Lipoblastoma-Like Tumor and Fibrosarcoma-Like Lipomatous Neoplasm Represent the Same Entity: A Clinicopathologic and Molecular Genetic Study of 23 Cases Occurring in Both Men and Women at Diverse Locations.

Lipoblastoma-like tumor (LLT) is a benign soft tissue tumor demonstrating mixed morphologic features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma but lacking genetic alterations associated with those tumors. LLT was originally thought to be specific to the vulva but has since been reported in the paratesticular region. The morphologic features of LLT overlap with those of "fibrosarcoma-like lipomatous neoplasm" (FLLN), a rare, indolent adipocytic neoplasm considered by some to form part of the spectrum of atypical spindle cell and pleomorphic lipomatous tumor. We compared the morphologic, immunohistochemical, and genetic features of 23 tumors previously classified as LLT (n = 17) and FLLN (n = 6). The 23 tumors occurred in 13 women and 10 men (mean age, 42 years; range, 17 to 80 years). Eighteen (78%) cases arose in the inguinogenital region, whereas 5 tumors (22%) involved noninguinogenital soft tissue, including the flank (n = 1), shoulder (n = 1), foot (n = 1), forearm (n = 1), and chest wall (n = 1). Microscopically, the tumors were lobulated and septated, with variably collagenized fibromyxoid stroma, prominent thin-walled vessels, scattered univacuolated or bivacuolated lipoblasts, and a minor component of mature adipose tissue. Using immunohistochemistry, 5 tumors (42%) showed complete RB1 loss, with partial loss in 7 cases (58%). RNA sequencing, chromosomal microarray, and DNA next-generation sequencing study results were negative for significant alterations. There were no clinical, morphologic, immunohistochemical, or molecular genetic differences between cases previously classified as LLT or FLLN. Clinical follow-up (11 patients [48%]; range, 2-276 months; mean, 48.2 months) showed all patients were alive without disease, and only one patient had experienced a single local recurrence. We conclude that LLT and FLLN represent the same entity, for which "LLT" seems most appropriate. LLT may occur in either sex and any superficial soft tissue location. Careful morphologic study and appropriate ancillary testing should allow for the distinction of LLT from its potential mimics.

Primary cardiac lipoblastoma of the right atrium.

Lipoblastoma is a rare neoplasm of the embryonal white fat. It occurs most commonly in children under the age of 3 years and usually inflicts the superficial soft tissues of trunk and extremities. We present the case of a 3-year-old male patient with a successfully resected primary cardiac right-atrial lipoblastoma with COL1A2::PLAG1 gene fusion.

Pediatric fibromyxoid tumor with PLAG1 fusion: An emerging entity with a novel intracranial location.

Translocations involving PLAG1 occur in several tumors, most commonly pleomorphic adenoma and lipoblastoma. Recently, a distinctive soft tissue tumor with a PLAG1 fusion has been reported in the pediatric age group. These are low grade tumors with a fibroblastic or mixed fibroblastic and myxoid morphology but no other lines of differentiation. They are typically immunopositive for desmin and CD34. The partner genes for these tumors have included YWHAZ, EEF1A1, ZFHX4l, CHCHD7, and PCMTD1. We report another case of this fibromyxoid tumor with a PLAG1 fusion, this time with COL3A1 as the partner gene. The fusion placed expression of a full-length PLAG1 protein under the control of the constitutively active COL3A1 promoter. Overexpression of PLAG1 was confirmed by diffusely positive immunostaining for PLAG1. The most novel aspect of this tumor is the intracranial location. Opinion has been divided over whether these tumors are a specific entity, or related to lipoblastoma, since that tumor also typically occurs in soft tissue in the pediatric age group and shows many of the same gene fusions. However, lipoblastoma has never been reported in an intracranial location and, thus, our case provides compelling evidence that this fibromyxoid tumor is indeed a distinct entity.

PLAG1 Immunohistochemical Staining Is a Surrogate Marker for PLAG1 Fusions in Lipoblastomas.

