions, and (123)I-MIBG identified only 184 lesions. In this patient group, the overall sensitivity of (68)Ga-DOTA-TOC PET on a lesion basis was 94.4% (McNemar p<0.0001) and that of (123)I-MIBG was 76.9% (McNemar p<0.0001).
Conclusion:
Our analysis in this relatively small patient cohort indicates that (68)Ga-DOTA-TOC PET may be superior to (123)I-MIBG gamma-scintigraphy and even to the reference CT/MRI technique in providing particularly valuable information for pretherapeutic staging of phaeochromocytoma and neuroblastoma.
In-111 Octreoscan is considered the gold standard for imaging of neuroendocrine tumors (NET). However, in the absence of morphologic imaging correlation, the exact localisation of the tumor is often difficult. Also the sensitivity of PET imaging is more than Gamma camera (SPECT) imaging. Ga-68 labelled somatostatin analogs (SMS-R) are interesting radiopharmaceuticals for PET receptor imaging of NET. Some other radiopharmaceuticals e.g. F-18 DOPA can also be used to assess metabolism and functional status of NET. The importance of these radiopharmaceuticals, especially SMS-R increases in the absence of any specific biochemical marker or clinical parameter for follow-up of patients after therapy (eg peptide receptor radionuclide therapy, surgery, chemoembolisation, etc). New criteria based on molecular, metabolic and morphologic imaging needs to be developed for correct assessment of response to therapy for these slow-growing, solid tumors.
In-111 Octreoscan is considered the gold standard for imaging of neuroendocrine tumors (NET). However, in the absence of morphologic imaging correlation, the exact localisation of the tumor is often difficult. Also the sensitivity of PET imaging is more than Gamma camera (SPECT) imaging. Ga-68 labelled somatostatin analogs (SMS-R) are interesting radiopharmaceuticals for PET receptor imaging of NET. Some other radiopharmaceuticals e.g. F-18 DOPA can also be used to assess metabolism and functional status of NET. The importance of these radiopharmaceuticals, especially SMS-R increases in the absence of any specific biochemical marker or clinical parameter for follow-up of patients after therapy (eg peptide receptor radionuclide therapy, surgery, chemoembolisation, etc). New criteria based on molecular, metabolic and morphologic imaging needs to be developed for correct assessment of response to therapy for these slow-growing, solid tumors.
After establishing a biochemical diagnosis, pheochromocytomas and extra-adrenal paragangliomas (PPGLs) can be localized using different anatomical and functional imaging modalities. These include computed tomography, magnetic resonance imaging, single-photon emission computed tomography (SPECT) using 123I-metaiodobenzylguanidine or 111In-DTPA-pentetreotide, and positron emission tomography (PET) using 6-[18F]-fluorodopamine (18F-FDA), 6-[18F]-fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA), and 2-[18F]-fluoro-2-deoxy-d-glucose. We review the currently available data on the performance of anatomical imaging, SPECT, and PET for the detection of (metastatic) PPGL as well as parasympathetic head and neck paragangliomas. We show that there appears to be no 'gold-standard' imaging technique for all patients with (suspected) PPGL. A tailor-made approach is warranted, guided by clinical, biochemical, and genetic characteristics. In the current era of a growing number of PET tracers, PPGL imaging has moved beyond tumor localization towards functional characterization of tumors.
A case of Von-Hippel Lindau (VHL) disease has been studied using 68Ga-DOTA-NOC PET/CT. PET/CT demonstrated the presence of somatostatin receptors within 2 focal areas in the cerebellum corresponding to the lesions detected by MRI. Considering the heterogeneous lesions localizations in VHL disease, PET/CT may be a useful imaging modality for diagnosing lesions of central nervous system and neuroendocrine lesions and for direct demonstration of somatostatin receptors for targeted treatment.
To assess the impact of imaging on pancreatic lesion management in von Hippel-Lindau disease (VHL).
We reviewed sequential computed tomography (CT) and magnetic resonance examinations (1997-2008) of 33 patients with VHL who had at least 1 pancreatic lesion.
One hundred sixty-seven imaging studies demonstrated innumerable simple pancreatic cysts and 58 complex pancreatic masses: 24 were complex cystic and 34 were solid (30 small [<or=2 cm] and 4 large [>2 cm]). Aggregate annual growth was significant in complex cystic and solid masses (mean, 0.39 cm/y [P = 0.006] and 0.14 cm/y [P = 0.045]). Solid mass growth differed by size (small: 0.06 cm/y [range, -0.09 to 0.31 cm/y]; large: 1.28 cm/y [range, 0-1.98 cm/y]). Thirteen masses were excised. No patient developed metastases. Arterial-phase CT improved (P = 0.0003) solid mass detection, but 28% of studies still underreported the total number.
Most pancreatic masses in VHL do not require annual surveillance. Arterial-phase CT improves mass detection, but many masses remain prospectively missed.
Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas1-3. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.
Von Hippel-Lindau disease is an autosomal dominant inherited disorder causing hemangioblastomas of the central nervous system (CNS), retinal hemangiomas, renal cell carcinomas, pheochromocytomas, pancreatic and liver cysts, and epididymal cystadenomas.
Since 1976, we have periodically screened for the lesions in a large affected family and were able to evaluate new strategies in detection and treatment.
A total of 23 individuals underwent the screening program. A multidisciplinary team of physicians was involved.
In 13 patients (7 females and 6 males), a total of 31 tumors was detected; hemangioblastoma of the CNS (9), retinal angioma (4), renal involvement (8), pheochromocytoma (4), pancreatic lesions (4), and liver lesions (2) were diagnosed by periodic family screening. On the basis of more than 10 years of experience and current literature, new criteria for diagnosis and treatment have been proposed.
The von Hippel-Lindau disease gene appears to be a tumor suppressor gene, and its absence or a defect in its structure is responsible for the predisposition to the disease. Tumor development depends on a somatic second mutation in the homologous allele. That means, in disease-gene carriers, tumor growth may begin at any age. Most of the lesions can be treated successfully when diagnosed in time. Periodic screening by a multidisciplinary team has to be continued lifelong.