Abstract:
Mesenchymal hamartoma of the liver is the second most common benign liver tumor in children, yet its biology and pathogenesis are poorly understood. It occurs in about 3% of the population. Typically, it presents as a large benign multicystic liver mass in children younger than three years, amenable to complete resection. Pathologically they are comprised of small irregular branching bile ducts that may be dilated and embedded in a fibrous stroma . Hepatic mesenchymal hamartoma is a hamartomatous growth of mesenchymal tissue in the liver of uncertain etiology. It is a space-occupying lesion that can potentially compress adjacent organs resulting in various complications including death. Most tumors gradually increase in size, some reaching enormous proportions, some can undergo incomplete spontaneous regression, and rarely, few have shown malignant transformation to undifferentiated (embryonal) sarcoma.
It makes up approximately 8% of all pediatric tumors and is second in occurrence only to hepatoblastoma when only pediatric hepatic tumors are considered. Eighty percent are found within the first 2 years of life and the remainder are detected by 5 years of age .Rare cases have been reported in adults.
INTRODUCTION
Mesenchymal hamartoma of the liver is a benign tumor of infancy characterized by an admixture of epithelial structures in a loose connective tissue stroma with fluid accumulation suggestive of lymphangiomatous channels. I present a very rare case of mesenchymal hamartoma along with a review of literature, which might be useful in understanding the etiology, pathogenesis, diagnosis, and management of this rare anomaly.
Mesenchymal hamartoma of the liver (MHL) is a benign lesion that classically presents as an enlarging abdominal mass in children before the age of two. Maresch initially described the tumor in 1903, but the term MHL was first used by Edmondson in 1956 [1]. MHL may affect either lobe of the liver and presents as a cystic or solid mass, and on occasion both components may be present. Alkaline phosphatase, ?-human chorionic gonadotropin, serum transaminases and a-fetoprotein are usually within normal limits in patients with MHL. Hematoxylin and eosin staining as well as immunohistochemical studies [2,3] have described MHL as having spindle cells positive for vimentin and smooth muscle actin and negative for CD31, CD34 and S100 proteins, while the ducts stain positive for cytokeratin 7 and negative for cytokeratin 20. Even though the exact pathogenesis of MHL is largely unknown, the most common theory is that it represents aberrant primitive mesenchyme development in the portal tract likely relating to the bile ducts.
CASE REPORT
A 31 years old pregnant ( 32 weeks) women came to our hospital with acute abdominal pain since 2 days ago. She had nausea and vomiting and was febrile since the day before coming.
It was her first pregnancy and all periodic historical maternal/fetus exams were normal .
In the time of admission, she was febrile ( 39 C ) ,BP =120/70 mmHg, PR=90/min and RR=18/min
RUQ and epigastric tenderness ,guarding and fullness was detected and obstetric examinations were normal.
WBC was 11800 ( time of arrival ) and rose to 13600 during observation and further evaluations ( 6 hours)
Hb was 12.1gr% and all other lab tests were in normal range.
Sonography ( ultrasound) demonstrated an epigastric cystic/solid mass 70*51*50 mm and their first impression was ovarian torsion or incarcerated hernia( bowel ).
The patient was brought the theatre as an acute abdomen and laparatomy done.
DISCUSSION ۱:
Typically a patient will present with an enlarging, non-tender abdominal mass. If the mass is very large, complications including ascites, jaundice, and even congestive heart failure can occur .Occasionally, the mass will expand rapidly, most likely because of rapid accumulation of fluid within cystic spaces .No specific panel of laboratory tests is characteristic of HMH. Laboratory studies often reveal normal liver function tests and various tumor markers, including B human chorionic gonadotropin, a-fetoprotein, and vanillylman-delic acid, are usually negative .Liver enzymes, including alanine aminotransaminase, aspartate aminotransaminase, gamma-glutamyl transferase, and alkaline phosphatase,range from normal to markedly elevated. Abdominal ultrasound can demonstrate either a multicystic or solid mass. Although not required for diagnosis, computed tomography and magnetic resonance imaging are useful for surgical planning.
