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The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.
toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan
(JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in
laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed
in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The stan-
dardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of ma-
terial included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes
spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes
observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted
and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confu-
sion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich
international exchanges of information among toxicologists and pathologists. (DOI: 10.1293/tox.27.1S; J Toxicol Pathol 2014; 27: 1S–107S
Keywords: diagnostic pathology, nomenclature, female reproductive, ovary, uterus, cervix, vagina
Address correspondence to: Darlene Dixon, D.V.M., Ph.D., DAVCP, Fellow, IATP, NIEHS, NTP, Head,
Molecular Pathogenesis, NTP Lab, P.O. Box 12233, MDB3-06/B341, 111 T.W. Alexander Drive, Bldg.101,
South Campus, RTP, North Carolina 27709, USA. e-mail: dixon@niehs.nih.gov
©2014 The Japanese Society of Toxicologic Pathology
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-
Commercial No Derivatives (by-nc-nd) License <http://creativecommons.org/licenses/by-nc-nd/3.0/>.
1S
2S DIXON ET AL.
Pedersen and Peters 1968) but because these classifications are Proestrus (Figures 1 and 2)
quantitative they are less useful for the screening evaluation At lower magnification, late tertiary follicles are the easi-
performed in routine toxicity studies. est component to identify at proestrus.
Primordial and growing follicles through the vesicular stage Follicles: Large tertiary follicles are evident at this stage
are observed in all stages of the estrous cycle and are not useful and are located near the surface of the ovary. Their granu-
for determining the stage of the estrous cycle. Healthy (non- losa cells are cuboidal and/or polygonal. Many of the antral
atretic) late tertiary follicles are generally present only during tertiary follicles may be atretic. Although discrimination of
proestrus and are useful for staging. healthy tertiary follicles from those undergoing early atre-
With the exception of late tertiary follicles at proestrus, sia is sometimes difficult at lower magnification, apoptotic
morphologic changes in the CL are the most useful ovarian granulosa cells are recognized in the atretic follicles. Follow-
morphologic characteristics to help determine the stage of the ing the peak in estrogen, the luteinizing hormone (LH) surge
estrous cycle. In the rodent ovary, the beginning of each cycle occurs and estrogen levels subsequently decline as the late
occurs with ovulation and the formation of a new generation tertiary follicle begins to produce progesterone in prepara-
of CL. CL are classified into new CL resulting from the most tion for ovulation.
recent ovulation, (1-5 days old); recent CL, which are those CL: CL from the last ovulation are large and the staining
resulting from ovulations within several cycles prior to the cur- characteristics start changing from basophilic to eosinophil-
rent cycle (approximately 5-20 days old); and old CL, which ic; by the end of proestrus, the CL are completely eosino-
are older than approximately 4 cycles ago (≥ 21 days old) and philic. Degenerative processes in these CL are characterized
have not yet undergone complete regression. New CL resulting by cytoplasmic vacuolation or apoptosis in the luteal cells.
from the most recent ovulation are further classified based on Occasionally large areas of necrosis and/or mononuclear cell
hematoxylin and eosin (H&E) staining characteristics as baso- infiltrates are present in these CL. Fibrous tissue prolifera-
philic and eosinophilic. Basophilic CL are observed at estrus, tion is noted in the eosinophilic CL from previous cycles.
metestrus and early diestrus. Immediately upon ovulation (es-
trus) basophilic CL are composed of small, ovoid, basophilic Estrus (Figures 3 and 4)
luteal cells with sparse cytoplasm. Initially, basophilic CL have At lower magnification, newly formed basophilic CL are
a dark central area of non-luteinized granulosa cells, though a feature of this stage.
as luteinization proceeds, a central fluid-filled cavity may de- Follicles: There is an absence of healthy (non-atretic) ter-
velop. During metestrus, the basophilic CL become larger and tiary follicles. A number of smaller vesicular follicles start
stain less intensely basophilic. The luteal cells become larger, to grow.
