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Block et al. Hepatoma Res 2019;5:21 I http://dx.doi.org/10.20517/2394-5079.2019.17 Page 7 of 8

patients in their database had three or more primary malignancies in which none of these patients had
HCC . Other retrospective studies reported similar results .
[5]
[6,7]
The most common sites of EHPMs in patients with HCC tend to correlate with the typical distributions of
cancers found in different geographic regions. For example, studies with patient cohorts of Asian descent
identified gastric and nasopharyngeal cancers as common EHPMs , whereas studies from Western nations
[2-4]
revealed genitourinary and colorectal cancers as the most common EHPMs .
[8]
In regards to risk factors for EHPMs, studies have found similar clinical characteristics in patients with HCC
who developed EHPMs. A retrospective analysis of 1506 Taiwanese patients found that in comparison to
HCC patients without EHPMs, patients with HCC who developed EHPMs were more likely to be older, have
earlier stage HCC, and exhibit better liver functional reserve . They also found that patients with HCC and
[3]
EHPMs were less likely to be chronically infected with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) .
[3]
Retrospective studies of American, Japanese, and South Korean cohorts found similar correlations [4,9,10] .

To date, studies have been inconclusive in identifying iatrogenic or hereditary factors that may contribute
to second primary malignancies in HCC patients. No clear treatment differences between HCC patients
with and without EHPMs have been identified . Similarly, genetic factors that may contribute to second
[2]
malignancies in HCC patients have not been determined. Indeed, HCC patients with and without EHPMs
have similar frequencies of family members with cancer , which suggests that patterns of inheritance may
[2]
be involved but these have not yet been elucidated.

In conclusion, improvements in surveillence, diagnosis, and treatment of HCC has led to an increased
occurrence in the diagnosis of second primary malignancies. The case discussed here presents a rare
presentation of HCC with two additional EHPMs, especially given the patient’s infection with chronic
HBV. Notably, these three malignancies occurred over a period of nearly two decades. This highlights the
importance of continued regular cancer screening in patients with HCC, particularly those with early stage
HCC with favorable prognoses. It is therefore important for physicians to be aware of EHPMs and to provide
appropriate cancer screening for early detection and treatment. With this increased awareness, we hope to
see an increase in overall survival in the patients with HCC and EHPMs in the future.

DECLARATIONS
Authors’ contributions
Provided care for the patient with HBV and HCC, the conception and the design of the manuscript: Hann
HW
Searched literature and wrote the text: Block PD, Shinn BJ
Radiological images and legends: Roth CG
Pathological examination and images: Baliff JP
Provided the lung cancer treatment: Zinner RG

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.