**6.3 Detection of malignant transformation**

The pathogenesis of malignant transformation of hepatocellular adenoma is still poorly understood. Some light was recently shed on the mechanisms of hepatocarcinogenesis, which suggest the importance of telomerase reverse transcriptase (TERT) promoter mutations beside the early event of β-catenin mutation. Apparently, only the β-catenin mutations that occur on exon 3 and not those on exon 7–8 are involved in malignant transformation of HA [49]. It still remains unclear if hepatocellular carcinoma emerges from hepatocellular adenoma or if the lesions are coincident. Malignant transformation of hepatocellular adenoma has been reported in 4% of women and 47% of men with HA [50]. The risk of malignancy is very high for β-HA, which is most frequently associated with glycogenosis type 1, androgenic hormone intake (many of these tumors expressing androgen receptors in men), and familial polyposis. It is important to remind that no HA subtype is devoid of risk of malignant transformation. Men are predisposed to hepatocellular carcinoma regardless of etiology, and for this reason, surgical treatment is strongly recommended for male patients diagnosed with HA. For women, an older age (50 years or older) or a younger age (15 years or less) is a risk factor for malignant degeneration that must be taken into account to refer these patients to surgeon for resection or at least to a hepatologist for very close and careful surveillance.

At present, no clinical assessment can distinguish between HA and degenerated HA, and no rules for surveillance of HA in both sexes are clearly defined according to subtypes. The methods and the periodicity of following these patients are variable. Radiological assessments could include CEUS, multidetector raw CT, and dynamic MRI. CEUS allows more sensitive recognition and specific exclusion of malignancy compared with CT and dynamic MRI and has the advantage that can be repeatedly performed without the risk associated with allergic reactions or radiation exposure. Moreover, MRI has the disadvantage that cannot be performed everywhere in the world because the technical skills and expertise are very much geographically dependent. Two main features must be taken into consideration at reassessment of these patients with HA: the size of the tumor and, more important, the hemodynamic changes that precede the tumor growth [50]. Malignant degenerations are considered when the tumor was first iso-attenuated when compared with normal liver during the nonenhanced and delayed phases and appeared homogenous in the early phase but, at a later examination, it becomes enhanced in the early phase and hypo-attenuated in the delayed phase. Also, the presence of a nodule within a nodule during the arterial phase is known as a sign of malignancy. β-HA often has cytological atypia and pseudoglandular pattern, and it is sometimes almost impossible to identify HCC.

**135**

*Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

**7. Management and current guidelines**

ence of symptoms, and complications.

**7.1 Surgical resection**

The surgeons must be convinced that HA subtypes are important for the management of the patients. From now on, a diagnosis of HA cannot be conceived without group classification. The number and location of HA play a great role in management, but various clinical conditions such as age, sex, etiology, background liver, or comorbidities must be taken into consideration. Other aspects also play a role in decision making, like where the patient lives, the degree of his/ her anxiety, and cost of surveillance. The management of patients with HA must be planned by a complex team formed by surgeons, hepatologists, pathologists,

There are no clear guidelines for the management of HA, because the treatment depends on many factors such as HA size, number, localization, gender, age, pres-

In young women treated with contraceptive pills, asymptomatic lesions under 5 cm in diameter should be kept under close observation with CT/CEUS repeated every 6 months [51] and repeated alpha-feto-protein, all the while ceasing to use contraceptive pills [52]. Any modification in imaging suggesting a malignant transformation or an increase in the serum tumor marker should lead to liver resection. There are some authors who advocate resection of adenomas of any size given their risk of malignization and bleeding, if the resection can be performed with acceptable risk. The facts that surgical excision guarantees a definitive diagnosis and

