Case Report: Giant Thyroid Angiolipoma-Challenging Clinical Diagnosis and Novel Genetic Alterations.

BACKGROUND: A 64-year-old man presented with a 7.8 cm lipomatous thyroid mass discovered on magnetic resonance imaging. METHODS: After two non-diagnostic fine needle aspirations (FNAs) were performed, computed tomography (CT) revealed features concerning for malignancy including central necrosis and infiltrative borders. A third FNA was still non-diagnostic. Total thyroidectomy was performed. RESULTS: Upon pathologic examination, the final diagnosis was primary thyroid angiolipoma. The lesion contained central fat necrosis with ischemic features, attributable to the FNAs. CONCLUSION: Ours is the third published case report of this rare entity. To date, no lipomatous thyroid tumor has undergone extensive genomic testing. Next-generation sequencing of our case revealed multiple genetic alterations, supporting the concept of angiolipomas being true neoplasms. Whereas the two previously reported cases in the literature were radiographically much smaller and appeared indolent, the large tumor in our case exhibited radiographic features concerning for liposarcoma, which belied the benign final pathologic diagnosis. Our case demonstrates that conservative surgical management (partial thyroidectomy) may be considered for lipomatous thyroid tumors, with further interventions to be determined only after final pathologic diagnosis.

Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex.

Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In lymphangioleiomyomatosis, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high-throughput screen utilizing the "Repurposing" library at the Broad Institute of MIT and Harvard (Cambridge, MA), with or without the autophagy inhibitor chloroquine. Ritanserin, an inhibitor of diacylglycerol kinase alpha (DGKA), was identified as a selective inhibitor of proliferation of Tsc2-/- mouse embryonic fibroblasts (MEF), with no impact on Tsc2+/+ MEFs. DGKA is a lipid kinase that metabolizes diacylglycerol to phosphatidic acid, a key component of plasma membranes. Phosphatidic acid levels were increased 5-fold in Tsc2-/- MEFs compared with Tsc2+/+ MEFs, and treatment of Tsc2-/- MEFs with ritanserin led to depletion of phosphatidic acid as well as rewiring of phospholipid metabolism. Macropinocytosis is known to be upregulated in TSC2-deficient cells. Ritanserin decreased macropinocytic uptake of albumin, limited the number of lysosomes, and reduced lysosomal activity in Tsc2-/- MEFs. In a mouse model of TSC, ritanserin treatment decreased cyst frequency and volume, and in a mouse model of lymphangioleiomyomatosis, genetic downregulation of DGKA prevented alveolar destruction and airspace enlargement. Collectively, these data indicate that DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis and promote proliferation. Targeting macropinocytosis with ritanserin may represent a novel therapeutic approach for the treatment of TSC and lymphangioleiomyomatosis. SIGNIFICANCE: This study identifies macropinocytosis and phospholipid metabolism as novel mechanisms of metabolic homeostasis in mTORC1-hyperactive cells and suggest ritanserin as a novel therapeutic strategy for use in mTORC1-hyperactive tumors, including pancreatic cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2086/F1.large.jpg.

Frequent activating PIK3CA mutations in sporadic angiolipoma.

BACKGROUND: Angiolipoma (AL) is considered as a lipoma variant that is characterized by the combination of mature adipocytes and capillary blood vessels diffusely distributed within the tumor. With the exception of recurrent PRKD2 mutations of uncertain pathogenetic significance, the genetic abnormalities of ALs are unknown, in the absence of any of the specific chromosomal aberrations described in other lipoma variants. METHODS: Formalin-fixed and paraffin-embedded blocks of 13 conventional ALs and 5 cellular ALs from 17 individuals were retrieved and analyzed for mutations in exons 9 and 20 of PIK3CA by polymerase chain reaction and Sanger sequencing. RESULTS: Activating PIK3CA mutations were identified in 14 tumors (78%). All PIK3CA-mutated samples carried the same exon 9 mutation, c.1634A>C (p.E545A). No mutation was detected in exon 20 of PIK3CA. No significant difference between PIK3CA-mutated and wild-type samples appeared to exist based on age, gender, and location of the tumor. All 5 cellular ALs carried the p.E545A PIK3CA mutation. CONCLUSION: The high frequency of the p.E545A PIK3CA mutation in both conventional and cellular ALs suggests that activation of the PI3K/AKT pathway plays a key role in AL pathogenesis and reinforces the concept that cellular AL should be regarded as a variant of AL.

