Primary hepatic neuroendocrine neoplasm diagnosed by somatostatin receptor scintigraphy:A case report

lNTRODUCTlON

Primary hepatic neuroendocrine neoplasm(NEN)is a rare condition with unclear clinical features.Obtaining a preoperative diagnosis of primary hepatic NEN can pose a challenge.In this report,we describe a case of hepatic NEN that initially mimicked hemangioma but gradually increased in size after close observation for 10 years.Immunohistological staining showed that the tumor cells were positive for somatostatin receptor(SSTR)2a/5.Postoperative somatostatin receptor scintigraphy(SRS)revealed no other significant site,which supported the idea that the tumor was of primary hepatic origin with gradual tumor progression.This case report was written in accordance with the SCARE guidelines[1].

CASE PRESENTATlON

Chief complaints

The patient had no complaints.

History of present illness

A 47-year-old Japanese woman underwent abdominal ultrasound for a medical check-up,which revealed a 12-mm hyperechoic hepatic mass in segment 4.Because the mass was suspected to be a hemangioma,the patient regularly underwent follow-up annual ultrasound examinations to assess its size.Ten years later,the mass had increased to 20 mm.The patient was then referred to our institute because the mass was suspected to be malignant.

There was not another young lady in the whole town who was as clever as she was in gnawing1 through the hardest wood, or who could drop from such a height on to a bed, or run away so fast if anyone was heard coming

History of past illness

The patient’s past medical history was not significant,except for uterine myomas.

Personal and family history

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Physical examination

At her first presentation to our clinic,physical examination revealed a soft,flat,and non-tender abdomen.

And yet standing10 beside the hospital bed watching the life ebb11 from my sleeping father was painful. I felt like a little girl at his bedside, unable to talk to him yet again. I became fixated with his fingers – fat and soft, lying gently curled beside him. Slowly they transformed from plump sausages to stone – white and immovable. It was his fingers that told me he had gone from this life, not the bleeping of monitors or the bustling12 of nursing staff.

Akabane M wrote the manuscript;Kobayashi Y contributed to the operation and follow-up,the manuscript design and coordination,and helped draft the manuscript;Kinowaki K contributed to pathological diagnosis;and all authors read and approved the final manuscript.

Laboratory examinations

Her laboratory data indicated that her renal and liver functions were normal.The Child-Pugh score was categorized as class A,and the indocyanine green retention at 15 min was 11.3%.The patient was negative for hepatitis B or C infection.The serum tumor markers,carcinoembryonic antigen,carbohydrate antigen 19-9,alpha-fetoprotein,and protein induced by vitamin K antagonist-II,were all within their normal ranges.All electrolytes were within normal limits.

Imaging examinations

Contrast-enhanced computed tomography(CT)revealed a 23-mm liver mass in segment 4,adjacent to the hepatic hilum.The mass exhibited a slight ring-like enhancement in the arterial phase.In the portal and delayed phases,the signal intensity of the mass was lower than that of the surrounding liver tissue(Figure 1).Contrast-enhanced magnetic resonance imaging(MRI)demonstrated a low signal on T1-weighted images and an intermediate signal on T2-weighted images.In the early phase,peripheral enhancement with a low signal was observed inside the mass.Diffusion-weighted images showed a significantly high signal,and the apparent diffusion coefficient(ADC)map demonstrated a low signal.A decreased uptake of gadoxetate sodium was also observed.Positron emission tomography(PET)/CT showed significant accumulation,with a maximum standardized uptake value of 10.1 at the mass.No other abnormal accumulations were observed.Esophagogastroduodenoscopy and colonoscopy revealed no malignant lesions.

FlNAL DlAGNOSlS

The authors declare that they have no conflict of interest.

TREATMENT

Posted to the Russian front, Leip never saw Lili or Marleen again. Some 20 years later he included Song of a Young Sentry in an anthology of his poems. Berlin composer Norbert Schultze spotted13 the poem, set it to music, entitled it Lili Marleen and offered it to tenor14 Jan Bayern---who turned it down as too simple.