Intrauterine HMHs have been well-documented in several reports. Laberge et al 5 reviewed 12 cases, 4 of which were lethal. The 8 surviving fetuses were diagnosed radiographically during the third trimester and the tumor was resected within the first 3 months of life. The infants for whom follow-up information was available were doing well. Of the 4 HMHs that were lethal, 1 was a neonatal demise and 3 were intrauterine demises. Intrauterine deaths are typically ascribed to the mass effect of this enlarging tumor .Adjacent structures such as the heart,lungs, kidneys, and large veins become compressed and organ failure ensues. Similarly, umbilical veins can show aneurysmal dilatation because of this distal compression .
MHL is a benign lesion of the liver representing the second most common pediatric liver tumor (after hepatoblastoma) and constitutes 8% of all pediatric tumors. Eighty percent of the lesions are found by the age of two and the remainder are identified by five years of age with the male to female ratio being 2:1 [2]. Intrauterine MHL cases have been documented in several reports. Laberge et al. [4] reviewed twelve cases with eight fetuses surviving to term after being diagnosed ultrasonographically in the third trimester. Tumor resection in these eight cases occurred in the first three months of life. In the four lethal intrauterine MHL cases, Laberge et al. attributed the fetal demise to mass effects of the tumor causing compression of the heart, kidneys and umbilical veins [4]. Although the majority of MHL cases reported are in the pediatric population, 30 cases have been reported in the English and Japanese language literature in adults ranging in age from 19 to 69 years (table 1) [5,6,7]. Of these 30 cases, 22 (73%) have been reported in females and only 8 (27%) in males, with an average age of 40 and 57, respectively. Thus, males are more often affected in the pediatric population while females are more often affected in the adult population.
Cases of adult MHL:
The clinical presentation of MHL appears to depend on the age of the patient. Most pediatric patients present with painless abdominal enlargement normally appreciated by the parent. If the mass becomes significantly large or liver function becomes compromised, ascites and jaundice may ensue. In severe cases there may be compression of the diaphragm and lungs causing respiratory difficulties. Although the adult case presented here was asymptomatic, Cook et al. [2] reported on eight adult cases, seven of whom were symptomatic, with the presenting complaint being diffuse abdominal pain. In agreement with Cook et al., a retrospective analysis of 17 cases by Yesim et al. [8] report that 10 cases were symptomatic. In addition to diffuse abdominal pain, reported symptoms and signs include hepatomegaly, right hypochondriac pain and left upper quadrant pain.
Radiographic appearance of MHL represents a continuum from predominantly cystic to mostly solid tumors. In pediatric patients the literature is unclear in regards to the cystic or solid nature of MHL. Early studies by Stocker and Ishak [9] describe nearly all pediatric cases as having cysts, however Chau et al. [10] reported that children more commonly have solid lesions. Interestingly, Chau et al. have also reported that adults have predominantly cystic lesions [10] while Hernandez et al. [5] have published that both pediatric and adult cases are primarily cystic. In the adult population, when solely cystic or solid tumors are present, females were more likely to have a cystic tumor, while males showed no predilection. When both cystic and solid portions of MHL were encountered, females were predominantly affected.
Location of the tumor in the liver appears to be different between pediatric and adult patients. MHL in children is primarily localized to the right lobe [10], while in adults, 12 cases (40%) were localized to the left lobe, 12 (40%) to the right lobe and in 6 (20%) tumors crossed into both lobes. Interestingly, adult males have a predilection for the right lobe of the liver, while females primarily have MHL in the left lobe. In situations when MHL was found in both lobes, females were more commonly affected than males.
