Diagnostic Cytology
p leo m o rp hism , coarse c hrom a tin , and p ro m in e n t nucleoli.
M ito sis and apoptosis are n o t u n c o m m o n , ind icating a hig h
tu rn o ve r rate. In contrast to th ym o m a , ly m p h o id cells are rela-
tiv e ly sparse (w ith the exception o f lym p h o e p ith e lio m a -lik e car-
cinom a). Basaloid subtype o f th ym ic carcinom a often shows no
overt cytologic a typ ia62 and m ay som etim es m im ic type A th y -
m om a, even in histo lo g ic samples. O n the o th e r hand, cytologic
d istin c tio n between type B1 o r B2 th y m o m a and the lym p h o -
e p ith e lio m a -like subtype o f th ym ic carcinom a can be d ifficu lt.
Im m u nocytochem ical study (Fig. 26.9A ) shows the charac-
teristic CD5 p o s itiv ity in the cytoplasm o f m any tu m o r cells
in th ym ic carcinom a (in clu d in g squam ous and basaloid sub-
types). CD117 (c-KIT) is also expressed. T his aberrant expression
o f CD 5 (a T-cell m arker) is useful in c o n firm in g th ym ic orig in.
T h is is in contrast to th y m o m a o r n o n th y m ic carcinom as, in
w h ic h the tu m o r cells are u su ally CD5-negative. C D 57 is va ri-
ab ly expressed in th y m o m a b u t n o t in th ym ic carcinom a.63
Practically speaking, the diagnostic d ile m m a often lies in the
d istin c tio n between th ym ic and n o n th y m ic (especially lung)
origins. C lin ico rad iolog ic correlation, as w e ll as im m u n o c y to -
chem ical study fo r CD 5 and o th e r origin-specific m arkers (such
as TTF-1 fo r lun g p rim a ry), are h e lp fu l in th is respect.
Key features of thymic carcinoma
• Low-power cytology: abundant tumor cells, often in co-
hesive sheets and sometimes associated with coagulative
tumor necrosis.
• High-power cytology: tumor cells with notable cellular
pleomorphism; morphologic details vary.
• Cell block sections: cohesive appearance of tumor cell
clusters better appreciated.
• Immunocytochemistry: cytokeratin-positive, CD5-positive,
CD117-positive, and CD57-negative.
• Cytologic differential diagnosis: metastatic carcinomas
(CD5-negative); thymoma with predominance of medullary
component (bland-looking and mitotically inactive spindle
cells, focally CD20-positive and CD57 variably and focally
positive); thymoma with predominance of cortical compo-
nent (bland-looking polygonal tumor cells with abundant
background TdT-positive lymphoid cells, dendritic cytokera-
tin staining pattern, and CD57-positive); thymic large-cell
neuroendocrine carcinoma (neuroendocrine markers dif-
fusely positive, CD5-negative, and TTF-1-negative); semi-
noma (dispersed cytokeratin-negative tumor cells); primary
mediastinal large B-cell lymphoma (B-cell markers positive
and cytokeratin-negative).
Thymic Neuroendocrine Tumors
T h y m ic neuroendocrine tu m o rs are rare and constitute about
2 -5 % o f all th ym ic e p ithelial neoplasm s.47 T he y often occur
in the a nte rio r m ed iastinum o f adults and m ay be associated
w ith Cushing's syndrom e (due to ectopic adrenocorticotrop ic
h o rm o n e
p rod u c tio n)
hyperpigm entation.
These tum ors
are fu rth e r classified in to w ell-d ifferentiated
neuroendocrine carcinom a (typical and atypical carcinoids) and
p o o rly d ifferentiated neuroendocrine carcinom a (large-cell and
sm all-cell neuroendocrine carcinom as). A b o u t 25% patients w ith
th ym ic carcinoid have a positive fa m ily h isto ry o f m u ltip le endo-
crine neoplasia type 1. D is tin c tio n between typical and atypical
carcinoids relies on histolog ic criteria, w h ic h include coagulative
tu m o r necrosis and m ito tic count. A lth o u g h th ym ic carcinoid is
often b la n d -lo o kin g and encapsulated, there is a sig nificant risk
fo r local recurrence, metastasis, and tum or-related death.
