PART TWO
Diagnostic Cytology
Table 30.8 Drug-i nduced Interstitial Pulmonary Fibrosis
Chemotherapy agent
Pulmonary toxicity
Bleomycin
Pulmonary fibrosis
Mitomycin C
Pulmonary fibrosis with
lymphocytes and eosinophils
Bis-chloroethyl-nitrosourea
Pulmonary fibrosis
Busulfan
Pulmonary fibrosis and possibly
dystrophic pulmonary calcification
and ossification
Cyclophosphamide
Pulmonary fibrosis
Chlorambucil
Pulmonary fibrosis
Melphalan
Pulmonary fibrosis
Methotrexate
Pulmonary fibrosis with
eosinophils and occasional nodular
aggregates of multinucleated
giant cells
«
Fig. 30.9 Methotrexate toxicity in the lung. The smear contains atypical
reactive epithelial cells with enlarged nuclei and multiple prominent nucleoli.
Bronchial brushing (Papanicolaou x MP).
cytotoxic a ctivity occurs th ro u g h o u t the cell cycle b u t is exagger-
ated d uring the p rolifera tive S phase.63
B usulfan was introd uced in 1961 and was the first chem o-
therapeutic drug to be associated w ith p u lm o n a ry to xic ity.64
T he chest radiograph u su ally reveals a diffuse lin e a r in filtra te ,
a lthoug h n o rm a l radiographs o r alveolar in filtra te find ing s have
also been reported.55 T he incidence o f clinical p u lm o n a ry toxic-
ity has been reported at 4% , w ith atypical histo lo g ic changes
reported as hig h as 12%.
T he histolog ic and u ltra struc tura l changes in the lungs due
to b usulfan to x ic ity are s im ila r to those reported fo r bleom ycin.
D ystrop hic calcification and p u lm o n a ry ossification have been
reported in a few cases.56 K yung-W han and G yorkey reported a
case o f b ro n c h io lo a lve o la r carcinom a, diffuse in te rs titia l fib ro -
sis, and atypical alveolar pneum ocyte hyperplasia occurring in
a p a tie nt after long -term b usulfan therapy, suggesting a possible
carcinogenic ro le .65
Cytology
T he p u lm o n a ry cytologic changes are s im ila r to those reported
in b leo m yc in toxicity.
Fig. 30.10 Busulfan changes in the uterine cervix. The squamous
cell changes resemble a high-grade dysplasia. Cervicovaginal smear
(Papanicolaou x MP).
The cytom egalic changes are n o t lim ite d to the lungs and
have been described in the pancreas, liver, adrenal glands, k id -
neys, u rin a ry bladder, esophagus, p itu ita ry gland, skin, breasts,
and u terine cervix in autopsy series.66-68 The e p ith elial cells are
m arked ly enlarged w ith cytoplasm ic vacuoles and display an
increased nucleocytoplasm ic ratio. The nuclei are m arked ly ple-
om orp hic, w ith irreg ular elongated and m u ltilo b u la te d form s
m easuring up to 50 pm in diam eter. C oarsely granular chrom a-
tin and n u c le oli are fo un d . M ito tic figures are n o t observed.65
The u terine cervix shows a decreased estrogen effect w ith a
preponderance o f parabasal and interm ed iate cells.69 T he strati-
fied squam ous e p ith e liu m contains a large n um b er o f scattered
cytom egalic cells, m a in ly located in th e upper layers. In som e
areas, the fu ll thickness is involved w ith ab norm al cells and
resembles carcinom a in situ except fo r the ab und ant cytoplasm ,
th in n in g o f the e p ith e liu m , and lack o f m ito tic figures. The cer-
vicovaginal sm ear m ay have the cellular changes o f a high-grade
dysplasia o r carcinom a in situ ( Fig. 30.10) .67,69 S im ila r cells
fro m the u rin a ry tra n sitio n a l m ucosa m ay be observed in u rin e
cytology.63
Key features of busulfan therapy
• N u c le a r e nlarg em ent;
• Irre g u la r n u c le a r b orders;
• P e rin u c le a r vacuoles;
• S m udged o r coarsely g ra n u la r c h ro m a tin ;
• Increased c ytop lasm ic d e nsity; and
• O ra n g e o p h ilia
Bladder
Thiotepa
T hiote p a (trie th yle n e th io p h o sp h o ra m id e ) is a p o lyfu n c tio n a l
a lkyla ting drug in s tille d intravesically in the tre atm e nt o f super-
ficial bladder cancers and carcinom a in situ. M ouse m odels
w ith n o rm a l bladder u ro th e liu m treated w ith th io te p a show
m ild lym p h oc ytic infiltrates. N o atypical changes o f the b lad -
der u ro th e liu m are fo u n d.70 In m ouse m odels w ith chem ically
induced u ro th e lia l neoplasm s, toxic effects include cellular
degeneration w ith cytoplasm ic vac uo lation and e xfolia tion .
960
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