BACKGROUND: The hallmark of lipoblastoma is a PLAG1 fusion. PLAG1 protein overexpression has been reported in sporadic PLAG1-rearranged lipoblastomas. METHODS: We evaluated the utility of PLAG1 immunohistochemical staining (IHC) in 34 pediatric lipomatous tumors, correlating the results with histology and conventional cytogenetics, FISH and/or next generation sequencing (NGS) results. RESULTS: The study included 24 lipoblastomas, divided into 2 groups designated as "Lipoblastoma 1" with both lipoblastoma histology and PLAG1 rearrangement (n = 16) and "Lipoblastoma 2" with lipoblastoma histology but without PLAG1 cytogenetic rearrangement (n = 8), and 10 lipomas with neither lipoblastoma histology nor a PLAG1 rearrangement. Using the presence of a fusion as the "gold standard" for diagnosing lipoblastoma (Lipoblastoma 1), the sensitivity of PLAG1 IHC was 94%. Using histologic features alone (Lipoblastoma 1 + 2), the sensitivity was 96%. Specificity, as defined by the ability to distinguish lipoma from lipoblastoma, was 100%, as there were no false positives in the lipoma group. CONCLUSIONS: Cytogenetics/molecular testing is expensive and may not be ideal for detecting PLAG1 fusions because PLAG1 fusions are often cytogenetically cryptic and NGS panels may not include all partner genes. PLAG1 IHC is an inexpensive surrogate marker of PLAG1 fusions and may be useful in distinguishing lipoblastomas from lipomas.

The histological and molecular spectrum of lipoblastoma: A case series with identification of three novel gene fusions by targeted RNA-sequencing.

Lipoblastoma is a rare benign mesenchymal neoplasm that typically occurs in infancy but may also occur in older age groups and various locations. Thus, there are often numerous clinical differential diagnoses. Moreover, lipoblastomas can show a broad histologic spectrum, which can hamper the correct diagnosis, particularly in small biopsies. At the genomic level, lipoblastomas are characterized by chromosomal fusions involving the PLAG1 gene. We investigated 11 lipoblastoma samples from 10 pediatric patients (age range five months to 12 years), including one patient with local recurrence, in view of their histopathological features, and performed targeted RNA sequencing. We found a broad histological spectrum with some tumors with prominent myxoid changes, but also tumors composed mainly of mature adipocytic cells, and classified the cases according to the literature as classic (mixed), maturing, or myxoid subtype. By targeted RNA sequencing analysis, we identified characteristic PLAG1 rearrangements in 70% of the investigated cases. Moreover, these analyses revealed three novel gene fusions, two affecting the PLAG1 gene and one involving HMGA2. Besides, we performed PLAG1 immunohistochemistry and identified positive cells, typically immature adipocytic cells and spindle cells, at various numbers in all cases. However, in the maturing areas, only very sparsely positive cells were found, limiting the value of the PLAG1 immunohistochemistry as an adjunct in the diagnosis of lipoblastoma, particularly for the maturing subtype and small biopsies. The presented case series confirms the broad morphological spectrum of lipoblastoma described in the literature and underlines the value of modern molecular diagnostic approaches as a supportive diagnostic tool in challenging cases and for gaining further insights into the molecular basis of this rare mesenchymal tumor.

Lipoblastoma phenotype contains a somatic PIK3CA mutation.

Lipoblastoma typically occurs in childhood and is associated with rearrangements of the PLAG1 gene. We present a patient with an isolated mass thought to be a lipoblastoma clinically, radiographically, and histologically. The lesion was diagnosed as a PIK3CA-adipose lesion after the tissue was negative for PLAG1 rearrangement and contained a somatic PIK3CA mutation (H1047R). Although PIK3CA variants are associated with PROS (PIK3CA-related overgrowth spectrum), this report illustrates a non-syndromic, lipoblastoma phenotype caused by a PIK3CA mutation.

Lipoblastomas presenting in older children and adults: analysis of 22 cases with identification of novel PLAG1 fusion partners.