Ultrasonography is typically the initial evaluation technique for suspected hepatic masses since it is readily accessible, can quickly delineate the cystic or solid nature of the lesion, and provides an estimate of mass size. CT imaging and/or MRI typically follow ultrasonography, particularly in preparation for surgical resection of the tumor. Ultrasonographic images of MHL show anechoic cystic regions with intervening thin septations, and axial imaging is helpful to further demonstrate the cystic or solid nature of MHL [11]. On contrast-enhanced CT the solid component of MHL will enhance while the cystic portion will not [11]. MRI shows a characteristic low signal intensity on T1-weighted images and high intensity imaging on T2-weighted imaging [12] .
Radiographie appearance of MHL :
Even though multiple radiographic imaging techniques may be employed in the evaluation of a hepatic mass, imaging results for MHL are nonspecific. The differential diagnosis for predominantly cystic lesions includes: simple hepatic cyst, hydatid cyst, subcapsular pseudocyst, biliary cystadenocarcinoma, and cystic metastasis. Mortele and Ros [13] depict the radiographic nature of a variety of cystic liver lesions, particularly noting CT and MRI subtleties that may be helpful in diagnosis. In the case of a solid lesion, focal nodular hyperplasia, hepatic adenoma, cavernous hemangioma, angiomyolipoma, solitary hamartoma, and hepatocellular carcinoma are among the more common lesions to consider. A solid MHL may present as a hypovascularized lesion on angiography [13], but this is a nonspecific finding and not helpful in differentiating from the aforementioned lesions. In the present case fine needle biopsy did not reveal a definitive diagnosis, necessitating surgical excision of the lesion.
Recent cytogenetic studies have shown MHL to involve rearrangements at chromosome 19. Analysis of eight MHL cases revealed the following genetic abnormalities: three involving t(11;19)(q13;q13.4), and single cases of t(11;19)(q13;q13.3), t(15;19)(q15;q13.4), a rearrangement of 11q2, 17q11 and 19q13.3, del(19)(q13.1q13.4) and t(11;19)(q11;q13.4) [14]. A significant finding is the similar genetic profile MHL shares with undifferentiated embryonal sarcoma (UES). UES is a rare pediatric malignancy composed of a sarcomatous mesenchymal component, as well as having hypercellular stroma, nuclear pleomorphism and mitotic activity, interspersed with benign branching ductal structures [3]. Over the past few years a number of cases of UES have developed within MHL, displaying similar genetic rearrangements in the region of 19q13.4 [3, 15, 16]. These include two cases of (19)(q13.4) and one case showing t(11;19) (q11;q13.3-13.4), nearly identical to genetic rearrangements seen in previous solitary cases of MHL [16]. Rajaram et al. [14] have postulated that the t(11;19) translocation is likely related to the development of solitary cases of MHL, but for progression of MHL to UES additional genetic alterations at other loci are required.
In addition to cytogenetic similarities, histological resemblance provides a potential link for progression from a benign MHL lesion to malignant UES. In cases described by Lauwers et al. [3] and Begueret et al. [15], UES regions were separated from MHL areas by transitional zones containing a histological mixture of the two entities. On further analysis, similar immunohistochemical characteristics and DNA ploidy of the three zones led Begueret et al. to conclude a coexistence of a well-differentiated phenotype (MHL) and a sarcomatous region (UES), separated by a zone containing a mixture of the two entities [15].
Hepatic angiosarcoma is the most common primary sarcoma of the liver and a solo case was recently reported to arise from an adult MHL [6]. Although hepatic angiosarcoma is usually associated with thorotrast, vinyl chloride and arsenic exposure, Li et al. [6] report a case of a woman with no prior carcinogen exposure presenting with an angiosarcoma arising from an untreated, previously diagnosed MHL. Though not direct evidence of MHL malignant transformation to angiosarcoma, the premalignant potential of MHL should be expanded to include UES and angiosarcoma, particularly when MHL is encountered in adult patients.
Although less invasive laparoscopic techniques are desirable, anatomic or nonanatomic resection with a negative margin is the standard treatment. The potential for massive tumor growth and possible degeneration to UES and/or angiosarcoma provides additional support against cautious clinical monitoring if the patient is a reasonable surgical candidate. Enlarging solid or cystic neoplasms of the liver that cannot be accurately diagnosed with radiographic imaging and histology should be considered for en bloc surgical resection with negative surgical margins.
