fibrolamellar hepatocellular carcinoma

{{Infobox medical condition (new)

| name = Fibrolamellar hepatocellular carcinoma

| synonyms = FHCC

| image = Fibrolamellar hepatocellular carcinoma -2- very high mag.jpg

| caption = Micrograph of fibrolamellar hepatocarcinoma showing the characteristic laminated fibrosis between the tumor cells with a low NC ratio. H&E stain.

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Fibrolamellar carcinoma (FLC) is a rare form of carcinoma that typically affects young adults and is characterized, under the microscope, by laminated fibrous layers interspersed between the tumor cells. It has been estimated that 200 new cases are diagnosed worldwide each year. However, in light of recent advances in our molecular understanding, this has recently been revised to suggest it may be at least ten times more common.{{cite journal |last1=Zack |first1=Travis |last2=Losert |first2=Kurt P. |last3=Maisel |first3=Samantha M. |last4=Wild |first4=Jennifer |last5=Yaqubie |first5=Amin |last6=Herman |first6=Michael |last7=Knox |first7=Jennifer J. |last8=Mayer |first8=Robert J. |last9=Venook |first9=Alan P. |last10=Butte |first10=Atul |last11=O'Neill |first11=Allison F. |last12=Abou-Alfa |first12=Ghassan K. |last13=Gordan |first13=John D. |title=Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data |journal=npj Precision Oncology |date=23 March 2023 |volume=7 |issue=1 |page=29 |doi=10.1038/s41698-023-00371-2|pmid=36959495 |pmc=10034241 |doi-access=free }} FLC, also known as fibrolamellar hepatocellular carcinoma, is different from the more common hepatocellular carcinoma (HCC) in that it afflicts young people with normal liver function and no known risk factors.{{cite journal |last1=Torbenson |first1=Michael |title=Fibrolamellar Carcinoma: 2012 Update |journal=Scientifica |date=2012 |volume=2012 |page=743790 |doi=10.6064/2012/743790|pmid=24278737 |pmc=3820672 |doi-access=free }}{{cite journal |last1=O'Neill |first1=Allison F. |last2=Church |first2=Alanna J. |last3=Perez-Atayde |first3=Antonio R. |last4=Shaikh |first4=Raja |last5=Marcus |first5=Karen J. |last6=Vakili |first6=Khashayar |title=Fibrolamellar carcinoma: An entity all its own |journal=Current Problems in Cancer |date=August 2021 |volume=45 |issue=4 |pages=100770 |doi=10.1016/j.currproblcancer.2021.100770|pmid=34272087 |s2cid=236001418 }}{{cite journal |last1=Lalazar |first1=Gadi |last2=Simon |first2=Sanford |title=Fibrolamellar Carcinoma: Recent Advances and Unresolved Questions on the Molecular Mechanisms |journal=Seminars in Liver Disease |date=February 2018 |volume=38 |issue=1 |pages=051–059 |doi=10.1055/s-0037-1621710|pmid=29471565 |pmc=6020845 }}{{Cite web |title=What is Fibrolamellar Carcinoma? |url=https://fibrofoundation.org/about-fibro/what-is-fibrolamellar-carcinoma/ |access-date=2023-01-10 |website=Fibrolamellar Cancer Foundation |date=20 February 2021 |language=en-US}}

