To conduct a rapid systematic review comparing the outcomes of primary tumor resection versus non-resection on patients with hepatic mesenchymal hamartoma.

We searched the Ovid MEDLINE, EMBASE, Scopus, PubMed, Web of Science, and Google Scholar databases from January 1, 2000 to March 31, 2022. Studies that described cases of hepatic mesenchymal hamartoma, including management and outcomes, were included.

62 articles met inclusion criteria with 95 cases in total. Patients were assigned to the primary tumor resection (n = 85) or non-resection (n = 10) cohort based on the described management. Similar rates of morbidity (17% vs 20%) and mortality (6 vs 10%) were identified between cohorts. There were no differences in sex, liver lobe involvement, or tumor size among study groups.

Complete tumor resection should remain the gold standard for hepatic mesenchymal hamartomas when an adequate liver remnant exists. Reports of non-resected tumors demonstrating spontaneous regression or stability with watchful waiting have poor long term follow-up and have inadequate evidence of a true mesenchymal hamartoma diagnosis.

Level I.

Adult hepatic mesenchymal hamartoma (HMH) is an extremely rare hepatic tumor. Recurrence following complete resection is uncommon. Liver transplantation (LT) is described as a possible treatment option in nonresectable HMH. We conducted a systematic review investigating LT in adult HMH followed by a case report describing evidence of extensive recurrence following complete resection of large right-sided HMH requiring LT.

A 46-year-old woman with symptomatic large right-hepatic HMH underwent right hemi-hepatectomy with histologic evidence of complete resection. Two and a half years postresection, she presented with abdominal pain and distension; imaging revealed large multi-septated hepatic cystic lesions within the liver suggestive of extensive recurrence of disease with concerns of malignant sarcomatous transformation. After a multidisciplinary team discussion, the lesion was deemed unresectable and the patient was referred for LT. Findings on transplantation included giant multiple hepatic cystic lesions occupying the entire abdomen and histopathological analysis confirmed recurrent HMH with no malignancy. The 6-month follow-up was unremarkable with no signs of postoperative complications or rejection.

We identified only 3 reported adult unresectable HMH cases in the English literature requiring LT, with good clinical outcome and no rejection on a 1-year follow-up. To our knowledge, we report the first recurrent HMH that required LT in the English literature. Current evidence suggests possible malignant sarcomatous transformation of those lesions. No guidelines exist on postresection surveillance for HMH; however, given their malignant potential, we suggest a benefit of imaging-based surveillance following HMH resection. Offering LT for nonresectable or recurrent HMH is a feasible treatment modality with a reported good outcome.

Mesenchymal hamartoma of the liver (MHL) is an uncommon benign hepatic tumor typically affecting children under 2 years of age. Only 5% of MHL occur after 5 years and are very rarely observed in adults. According to age, MHL may differ in their morphologic features. We report a case of an 11-year-old boy with MHL, resembling a malignant lesion from a clinical point of view, characterized by unusual histologic features: a prominent myxoid stroma, with a minimal ductular component, and absent cystic spaces. The present case and others reported in older children or adults demonstrate that these lesions may represent a potential diagnostic pitfall when occurring outside their classic clinical context especially because of their peculiar histologic findings. Moreover, it may be hypothesized that variation in morphology might be related to different evolutive stages of the cell of origin. To support this hypothesis, we therefore studied the presence of components of the Notch pathway inside and outside the lesion. Their absence inside the tumor and, in contrast, the expression of Notch2 and HES1 evident in overrepresented bile ducts present at the periphery might explain not only the lack of bile ducts, but also indicate a more adult phenotype compared with classic pediatric MHL, which show more bile ducts and liver trabeculae embedded in the mesenchymal matrix.

