gemcitabine is a chemotherapy agent frequently elected to treat solid tumors , including breast , colonic , ovarian , pancreatic , and non - small cell lung cancers [ 112 ] .
metastatic gallbladder cancer is a complex and uncommon event [ 1417 ] . in this report
, we describe a case of gallbladder metastatic colonic adenocarcinoma associated with fatal gemcitabine - induced pulmonary toxicity and discuss the histologic appearance of this dysfunction .
a 72-year - old male patient experienced an incidental diagnostic of tubular adenocarcinoma inside the gallbladder after elective laparoscopic cholecystectomy for chronic cholecystitis .
four days after cholecystectomy , he was submitted to laparotomy aiming radical resection ; however , peritoneal carcinomatosis was observed .
the patient was submitted to a tumor screening and a pet scan pointed out a hot - spot in the left colon .
this lesion was removed by colonoscopy and a histological examination confirmed a margin - free resection of a tubular adenocarcinoma .
the patient was finally scheduled to receive three sections of gemcitabine ( 1,600  mg / m ) once a week .
three weeks after the completion of chemotherapy , he developed an important respiratory distress requiring ventilator support .
a helicoidal ct scan showed bilateral and diffuse lung infiltrates ( fig .  1 ) .
a surgical lung biopsy was done and an accelerated usual interstitial pneumonia ( uip ) ( fig . 
2 ) , consistent with drug - induced toxicity , was observed . the patient presented with progressive impairment of respiratory function , coagulopathy , hypotension , and acute renal failure despite the use of methylprednisolone pulse therapy , large spectrum antimicrobial therapy , and full respiratory , hemodynamic and dialytic support .
he died 1  month later . to assess the probability that the event was caused by gemcitabine we computed a naranjo et al .  
average point score , which is based on the direction of causality between the drug and the manifestation of adverse effects .
naranjo s method estimates gemcitabine as the probable cause of pulmonary toxicity in the current report.fig . 
1a coronal reformatted images demonstrate involvement of all lung zones and predominantly upper lobe distribution of the ground - glass opacities and areas of consolidation . also noted are reticulation and small cysts in the subpleural and basal regions of the lungs .
b high - resolution ct image at the level of the main bronchi shows extensive bilateral ground - glass opacities and dependent areas of consolidation .
2lung surgical biopsy specimen showing accelerated usual interstitial pneumonia ( uip ) . a characteristic area of honeycomb change
is shown at low magnification ( a ) . at lower left corner ( a )
higher magnification of area showed in lower left corner ( b , c ) highlights the fibroblasts and chronic inflammation within alveolar septa and shows associated hyaline membranes ( arrow ) .
note also the squamous metaplasia ( arrows ) of bronchiolar epithelium from adjacent honeycomb area ( d ) .
this finding is another sign of superimposed acute lung injury a coronal reformatted images demonstrate involvement of all lung zones and predominantly upper lobe distribution of the ground - glass opacities and areas of consolidation
. also noted are reticulation and small cysts in the subpleural and basal regions of the lungs .
b high - resolution ct image at the level of the main bronchi shows extensive bilateral ground - glass opacities and dependent areas of consolidation . some emphysema can also be seen lung surgical biopsy specimen showing accelerated usual interstitial pneumonia ( uip ) .
a characteristic area of honeycomb change is shown at low magnification ( a ) . at lower left corner ( a )
higher magnification of area showed in lower left corner ( b , c ) highlights the fibroblasts and chronic inflammation within alveolar septa and shows associated hyaline membranes ( arrow ) .
note also the squamous metaplasia ( arrows ) of bronchiolar epithelium from adjacent honeycomb area ( d ) .
there are several papers reporting pulmonary toxicity due to gemcitabine used as a single agent [ 18 ] or in combination with other antineoplastic agents [ 913 ] .
the treatment of this event includes early use of steroid therapy administered either as pulses or continuously , mainly using methylprednisolone ; nevertheless , most cases have a dramatic and fatal evolution .
our patient obtained fatal evolution in spite of the use of steroids as recommended in the literature .
belknap et al . , reviewed data from spontaneous reports to research on adverse drug events and reports of pharmacovigilance ( radar ) program and appraised the clinical feature of gemcitabine - associated severe acute lung injury . among 178 reports of gemcitabine - induced pulmonary injury ( 55 from clinical trials and 92 from spontaneous reports )
dyspnea , fever , and pulmonary infiltrate were the most frequent symptoms of gemcitabine - induced pulmonary injury .