Cause

A 2014 study showed the presence of the DNAJB1-PRKACA chimeric transcript (resulting from a 400kb somatic deletion on chromosome 19) in 100% of the FLCs examined (15/15).{{Cite web | url=https://www.nbcnews.com/health/cancer/teen-makes-genetic-discovery-her-own-rare-cancer-n75991 | title=Teen Makes Genetic Discovery of Her Own Rare Cancer| website=NBC News| date=16 April 2014}}{{cite journal|vauthors=Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim II, Gleason CE, Murphy JM, Rosenberg BR, Teegan L, Takacs CN, Botero S, Belote R, Germer S, Emde AK, Vacic V, Bhanot U, LaQuaglia MP, Simon SM |title=Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma|journal=Science|date=28 February 2014|volume=343|issue=6174|pages=1010–4|doi=10.1126/science.1249484|pmid=24578576|pmc=4286414|bibcode=2014Sci...343.1010H}} This gene fusion has been confirmed in many other studies.{{cite journal |last1=Graham |first1=Rondell P |last2=Jin |first2=Long |last3=Knutson |first3=Darlene L |last4=Kloft-Nelson |first4=Sara M |last5=Greipp |first5=Patricia T |last6=Waldburger |first6=Nina |last7=Roessler |first7=Stephanie |last8=Longerich |first8=Thomas |last9=Roberts |first9=Lewis R |last10=Oliveira |first10=Andre M |last11=Halling |first11=Kevin C |last12=Schirmacher |first12=Peter |last13=Torbenson |first13=Michael S |title=DNAJB1-PRKACA is specific for fibrolamellar carcinoma |journal=Modern Pathology |date=June 2015 |volume=28 |issue=6 |pages=822–829 |doi=10.1038/modpathol.2015.4|pmid=25698061 |doi-access=free }}{{cite journal |last1=Xu |first1=Lei |last2=Hazard |first2=Florette K. |last3=Zmoos |first3=Anne-Flore |last4=Jahchan |first4=Nadine |last5=Chaib |first5=Hassan |last6=Garfin |first6=Phillip M. |last7=Rangaswami |first7=Arun |last8=Snyder |first8=Michael P. |last9=Sage |first9=Julien |title=Genomic analysis of fibrolamellar hepatocellular carcinoma |journal=Human Molecular Genetics |date=1 January 2015 |volume=24 |issue=1 |pages=50–63 |doi=10.1093/hmg/ddu418|pmid=25122662 |pmc=4262492 }}Dinh TA, Vitucci EC, Wauthier E, Graham RP, Pitman WA, Oikawa T, Chen M, Silva G, Greene KG, Torbenson MS, Reid LM, Sethupathy P (2017) Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.

Sci Rep 7:44653. doi: 10.1038/srep44653 That this genomic deletion is sufficient to produce FLC was shown by creating this deletion, and formation of the DNAJB1::PRKACA chimeric gene, using CRISPR/Cas9 in the livers of mice.{{cite journal |last1=Kastenhuber |first1=Edward R. |last2=Lalazar |first2=Gadi |last3=Houlihan |first3=Shauna L. |last4=Tschaharganeh |first4=Darjus F. |last5=Baslan |first5=Timour |last6=Chen |first6=Chi-Chao |last7=Requena |first7=David |last8=Tian |first8=Sha |last9=Bosbach |first9=Benedikt |last10=Wilkinson |first10=John E. |last11=Simon |first11=Sanford M. |last12=Lowe |first12=Scott W. |title=DNAJB1–PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma |journal=Proceedings of the National Academy of Sciences |date=12 December 2017 |volume=114 |issue=50 |pages=13076–13084 |doi=10.1073/pnas.1716483114|pmid=29162699 |pmc=5740683 |bibcode=2017PNAS..11413076K |doi-access=free }}{{cite journal |last1=Engelholm |first1=Lars H. |last2=Riaz |first2=Anjum |last3=Serra |first3=Denise |last4=Dagnæs-Hansen |first4=Frederik |last5=Johansen |first5=Jens V. |last6=Santoni-Rugiu |first6=Eric |last7=Hansen |first7=Steen H. |last8=Niola |first8=Francesco |last9=Frödin |first9=Morten |title=CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma |journal=Gastroenterology |date=December 2017 |volume=153 |issue=6 |pages=1662–1673.e10 |doi=10.1053/j.gastro.2017.09.008|pmid=28923495 |pmc=5801691 |doi-access=free }} That the actual formation of the DNAJB1::PRKACA was responsible, and not the deletion, was shown by expression of the DNAJB1::PRKACA from a transposon.

