30
Effects of Therapy on Cytologic Specimens
Fig. 30.7 Bleomycin toxicity in the lung. The pulmonary parenchyma
has marked interstitial fibrosis with a proliferation of atypical type II alveolar
pneumocytes. Open lung biopsy (H&E x MP).
therapy, c o m b in a tio n chem otherap y in non -H od g kin's ly m p h o -
mas, and h ig h partial pressures o f oxygen d uring anesthesia.56
T he histolog ic and ultrastructural changes in bleom ycin-
induced p u lm o n a ry to xic ity have been w e ll docum ented in a ni-
m al m od els.58-60 Like rad ia tio n changes, the end othelial cells and
pneum ocytes are m ost sensitive. The earliest changes are endothe-
lia l and perivascular edema o f p u lm o n a ry vessels. U ltrastructural
studies show sub end othelial blebbing w ith intracytoplasm ic
edema. These progress to in te rstitia l edema. A lve olar epithe-
liu m reveals type I pneum ocyte necrosis w ith a p ro life ra tio n and
desquam ation o f type II pneumocytes. The type II pneum ocytes
have bizarre elongated cytoplasm ic shapes, nuclear pleom or-
phism , hyperchrom asia, occasional m ito tic figures, and m eta-
plastic change in squam ous e p ith elium . Intra-alveolar fib rin
d ep osition due to vascular leakage also occurs. The in te rs titiu m
develops septal fibrosis w ith collagen/elastin fib er d eposition
and sm o oth m uscle p ro life ra tio n . End-stage b ib asilar fibrosis
develops, leading to a sequela o f "h o n e yc o m b " lung (Fig. 30.7) .
Cytology
S p utum , b ron c hial, and FN A b iopsy cytology m ay y ie ld dis-
tin c tly d iffe re n t finding s
in bleom ycin-ind uced p u lm o n a ry
toxicity. In the sp utum o f treated patients as com pared w ith
m atched controls, Bedrossian and C orey reported increased
c ilio c yto p h o ria (3 0 -5 6 .2 % ) and increased low-grade dysplasia
(1 0 -3 7 .5 % ) in the treated g roup.61 N o sig nificant difference in
in fla m m a tio n o r atypical c o lu m n a r cells was fo un d . In a d d ition,
4 0% o f the treated patients had ab no rm a lities o f the squam ous
cells in the oral cavity. The low -grade dysplastic cells varied in
size and shape and had a m p h o p h ilic cytoplasm and irregular
hyp erchrom atic nuclei. T he a b norm alities occurred as early as
12 weeks after the start o f therapy.
B ronchial cytology contains a m a jo rity o f n o rm a l b ron c hial
cells and occasional scattered large ab norm al c o lu m n a r cells
w ith b izarre large nuclei. The c hrom a tin is clum ped, and p ro m i-
n e n t large e o sin o p h ilic n u c le oli are also fo un d . Despite these
m a lig n a n t features, the cells m a in ta in th e ir delicate translucent,
b asop hilic cytoplasm , and w ell-d efined cilia as evidence o f th e ir
benign nature.62
Fig. 30.8 Bleomycin toxicity in the lung. The smear contains large
atypical multinucleated type II alveolar pneumocytes with fine cytoplasmic
vacuoles, large nuclei with smooth membranes, and macronucleoli. The
background contains multinucleated alveolar macrophages with mixed
inflammatory cells. Bronchoalveolar lavage (Papanicolaou x MP).
Fine-needle aspirates are lo w to m od erately cellular, depend-
ing on the degree o f fibrosis. Scattered lym phocytes and plasm a
cells are in the background. A typical e p ith elial cells fo rm cohe-
sive tw o -d im e n sio n a l sheets w ith a fe w scattered single cells. The
cells are large, polyg onal, and p leom orp hic, w ith w ell-d efined
cell m em branes. T he cytoplasm is dense (sq uam oid ) and m ay
be tw o-to ne d w ith slig ht o ra ng op h ilia o r a m p h o p h ilia . Peri-
nuclear m icrovacuoles are also found . M in im a l cellular overlap
is seen. The cohesive clusters resem ble a reparative ep ithelial
arrangem ent. The nuclei are central o r eccentric, w ith a sm o oth
m em brane, coarsely granular chrom a tin , and single o r m u lti-
ple m acronucleoli. The cytologic appearance m im ics m a lig n a n t
change (Fig. 30.8) . The clinical h is to ry is essential to v e rify a
benign reactive process. T he cellular changes observed in b leo -
m ycin-induced p u lm o n a ry to x ic ity are s im ila r to rad ia tio n-
induced changes.
N o effective therapy is available fo r bleom ycin-ind uced p u l-
m o n a ry fibrosis. The drug-induced toxic p u lm o n a ry changes
and subsequent end-stage fibrosis are n o t u n iq u e to b leom ycin
and m ay be fo u n d in o th e r cases in v o lv in g antineop lastic drugs
and n itro fu ra n to in s (Table 30.8 and Fig. 3 0.9).
Key features of bleomycin therapy
• N u c le a r e nlarg em ent;
• 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 .
Busulfan
B usulfan is an a lkyla ting agent th a t binds to n uc le op h ilic sites
(oxygen and nitro g en ) o f D N A bases. It belongs to a group
o f a lkyl sulfonates, w h ic h are one o f the five m a jo r groups o f
a lkyla ting agents. T h is activity leads to the m isreading o f the
D N A codes, single-strand breaks, and cross-linking o f D N A . The
repair o f the la tte r w o u ld require excision o f b o th bases d isrup t-
ing the D N A tem plate. The d isru p tio n o f the tem p late is m ost
dam aging because o f in h ib itio n o f rep lica tio n o f the D N A . The
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