Consistent Involvement of Chromosome 13 in Angiolipoma.

BACKGROUND/AIM: Angiolipoma is a rare benign soft tissue tumor composed of mature adipocytes and blood vessels. Genetic information on angiolipomas is scarce. With the single exception of one tumor which carried a t(X;2)(p22;p12), all angiolipomas hitherto investigated cytogenetically had normal karyotypes. MATERIALS AND METHODS: G-banding chromosome analysis was performed on three short-term cultured angiolipomas. Fluorescence in situ hybridization (FISH) analysis using a commercially available RB1 deletion probe was also done. RESULTS: All three angiolipomas had abnormal karyotypes with loss or structural rearrangement of chromosome 13. The first tumor had the karyotype 46,XY,-6,del(13)(q14),+mar[cp5], the second had 44~45,XY,t(1;10;15)(p21~22;q24;q24),-13[cp5], and the third karyotype was 43,XX,t(13;22;17) (q12;q13; q22~23)[14]. FISH analysis showed heterozygous and homozygous deletion of the RB1 probe in case 2 and 3, respectively. FISH analysis failed in case 1. CONCLUSION: Chromosome 13 was consistently involved in all three angiolipomas.

Lipomatous tumors of the breast: A contemporary review.

Breast tumors with lipomatous or liposarcomatous components are infrequently encountered, but can be a source of diagnostic difficulty if the context of the fatty differentiation is not recognized. Among the true adipocytic tumors, lipoma is the most common lipomatous tumor arising in the breast. Several mammary spindle cell tumors may show adipocytic differentiation, including fibroepithelial tumors and myofibroblastoma. Liposarcomatous components most often arise in malignant phyllodes tumors, as opposed to primary liposarcomas of the breast which are believed to be uncommon. This article will review the spectrum fat-containing tumors of the breast with an emphasis on differential diagnosis and insights from recent molecular studies.

Frequent low-level mutations of protein kinase D2 in angiolipoma.

Tumours displaying differentiation towards normal fat constitute the most common subgroup of soft tissue neoplasms. A series of such tumours was investigated by whole-exome sequencing followed by targeted ultra-deep sequencing. Eighty per cent of angiolipomas, but not any other tumour type, displayed mutations in the protein kinase D2 (PRKD2) gene, typically in the part encoding the catalytic domain. The absence of other aberrations at the chromosome or RNA level suggests that PRKD2 mutations are critical for angiolipoma development. Consistently, the mutated PRKD2 alleles were present at low (3-15%) frequencies, indicating that only a subset of the tumour cells is affected. Indeed, by sequencing mature fat cells and other cells separately, the former typically showed the highest mutation frequencies. Thus, we hypothesize that altered PRKD2 signalling in the adipocytic cells drives tumourigenesis and, in agreement with its pivotal role in angiogenesis, induces the vessel formation that is characteristic for angiolipoma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hepatic angiomyolipomas may overexpress TFE3, but have no relevant genetic alterations.

The fusion or amplification of TFE3 has been identified as one of the molecular events underlying tumorigenesis in perivascular epithelioid cell tumors (PEComas). TFE3 rearrangements in PEComas are related to the morphological features of the epithelioid appearance and weaker expression of immunohistochemical muscular markers. This study aimed to clarify whether these genetic alterations are involved in hepatic angiomyolipomas (AMLs), which are a member of the PEComa tumor family. We examined 28 liver specimens (15 biopsies and 13 surgical specimens) of hepatic AMLs obtained from 26 patients. Renal AMLs (n=20), extrahepatorenal PEComas (n=3), lymphangiomyomatosis (n=8), and hepatocellular carcinomas (n=40) were used as a control. A histologic comparison between hepatic and renal AMLs revealed that the epithelioid appearance was more common in hepatic tumors (38% versus 0%, P=.006). In immunohistochemistry, the expression of HMB45 and Melan-A appeared to be more widespread in hepatic AMLs than in renal AMLs, whereas smooth muscle actin and desmin were less broadly expressed in hepatic tumors (all P<.001). TFE3 also appeared to be overexpressed in 6 (21%) of 26 hepatic AMLs and 3 (100%) of 3 PEComas, but in none of the renal AMLs. In fluorescence in situ hybridization, although all PEComas harbored a TFE3 rearrangement or amplification, no genetic alterations were found in any hepatic AMLs. In conclusion, although hepatic AMLs and TFE3-rearranged PEComas share pathological features such as the epithelioid appearance and immunoreactivity to TFE3, TFE3 alterations are less likely to be a major molecular event driving tumorigenesis in hepatic AMLs.