To determine if the DNAJB1::PRKACA was only involved in triggering the tumor, or if it continued to drive the tumor, a small hairpin RNA was used to eliminate the DNAJB1::PRKACA. The tumors died, which demonstrated not only that DNAJB1::PRKACA is continuing to drive FLC, but that the tumor has become oncogenically addicted.{{cite journal |last1=Neumayer |first1=Christoph |last2=Ng |first2=Denise |last3=Jiang |first3=Caroline S. |last4=Qureshi |first4=Adam |last5=Lalazar |first5=Gadi |last6=Vaughan |first6=Roger |last7=Simon |first7=Sanford M. |title=Oncogenic Addiction of Fibrolamellar Hepatocellular Carcinoma to the Fusion Kinase DNAJB1-PRKACA |journal=Clinical Cancer Research |date=4 January 2023 |volume=29 |issue=1 |pages=271–278 |doi=10.1158/1078-0432.CCR-22-1851|pmid=36302174 |pmc=9811160 }}

Pathology

The histopathology of FLC is characterized by laminated fibrous layers, interspersed between the tumor cells. Cytologically, the tumor cells have a low nuclear to cytoplasmic ratio with abundant eosinophilic cytoplasm. Tumors are non-encapsulated, but well circumscribed, when compared to conventional HCC (which typically has an invasive border).{{citation needed|date=August 2020}}

Diagnosis

Due to lack of symptoms, until the tumor is sizable, this form of cancer is often advanced when diagnosed. Symptoms include vague abdominal pain, nausea, abdominal fullness, malaise and weight loss. They may also include a palpable liver mass.{{Cite journal | last1 = Yen | first1 = JB. | last2 = Chang | first2 = KW. | title = Fibrolamellar hepatocellular carcinoma- report of a case. | journal = Chang Gung Med J | volume = 32 | issue = 3 | pages = 336–9 | pmid = 19527614 | year=2009}} Other presentations include jaundice, ascites, fulminant liver failure, encephalopathy, gynecomastia (males only), thrombophlebitis of the lower limbs, recurrent deep vein thrombosis, anemia and hypoglycemia.{{citation needed|date=August 2020}}

The usual markers for liver disease – aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase – are often normal or only slightly elevated. FLC often does not produce alpha fetoprotein (AFP), a widely used marker for conventional hepatocellular carcinoma. In a subset of FLC patients elevated plasma neurotensin levels may be present.{{cite journal |last1=Collier |first1=N.A. |last2=Bloom |first2=S.R. |last3=Hodgson |first3=H.J.F. |last4=Weinbren |first4=K. |last5=Lee |first5=Y.C. |last6=Blumgart |first6=L.H. |title=Neurotensin Secretion by Fibrolamellar Carcinoma of the Liver |journal=The Lancet |date=March 1984 |volume=323 |issue=8376 |pages=538–540 |doi=10.1016/s0140-6736(84)90934-6|pmid=6199633 |s2cid=28566123 }} Likewise, in a subset of FLC patients, elevated serum vitamin B12 binding globulin levels may be present.{{cite journal |last1=Paradinas |first1=F J |last2=Melia |first2=W M |last3=Wilkinson |first3=M L |last4=Portmann |first4=B |last5=Johnson |first5=P J |last6=Murray-Lyon |first6=I M |last7=Williams |first7=R |title=High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. |journal=BMJ |date=25 September 1982 |volume=285 |issue=6345 |pages=840–842 |doi=10.1136/bmj.285.6345.840|pmid=6288165 |pmc=1499744 }}