Lipoblastomas are benign neoplasms of embryonal white fat that typically present in the first 3 years of life and show a lobular arrangement of maturing adipocytes with variable degrees of myxoid change. We systematically studied the clinicopathologic and genetic features of lipoblastomas arising in older children and adults. Cases with a diagnosis of lipoblastoma or maturing lipoblastoma in patients >3 years of age were retrieved from our archives. Immunostaining for CD34 and desmin and molecular studies (FISH, RNA sequencing) were performed. Twenty-two cases (8F; 14M) were identified in patients ranging from 4 to 44 years of age (median 10 years). Sites included extremity (n = 15), head and neck (n = 4), and trunk (n = 3) with tumor sizes varying from 1.6 to 17.5 cm (median 5). Only three tumors had histologic features of "conventional" lipoblastoma. The majority of tumors (n = 14) were composed of variably sized lobules of mature adipose tissue partitioned by thin fibrous septa ("maturing"). The remaining five cases consisted predominantly of bland spindled to plump ovoid cells embedded in a fibrous stroma, with a vaguely plexiform arrangement of small myxoid and adipocytic nodules ("fibroblastic"). CD34 was diffusely positive in all cases tested (21/21), while desmin immunoreactivity was identified in 12 of 21 cases (diffuse = 7, focal = 5). PLAG1 rearrangements were identified in 13 tumors in the entire cohort (59%), including all 5 fibroblastic tumors. RNA sequencing detected eight PLAG1 fusion partners, of which two were known (CHCHD7 and COL3A1) and six were novel (SRSF3, HNRNPC, PCMTD1, YWHAZ, CTDSP2, and PPP2R2A). Twelve cases had follow-up (1-107 months; median 21 months), and no recurrences were reported. Lipoblastomas may occur in older children and adults and may be difficult to recognize due to their predominantly adipocytic or fibrous appearance. Awareness that lipoblastomas may occur in older patients, careful evaluation for foci showing more typical morphologic features, ancillary immunohistochemistry for CD34 and desmin, and molecular genetic studies to identify PLAG1 rearrangements are the keys to recognizing these tumors.

Lipoblastoma-like tumor of the spermatic cord: case report and review of the literature.

Lipoblastoma-like tumor is a very rare mesenchymal tumor believed to be restricted to female patients and only recently reported in the spermatic cord of a male patient. We describe herein an additional case of lipoblastoma-like tumor occurring in the spermatic cord, describing its histopathological, immunohistochemical, and molecular features.

New molecular insights into the pathogenesis of lipoblastomas: clinicopathologic, immunohistochemical, and molecular analysis in pediatric cases.

Lipoblastomas can occasionally require further molecular confirmation when occurring outside of the usual age groups or demonstrating unusual morphology. We reviewed 28 lipoblastomas with 16 controls. Lipoblastomas were subdivided into myxoid (n = 7), classic (n = 9), or lipoma-like (n = 12) subtypes. PLAG1 immunohistochemistry, PLAG1 fluorescence in situ hybridization (FISH), and targeted RNA sequencing were performed on formalin-fixed paraffin-embedded tissue. Karyotypes were available in a subset of lipoblastomas (n = 9). Gene rearrangements were identified in 17/25 (68%) lipoblastomas, including PLAG1 (15/25, 60%) and HMGA2 (2/25, 8%). Five novel fusion partners (DDX6, KLF10, and KANSL1L with PLAG1 and EP400 and FGD6 with HMGA2) were found. PLAG1 immunohistochemistry was positive (nuclear, moderate/strong) in myxoid and classic subtypes lipoblastomas with preferential expression in mesenchymal cells within myxoid stroma and fibrous septa and negative in all controls. When comparing PLAG1 immunohistochemistry with molecular testing (FISH and/or RNA sequencing and/or karyotype), concordant results were noted in 13/25 (52%) cases, increasing to 15/25 (60%) after slight adjustment of the PLAG1 FISH positive threshold. In myxoid and classic lipoblastomas, PLAG1 immunohistochemistry seems to be a better surrogate marker for PLAG1 rearrangement, as compared with lipoma-like subtypes. In lipoma-like subtypes, targeted RNA sequencing appears to detect PLAG1 fusions better than FISH and immunohistochemistry. The preferential expression of PLAG1 in the mesenchymal and fibroblast-like cells deserves further investigation as the putative cell of origin in lipoblastoma.