rounder, and slightly vacuolated; the centers become filled with CL: New basophilic CL, formed after the current ovu-
luteal cells although CL with incomplete centers can still be lation, are characteristically observed at this stage. They
found. During diestrus, the basophilic CL reaches its largest are composed of basophilic, small, spindle-shaped luteal
size; the CL is composed of large, polygonal, lightly basophil- cells that closely resemble granulosa cells. The presence of
ic, finely vacuolated luteal cells, usually with completely filled newly forming blood vessels (angiogenesis) makes the new-
centers. There is no luteolysis. At proestrus, the basophilic CL ly formed basophilic CL easily and clearly distinguishable
start to become eosinophilic. In early proestrus, areas of the from the large follicles or atretic follicles, in which, blood
basophilic CL can be seen turning eosinophilic, but basophilic vessels are absent in the granulosa cell layer. Sometimes
areas are still present. As proestrus proceeds, the CL formed the newly formed basophilic CL have central cavities which
from the most recent ovulation become completely eosino- may or may not completely fill in as the cycle progresses.
philic. In late proestrus, luteolysis (characterized by apopto- Eosinophilic CL from the immediately previous cycle (i.e.,
sis of individual cells) and/or vacuolation can be observed in from the immediately preceding proestrus) are still large but
these eosinophilic CL from the most recent ovulation. Thus, degenerative processes including apoptosis and fibrosis are
by late proestrus, completely basophilic CL are generally not more advanced.
observed in the ovary of a normally cycling rodent.
Recent CL (those CL within approximately 1-4 cycles of Metestrus (Figures 5 and 6)
the last or current ovulation) are also eosinophilic. However, At lower magnification, basophilic CL are easily recog-
they have subtle morphologic differences from the eosinophilic nized at metestrus.
CL of current ovulations. Eosinophilic CL from recent cycles Follicles: There are no healthy large late tertiary follicles,
show decreased luteal cell vacuolation and increased fibroblast but many growing follicles of various types are present.
infiltration compared to those from the current ovulations. CL: CL of the current ovulation are characteristically in-
These differences are sometimes difficult to discern. Old CL creased in size compared to those at estrus, but still smaller
(>4 cycles old) are relatively easy to discern. They have a more than those at diestrus. The luteal cells still have basophilic
central position in the ovary, are small and composed of less cytoplasm with large nuclei. Their nucleoli are prominent.
intensely staining eosinophilic luteal cells separated by fibrous The CL sometimes contain fluid-filled central cavities of
tissue. They are evidence of previous ovulation. various sizes though their incidence is decreased compared
to that seen at estrus. CL from the immediately previous cy-
4S DIXON ET AL.
cle demonstrate advanced fibrosis, but their size is still simi- the luminal epithelium become slightly more prominent at
lar to those CL formed during the last ovulation. In rodents, the end of the metestrus phase with transition to the diestrus
CL produce progesterone at metestrus. Progesterone levels phase and a few eosinophils may be present.
rise briefly during this phase but fall again, in the absence of
cervical stimulation, as the CL begin to preferentially pro- Diestrus (Figures 15 and 16)
duce 20alpha-OH-progesterone and the levels of progester- During the diestrus phase, in which the elevated proges-
one decline. terone levels return to baseline, the uterus is small and has
quite inactive glands that are lined with cuboidal to low co-
Diestrus (Figures 7 and 8) lumnar epithelial cells. The lumen of the horns is slit-like
At lower magnification, the CL from the current ovula- and can show a saw-tooth appearance. The stroma is com-
tion are lightly basophilic and have reached maximum size. pact. Mitotic activity is low because of the low estrogen lev-
Tertiary follicles preparing for next ovulation are increased els during this phase and a few eosinophils may be present.
in size.
Follicles: Tertiary follicles are increased in number, but C. Cyclical changes in the vagina and cervix of rodents
are smaller than those observed at proestrus. Proestrus (Figures 17–19)
CL: CL of the current ovulation have attained the maxi- The beginning of proestrus is defined by the formation of
mum size. The luteal cells have foamy, slightly basophilic a layer of flattened, keratohyaline rich epithelial cells called
cytoplasm. There is no evidence of luteolysis in these CL. the stratum granulosum which overlays the basal epithelium
CL from the immediately prior cycle are eosinophilic and (stratum germinativum). During early proestrus, mitotic fig-
vacuolated and fibrous tissue infiltration is advanced. ures are present and the superficial mucoid layer (stratum
mucification) begins to develop giving the vaginal epitheli-
B. Cyclical changes in the uterus of rodents um 3 distinct layers (basal epithelium, stratum granulosum,
Proestrus (Figures 9 and 10) and the superficial mucoid layer). As proestrus progresses, a
During the proestrus phase of the cycle, estradiol from 4th layer begins to form, the stratum corneum, between the
rapidly growing teritiary follicles rises and peaks resulting in stratum granulosum and the mucoid layer. By late proestrus,
significant changes in the rodent uterus. Under the influence the fully keratinized stratum corneum results in an intensely
of estradiol, the luminal and to a lesser extent the glandular eosinophilic band underlying the prominent superficial mu-
epithelium undergoes hypertrophy. The epithelial cells lin- coid layer, which may show signs of desquamation. Only oc-
ing the lumen and glands increase in height from low to more casional granulocytes are observed during this time.