OUTCOME AND FOLLOW-UP

Gross examination revealed a 2.5 cm × 2.0 cm × 3.0 cm yellowish-white mass with hemorrhage(Figure 2).Histologically,atypical cells with small round nuclei and eosinophilic cytoplasms were arranged in an alveolar,reticular,or trabecular pattern.The cells were characterized by nuclear division,with 2 per 10 high-power fields.Immunohistological staining showed that the tumor cells were positive for chromogranin A/synaptophysin and negative for CD56t.The Ki-67 labeling index was found to be 7%.Thus,a diagnosis of hepatic NEN(grade 2)was made.With respect to SSTR,the scores were 3 for SSTR2a and 2 for SSTR5(Figure 3).SRS performed in the outpatient clinic identified no other significant accumulation,which cast doubt on the possible existence of primary sites other than the liver.Taking these findings into account,we concluded that the tumor originated in the liver;however,continuous follow-up is essential to completely rule out the possible existence of other primary sites or to identify the appearance of new hepatic lesions in the future.Regular follow-up with imaging studies has been performed since the operation,considering possible recurrence.At the 1-year follow-up,the patient was in good health and free from recurrence.

DlSCUSSlON

NEN is a primary malignant tumor arising from neuroendocrine cells throughout the body.The most common primary sites of NEN are the gastrointestinal tract(67.5%)and the lung/bronchus(25.3%)[2].Within the gastrointestinal tract,the small intestine(25.3%),rectum(27.4%),and stomach(8.7%)are the most commonly involved organs[2].Primary hepatic NEN is extremely rare(0.4%)[2]and has no specific imaging findings or biomarkers.Thus,the diagnosis of hepatic NEN is generally difficult.The fact that the liver is frequently the metastatic site of NEN makes this diagnosis even more challenging.Furthermore,early diagnosis is often difficult because patients may have nonspecific symptoms or be asymptomatic,and the growth of NEN is generally slow.In the present case,the doubling time of the mass was calculated to be 46.4 mo,and such a gradual increase might have caused a delay in diagnosis.To the best of our knowledge,the longest observation period before surgery of a hepatic NEN in previous reports was 26 years[3].

Surgical resection was planned as a treatment option.Intraoperatively,we found no ascites,dissemination,or distant metastasis.Although intraoperative ultrasound demonstrated an apparent capsule around the mass in segment 4,the mass was located just on the hilar plate and was stiffly attached to Glisson’s capsule.Therefore,a left hepatectomy was performed to obtain a surgical margin.The postoperative clinical course was unremarkable,and the patient was discharged on postoperative day 14.

Regarding imaging modalities for the diagnosis of primary hepatic NEN,contrast-enhanced CT is often nonspecific because it shows the contrast effect in the arterial phase and washout in the portal phase,which is similar to the classic contrast pattern of hepatocellular carcinoma[4,5].MRI can depict a low signal on ADC maps/T1-weighted images and a high signal on T2-weighted images[4].The detection rate of NENs on PET/CT is 25%-73%,which is not very high and may be explained by the fact that NENs have relatively low tumor growth activity compared to carcinomas[6].However,PET has been reported to be useful in the search for metastasis and the diagnosis of recurrence in patients with high-grade tumors,such as those with abnormal accumulation in the primary lesion[7].Thus,PET/CT may be useful for differentiating metastatic NENs in the liver.In the present case,peripheral enhancement on CT and MRI and high accumulation on PET/CT also raised the possibility of intrahepatic cholangiocarcinoma with marginal vascular regeneration around the tumor.However,the extremely slow increase in tumor rate made us doubtful of the possibility of cholangiocarcinoma.The present case is noteworthy in that primary hepatic NEN exhibited significant accumulation on PET/CT.To the best of our knowledge,there are no reports showing accumulation at the site of primary hepatic NEN on PET/CT.

Although no clear clinical guidelines have been established for the treatment of primary hepatic NEN,surgical resection remains the basic treatment when feasible[8].Knox[9]reported a 5-year postoperative survival rate of 74%-78%,10-year survival rate of 68%,and recurrence rate of 18%.Although it is often difficult to determine whether NEN is a primary or metastatic lesion preoperatively,there are reports of improved prognosis after tumor reduction surgery even in unresectable or recurrent cases,regardless of whether the tumor is primary or metastatic[10].Therefore,aggressive surgical resection should always be considered.