Autosomal-dominant familial angiolipomatosis.

Angiolipomas are among the most common benign soft-tissue tumors and usually present as solitary nodules; however, angiolipomas also may present as multiple subcutaneous nodules, typically on the arms and trunk of young men. Although multiple angiolipomas most often occur sporadically, a family history can be identified in a minority of cases. Familial angiolipomatosis is a rare condition with an autosomal-recessive transmission pattern that is characterized by multiple subcutaneous tumors and a family history of similar lesions, which are not associated with malignant neoplasms. We report a case of familial angiolipomatosis with an unusual autosomal-dominant transmission pattern. Our patient presented with multiple angiolipomas that were highly suggestive of familial angiolipomatosis transmitted in an autosomal-dominant fashion, as he had several family members with a history of similar fatty tumors. Autosomal-dominant familial angiolipomatosis may be misdiagnosed as neurofibromatosis type I. Therefore, in cases of multiple subcutaneous tumors and a family history of similar lesions, histologic examination is important to establish the correct diagnosis.

[Adipocytic tumors]. / Tumeurs adipeuses.

Adipocytic tumors are the most common mesenchymal neoplasms, liposarcoma accounting for approximately 20% of soft tissue sarcomas. The differential diagnosis between benign and malignant tumors is often problematic and represents a significant proportion of consultation cases. The goal of this article is to review liposarcoma subtypes, the main benign adipocytic neoplasms: lipoblastoma, hibernoma, spindle/pleomorphic cell lipoma, chondroid lipoma, as well as non adipocytic neoplasms with a lipomatous component such as lipomatous solitary fibrous tumor, emphasizing on practical differential diagnosis issues, and immunohistochemical and molecular tools allowing their resolution.

Tri-filial presentation of familial tuberous sclerosis with renal tumors.

Tuberous sclerosis is a rare neuro-cutaneous syndrome with autosomal dominant penetrance. Only some organs are involved, e.g., skin (earthy skin thickenings, ash leaf patches), cerebral cortex (hamartomatous nodules) and kidneys, (angiolipoma, adenocarcinoma). These hamar-tomatous swellings resemble potatoes and hence, referred to as tubers. We herein report on three patients (all familial), father, son and granddaughter, with this rare involvement, from the eastern part of India. The father and son had involvement of only the skin (i.e. nose) and kidneys while the disease penetrated further in the subsequent filial generations with son and granddaughter having skin, brain and bilateral kidney involvement. This kind of tri-filial progression has not till date, been reported from this region, making it an interesting case presentation.

Combined anomalies of the palate in Mohr syndrome: is preoperative electromyography of the palate useful?

The authors present a girl with typical characteristics of oral-facial-digital syndrome type II (Mohr syndrome) with a cleft soft palate and pendulous tongue nodules. Because of feeding difficulties, electromyography was performed of both morphologically identical halves of the soft palate. One half showed a normal muscle action potential and in the other half electrical silence was registered. Exploratory surgery during palatoplasty showed a fatty hamartoma in the half of the palate in which no electric potentials had been registered.

[Classic form of Bourneville-Pringle disease in a daughter and appearance of hypopigmented macules of her father's skin]. / Klasyczna postac choroby Bourneville'a-Pringle'a u córki i wystepowanie plam odbarwieniowych na skórze u ojca.

Tuberous sclerosis (Bourneville-Pringle disease) is an genetic autosomal dominant disease, but in over 50% cases there are new spontaneous mutations. During this disease visceral hamartomas do tend to develop in various tissues. Earlier it was considered that in order to set a diagnosis the knowledge of Vogt's triade was required (angiofibroma, epilepsia, mental retardation). But new not typical forms occur, that do not contain all the above mentioned three elements. The phenomenon is connected with the appearance of a new mutations of the gene or with a variable gene penetrance. In these study case we present a 21-year old patient who shows the fully blown symptoms of Vogt's triad and her father who only has hypopigmented macules on his back.

Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors.