DISCUSSION ۲:
Mesenchymal hamartoma is a rare, benign, developmental tumor of the liver, with occasional risk of malignancy. Histologically, it appears as a disordered arrangement of the mesenchyme, bile ducts, and hepatic parenchyma. Cords of normal – appearing hepatocytes are separated by zones of loose, poorly cellular mesenchyme. The porous nature of the mesenchyme permits accumulation of fluid.[1] Grossly, it has stromal and cystic components with no capsules, and can grow to large sizes.[2] Rarely, is the tumor solid.
Although such a mass was first described by Maresh in 1903, Edmondson was the first to use the term “mesenchymal hamartoma” of the liver for describing the four cases that he had observed, and he distinguished mesenchymal hamartoma from other cystic and tumor-like lesions of the liver.[3] He suggested that the lesion might result from a failure in the normal development of the embryonic fetal liver or that some cases might represent a degenerative change of an accessory lobe. Denher et al. and Packard and Palmer[4,5] suggested that it was a developmental anomaly of the portal connective tissue during fetal life rather than a true neoplasm. Clinically, patients with mesenchymal hamartoma present in the first two years of life, with a median age of 10 months (0 – ۱۹ years). The male to female ratio is 2:1, the right lobe being affected more frequently than the left (6:1).[1,4]
The typical presentation is one of asymptomatic, rapid abdominal distention with a palpable mass on physical examination. The rapid expansion of the tumor is believed to be due to degeneration of the mesenchyme and fluid accumulation. Other uncommon associated symptoms are vomiting, fever, constipation, diarrhea, and weight loss.[1] Laboratory investigations usually reveal normal liver function with elevated alpha-fetoprotein, which is believed to be secreted by the proliferating hepatocytes within the tumor.[6] The radiological appearance is one of a large, uni – or multicystic, avascular mass occupying part of the liver.[2] Surgical resection has been the standard treatment for this tumor. Marsupialization is also proposed in cases not amenable to resection.[7] In previously reported cases of mesenchymal hamartoma occupying part of the liver, the tumors were successfully treated by surgical resection, and the remaining liver tissue provided adequate liver function.[7] Aspiration of the fluid was undertaken in order to relieve discomfort and reduce tension and to encourage the remaining normal liver tissue to grow. Marsupialization of the cysts was considered if this did not contain the problem.
In summary, mesenchymal hamartoma is one cause of a cystic liver mass; the lesion is benign. Management depends on the location of the lesion and assessment of resectability as depicted by the imaging.
Clinical presentation:
Abdominal enlargement and respiratory distress are thought to be the most common presenting features in children. They can very rarely present in adults.
Pathology:
The lesions are characterised by an admixture of ductal structures (blood vessels, small groups of hepatocytes, and bile ducts) within a copious loose/oedematous connective tissue stroma .
On a cut surface, there are typically multiple cysts in an oedematous stroma; the cysts can vary in size ranging from a few millimeters to 16 cm, and in number and distribution, being discrete or connected .
Mesenchymal hamartomas in adults may show a series of histologic modifications: progressive loss of hepatocytes, degeneration of bile duct epithelium, and cystic changes of the mesenchymal component .
Radiographic features:
*General:
Mesenchymal hamartomas can show a wide spectrum of radiological features, from being a predominantly cystic tumour, to a multiseptated cystic tumour, to a mixed solid and cystic tumour, to even a completely solid tumur.
The dominant radiographic pattern, however, is a large (often around 12-15 cm 8), predominantly cystic mass with internal septations . There can be considerable variation in the size of septae and cystic spaces .
*Conventional radiogaph:
Although nonspecific, radiographs may show a large, noncalcified mass in the right upper quadrant .
*Ultrasound:
It usually appear as a multiseptated cystic lesion interspersed with solid components. Detection is difficult for pedunculated lesions. In some lesions may be the predominance of solid structures .
