30
Effects of Therapy on Cytologic Specimens
N uclear changes are rare. N e ith e r m u ltin u c le a tio n n o r m itoses
are fo un d . In n o rm a l dog u ro th e liu m treated w ith th io te p a at
w eekly intervals, the in itia l changes includ e h yp e rce llu la rity
and cytoplasm ic vac uo lation (at weeks 2 -3 ). These are fo llo w e d
b y nuclear and nucleolar enlargem ent and m u ltin u c le a tio n at
weeks 3 -5 . The nuclei degenerate, becom ing p yknotic and kary-
orrhectic at weeks 5 -1 0. A t autopsy (10 weeks), the u ro th e liu m
is hyperplastic, and in d ivid u a l cells have nuclear enlargem ent
and m u ltip le n u c le o li.71,72
Cytology
In hum ans, thiotep a-related changes are s im ila r to reactive
changes and d iffe r fro m neoplastic changes. T he nuclei become
s lig h tly to m arked ly enlarged, w ith o u t a sig nificant a lte ratio n in
chrom a tin . M ild to m oderate hyperchrom asia m ay be noted in
rare cells, b u t the nuclei are smudged, lacking sharp ly defined
c h ro m a tin detail. The nuclei are ro u n d to oval and have sm o oth
m em branes. C e llu la r degeneration m ay cause the nuclear m em -
brane to w rin kle . Large m ultin u clea te d cells m ay be present.
T he cytoplasm has vacuoles and frayed borders. The changes
are m ost p ro m in e n t in the large superficial u m b re lla cells (Fig.
30.11) . S im ila r changes m ay be fo u n d after ra d ia tio n therapy
o r after use o f o the r a lkyla ting drugs, such as m ito m yc in C. The
changes are easily disting uishab le fro m neoplastic changes and
do n o t obscure the presence o f occult neoplasia.71,73,74
Cyclophospham ide
C yclophospham ide is an a lkyla ting agent th a t is m etabolized
in the liv e r and activated in a m ultistep process to the active
m eta b o lite phosp horam id e m ustard. The m etabolites are rap-
id ly excreted in the urine. A side p roduct o f the reaction is acro-
le in , a w eakly cytotoxic com p ound responsible fo r the c om m on
side effect o f hem orrhagic cystitis.75,76 T he presenting signs and
sym ptom s o f to x ic ity includ e u rin a ry frequency, hem aturia, and
sterile cystitis. In a nim a l m odels, extensive u ro th e lia l ulceration
occurs 1 day after in itia tin g therapy. T he ulcerated areas contain
necrotic e p ith e liu m w ith an associated b lo o d y in fla m m a to ry
exudate. The m ucosa in the intact areas is th in ne d . The u ro th e lia l
cells show atypia and karyorrhexis. Surface re-e p ith e lia liza tio n
Fig. 30.11 Thiotepa changes in the urinary bladder. The smear
contains markedly enlarged multinucleated superficial umbrella cells,
with fine cytoplasmic vacuoles, neutrophil phagocytosis, and irregular
frayed cytoplasmic membranes. The background has reactive urothelial
cells, glandular cells, and mixed inflammatory cells. Bladder washing
(Papanicolaou x MP).
starts b y the fo u rth day. By day 8, the ulcerated area is covered
w ith an attenuated regenerating mucosa. A fte r 1 2 -1 3 days, the
n o rm a l m ucosa is intact and the o n ly evidence o f an in s u lt is
hem osid erin-lad en histiocytes w ith in the subm ucosa.77,78 F ifty
percent o f the patients develop hem aturia. Long-term exposure
to cyclophospham ide greater th an 2.7 years and a cum ulative
dose greater th a n 100 g increases the risk o f developing bladder
carcinom a. There is an overall 5% risk o f developing bladder
carcinom a at 10 years and 16% risk at 15 years.79,80
Cytology
The u ro th e lia l changes in hum ans are rad io m im e tic. The nuclei
are enlarged and eccentric, w ith a s lig h tly irreg ular o u tlin e .81
The c hro m a tin is coarsely granular. Occasional large c hrom o -
centers and n uc le oli w ith distorted, irreg ular borders are found .
These changes can m im ic high-grade u ro th e lia l cell carcinom a.
Late changes include nuclear pyknosis w ith c h ro m a tin sm udg-
ing. Occasional m u ltin u clea te d cells are fo un d . The cytoplasm
is also enlarged w ith degenerative vacuoles, frayed borders,
phagocytosis o f foreig n debris,
and n e u tro p h il in filtra tio n
(Fig. 3 0.1 2 ) . The late effects o f cyclophospham ide therapy also
include u ro th e lia l cell carcinom a. The background o fte n con-
tains num erous erythrocytes, cellular debris, and n eu trop h ils.78
The late effects o f cyclophospham ide therapy also include
u ro th e lia l cell carcinom a.82,83
Key features of cyclophosphamide therapy
• E nlarg ed n u c le i;
• Irre g u la r n u c le a r b orders;
• S m udged c h ro m a tin ;
• V a cuolated c ytop lasm ; and
• Frayed c yto p la sm ic borders.
Antineoplastic Biologic Response Modifiers
B iologic response m od ifiers are designed to m im ic , alter, o r aug-
m e n t h ost responses to tu m o rs .84,85 T hese generally result in local
destruction, atrophy, o r increased in fla m m a to ry responses in the
v ic in ity o f the tu m o r. U n lik e chem otherap eutic and rad iothera-
peutic agents, w h ic h cause m ost o f th e ir damage th rou g h D N A
m uta tion s, these do n o t induce the cytologic atypia associated
w ith the ra d io m im e tic agents. T h e ir effects are caused b y altera-
tio n s o r b locking o f physiologic pathways and are less lik e ly to
be confused w ith carcinom a th a n are the effects o f rad iotherap y
o r chem otherapy. Som e o f the m ore c om m o n b iolog ic response
m od ifiers and th e ir m a jo r effects are listed in Table 30.9.
Interferons are classified as alpha, beta, o r gam m a and are
derived fro m leukocytes, fibroblasts, and activated lym phocytes,
respectively. T h e ir effects includ e in d u c tio n o f d iffe re n tia tio n
in cell p o p ulatio ns as w e ll as s tim u la tio n o f an in fla m m a to ry
response. A lp h a -in te rfe ro n has been used in the tre atm e nt o f
lym p hom as, m yelom a, renal cell carcinom a, and h a iry cell
leukem ia. In te rle u kin -2 , a lym p h o kin e , has been used in the
tre atm e nt o f m elanom as and renal cell carcinom a. Its side
effects include an increase in cap illary p e rm e ab ility and flu id
extravasation. T u m o r necrosis factor is a glycop rotein produced
as a response to e nd o toxin and leads to hem orrhagic necrosis o f
tissues. C o lo n y-s tim u la tin g factors have been used to aid in the
recovery o f bone m a rro w after chem otherapy. M o n o c lo n a l a n ti-
b od y therapy has been used to induce an antibod y-dependent
cellular cytoto xic ity against tu m o r cells.86 T his therapy has been
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