Deletions and structural rearrangements of the long arm of chromosome 13 are frequently observed in benign and low-malignant lipomatous tumors, but nothing is known about their molecular genetic consequences. We assessed the karyotypes of 40 new and 22 previously published cases (35 ordinary lipomas, 15 spindle cell/pleomorphic lipomas, 2 myxolipomas, 1 angiomyxolipoma and 9 atypical lipomatous tumors) with chromosome 13-abnormalities, and found bands 13q12-22 to be frequently affected. Twenty-seven cases with structural abnormalities within this region were selected for breakpoint and deletion mapping by metaphase fluorescence in situ hybridization (FISH), using a set of 20 probes. Deletions were found in 23 of 27 cases. The remaining 4 cases had seemingly balanced rearrangements. The breakpoints were scattered but clustered to band 13q14, and in all cases with unbalanced abnormalities, a limited region within band 13q14 was partially or completely deleted. A deletion within band 13q14 was found together with a breakpoint on the other homologue in 5 cases, 4 of which could be tested further with regard to the status of the retinoblastoma (RB1)-gene. In all 4 cases, only 1 copy of the gene was deleted. In addition to the breaks and deletions in the vicinity of the RB1-locus, several other regions of 13q were recurrently affected, e.g., in the vicinity of the hereditary breast cancer (BRCA2; 13q12)- and lipoma HMGIC fusion partner (LHFP; 13q13)- genes. Our findings strongly indicate that deletion of a limited region (approximately 2.5 Mbp) within 13q14, distal to the RB1-locus, is of importance in the development of a subset of lipomatous tumors.

A case of familial angiolipomatosis with Lisch nodules.

Familial angiolipomatosis is a rare syndrome that may be confused clinically with neurofibromatosis type 1. This condition is most often inherited in an autosomal recessive manner; however, several reports have been published suggesting an autosomal dominant mode of inheritance. Angiolipomatosis, although somewhat disfiguring, is a benign condition with no known association with malignant neoplasms. This is in contradistinction to neurofibromatosis, an autosomal dominant syndrome associated with a myriad of benign and malignant neoplasms. It is, therefore, important to discriminate this entity from neurofibromatosis when a patient presents with multiple subcutaneous tumors and a family history of similar lesions. Described is a case of a prison inmate with a history of seizures and "neurofibromatosis" without clinical documentation. Lisch nodules were noted on the irides. Postmortem examination showed multiple subcutaneous yellow tumors on the chest and arms. Fine-needle aspiration of 1 mass yielded adipose tissue with prominent vessels; histologic sections of another mass showed angiolipoma. The remainder of the autopsy showed significant coronary artery disease and a remote cerebral infarction of the temporal lobe but no signs of neurofibromatosis. We feel that the presence of multiple angiolipomas in combination with Lisch nodules lends credence to the proposed relationship between fatty tumors and neurofibromatosis suggested by other authors.

Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group.

Subcutaneous angiolipomas are benign soft-tissue lesions consisting of two mesenchymal elements (i.e., adipose tissue and blood vessels) and having distinct clinical features. They usually are multiple, with an obvious male predominance, and hereditary occurrence has been described. Twenty subcutaneous angiolipomas from 10 patients with typical clinical and morphologic features were reviewed. All lesions had a normal karyotype. This finding is in striking contrast with ordinary lipomas, spindle-cell and pleomorphic lipomas, lipoblastomas, and hibernomas, most of which have characteristic clonal chromosomal aberrations. The normal karyotype of subcutaneous angiolipoma as well as its distinct clinical and morphologic features suggest a different pathogenesis from pure lipomas.

[Genetic studies of differential fatty tissue tumor diagnosis]. / Genetische Untersuchungen zur Differentialdiagnose von Fettgewebstumoren.

Adipose tissue tumors are often characterized by typical or even specific chromosomal alterations. In some of the cases the molecular background of these microscopically visible alterations was already elucidated. In myxoid liposarcomas the translocation t(12;16) creates a fusion gene between the CHOP gene and the FUS gene and in lipomas the HMGI-C gene becomes rearranged by structural aberrations involving chromosomal region 12q14-15. Based on examples of a lipoma, a well-differentiated liposarcoma, a myxoid liposarcoma, and an aggressive angiomyxoma it is demonstrated in the present paper how cytogenetic investigation can be used as an additional tool for an improved diagnosis of adipose tissue tumors. Furthermore, the detection of molecular mechanisms underlying the visible cytogenetic alterations will certainly significantly increase our knowledge about the pathogenesis of these diseases.