tall columnar cells. Also mitotic activity increases within the
epithelium and mitotic figures can be numerous. The stroma Estrus (Figures 20)
can show a more prominent vasculature and early edema. By early estrus, there is a decrease in the number of mi-
Inflammatory cells start to increase in number and peak at totic figures and the mucoid layer has sloughed, revealing
estrus. The lumen becomes markedly dilated and filled with the now superficial stratum corneum. During estrus there
clear fluid towards the end of this phase. is progressive shedding of the cornified layer with sloughed
cornified cells and debris present within the vaginal lumen.
Estrus (Figures 11 and 12) There is an increase in neutrophil and possibly eosinophil in-
During the estrus phase (beginning with ovulation), the filtrations, but numbers may be variable. During late estrus,
uterus is morphologically characterized by the appearance detachment of the stratum corneum begins.
of apoptotic epithelial cells. This epithelial cell death starts
within the glands but soon also involves the luminal epithe- Metestrus (Figures 21)
lium. Although mitotic figures still can be detected between The beginning of metestrus is marked by the complete
the apoptotic cells, their number decreases rapidly. In the be- dehiscence of the stratum corneum. Residual squames and
ginning of this phase, the uterine lumen is dilated, but in late debris may be present in the lumen and some cornified epi-
estrus the lumen of the uterine horns returns to its normal thelium may persist with continued desquamation through-
shape and volume. The number of inflammatory cells is high out metestrus. There is progressive loss of the stratum gran-
during this phase. Circulating progesterone levels (produced ulosum and the superficial layers of the basal epithelium.
by the follicle) fall during estrus. There is an increase in the number of granulocytes present.
References
Frith and Chandra (1991), Greaves (2012), Maekawa et al.
(1996), Myers and McGavin (2007), National Toxicology
6S DIXON ET AL.
References Comment
Alison et al. (1990), Davis et al. (1999), Greaves (2012), This is a common lesion in both mice and rats. Cysts that
Tamura et al. (2009) are present at the hilus or extend into the ovary at the hilus or
connect to intraovarian structures at the hilus are part of the
Cyst, rete ovarii (N) Ovary (Figures 39 and 40) rete system and should be termed ‘cyst, rete ovarii’. The term
Species ‘paraovarian cyst’ should be used only for those epithelial
Mouse; Rat. cysts present in tissues adjacent to the ovary that do not have
an apparent connection to the ovary to allow determination
Synonym(s) of the origin.
Diagnostic Features Cyst, NOS (N) Ovary; Uterus; Uterine Cervix; Vagina
• Paraovarian cysts are located in the mesovarium or me- Species
sosalpinx with no apparent connection to hilar or intra- Mouse; Rat.
ovarian structures.
• The cysts are lined by cuboidal or columnar epithelial Pathogenesis/cell of origin
cells which become flattened if the structure is dilated. Mesonephric tubules/ducts, endometrial epithelium,
• May have smooth muscle tissue within the cyst wall. proximal cervical epithelium, and/or cutaneous adnexal
• Epithelium may be ciliated. structures.
• Particularly in mice, frequently compress and/or distort
the ovarian architecture. Diagnostic Features
• Dilated, fluid- or keratin-filled structure.
Differential Diagnoses • Epithelial lining often obvious with variable amounts of
Cyst, rete ovarii: compressive atrophy.