*CT scan:
On unenhanced CT, it usually has a heterogeneous appearance. The stromal elements often appear hypoattenuating, whereas the cystic components have water attenuation. The appearance of cystic and solid portions has been likened to Swiss cheese. On a postcontrast CT scan, solid portions or thick septa of the tumours can show heterogeneous enhancement .
*MRI:
Prominent cystic components, multifocality is uncommon.MR imaging appearance of mesenchymal hamartoma can also vary dependant on the presence of stromal elements as well as protein content of the fluid .
*DSA: angiography:
While not being a standard diagnostic imaging modality of choice, angiography may show peripheral hypervascularity to the lesion with a septated avascular center.
Complications:
There are fatal complications associated with a hepatic masenchymal hamartoma (particularly in the prenatal group). These generally result from the size of lesion and include :
fetal hydrops
respiratory distress: neonatal respiratory distress
circulatory complications/compromise owing to a large space-occupying abdominal lesion
Treatment and Prognosis:
Mesenchymal hamartomas are benign lesions and are best treated by surgical resection, which usually results in cure . There are occasional reports of ultrasound-guided intraoperative aspiration of fluid from the cystic components of the tumour to reduce its volume, facilitating surgical resection .
Differential diagnosis:
* Hepatic abscess
* Hepatoblastoma (especially when there is a predominance of the solid component and no increase in alpha-fetoprotein)
*Embryonal sarcoma
* Infantile hemangioendothelioma
* Simple hepatic cyst
PATHOGENESIS :
The pathogenesis of HMH is still debated. A handful of series have shown an association with mesenchymal stem villous hyperplasia of the placenta. Mesenchymal stem villous hyperplasia is characterized by diffuse edema of stem villi with preservation of terminal villi. Often these stem villi contain areas of large muscularized vessels. The histologic picture is similar to a partial hydatidiform mole but without the trophoblastic scalloping orproliferation. Whether these 2 entities are somehow related is still in question, but the hypothesis that they arise from synchronous abnormal mesodermal development rather than a true developmental abnormality (as originally thought) is gaining acceptance.
Because placentas have seldom been examined in infants who develop large hepatic masses, the data are limited. Several investigators have reported a balanced translocation between the long arms of chromosome 11 and chromosome 19. Rakheja et al , recently reported a case of HMH in an month old boy that demonstrated a break point at 19q13.4, which was similar to the previous 4 reported cases that had a documented karyotypic abnormality. Using histologic, immunohistochemical, flow cytometric, and cytogenetic data, Lauwers et al 12 elegantly demonstrated a case of embryonal sarcoma arising from an HMH in a 15-year-old girl. The transformed component had the 19q13.4 breakpoint in addition to several other numerical and structural chromosomal abnormalities. Taken together, this raises the possibility that perhaps a subset of HMHs is truly neoplastic.
TREATMENT :
Fetal intervention in the form of ultrasound-guided percutaneous cyst aspiration has been shown to dramatically affect outcomes. Tsao et al 6 reported 2 fetuses with intrauterine cystic HMHs: one who underwent cyst aspiration and the other who did not. The former underwent a total of 3 antenatal aspirations. After each aspiration, fluid did reaccumulate, but in the end, there was cyst shrinkage. The fetus was delivered vaginally at 35 weeks, and at 2 weeks postpartum both mother and child were well. The latter fetus who was not treated with prenatal cyst aspiration experienced rapid cyst enlargement, such that before appropriate intervention could be initiated, the mother had premature rupture of membranes, followed by preterm labor and delivery also at 35 weeks. Postpartum complications included intraventricular hemorrhage, cystic encephalomalacia, and renal failure, which were all thought to be related to ischemia secondary to vascular compression. The infant subsequently died. Surgery, consisting of either enucleation or lobectomy,traditionally has been the treatment of choice in the postpartum period; however, less invasive techniques, such as laparoscopic fenestration have also been used successfully.
Because the natural course of this tumor is to initially rapidly increase in size and subsequently decrease in size, some investigators have opted for ‘‘watchful waiting’’ in asymptomatic patients.