Correlation between clinicopathological features and karyotype in lipomatous tumors. A report of 178 cases from the Chromosomes and Morphology (CHAMP) Collaborative Study Group.

Soft tissue tumors commonly show cytogenetic abnormalities, some of which are tumor specific. Lipomatous tumors represent the largest category of soft tissue neoplasms, and numerous karyotypic aberrations have been identified. However, clear-cut correlation between morphology and karyotype has not been undertaken on a systematic basis in a double-blind setting. The morphological features and histological diagnosis of 178 lipomatous neoplasms were reviewed independently without knowledge of the clinical data. The consensus diagnoses were then correlated with the clinical findings and compared with the tumors' karyotypes, using G-banded preparations from short-term cultures. The data were collated by a multicenter collaborative group of pathologists, geneticists, and surgeons. Clonal chromosomal abnormalities were identified in 149 cases studied (84%) and, to a large extent, the karyotype correlated with the morphological diagnosis. Specifically, 26 (96%) of 27 myxoid liposarcomas and its poorly differentiated variants showed a t(12;16); 29 (78%) of 37 atypical lipomatous tumors (including 5 dedifferentiated cases) showed ring chromosomes; 74 (80%) of 93 subcutaneous and intramuscular lipomas had karyotypic aberrations affecting mainly 12q, 6p, and 13q; 7 of 8 spindle cell and pleomorphic lipomas had aberrations of 16q; 3 lipoblastomas showed 8q rearrangements; and 2 hibernomas showed 11q abnormalities. We conclude that cytogenetic abnormalities are common in lipomatous tumors, correlate reliably with morphological sub-type in many cases, and can be of diagnostic value in histologically borderline or difficult cases.

Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors.

Chromosome studies of lipomas have revealed an extensive cytogenetic heterogeneity. To investigate the frequencies of previously recognized cytogenetic subgroups and to find out if more recurrent rearrangements can be identified, we have analyzed cytogenetically short-term tissue cultures of 237 samples from 188 adipose tissue tumors obtained from 142 patients. Only one of 58 tumors from 18 patients with multiple lipomas (more than two tumors) had karyotypic changes. Among the sporadic lipomas, 20 tumors had supernumerary ring chromosomes of unknown origin, 55 had different aberrations involving chromosome segment 12q13-15, 11 had changes of 6p or chromosome 13, but no rings or 12q13-15 changes, and 14 had various other aberrations. Ring chromosomes were found in all cytogenetically abnormal lipomas histologically classified as atypical and in nine tumors classified as typical lipoma or spindle cell lipoma. Recombinations between 12q13-15 and a few other bands or segments were seen more than once: 3q27-28 (15 tumors), 2p22-24 and 2q35 (four tumors), 1p32-34 and 13q12-14 (three tumors), and 5q33 (two tumors). Recombinations of 12q13-15 with 2q35 and 13q12-14 have not been described before. Of eight tumors with chromosome 13 aberrations, five had loss of 13q material. Aberrations of 12q13-15, 6p, and/or chromosome 13 were found simultaneously in nine tumors. Two to four samples from the same tumor were investigated in 29 tumors with clonal aberrations. Thirteen of these tumors displayed clonal evolution, also noted in another 17 tumors in which only one sample had been investigated. Thus clonal evolution occurred in 30% of the tumors and was particularly frequent in atypical lipomas.

Multiple cerebral aneurysms, multiple meningiomas and multiple subcutaneous angiolipomas: a case report.

The simultaneous occurrence of multiple meningiomas, multiple distally located cerebral aneurysms and numerous subcutaneous lipomata in a 48-year-old man is reported. There was no evidence of neurofibromatosis, connective tissue disease or abnormality of collagen synthesis. We propose a possible genetic link between these three disparate conditions in our patient.

Scalp lipomas and cerebral malformations--report of a case and review of the literature.

A child is reported with a scalp lipoma and underlying bony skull defect and porencephaly. The clinical picture is compatible with a diagnosis of encephalocraniocutaneous lipomatosis, although there is no alopecia overlying the lipoma and no scleral lesions. In addition, this child has unilateral ptosis and syndactyly. This report extends our appreciation of the phenotype of this neurocutaneous disorder.