Co esponding au ho : ERGITA NELAJ
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A case o neu oendoc ine umo wi h mul iple me as a ic hepa ic lesions and an
unknown p ima y si e
IRIDA KECAJ 1, ERGITA NELAJ 1, *, ATHINA PAPADHOPULLO 2, KEI XHIXHABESI 3, ILIR GJERMENI 1 and INA
REFATLLARI 4
1 Depa men o In e nal Medicine, Uni e si y Hospi al Cen e “Mo he Te esa”, Ti ana, Albania.
2 Depa men o Oncology, Uni e si y Hospi al Cen e “Mo he Te esa”, Ti ana, Albania.
3 Facul y o Medicine, Uni e si y o Medicine, Ti ana, Albania.
4 Depa men o Ca diology, Uni e si y Hospi al Cen e “Mo he Te esa”, Ti ana, Albania.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(01), 1618-1623
Publica ion his o y: Recei ed on 07 June 2025; e ised on 15 July 2025; accep ed on 17 July 2025
A icle DOI: h ps://doi.o g/10.30574/wja .2025.27.1.2699
Abs ac
In oduc ion: Neu oendoc ine neoplasms (NEN) a e ypically cha ac e ized by an indolen and slow-g owing na u e.
Due o hei g adual p og ession, hese umo s a e o en de ec ed inciden ally, p esen ing as me as a ic deposi s a he
han p ima y masses. Neu oendoc ine umo s (NET) wi h an unknown p ima y o igin a e ela i ely common in clinical
p ac ice, accoun ing o app oxima ely 12–22% o NEN cases. In such ins ances, biopsy plays a c ucial ole, enabling
pa hologis s o de e mine he umo ype and, whe e possible, he si e o he p ima y umo h ough his opa hological
analysis. The classi ica ion o NETs is based on hei his ological di e en ia ion and g ading. Low-g ade, well-
di e en ia ed umo s end o ollow a mo e indolen cou se, while high-g ade, poo ly di e en ia ed neoplasms exhibi
apid g ow h and agg essi e beha io . This classi ica ion is closely linked o he clinical p esen a ion and p ognos ic
ou comes o he pa ien s.
P esen a ion o he Case: A 74-yea -old emale hospi alized a he in e nal medicine se ice due o di icul y in
b ea hing du ing mino physical exe ion, ho acic-abdominal discom o , leg edema, a e exclusion o pulmona y
h omboembolism wi h pulmona y angio-CT and acu e co ona y synd ome in he eme gency depa men . Abdominal
ul asound aised he suspicion o a cholecys ic umo wi h mul iple hepa ic me as ases. Subsequen examina ions wi h
con as CT and MRI abdomen, EGD, and colonoscopy esul ed in mul iple seconda y hepa ic lesions and cholecys ic
calculi. CT-guided biopsy and immunohis ochemical analysis o he li e mass iden i ied poo ly di e en ia ed small cell
ca cinoma wi h posi i e s aining o PanCK, Ch omog anin, CD56, and a Ki67 p oli e a ion index o 70%. A e ex ensi e
examina ions we e unable o de e mine he p ima y o igin o he umo , oncological assessmen ecommended
chemo he apy wi h cispla in and e oposide o he ea men o s age IV small cell neu oendoc ine umo o unknown
p ima y o igin wi h li e me as asis. Conside ing he ad anced s age o he disease, he pa ien op ed o pallia i e ca e.
Conclusion: In cases o neu oendoc ine umo s wi h well-di e en ia ed cells, mo e de ailed diagnos ic examina ions
a e pe o med o ind he p ima y si e, o pe o m su gical in e en ion, o o s a sys emic he apy depending on
loca ion. The loca ion o he p ima y si e is also impo an in de e mining he p ognosis o neoplasia. In he case o
poo ly di e en ia ed neoplasms, de ailed diagnos ic in es iga ions o iden i y he p ima y sou ce do no a ec he
p ognosis o he disease.
Keywo ds: Gallbladde ; Hepa ic; Me as asis; Neu oendoc ine
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1. In oduc ion
Neu oendoc ine neoplasms (NENs) a e a e umo s ha o igina e om cells wi h a neu oendoc ine pheno ype. They
cons i u e only 0.5-1% o all malignancies, wi h an es ima ed incidence o 2-4 pe 100,000 and a highe p e alence in
emales [1]. NENs occu almos e e ywhe e in he body, bu mos commonly in he Gas o-In es inal ac , panc eas,
and he lungs, causing a ange o symp oms leading o hei de ec ion [2,3]. None heless, he e a e ins ances whe e
NENs p esen as me as a ic deposi s, whose p ima y umo is occul o clinically unde ec able. These neoplasms a e
e e ed o as NEN o Unknown P ima y Si e and comp ise 12-22% o all NENs [4]. The p ima y umo si e plays a
c ucial ole in de e mining bo h ea men op ions and p ognosis. Howe e , when he p ima y si e canno be
de ini i ely iden i ied, ea men s a egies a e guided by umo di e en ia ion and g ading.