the median time to the diagnosis of this toxicity is 48  days ( range 1529 ) after initiation of gemcitabine .
eleven phase ii or phase iii clinical trials enrolling 317 patients identified pulmonary injury rates greater than 10% .
highest rates of this toxicity ( 22 and 42% ) were observed in phase iii clinical trials in which patients with hodgkin s disease were treated with gemcitabine and bleomycin .
the authors concluded that high rates of gemcitabine - associated severe lung injury were observed , mainly when gemcitabine was combined with other agents that can also cause lung injury .
just recently , arrieta et al . , observed that radiotherapy and gemcitabine for locally advanced non - small cell lung cancer is associated with excessive pulmonary toxicity .
differently , czarnecki and voss   reviewed records of patients with pulmonary toxicity at fda freedom of information ( fda - foi ) database and observed that there was no substantial difference in pulmonary toxicity with the combination of gemcitabine and taxanes in comparison with gemcitabine alone . indeed , gemcitabine - induced pulmonary toxicity is a dramatic condition . in the current case ,
the patient presented with rapidly progressive respiratory failure and the lung biopsy showed an accelerated uip complicated by superimposed acute lung injury .
most reported cases have occurred in patients with known uip , but the lesion can occur in patients with clinically unrecognized uip .
the etiology of acute lung injury in uip is unknown , but most cases are assumed to represent an inherent part of the natural history of uip .
histologically , however , the changes can not be separated from other causes of acute lung injury ( such as viral infections , aspiration , sepsis , drug reactions , or toxic inhalants ) , and it is entirely possible that some cases may represent reactions to clinically unrecognized extrinsic lung insults .
pathologically , the diagnosis is not usually difficult if all microscopic changes are taken into consideration .
classically , there are easily recognizable areas of uip with patchwork pattern and honeycomb change .
focus of diffuse alveolar damage ( dad ) recognizable by larger and more confluent interstitial fibroblast proliferation smaller than fibroblast foci of uip are usually present .
. other findings of the diagnosis include squamous metaplasia in bronchiolar epithelium lining honeycomb areas . in the current case , naranjo s method identified gemcitabine as the probable agent of pulmonary toxicity .
the liver is the most common site of metastatic dissemination of a colonic tumor ; however , a tumor from this region is very rare .
in fact , this is the first report of metastasize inside the gallbladder from a tumor of colon origin .
the prognostic of these patients was very poor with most of them achieving < 1-year survival . in summary
, physicians should suspect pulmonary toxicity in patients with respiratory distress after gemcitabine chemotherapy , mainly in elderly patients that received high doses of this drug .
 gemcitabine is a chemotherapy agent that may cause unpredictable side effects . in this report 
 , we describe a fatal gemcitabine - induced pulmonary toxicity in a patient with gallbladder metastatic adenocarcinoma . 
 a 72-year - old patient was submitted to an elective laparoscopic cholecystectomy , and a tubular adenocarcinoma in the gallbladder was incidentally diagnosed . 
 ct scan and ultrasound before the surgery did not show any tumor . 
 after the surgery a pet scan was positive for a hot - spot in the left colon . 
 the colonic lesion was conveniently removed and the histology evaluation confirmed the diagnosis of adenocarcinoma tubular . 
 the patient was then submitted to three sections of 1,600 mg / m2 of gemcitabine with intervals of 1  week . 
 three weeks later he developed severe respiratory distress . 
 a helicoidal ct scan showed diffuse and severe interstitial pneumonitis , and lung biopsy confirmed accelerated usual interstitial pneumonia consistent with drug - induced toxicity . 
 the patient presented unfavorable evolution with progressive worsening of respiratory function , hypotension , and renal failure . 
 he died 1  month later in spite of methylprednisolone pulse therapy , large spectrum antimicrobial therapy , and full support of respiratory , hemodynamic and renal systems . 
 gemcitabine - induced pulmonary toxicity is usually a dramatic condition . 
 physicians should suspect pulmonary toxicity in patients with respiratory distress after gemcitabine chemotherapy , mainly in elderly patients . 
Introduction
Case report
Comments