DIFFERENTIAL DIAGNOSIS:
Pediatric hepatic masses include both neoplastic and nonneoplastic proliferations as well as infectious etiologies. Radiographically, the differential diagnoses include hepatoblastoma, embryonal sarcoma, hemangioma, infantile hemangioendothelioma, and hepatic hydatid disease.15 All these entities can have varying amounts of solid and cystic areas.
Rendering a diagnosis from a needle biopsy or a fine-needle aspiration biopsy can be difficult if not approached in a systematic fashion. If the sample is hypocellular, which is not uncommon with HMH, the difficulties in arriving at a diagnosis could be compounded. Clusters of normal bile duct epithelium and hepatocytes admixed with bland mesenchymal cells in a myxoid background is highly suggestive of HMH.
Immunohistochemistry is used primarily to rule out other entities. In HMH, bile ducts and hepatocytes are cytokeratin positive, whereas the mesenchyme and pseudocysts are vimentin positive. Myxomatous infantile hemangioendotheliomas can resemble HMH on fine-needle aspiration biopsy, but the plump endothelium of the former is positive for factor VIII-related antigen, CD31, and CD34 immunohistochemical stains. Although a localized vascular proliferation within an HMH will stain similarly, careful attention to the amount of positive-staining cells within the entire set of aspirates will reveal the true nature of the mass.
Of the different histologic patterns of hepatoblastoma, mixed epithelial-mesenchymal hepatoblastoma is most similar to HMH. This particular type of hepatoblastoma can be composed of relatively bland appearing hepatocytes (of the fetal type) with spindle/stellate mesenchyme. In general, fine-needle aspiration biopsies of hepatoblastomas tend to be very cellular and the mixed epithelial-mesenchymal type can contain fragments of osteoid or cartilage as well. Using immunohistochemical stains for this differential diagnosis can potentially be misleading because fetal-type epithelial cells stain similar to adult-type hepatocytes (positive for cytokeratin [CK8, CK18] and hepatocyte [Hep Par 1]). In addition, the mesenchymal components of both HMH and hepatoblastoma are strongly positive for vimentin.
Finally, distinguishing embryonal sarcoma from HMH is based on identifying atypical, pleomorphic stellate cells that are frequently set in a background of hemorrhage and/or necrosis. Within these tumor cells and occasionally in the stroma itself, periodic acid-Schiff–positive and diastase resistant hyaline globules similar to those seen in yolk sac tumor may be present. In contrast to HMH, an epithelial component is lacking in embryonal sarcoma.
SUMMARY:
Hepatic mesenchymal hamartoma is a benign tumor that is typically diagnosed in childhood; its etiology has not been completely elucidated.
Histologically, it is composed of bland spindled cells in a myxoid to fibrous stroma with pseudocysts and normal-appearing bile ducts and hepatocytes. The differential diagnosis consists of other pediatric hepatic masses as well as select infectious cysts. Specimens with small amounts of diagnostic tissue(as in core needle biopsy or fine-needle aspiration biopsy) should be carefully examined for the histologic components described previously. Judicious use of immunohistochemical stains will help rule out other possibilities. Complications of an enlarging HMH stem from compression of adjacent vital organs and structures. Prognosis is excellent with complete resection.
Conclusion:
MHL in adults is a rare and potentially premalignant lesion that presents as a solid/cystic neoplasm. Symptoms are typically nonspecific, though abdominal pain is the most common. Laboratory results are noncontributory and radiographic imaging is variable and inconclusive. Needle biopsy is rarely diagnostic and surgical excision of symptomatic or enlarging lesions is recommended to exclude the possibility of malignancy and to establish a further diagnosis. The emerging literature suggests a relationship between MHL and UES in regards to histological similarities and cytogenetic analysis, and supports a recommendation for aggressive surgical management when feasible.
Dr.Amir Mirabolfathi, MD. FIAS
General &Laparascopic Surgeon
Erfan hospital
۴ / May / 2015