Undifferentiated myxoid lipoblastoma with PLAG1 gene rearrangement in infant.

OBJECTIVES: To analyze the clinicopathologic feature, diagnosis and differential diagnosis of undifferentiated myxoid lipoblastoma in infant. METHODS: The study included 2 cases of undifferentiated myxoid lipoblastoma in infant according to the molecular genetic diagnosis. The relevant clinicopathologic feature was investigated. RESULTS: We describe 2 cases of undifferentiated myxoid lipoblastoma in infant. The both large circumscribed masses are located in deep soft tissue. Unlike most lipoblastoma, lobulated appearance was not obvious in one case and completely absent in another. The both cases presented prominent myxoid change with a plexiform vascular pattern. There were some spindle-shaped or stellate mesenchymal cells, while no any mature adipocytes. The initial suggestion of case 1 was myxoid liposarcoma, and case 2 was aggressive angiomyxoma. However, few S-100 positive lipoblasts suggested the origin of the tumor. FISH analysis using a PLAG1 break apart probe confirmed a PLAG1 rearrangment. The final diagnosis was undifferentiated myxoid lipoblastoma. CONCLUSIONS: The undifferentiated myxoid lipoblastoma is a very rare tumor in infant. Histologically, prominent myxoid change, a plexiform vascular pattern and lacking of mature adipocytes make it indistinguishable from myxoid liposarcoma, PMMTI and aggressive angiomyxoma. The S-100 positive lipoblasts and genetic rearrangement of PLAG1 helps in confirming the diagnosis. Even if there were no mature adipocytes, myxoid lipoblastoma was still a diagnosis that can not be ignored in myxoid tumors in children.

Three Novel Aberrations Involving PLAG1 Leading to Lipoblastoma in Three Different Patients: High Amplification, Partial Deletion, and a Unique Complex Rearrangement.

Lipoblastoma is a rare benign neoplasm with overlapping histology with other lipomatous tumors. Genetic aberrations including translocations of 8q and splitting of the PLAG1 probe leading to "promoter swapping" and gains of chromosome 8 or PLAG1 foci have been described in lipoblastoma. Here, we report 3 lipoblastomas revealing novel genetic aberrations involving PLAG1: a high level of PLAG1 amplification up to 50 copies in a 4-year-old girl with recurrence of a right flank mass, a partial deletion of PLAG1 with the flanking junction breakpoints involving the 3'PLAG1 and 5'HAS2 genes in a 17-month-old boy with a retroperitoneal mass, and an insertion of 2q31 into 8q11.2 and translocation of 8q to 2q with the latter translocated onto 12q leading to separation of the PLAG1 FISH probe in a 5-year-old girl with a left back mass. Our novel cytogenetic findings further expand the mechanisms of PLAG1 transcriptional upregulation in lipoblastoma pathogenesis.

Identification of a novel BOC-PLAG1 fusion gene in a case of lipoblastoma.

Lipoblastoma is a rare benign adipose tissue tumor that occurs mostly in infants and children. Histological diagnosis of lipoblastoma is sometimes difficult because it closely resembles other lipomatous tumors. The detection of PLAG1 gene rearrangement is useful for the diagnosis of lipoblastoma. Four PLAG1 fusion partner genes are known in lipoblastoma: HAS2 at 8q24.1, COL1A2 at 7q22, COL3A1 at 2q32, and RAB2A at 8q12. Herein, we describe a novel fusion gene in a case of lipoblastoma of left back origin. We identified a potential PLAG1 fusion partner using 5' rapid amplification of cDNA ends, and sequence analysis revealed the novel fusion gene, BOC-PLAG1. The BOC-PLAG1 fusion transcript consists of the first exon of the BOC gene fused to exon 2 or exon 3 of the PLAG1 gene. PLAG1 expression was found to be 35.7 ±â€¯2.1 times higher in the tumor specimen than in human adipocytes by qRT-PCR. As a result of the translocation, the constitutively active promoter of BOC leads to PLAG1 overexpression. The identification of the BOC-PLAG1 fusion gene will lead to more accurate diagnosis of lipoblastoma.