The indications for surgery in nonemergent cases are: HA > 5 cm, female patients

taking oral contraceptives with HA > 3 cm [47], HA with growing size, HA with HCC or dysplastic foci, β-catenin-activated HA, imaging features of malignant transformation, increased serum alpha fetoprotein, HA in males regardless of the tumor size, HA in GSD, symptomatic patients, or when malignancy cannot be excluded [54]. The type of resection depends mainly on number, size, histological type, and localization of HA. The resection techniques vary from simple enucleation to liver transplantation [55]. Liver resection for HA can be anatomic or nonanatomic. Anatomic resections reported in the literature for HA refer to minor hepatectomies that imply the removal of the tumor with one or two segments of the liver [56], but also major hepatectomies like left and right hemihepatectomy, mesohepatectomy [57], and left or right extended hepatectomy [26, 58]. Nonanatomical resections are wedge resections [59]. Enucleation seems to be a choice for such benign tumor, but is not advisable due to the risk of remnant tumor that can cause tumor recurrence or, worse, malignant degeneration, especially for β-catenin HA. It was speculated that the classical 1 cm oncological safety margin could be lowered to 0.5 cm for HA. The safety margin at the edge of resection is mandatory, if any suspicion of HCC exists. Surgery in elective cases is less than 1% and most tumors can be operated laparoscopically, with significant advantages [59–61]. A better cosmetic result, a shorter hospitalization (4 days) with early return to normal life, and a lower incisional rate are the main advantages that laparoscopy has comparative with open approach. However, laparoscopy should be performed only in specialized centers with extensive experience in both hepatic and laparoscopic surgery. The first non-anatomical laparoscopic liver resection for HA reported by Ferzli et al. [62] in 1995 was followed one year later by the first anatomic laparoscopic resection for HA performed by Azagra et al. [63]. Pure laparoscopic procedure can be performed for HA with no mortality and reduced morbidity even in

radiologists, gastroenterologist, molecular biologists, and geneticists.

long-term cure favor the universal indication of surgery for HA [53].

*Liver Disease and Surgery*

tions like inflammation and abscess.

and/or resection may still be necessary.

**6.3 Detection of malignant transformation**

Ga, and technetium-99 pyridoxyl-5-methyltryptophan (PMT) uptake may help establish the correct diagnosis [47]. Most adenomas do not take up technetium Tc-99m sulfur colloid so they appear as a "cold" spot in the parenchyma of the liver. This examination is not particularly good in diagnosing an adenoma but in distinguishing one from a FNH, which shows equal or greater uptake of the radiolabeled agent compared with surrounding liver [48]. 99mTc-labeled DISIDA (dimethyliminoacetic acid) liver scintigraphy has also been used by some authors for diagnosis of HA [47]. Positron emission tomography (PET) scanning with fluorine-18-fluorodeoxyglucose (18FDG) is useful in differentiating HAs from malignant tumors, because malignant tumors show uptake of 18FDG but not benign tumors, with some excep-

Although CEUS, CT, MRI, and nuclear studies help in characterization of hepatic lesions as adenomas, the findings sometimes are nonspecific, and biopsy

The pathogenesis of malignant transformation of hepatocellular adenoma is still poorly understood. Some light was recently shed on the mechanisms of hepatocarcinogenesis, which suggest the importance of telomerase reverse transcriptase (TERT) promoter mutations beside the early event of β-catenin mutation. Apparently, only the β-catenin mutations that occur on exon 3 and not those on exon 7–8 are involved in malignant transformation of HA [49]. It still remains unclear if hepatocellular carcinoma emerges from hepatocellular adenoma or if the lesions are coincident. Malignant transformation of hepatocellular adenoma has been reported in 4% of women and 47% of men with HA [50]. The risk of malignancy is very high for β-HA, which is most frequently associated with glycogenosis type 1, androgenic hormone intake (many of these tumors expressing androgen receptors in men), and familial polyposis. It is important to remind that no HA subtype is devoid of risk of malignant transformation. Men are predisposed to hepatocellular carcinoma regardless of etiology, and for this reason, surgical treatment is strongly recommended for male patients diagnosed with HA. For women, an older age (50 years or older) or a younger age (15 years or less) is a risk factor for malignant degeneration that must be taken into account to refer these patients to surgeon for resection or at least to a hepatologist for very close and careful surveillance. At present, no clinical assessment can distinguish between HA and degenerated HA, and no rules for surveillance of HA in both sexes are clearly defined according to subtypes. The methods and the periodicity of following these patients are variable. Radiological assessments could include CEUS, multidetector raw CT, and dynamic MRI. CEUS allows more sensitive recognition and specific exclusion of malignancy compared with CT and dynamic MRI and has the advantage that can be repeatedly performed without the risk associated with allergic reactions or radiation exposure. Moreover, MRI has the disadvantage that cannot be performed everywhere in the world because the technical skills and expertise are very much geographically dependent. Two main features must be taken into consideration at reassessment of these patients with HA: the size of the tumor and, more important, the hemodynamic changes that precede the tumor growth [50]. Malignant degenerations are considered when the tumor was first iso-attenuated when compared with normal liver during the nonenhanced and delayed phases and appeared homogenous in the early phase but, at a later examination, it becomes enhanced in the early phase and hypo-attenuated in the delayed phase. Also, the presence of a nodule within a nodule during the arterial phase is known as a sign of malignancy. β-HA often has cytological atypia and pseudoglandular pattern, and it is sometimes almost impossible to identify HCC.

**134**