Diagnosis is normally made by imaging (ultrasound, CT or MRI) and biopsy.{{cite journal |last1=Malouf |first1=G |last2=Falissard |first2=B |last3=Azoulay |first3=D |last4=Callea |first4=F |last5=Ferrell |first5=L D |last6=Goodman |first6=Z D |last7=Hayashi |first7=Y |last8=Hsu |first8=H-C |last9=Hubscher |first9=S G |last10=Kojiro |first10=M |last11=Ng |first11=I O |last12=Paterson |first12=A C |last13=Reynes |first13=M |last14=Zafrani |first14=E-S |last15=Emile |first15=J-F |title=Is histological diagnosis of primary liver carcinomas with fibrous stroma reproducible among experts? |journal=Journal of Clinical Pathology |date=1 June 2009 |volume=62 |issue=6 |pages=519–524 |doi=10.1136/jcp.2008.062620|pmid=19155239 |s2cid=206987786 }} However, even with a biopsy, there is often disagreement over the diagnosis. Since the characterization of the DNAJB1::PRKACA fusion, the most reliable diagnosis is through molecular characterization such as PCR to detect the fusion,{{cite journal |last1=Levin |first1=Solomon N. |last2=Tomasini |first2=Michael D. |last3=Knox |first3=James |last4=Shirani |first4=Mahsa |last5=Shebl |first5=Bassem |last6=Requena |first6=David |last7=Clark |first7=Jackson |last8=Heissel |first8=Søren |last9=Alwaseem |first9=Hanan |last10=Surjan |first10=Rodrigo |last11=Lahasky |first11=Ron |last12=Molina |first12=Henrik |last13=Torbenson |first13=Michael S. |last14=Lyons |first14=Barbara |last15=Migler |first15=Rachael D. |last16=Coffino |first16=Philip |last17=Simon |first17=Sanford M. |title=Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma |journal=Science Advances |date=23 June 2023 |volume=9 |issue=25 |pages=eadg7038 |doi=10.1126/sciadv.adg7038|pmid=37343102 |pmc=10284549 |bibcode=2023SciA....9G7038L }} or genomic sequencing, or using a fluorescent in-situ hybridization.

Treatment

FLC can often be surgically removed. Liver resection is the optimal treatment and may need to be performed more than once, since this disease has a very high recurrence rate. Due to such recurrence, periodic follow-up medical imaging (CT or MRI) is necessary.

When the tumor cannot be removed surgically or when there is distant spread, many different systemic therapies are currently being used to treat the disease. However, no standard of care currently exists for FLC. Consequently, there remains a pressing need to identify proven, effective systemic therapies for the cancer. Radiotherapy has been used but data is limited concerning its use.

The Fibrolamellar Registry,{{cite web |title=Home |url=http://fibroregistry.org |website=The Fibrolamellar Registry}} a patient and family run medical registry has collected data from over 250 patients. This work has been used in multiple publications which include extended information on patient outcomes, efficacy of immune checkpoint inhibitors, efficacy of specific drugs and understanding the basis of high ammonia in FLC.{{cite journal |last1=Berkovitz |first1=Amichai |last2=Migler |first2=Rachael D. |last3=Qureshi |first3=Adam |last4=Rosemore |first4=Carly |last5=Torbenson |first5=Michael S. |last6=Vaughan |first6=Roger |last7=Marcotte |first7=Erin |last8=Simon |first8=Sanford M. |title=Clinical and demographic predictors of survival for fibrolamellar carcinoma patients—A patient community, registry‐based study |journal=Hepatology Communications |date=December 2022 |volume=6 |issue=12 |pages=3539–3549 |doi=10.1002/hep4.2105|pmid=36245434 |pmc=9701473 }}{{cite journal |last1=Chen |first1=Krista Y. |last2=Popovic |first2=Aleksandra |last3=Hsiehchen |first3=David |last4=Baretti |first4=Marina |last5=Griffith |first5=Paige |last6=Bista |first6=Ranjan |last7=Baghdadi |first7=Azarakhsh |last8=Kamel |first8=Ihab R. |last9=Simon |first9=Sanford M. |last10=Migler |first10=Rachael D. |last11=Yarchoan |first11=Mark |title=Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors |journal=Cancers |date=30 October 2022 |volume=14 |issue=21 |pages=5347 |doi=10.3390/cancers14215347|pmid=36358766 |pmc=9655068 |doi-access=free }}{{cite journal |last1=Shebl |first1=Bassem |last2=Ng |first2=Denise |last3=Lalazar |first3=Gadi |last4=Rosemore |first4=Carly |last5=Finkelstein |first5=Tova M. |last6=Migler |first6=Rachael D. |last7=Zheng |first7=Guangrong |last8=Zhang |first8=Peiyi |last9=Jiang |first9=Caroline S. |last10=Qureshi |first10=Adam |last11=Vaughan |first11=Roger |last12=Yarchoan |first12=Mark |last13=de Jong |first13=Ype P. |last14=Rice |first14=Charles M. |last15=Coffino |first15=Philip |last16=Ortiz |first16=Michael V. |last17=Zhou |first17=Daohong |last18=Simon |first18=Sanford M. |title=Targeting BCL-XL in fibrolamellar hepatocellular carcinoma |journal=JCI Insight |date=8 September 2022 |volume=7 |issue=17 |pages=e161820 |doi=10.1172/jci.insight.161820|pmid=36073545 |pmc=9536265 }}