The upda ed WHO classi ica ion sys em (2022) iden i ies wo dis inc g oups based on gene ic ea u es, mo phology,
and clinical beha io . Well-di e en ia ed neu oendoc ine neoplasms (NENs) a e classi ied as neu oendoc ine umo s
(NET G1, G2, G3), while poo ly di e en ia ed neoplasms a e ca ego ized as neu oendoc ine ca cinomas (NEC, G3),
which a e u he subdi ided in o small cell and la ge cell ca cinomas [5]. The i s g oup o umo s has a mo e indolen
cou se, while he la e p esen s apidly and mo e agg essi ely, closely associa ed wi h clinical p esen a ion and
p ognosis. This case epo p esen s ou expe ience wi h his a e ype o neoplasm and ou challenges in de e mining
he si e o o igin.
2. P esen a ion o he case
A 74-yea -old emale p esen ed o ou eme gency depa men complaining o di icul y b ea hing du ing mino
exe ion, ches pain, abdominal discom o , nausea, a igue, weakness and leg swelling o nea ly wo mon hs,
wo sening p og essi ely. She had a medical his o y o hype ension and ype 2 diabe es melli us. A e excluding
pulmona y h omboembolism and acu e co ona y synd ome in he eme gency oom, he pa ien was admi ed o he
in e nal medicine depa men wi h a diagnosis o igh -sided hea ailu e.
On physical examina ion, he e was inspec ed pe iphe al edema and skin pallo ; non ende abdomen on palpa ion,
al hough he e was no ed a mild discom o in he igh uppe quad an ; pulmona y wheezing on auscul a ion. Blood
es s showed ele a ed le els o NTp oBNP (3215 pg/mL), Fib inogen (446 mg/dL), D- dime (3,31 ug/mL), CRP (5.73
mg/dL), LDH (461 U/mL); ull blood coun e ealed hypoch omic mic ocy ic anemia (RBC 3.01 x 106; Hgb 8.4 g/dL;
HCT 26.1%; MCV 86.6 μm3); o he alues (li e unc ion, u ea and c ea inine, elec oly es, albumin, o al p o ein) we e
wi hin no mal anges.
Echoca diog am showed no mal le en icle size and ejec ion ac ion; dila ed igh en icle and igh a ium; mild
icuspid egu gi a ion; PsPA 80 mmHg; no pe ica dial e usion. A ou ine abdominal ul asound e ealed an enla ged
li e wi h mul iple hepa ic nodules, sugges i e o seconda y lesions; i egula wall hickness o he gallbladde nea he
undus, as well as a calculus 25 mm in diame e (Fig. 1).
Figu e 1 Gallbladde ul asound showing i egula wall hickness and a calculus nea he gallbladde neck
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Abdominal ul asound aised he suspicion o gallbladde cance wi h mul iple hepa ic me as ases. Subsequen ly, he
pa ien unde wen u he in es iga ions, including a o al body CT scan wi h IV con as , which e ealed an enla ged
li e wi h mul iple di use he e ogeneous lesions exhibi ing pe iphe al enhancemen , i egula hickening o he
gallbladde undus wall, and h ombosis o he le b anch o he po al ein. Abdominal MRI also e ealed mul iple
hepa ic umo lesions up o 90 mm in diame e (Fig. 2); gallbladde calculi (Fig.3); dila ed cys ic duc ; images sugges ing
Mi izzi Synd ome.
Figu e 2 Mul iple hepa ic umou lesions in MRI
Figu e 3 MRI image o gallbladde calculi
A his poin , all he imaging da a sugges gallbladde cance wi h li e me as asis. To con i m he diagnosis, a CT-guided
biopsy o he li e lesions was pe o med. His opa hological examina ion and immunohis ochemical s aining e ealed
in il a ion o neu oendoc ine ca cinoma (NEC), which, acco ding o he new WHO classi ica ion sys em, is a poo ly
di e en ia ed neoplasm. The umo cells we e posi i e o Ch omog anin A (Fig.4), PanCK (Fig.5), CD56, which con i ms
neu oendoc ine o igin; nega i e o HSA, CDX-2, CK7, CK20, CEA, TTF1, HMB45, Vimen in. Ki67 e ealed a p oli e a i e
index o 70%.