Gait disturbance and lower limb pain in a patient with PIK3CA-related disorder.

Post-zygotic activating mutations in PIK3CA and other genes encoding members of PI3K-AKT-mTOR pathway have been found in various overgrowth syndromes that have been grouped together as PIK3CA-related overgrowth spectrum (PROS). We report a female patient with gait disturbance, leg pain, isolated macrodactyly of the foot, and mild intellectual disability. Imaging of the lower limb showed a lipoblastoma of the right thigh. A mosaic gain-of-function mutation in the catalytic domain of PIK3CA (c.3140 A > G; p.His1047Arg) was detected in the adipose tissue and in skin cultured fibroblasts from the macrodactyly but not in blood. The leg pain and the severe walking disturbance improved slightly over time and serial MRI of the lower limbs suggested that the size of the lipoblastoma relative to the lower limb muscles or to the whole lower limb was unchanged as consequence of limb growth. This case report illustrates that pain and gait disturbance can be features of PROS and highlights the need of better knowledge about the natural history of the disease.

Fine-needle aspiration of lipoblastoma: Cytological, molecular, and clinical features.

BACKGROUND: Lipoblastomas are rare, benign adipocytic tumors that present mostly during infancy. In about 70% of cases, these tumors carry abnormalities in chromosome 8, mainly leading to rearrangements of the PLAG1 gene. METHODS: We report a series of histologically proven lipoblastomas with previous fine-needle aspiration (FNA) cytology from 9 patients (n = 10 samples) and describe their clinical, cytological, and molecular features. RESULTS: Our cohort included 5 boys and 4 girls (median age, 2.5 years [range, 10 months to 13 years]) who presented with soft tissue masses in the thorax (n = 3), abdomen (n = 2), axilla (n = 2), and thigh (n = 2). In 1 patient, the FNA diagnosis was inconclusive due to hypocellularity, and in another patient a diagnosis of benign lipomatous tumor was made. In the remaining 8 samples (one of which confirmed relapse), a correct preoperative FNA diagnosis was rendered. Smears were hypo- to moderately cellular and contained fragments of mature adipose tissue with thin branching vessels admixed with some lipoblasts in a myxoid matrix. Spindle cells and naked oval nuclei with no atypia were observed in the background. Of the 4 patients tested for PLAG1 rearrangement using FISH probes, 3 harbored this alteration (1 was made on a FNA smear and 1 was made in a tumor imprint). All the patients are alive and well, except for 1 patient with a retroperitoneal tumor who, after an initial incomplete excision, died of local disease progression. CONCLUSION: FNA, especially if used together with molecular biology techniques (eg, PLAG1 FISH analysis), is a reliable and accurate diagnostic tool. Cancer Cytopathol 2017;125:934-9. © 2017 American Cancer Society.

Lipoblastoma of the Labia: A Case Report.

BACKGROUND: Vulvar masses are rare in prepubertal girls. Lipoblastomas are benign adipose tumors that arise from embryonic white fat and occur almost exclusively in infants and children. CASE: An 18-month-old female infant presented with a 2-cm mobile mass in the left labia majora. Imaging and examination revealed normal prepubertal gynecologic structures and a 4.5 cm fatty mass in the left labia. Surgical excision revealed a 3.8 cm well circumscribed adipose tissue mass consistent with maturing lipoblastoma on microscopic examination. Cytogenetic analysis revealed 79,XXX [7]/46,XX[13], a near-triploid clone. SUMMARY AND CONCLUSION: The differential diagnosis of vulvar masses in children should include lipoblastoma. Although preoperative imaging has limited ability to differentiate lipomatous tumors, magnetic resonance imaging is the modality of choice for evaluating tumor extension and for surgical planning. Treatment is complete surgical excision with close follow-up for at least 5 years because of the high recurrence rate.