【病理每周一题】No.463（2016.2.29—2016.3.13，答案已公布）

p****y

本周病例（2016.2.29—2016.3.13）

女，2岁，无意发现肝脏包块1月，直径8cm。

1、你考虑什么诊断？
2、需要做什么鉴别诊断？
3、本病预后如何？

旧**迹

好病例，前来学习。

f****g

诊断：肝细胞癌。患儿年轻，肿瘤组织实性生长，细胞内可见胆汁淤积，细胞核染色较深，胞质丰富，淡染，考虑是来源于肝细胞的肿瘤，鉴别诊断包括发生于儿童的其他的形态相似的肝脏肿瘤，期待版主的讲解，以便学习。

邱*实

首先追溯家族遗传病源，这么小，可怜

邱*实

有无外伤，这才叫先天性，宁愿是外伤

p****y

本周病例（2016.2.29—2016.3.13）

1、你考虑什么诊断？
高分化肝母细胞瘤（Well-differentiated hepatoblastoma）

肝母细胞瘤是一种具有多种分化方式的恶性胚胎性肿瘤，由相似于胎儿性上皮性肝细胞、胚胎性细胞以及分化的间叶成分（包括骨样基质、纤维结缔组织和横纹肌纤维）组成。肝母细胞瘤是儿童中最常见的肝肿瘤。4％的肝母细胞瘤见于新生儿，68％发生于2岁以内，90％发生于5岁以内，仅有3％的患者＞15岁。诊断时90％患者AFP水平的升高，AFP水平与疾病过程平行，当肿瘤完全切除时AFP降至正常而随病变复发AFP水平升高，在小细胞未分化肝母细胞瘤中AFP水平可以正常或轻度升高。

免疫组化染色
GPC3（Glypican 3）

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β-catenin

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GS（Glutamine Synthetase）

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Clinically, hepatoblastoma usually presents as an abdominal mass and an elevated serum AFP level. Grossly, they are well-circumscribed, solid tumors with heterogeneous areas of hemorrhage and necrosis, especially after treatment.

There are several histologic patterns seen in hepatoblastomas which resemble various stages of hepatocyte development, which are then grouped into larger histologic subtypes. The most commonly seen subtype is the epithelial subtype, which includes fetal, crowded fetal, embryonal, macrotrabecular and small cell undifferentiated (also called anaplastic) patterns. Other subtypes include mesenchymal and a catch-all category of other components. Overall, hepatoblastoma histology is quite variable. However, epithelial patterns, either purely or mixed with other subtypes, account for more than 95% of hepatoblastomas.

Pure well-differentiated fetal pattern: 100% of neoplastic hepatocytes display a recapitulation of fetal liver parenchyma with smaller hepatocyte size and nuclear to cytoplasmic ratio, abundant eosinophilic, amphophilic or clear cytoplasm and small central nuclei with no nucleoli. The lesional cells are arranged in 2-cell-thick cords with rare (<2/10hpf) mitoses. Low power views of this pattern have a characteristic "light and dark" appearance due to cytoplasmic tinctorial qualities. This diagnosis can only be suggested on biopsy, but can be made definitively on resection if the specimen is well sampled and the entire tumor is composed of this single histologic pattern.

Crowded fetal pattern (also called "mitotically active" fetal HB): architecturally resembles the fetal pattern, but with a larger nuclear to cytoplasmic ratio, more eosinophilic cytoplasm and more numerous mitoses (less than 2/10hpf). This pattern is usually intermixed between areas of fetal pattern and embryonal pattern, and frequently bridges and merges the two. Extramedullary hematopoiesis can be seen.

Embryonal pattern: emulates the embryonal stage of liver development and features high nuclear to cytoplasmic ratio with indistinct cell borders and a large nucleus with prominent nucleolus. The nuclei may be angulated and are larger than in fetal patterns. Crowding of cells and frequent mitoses are also features of this pattern. Extramedullary hematopoiesis is a more prominent feature than in the crowded fetal pattern, but is not a reliable measure for distinguishing the patterns from each other.

Small cell (anaplastic or undifferentiated) pattern: resembles the most primitive stage of liver development and consists of round blue cells with large nuclear to cytoplasmic ratio, nuclei that vary from pale and vesicular to hyperchromatic, and indistinct cell borders. Rhabdoid features including eccentric nucleoli and eosinophilic cytoplasmic globules can be seen. Mitoses can be numerous, but can also be rare. This pattern is usually seen as a small component intermixed with other epithelial subtypes but rarely can be the predominant component (>70%) in which case they may be associated with loss of INI1 staining seen in the group of malignant rhabdoid tumors.

Mixed mesenchymal-epithelial subtypes of hepatoblastoma are tumors which can include osteoid, rhabdomyomatous, or primitive spindled cell components. Patterns containing ductular components (cholangioblastic) melanin pigment and retinal epithelium or immature neuroepithelium (teratoid), and even squamous or mucinous epithelium can also be seen.

Immunohistochemical staining patterns can be an important part of the diagnosis, especially with the variation in histologic appearance and when differentiating hepatoblastoma from adenoma and hepatocellular carcinoma. Since a majority of hepatoblastomas have defects in the WNT signaling pathway, beta-catenin staining is useful, showing a nuclear staining pattern in most cases with or without significant cytoplasmic staining. This can be seen in all histologic subtypes, though the well-differentiated fetal pattern can have less nuclear staining compared to other epithelial subtypes. However, a small subset of pediatric hepatocellular carcinomas is also positive for beta-catenin, as are the beta-catenin mutated adenomas. Glypican 3 is positive in a cytoplasmic pattern in the pure fetal, crowded fetal, and embryonal patterns, with a fine granular staining often seen in the fetal histologic type (as in this case). Glypican 3 staining will distinguish hepatoblastomas and hepatocellular carcinomas from benign processes such as adenoma and focal nodular hyperplasia. Glutamine synthetase is also positive in the pure fetal and crowded fetal histologic patterns and is variably positive in the embryonal pattern. Together, positivity for beta-catenin, glypican 3 and glutamine synthetase would strongly favor a diagnosis of hepatoblastoma and be further supported by the proper clinical context.

2、需要做什么鉴别诊断？
主要与高分化肝细胞癌、肝细胞腺瘤等相鉴别

3、本病预后如何？
完全切除病变与预后直接相关，即初次手术后达到Ⅰ期还是Ⅱ期。化疗和肝移植使得90％的病例可手术切除，以致总体存活率达65%～70％。Ⅰ期存活率几乎为100％，Ⅱ期存活率为80％。观察AFP水平对手术和化疗的反应可以预测疾病的预后。初次诊断AFP水平在100～1000000ng/ml预后较好；<100mg/ml或>1000000ng/ml，预后则较差。其他预后相对较好的因素有肿瘤限于1叶、胎儿型和多灶性播散（较肝内单一病灶而有远处转移和血管浸润好）。

－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－

本期病例比较少见，作为发生于婴幼儿肝脏最常见的恶性肿瘤，临床病史及组织学形态典型时不难诊断，而在分化良好酷似正常肝细胞时，极易于高分化肝细胞癌和肝细胞腺瘤混淆，结合临床表现和组织学形态，辅以免疫组化有助于诊断。综合回答思路，fusuyong累积半分，旧日足迹、邱老实鲜花鼓励！

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