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Riding home with her aunts, Margie could tell they were speaking in low tones9 about her wish. She hoped that they would keep her secret. As the next Sunday came around, Margie was getting ready for church when Grandma asked, “Why are you so fidgety” You haven’t’ sat still all morning.”

Tumors of neuroendocrine origin usually have cell surface receptors with an affinity for somatostatin[11].SRS is an imaging technique in which gamma-ray emitting radionuclides are labeled on octreotide,which shows an affinity for SSTR expressed on the cell membrane of lesions.Thus,SSTR is expressed in lesions with accumulation on SRS.SSTR has five subtypes,and subtypes 2a and 5 are characteristic of NEN.Volante[12]defined scores of 2(membranous reactivity in less than 50% of tumor cells)and 3(circumferential membranous reactivity in more than 50% of tumor cells)as positive.Hasegawa[13],who analyzed 16 cases of NEN,reported that the concordance rate between accumulation in a lesion on SRS and pathological SSTR2a expression was 93.8%.

SRS has been reported to have an 89% sensitivity to NEN[14].However,there are some reports of high accumulation in meningiomas and small cell lung cancer[15],as well as accumulation in nontumorous conditions including pneumonia,surgical wounds,and the breast[16].When SRS is performed to investigate the possibility that the primary tumor is located in another organ,as in this case,the interpretation of whether the site of accumulation is the primary site or a false positive should be carefully made in consideration of the other imaging modalities.

The Mayoress, a long thin stick of a woman, enraged17 at the insult done to her husband, seized his free arm and tore at it with all her might, with the only result that she too was forced to swell18 the procession

CONCLUSlON

We observed a long course of gradual tumor growth of hepatic NEN,considered the primary origin,for 10 years.Close preoperative observations,including PET/CT studies,enabled surgical decision-making and curative resection.Postoperative SRS after histological studies may be beneficial in making a final diagnosis.

In the present case,SRS was performed to identify the presence of a primary site in another organ after histological diagnosis.Scigliano[17]reported high sensitivity,specificity,and accuracy(89%,94%,and 91%,respectively)for SRS as a detection method for recurrence.Considering the gradual clinical course and postoperative investigation for another primary site,we thought that the hepatic tumor was most likely to be of primary hepatic origin.In this case,SRS revealed no possible primary or metastatic sites in other organs,and recurrence could be detected by comparative appraisal with the present results of SRS in the future.Therefore,continuous follow-up and preoperative observation are essential.Several reports[18,19]on the usefulness of SRS as a preoperative staging assessment for pancreatic and gastrointestinal NENs have been reported.However,to the best of our knowledge,SRS has not reportedly been performed in a patient with suspected primary hepatic NEN to postoperatively evaluate the possible existence of other primary lesions.

FOOTNOTES

19.If your mother only knew,/ Her heart would surely break in two: This refrain is repeated often throughout the tale. It reminds us that while the princess is loved and cherished by someone, she can no longer rely on the protection of that love now that she is an adult and must fend74 for herself in the world.

The patient had no remarkable family history.She denied any specific personal history of other diseases.

Considering these preoperative imaging studies,malignancy was considered as a differential diagnosis.

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See:https://creativecommons.org/Licenses/by-nc/4.0/

Japan

Miho Akabane 0000-0002-6705-5730;Yuta Kobayashi 00000-0001-6013-456X;Keiichi Kinowaki 0000-0001-7915-9177;Satoshi Okubo 0000-0002-4176-3851;Junichi Shindoh 0000-0002-8599-5267;Masaji Hashimoto 0000-0003-0616-3348.

The Prince, nothing loth, was for springing at once into deep water, but he was gently but forcibly held back and only allowed to stand where it was about an inch deep, and he was nearly wild with impatience60 when he found that this process was to be repeated every day in spite of all he could say or do, the water rising higher and higher by inches, so that for sixty days he had to live in perpetual silence, ceremoniously conducted to and fro, supping all his meals through the long reed, and looking on at innumerable games of chess, the game of all others which he detested61 most

Wang JJ

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Wang JJ