Benign hepatic tumors are commonly observed in adults, but rarely reported in children. The reasons for this remain speculative and the exact data concerning the incidence of these lesions are lacking. Benign hepatic tumors represent a diverse group of epithelial and mesenchymal tumors. In pediatric patients, most benign focal liver lesions are inborn and may grow like the rest of the body. Knowledge of pediatric liver diseases and their imaging appearances is essential in order to make an appropriate differential diagnosis. Selection of the appropriate imaging test is challenging, since it depends on a number of age-related factors. This paper will discuss the most frequently encountered benign liver tumors in children (infantile hepatic hemangioendothelioma, mesenchymal hamartoma, focal nodular hyperplasia, nodular regenerative hyperplasia, and hepatocellular adenoma), as well as a comparison to the current knowledge regarding such tumors in adult patients. The current emphasis is on imaging features, which are helpful not only for the initial diagnosis, but also for pre- and post-treatment evaluation and follow-up. In addition, future perspectives of contrast-enhanced ultrasound (CEUS) in pediatric patients are highlighted, with descriptions of enhancement patterns for each lesion being discussed. The role of advanced imaging tests such as CEUS and magnetic resonance imaging, which allow for non-invasive assessment of liver tumors, is of utmost importance in pediatric patients, especially when repeated imaging tests are needed and radiation exposure should be avoided.

Mesenchymal hamartomas of the liver (MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography (CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen included intraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg (dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months after transplantation, the patient remains well and is fulfilling all normal activities. Adult giant MHL is extremely rare. Symptoms, physical signs, laboratory results, and radiographic imaging are nonspecific and inconclusive. Surgical excision of the lesion is imperative to make a definite diagnosis and as a cure. Liver transplantation should be considered as an option in the treatment of a non-resectable MHL.

Clinical experience shows that the primary diagnosis of mesenchymal hamartoma (MHL) and embryonal sarcoma of the liver (ESL) recurrently is mistaken, leading to inadequate managements. We evaluated the accuracy of the primary diagnosis of those liver tumors, compared with the final histological diagnosis.

Records of 25 children (0-16 years, treated 01/1989-01/2013) with final diagnosis of MHL or ESL were analyzed.

Final diagnosis was MHL in 18/25 children (10 solid-cystic, 2 cystic, 6 solid) and ESL in 7/25 (4 solid-cystic, 1 cystic, 2 solid). Only 3/7 ESL patients and 15/18 MHL patients fell into the "typical" age group. In 13/25 children primary diagnosis was based on imaging only. Overall, primary diagnosis was concordant with the final diagnosis in 17/25 patients. Of 99/25 biopsied cases, 4/9 biopsy results exposed the wrong final diagnosis; of cystic-solid masses 4/14 were mistaken, of cystic masses 1/3, of solid masses 3/8.

Preoperative diagnosis of MHL and ESL is challenging because of atypical clinical presentation, misleading "typical" radiological findings, and difficult interpretation of biopsies. If feasible, complete surgical resection of, in particular, solid-cystic liver masses in the pediatric age group must be aimed for, to get a definitive, final diagnosis, followed by an adequate treatment strategy.

Recurrent genetic alterations found in hepatic mesenchymal hamartoma include either androgenetic-biparental mosaicism or chromosomal rearrangements involving chromosome 19q13.4, in the vicinity of the chromosome 19q microRNA cluster (C19MC). Abnormal activation of C19MC, which is subject to paternal imprinting and is normally expressed only in placenta, could account for both genetic associations because androgenetic cells carry only paternal chromosomes. In this study, a 4.2-Mb deletion involving the 5'-end of C19MC was detected in a sporadic mesenchymal hamartoma by chromosomal microarray. Fluorescence in situ hybridization studies showed that the deletion localized to mesenchymal cells in the stroma of the hamartoma. Quantitative real-time polymerase chain reaction analysis of this tumor, 9 other sporadic hepatic mesenchymal hamartomas, and 3 hamartomas associated with androgenetic-biparental mosaicism demonstrated C19MC microRNA expression in all but 2 sporadic cases, with no significant expression in control liver. The findings support a pathogenetic model for mesenchymal hamartoma as a consequence of "ectopic" activation of C19MC in hepatic stroma, due to either chromosomal rearrangements or paternal uniparental disomy.