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Figu es 4 and 5 Ch omog anin A and Panke a in posi i e s ain
Ou challenge, so a , has been o de e mine he p ima y si e o help us guide he ea men decisions. The pa ien
unde wen EGD and colonoscopy o ind a possible si e in he GI ac , bu he esul s we e nega i e o neoplasm.
Gi en he a o emen ioned imaging and endoscopic da a, he loca ion o he p ima y si e emained ques ionable, so ou
only guide was he umo his ology. Unlike in NETs, immunohis ochemis y plays a mo e limi ed ole in de e mining
he si e o o igin o NECs. TTF-1 would sugges isce al o igin, while CK20 would sugges cu aneous o igin, bu bo h o
hese ma ke s a e nega i e in ou case. Excep o in si u hyb idiza ion o HR-HPV (associa ed wi h anogeni al and
occasionally head and neck o igins), he e a e cu en ly no eliable ma ke s o di e en ia e be ween si es o o igin in
isce al NEC [6].
A e managing he ac ual hea condi ion, he pa ien was e alua ed by he oncology eam. Since all he pe o med
examina ions we e no able o iden i y a p ima y sou ce o he umo , hey ecommended chemo he apy ea men wi h
pla inum-based agen s and e oposide ( ecommended chemo he apy egimen o s age IV small cell NET o unknown
p ima y si e wi h li e me as asis [7,8]. Conside ing he ad anced s age o he disease, he pa ien chose pallia i e
ea men .
3. Discussion
When a neu oendoc ine umo o unknown p ima y is diagnosed, iden i ying he o igin o he neoplasm is c ucial o
help guide he ea men decisions. I he p ima y si e emains uniden i ied a e a ho ough e alua ion, ea men is
ypically based on he umo 's his ology [9]. In ins ances o well-di e en ia ed neu oendoc ine umo s, he si e o o igin
holds conside able p ognos ic and he apeu ic signi icance [10]. On he o he hand, in cases o poo ly di e en ia ed
neu oendoc ine neoplasms, de ailed diagnos ic in es iga ions o iden i y he p ima y sou ce do no a ec he p ognosis
o he disease and should be ea ed simila ly o small cell lung cance , including pla inum-based chemo he apy wi h
e oposide [9].
Howe e , o he ea men op ions a e a ailable. Fi s ly, checkpoin inhibi o he apy has p o en o be highly e ec i e
in Me kel cell ca cinoma bu only mode a ely so in isce al NECs and has quickly become he i s -line ea men o
his umo ype. [6,11]. Secondly, ex apulmona y isce al NECs a e inc easingly managed wi h egimens e ec i e in
si e-speci ic non-neu oendoc ine ca cinomas (e.g., FOLFOX, FOLFIRI o GEP-NECs) o wi h eme ging ea men
p o ocols such as pla inum/i ino ecan and CAPTEM. [6,12]. Ano he use ul index ha plays a ole in p ognosis and
ea men decisions is Ki-67. Ki67 immunohis ochemis y may also be ele an o NECs, whe e highe p oli e a ion
indices a e linked o poo e p ognosis, imp o ed esponses o pla inum-based chemo he apy, and diminished
e ec i eness o emozolomide-based ea men s [6,13].
Howe e , in ou clinical case, i was no possible o de e mine he exac umo o igin. Gi en ha a highe Ki67 index is
associa ed wi h a be e esponse o pla inum-based agen s, chemo he apy wi h cispla in and e oposide was
ecommended o he pa ien .
Fu he s udies wi h o he chemo he apeu ic and no el agen s need o be done o achie e be e ea men ou comes.
Un il hen he s anda d ea men emains pla inum in combina ion wi h e oposide, which p o ides a modes su i al
bene i .
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4. Conclusion
In cases o neu oendoc ine umo s, mo e de ailed diagnos ic examina ions a e pe o med o ind he p ima y si e, o
pe o m su gical in e en ion, o s a sys emic he apy depending on loca ion. In he case o poo ly di e en ia ed
neoplasms, de ailed diagnos ic in es iga ions o iden i y he p ima y sou ce do no a ec he p ognosis o he disease.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
The au ho s decla e ha hey ha e no con lic o in e es .
S a emen o e hical app o al
The s udy was designed in compliance wi h he e hical guidelines o he 1975 Decla a ion o Helsinki. In o med consen
was ob ained.
S a emen o in o med consen
In o med consen was ob ained om all indi idual pa icipan s included in he s udy.
Funding
This wo k did no ecei e any speci ic g an om any unding agency.
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