The survival rate for FLC largely depends on whether (and to what degree) the cancer has metastasized, i.e. spread to the lymph nodes or other organs. Distant spread (metastases), significantly reduces the median survival rate. Five-year survival rates vary between 40 and 90%.

Epidemiology

FLC accounts for 1–10% of primary liver cancers.Lafaro KJ, Pawlik TM (2015) Fibrolamellar hepatocellular carcinoma: current clinical perspectives. J Hepatocell Carcinoma 2:151–157 doi: 10.2147/JHC.S75153 It typically has a young age at presentation when compared to conventional HCC. Previously it was estimated to be 20–40 years, mean ages 27 years,{{cite journal |vauthors=Stipa F, Yoon SS, Liau KH, etal |title=Outcome of patients with fibrolamellar hepatocellular carcinoma |journal=Cancer |volume=106 |issue=6 |pages=1331–8 |date=March 2006 |pmid=16475212 |doi=10.1002/cncr.21703|doi-access=free }} but when analysis is restricted to those patients who are confirmed with a molecular test to have FLC, the age range is 10-40 and mean age of 21 years. Unlike the more common HCC, patients most often do not have coexistent liver disease such as cirrhosis.

History

This disease was first described by Hugh Edmondson in a 14-year-old female with no underlying liver disease.Edmondson HA (1956) Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA J Dis Child 91(2):168–186 The name fibrolamellar hepatocellular carcinoma was coined by Craig et al. in 1980.Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46(2):372–379 It was not recognized as a distinct form of cancer by the WHO until 2010.Bosman FT (2010) World Health Organization. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on Cancer

Starting in 2010, some patients and their family members started to examine the molecular basis of FLC.{{cite journal |last1=Simon |first1=Sanford M. |title=Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma |journal=Nature Reviews Cancer |date=May 2023 |volume=23 |issue=5 |pages=335–346 |doi=10.1038/s41568-023-00554-w|pmid=36932129 |pmc=10022574 }} They gathered samples through social media,{{cite web |title=Teen Makes Genetic Discovery of Her Own Rare Cancer |url=https://www.nbcnews.com/health/cancer/teen-makes-genetic-discovery-her-own-rare-cancer-n75991 |website=NBC News |language=en |date=16 April 2014}}{{cite web |title=Fibrolamellar Liver Cancer Research | website=YouTube |url=https://www.youtube.com/watch?v=Y5lkp_uK9Ww& |language=en}} sequenced the genome, and analyzed the immunological response. Since there are few patients at any one institution, they formed their own medical registry called the Fibrolamellar Registry, which allowed them to follow patients as they changed institutions. This work led to the identification of the chimeric fusion driver and the first characterization of the transcriptome and proteome. The work was heralded by Francis Collins when he presented to the Senate Appropriations committee{{cite web |title=Senate Appropriation Hearings on the NIH: Francis Collins | website=YouTube |url=https://www.youtube.com/watch?v=XPeQ0gVbDC8}} and was used by President Obama at the launch of The Precision Medicine Initiative at the White House.{{cite web |title=Launching of the Precision Medicine Initiative Jan 30, 2015 | website=YouTube |url=https://www.youtube.com/watch?v=qHD-_NYOcVA |language=en}}