Mesenchymal hamartoma of the liver (MHL) is an uncommon benign primary liver tumor that typically occurs in the pediatric population, although cases have been described in adults. MHL is sometimes associated with the highly malignant undifferentiated embryonal sarcoma (UES), and the synchronous or metachronous occurrence of MHL and UES suggests they share a common genetic link. Although the exact mechanism of tumorigenesis has not been identified, MHL cases harbor recurring chromosomal rearrangements involving 19q13.

In order to provide more details on the genetic events of MHL tumorigenesis, capture-based next generation sequencing (NGS) targeted to loci recently shown to be involved in a translocation in a case of UES arising in MHL (specifically, the MALAT1 gene on chromosome 11 and a gene poor region termed MHLB1 on chromosome 19) was performed on formalin fixed paraffin embedded tissue from seven cases of MHL.

Chromosome rearrangements involving the MHLB1 locus were identified in three of the seven cases, including the translocation t(11,19)(q13.1;q13.42) involving the MALAT1 gene; the translocation t(2,19)(q31.1;q13.42) involving AK023515, an uncharacterized noncoding gene; and the inversion inv(19,19)(q13.42;q13.43) involving the PEG3 gene encoding a Kruppel-type zinc-finger protein. Rearrangements were exclusively identified in pediatric tumors. In each case, the presence of the rearrangement was confirmed by PCR and interphase FISH. Interphase FISH also demonstrated that the arrangements occur within the spindle cell component but not within the epithelial components of the tumor.

Since the MHLB1 locus contains a CpG-rich region whose methylation regulates C19MC miRNA genes, rearrangements that disrupt this region may contribute to MHL development through alteration of miRNA expression. The demonstration that the loose stromal cells harbor the rearrangements indicates that (some cases of) MHL are a neoplastic process due to a somatic genetic change and not a germline abnormality.

The incidence of hepatic mesenchymal hamartoma (HMH) is increased in patients with placental mesenchymal dysplasia (PMD), which appears to be caused by androgenetic-biparental mosaicism (ABM). We hypothesized that occult ABM might underlie cases of HMH with no known history of PMD. Formalin-fixed, paraffin-embedded HMH specimens from 10 such patients and liver specimens from 6 non-HMH controls were identified retrospectively from the surgical pathology records of a pediatric hospital. The relative abundance of maternal and paternal alleles was assessed by quantitative polymerase chain reaction amplification of polymorphic short tandem repeats and single nucleotide polymorphisms located on 15 different chromosomes. Androgenetic-biparental mosaicism was diagnosed in one patient based on global allelic imbalances at all informative loci. In that patient, the greatest imbalances were observed in stroma-rich portions of the hamartoma, with no significant imbalance in histologically normal liver or epithelium-rich portions of the hamartoma. A retrospective, unbiased review of the histology and clinical records from all 10 patients revealed no morphologic or clinical correlates to distinguish the affected patient, except that she had multiple cutaneous hemangiomas, which like HMH, appear to be more common in patients with PMD. Our findings suggest that other patients with apparently sporadic HMH, hemangioma, or other lesions seen more frequently with PMD may harbor occult ABM. Recognition of ABM may be important because its long-term consequences are unknown but may be significant.

ABSTRACT A mesenchymal hamartoma of the liver (MHL) from a 20-month-old girl was studied cytogenetically. The karyotype was 46,XX,inv(19)(p13q13.4)[38], and fluorescence in situ hybridization using bacterial artificial chromosome probes refined the breakpoints to 19p13.11 and the subtelomeric region of 19q. This is the first report of inversion (19) in MHL, and the q-arm breakpoint is different from that reported previously in other rearrangements.

Mesenchymal hamartoma of liver (MHL) is a rare liver tumor of childhood. About 200 cases have been reported till now. Most of the work on MHL is limited to case reports and there are not many long term follow-up studies. We present our 20 years of experience with this uncommon entity. This study aims to highlight clinical features, diagnosis and treatment of MHL.