T h ym ic neuroend ocrine tu m o rs show cytologic find ing s s im -
ila r to those occurring in o the r n o n th y m ic sites, inc lu d in g th e ir
p u lm o n a ry counterparts. As fo r th ym ic carcinoid, the cytologic
preparations are often hyp ercellular and com posed o f dispersed
o r loo se ly cohesive m o n o to n o u s p o p u la tio n o f tu m o r cells w ith
freq uent "p la sm a c yto id " appearance (Fig. 26.10A ). H ig h-p ow er
e xa m in ation shows sm all to m ed ium -sized tu m o r cells w ith lo w
cytologic grade. T he y contain ro u n d to ovoid , regular u n ifo rm
and eccentric nuclei, fin e ly stippled "sa lt in pepper"-type chro-
m atin , delicate nuclear m em brane, som etim es sm all d istinct
nuc le oli, scanty to m oderate am ounts o f granular e osin o p hilic
cytoplasm , and discrete cell borders (Fig. 26.10B), recap itulat-
ing the hig h-p ow er m o rp h o lo g y seen in histo lo g ic sections
(Fig. 26.10C ).29 In a d d itio n, there is o fte n paranuclear, som e-
tim es inc lu sio n-like, cytoplasm ic accentuation,64 w h ic h corre-
sponds to focal aggregates o f dense-core neurosecretory granules
associated w ith interm ed iate filam ents in th is region und e r elec-
tro n microscopy. Occasional pseudonuclear cytoplasm ic in c lu -
sions, as w e ll as binucleated form s, are noted. O ne interesting
fin d in g in cytologic smears is th e focal "c o m e t-lik e " p h e n o m -
enon, w ith tu m o r cell nuclei dragging the cytoplasm behind.
Elongated tu m o r cells can be seen in sp indle cell carcinoid,65
w h ic h accounts fo r less th an 10% o f a ll th ym ic neuroendocrine
tu m o rs.66 T he d istin c tio n fro m retrosternal m e d u lla ry carcinom a
o f th y ro id can be d iffic u lt w ith o u t im m unocytochem ical study
fo r calcitonin. A lip id -ric h va ria n t o f th ym ic carcinoid, w ith
num erous intracytop lasm ic lip id -c o n ta in in g vacuoles id en tifie d
in cytologic preparations, is also on record.67 A p o p to tic bodies,
ting ib le-b od y macrophages, and necrotic debris seen in fine-
needle aspirates o f atypical carcinoid m ay give rise to a super-
ficial resem blance to m a lig n a n t lym p h o m a . Lym p hog land ular
bodies, however, are n o t seen. C ytolog ic d istin c tio n between
typical and atypical carcinoids m ay n o t be possible, especially if
the necrotic foci are n o t sampled.
Im m unocytochem ical study shows th a t the tu m o r cells d if-
fusely express neuroendocrine m arkers (in clu d in g chrom ogranin,
synaptophysin, and C D 56 [m em branous staining]). C ytokeratin
(e.g. C am 5.2 and A E 1/A E 3) staining is u su ally positive and shows
a paranuclear "d o t-lik e " pattern.64 Som etim es, in vie w o f the s im -
ila r im m unop henotyp e, the d ifferential diagnosis o f metastatic
p u lm o n a ry sm all-cell carcinom a m ay be considered.68 U ltrastruc-
tural exam ination reveals the presence o f dense-core neurosecre-
to ry granules in the cytoplasm . In general, fine-needle aspiration
cytology o f th ym ic carcinoid is often diagnostic and represents an
im p o rta n t to o l in guiding subsequent m anagem ent.69-73
Very rarely, g ranular cell tu m o r m ay occur in the m ed iasti-
n u m and m im ic th ym ic carcinoid on fine-needle asp iration
cytology.74 For g ranular cell tu m o r, fine-needle asp iration yields
dispersed large polyg onal to sp ind le cells w ith e osin o p h ilic gran-
u la r cytoplasm and in d istin c t cell borders. A reliab le diagnosis
can be m ade w ith the help o f im m u n o c yto c h e m istry (S-100 p ro -
te in -p ositive fo r g ranular cell tu m o r) and u ltra struc tura l study
(show ing ab und ant lysosom es, w ith o u t dense-core neurosecre-
to ry granules) applied o n aspirated m aterials. C ytolog ic finding s
o f H u rth le cell neoplasm arising in ectopic th y ro id tissue in the
m ed iastinu m , a no the r m orp h o lo g ic m im ic k e r o f th y m ic carci-
n oid , have been described.34,75 O th e r rare d iffe re n tia l diagnosis
also includes m etastatic fib ro la m e lla r hep atocellular carcinom a
to the m ed iastinu m , w h ic h m ay on fine-needle asp iration yie ld
ab und ant tu m o r cells w ith oncocytic cytoplasm .76
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