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Histological and genetic heterogeneity in synchronous hepatocellular carcinoma
  1. F CETTA,
  1. M T del VECCHIO
  1. Institute of Surgical Clinics
  2. University of Siena, Italy
  3. Institute of Pathology
  4. University of Siena, Italy
  5. Department of Surgery and Liver Transplantation
  6. University of Bologna,Italy
  1. Dr F Cetta, Institute of Surgical Clinics, University of Siena, Nuovo Policlinico-Viale Bracci-53100 Siena, Italy.cetta{at}

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Editor,—The recent paper by Sirivatanauksornet al (OpenUrlCrossRefPubMedWeb of Science) focused once again on the unresolved question as to whether (i) hepatocellular carcinoma (HCC) in human liver develops from a single clone or from multiple parallel clones and (ii) among multiple tumour nodules present in many patients, the smaller lesions represent intrahepatic metastases or “de novo” cancers. The authors correctly acknowledge that “information on the clonal origin of tumours will influence management strategies for prevention of recurrence after operation”. They used arbitrarily primed polymerase chain reaction (AP-PCR)1 to compare the DNA fingerprint of HCCs and regenerative nodules (RNs) removed from 13 cirrhotic explant livers. They found considerable genomic heterogeneity in 54 HCCs and 31 RNs that were microdissected. No two nodules (either RNs or HCCs) had identical electrophoretic patterns. Contrary to expectation, even “satellite” nodules in close proximity within the same segment of the liver were found to have distinct genomic patterns. They concluded that their data suggest poor patient survival after surgical resection if the smaller tumours are “de novo” lesions rather than metastases.

We would like to make some comments. HCC arising in cirrhosis is frequently multifocal. This is supported by epidemiological studies and by the fact that a diffuse underlying viral disease facilitates multifocality, in particular when HCC is related to hepatitis C viral infection. In addition, primary multifocality is supported by the high incidence of “preneoplastic lesions” such as dysplastic nodules in the surrounding liver. However, a word of caution is suggested before extrapolating data and conclusions from this paper to all HCCs.2 ,3 In fact, there is a selection bias that could be responsible for the observed findings. Cirrhotic explant livers are selected for liver transplantation because of a diffuse, usually viral related cirrhosis in the absence of clinically evident large nodules. In these cases HCC is often an incidental finding and is mostly, if not always, multifocal. On the contrary, in a consecutive surgical series of resected patients, 44 of 49 patients without cirrhosis (88.2%) had a unique macroscopic nodule restricted to the right lobe, larger than 5 cm in nine of 44, whereas right lobe involvement occurred in 66 of 104 patients with cirrhosis (63.4%; p=0.0014 ,5). Satellite nodules were found in only four of the 49 patients of the former group (8%).5 Viral infection was detected in 38.7% of patients in the former group compared with 93.7% of patients with cirrhosis (p<0.001).5 In particular, the following findings were observed: (1) an as yet not well defined proportion of patients (10–20%) showed uninodular HCCs which were well capsulated, located in the right liver, with low tendency to vascular spread, and usually not associated with viral infection and/or clinically evident cirrhosis. Interestingly, these lesions remained unique even when greater than 5–6 cm (up to 10 cm) without satellite lesions; (2) when larger than 10 cm, these HCCs had conspicuous histological and genomic heterogeneity within the same initial nodule, showing different histological variants (up to five), each of which had a different genetic pattern. In these very large tumours, satellite nodules were similar to one of these five variants, or even different, but were still nodules originating from the initial “mother” lesion. In fact, in most cases, they remained restricted to the right lobe, close to the larger nodule, without left lobe involvement.5Therefore, even if genetic analysis is a powerful tool in detecting that two samples with the same genetic fingerprints belong to the same clone, a word of caution is suggested before stating the opposite, namely that a satellite nodule in close proximity to a larger lesion, within the same liver segment, is a different tumour, a “de novo” lesion, rather than a metastasis from the original tumour, simply because of genetic heterogeneity.


The study was supported in part by: the National Research Institute (CNR) (grants No 93.00239.CT04, No 94.02376.CT04, No 95.00897.CT04); Regione Toscana (grant No 358/C, 1995); Murst 40%–Murst 60%; and Telethon (grant E611).