All patients with a diagnosis of MHL in last 20 years were included in this retrospective study. The patients were evaluated clinically, radiologically and pathologically.

The total number of patients with a diagnosis of MHL was nine. Mean age of the patients was 19.89 ± 2.75 months. Right lobe was involved in eight patients. The prominent clinical features were distension of abdomen and anorexia. Surgical options used were hepatic lobectomy, wedge resection and enucleation. Histopathology of the specimens showed cysts of variable size with normal hepatocytes, bile ducts and connective tissue stroma. Overall mortality was one (11.11%).

MHL is a benign tumor that can present with various clinical features. It should be differentiated carefully from other liver masses especially malignant ones. The diagnosis can be made with the help of radiology and histopathology. Adequate resection is curative in most of the cases and long-term follow up is satisfactory.

Hepatic mesenchymal hamartoma (HMH) is a rare benign liver tumor generally occurring in young children. Abnormalities of chromosome 19q13.4 and chromosomal aneuploidy detected by flow cytometry have been reported in HMH. We recently analyzed a HMH in a 14-month-old girl and identified additional novel chromosome abnormalities, including hypodiploidy with deletions of several chromosomes, without rearrangement of 19q13.4 on both routine chromosome analysis and fluorescent in-situ hybridization analysis using subtelomere probes for chromosome 19q. This case underscores the need for chromosome analysis of all HMH and the need to report these changes to better understand the pathophysiology and the entire spectrum of cytogenetics of this uncommon tumor.

Undifferentiated embryonal sarcoma of the liver is a highly malignant and aggressive tumor that occasionally arises within mesenchymal hamartoma of the liver (MHL), a benign tumor that typically occurs in young children. Undifferentiated embryonal sarcoma arising in MHL, as well as uncomplicated MHL, frequently harbor rearrangements of band 19q13.4, including the translocation t(11;19)(q13;q13.4). In this study we report the cloning and DNA sequence analysis of the translocation breakpoints in an undifferentiated embryonal sarcoma arising in MHL known to harbor t(11;19). In this case, the breakpoint at 11q13 occurred in the MALAT1 gene, also known as ALPHA. MALAT1 is rearranged in renal tumors harboring the t(6;11)(p21;q13) translocation, and noncoding MALAT1 transcripts are overexpressed in a number of human carcinomas. The breakpoint at 19q13.4 occurs at a locus we refer to as MHLB1, for Mesenchymal Hamartoma of the Liver Breakpoint 1. Although the MHLB1 locus does not contain a known gene, several human ESTs map to the region (a subset of which show homology to the nuclear RNA export factor (NXF) gene family), and the region is conserved between many mammalian species.

A 5-month-old girl with clinical features of Beckwith-Wiedemann syndrome (BWS), including a repaired omphalocele, an earlobe crease, enlarged adrenal glands, renal size discrepancy, and hyperinsulinemic hyperglycemia, presented with a 1.9-cm liver nodule. Markedly increased serum alpha-fetoprotein (AFP) levels (1,060,000 mg/L), highly suspicious for hepatoblastoma, were detected, and resection of the liver mass was performed. Histologic sections showed features characteristic of a mesenchymal hamartoma of the liver (MHL). No features of embryonal or fetal hepatocellular proliferation or heterologous stromal components were noted. By immunohistochemistry, the hepatocytes expressed AFP, but no nuclear accumulation of beta-catenin was present. Electron microscopy revealed normal, mature hepatocytes. Here we address the diagnostic challenge of the uncommon association of MHL and BWS in the setting of markedly elevated serum AFP levels. In addition, we analyze the unusual pancreatic lesion (focal endocrine adenomatosis) leading to severe hyperinsulinemic hypoglycemia in a patient with possible BWS. We emphasize that MHLs may present with markedly increased serum AFP levels, mimicking hepatoblastomas, and may also be part of the expanding spectrum of findings of BWS.