• Present adjacent to or within the ovary, often at the hilus. • May have a smooth muscle wall (mesonephric duct rem-
• Lined by flattened, cuboidal or columnar epithelium; of- nant).
ten have apical nuclei. • No apparent connection to extra-ovarian or ovarian hilar
• Epithelium may be ciliated. structures, or to ovarian surface epithelium.
• May be associated with smooth muscle. • May have squamous metaplasia and/or keratinization.
• Connection to paraovarian structures in the mesovarium
may be seen. Differential Diagnoses
• Usually distorts the ovarian architecture. Cystadenoma:
Cyst, bursal: • Cystadenomas often contain multiple cystic spaces, are
• Envelops ovary but not present within ovary proper. more densely cellular, and contain mitotic figures.
• Lined by simple squamous epithelium. Ovarian cysts:
Cyst, epithelial: • The origin of the cyst is apparent (follicle, corpus lute-
• Present within the ovary. um, rete ovarii, surface epithelium). See descriptions of
• Lined by flattened cuboidal to low columnar epithelium. individual types of ovarian cysts.
• Connection to surface epithelium is apparent. Paraovarian cysts:
Follicle, luteinized (+/- modifier cystic): • Paraovarian cysts are located in the mesovarium or me-
• Wall comprised of granulosa cells with irregular clumps sosalpinx with no apparent connection to hilar or intra-
or groups of large, round to polygonal luteinized cells. ovarian structures.
• Degenerate oocyte can sometimes be observed within • The cysts are lined by cuboidal or columnar epithelial
the follicle. cells which become flattened if the structure is dilated.
• Luteinized follicle is not larger than a normal late ter- • May have smooth muscle tissue within the cyst wall.
tiary follicle. • Epithelium may be ciliated.
• The cystic luteinized follicle is larger than a normal late • Particularly in mice, frequently distort the ovarian archi-
tertiary follicle and has cystic center. tecture.
Cyst, NOS:
• If the origin/type of ovarian cyst is not apparent, the Comment
term Cyst, NOS may be a more appropriate diagnosis. Cystic structures may be encountered in multiple sites
in the female reproductive tract. Depending on the location,
Comment size, and chronicity of the cyst it may be difficult to accu-
This is a common lesion in both mice and rats. Cysts that rately identify the origin; in these cases, the term Cyst, NOS
are present at the hilus or extend into the ovary at the hilus or is recommended.
connect to intraovarian structures at the hilus are part of the
rete system and should be termed ‘cyst, rete ovarii’. The term References
‘paraovarian cyst’ should be used only for those epithelial Leininger and Jokinen (1990)
cysts present in tissues adjacent to the ovary that do not have
an apparent connection to the ovary to allow determination Follicle, luteinized (N) Ovary (Figures 43 and 44)
of the origin. Species
Mouse; Rat.
References
Davis et al. (1999), Greaves (2012), Greaves et al. (1992), Synonym(s)
Long (2002), Montgomery and Alison (1987), Genadry et Luteinized, nonovulatory follicle; Luteinized unruptured
al. (1977), Lee et al. (2011), Clow et al. (2002), Wenzel and follicle.
Odend’hal (1985)
Lesions of the Female Reproductive System 11S
Comment Modifier
Increased or decreased vacuolation may be associated Increased; Decreased.
with alterations of steroid synthesis or phospholipidosis. Cat-
ionic amphiphilic compounds can induce phospholipidosis. Pathogenesis/cell of origin
On ultrastructural examination, the vacuoles contain abnor- Vacuolation of interstitial cells can occur due to inhibi-
mal lamellated inclusions. tion of steroid synthesis leading to lipid accumulation within
the cells. Other steroid producing cells, such as the adrenal
References gland, may also be affected.
Lúllmann-Rauch and Reil (1974)
Diagnostic Features
Vacuolation, granulosa cell (N) Ovary (Figure 46) • Interstitial cells have a normal fine vacuolation related to
Species steroid synthesis. Increased and decreased vacuolation
Mouse; Rat. should be more or less than that normally present.
• Cells with increased vacuolation may appear larger than
Synonym(s) normal.
Fatty change.
Differential Diagnoses
Modifier Vacuolation, theca cell:
Increased; Decreased. • Fine vacuolation related to steroid synthesis. Increased
vacuolation should be more than that normally present.
Pathogenesis/cell of origin • Cells with increased vacuolation may appear larger than
Vacuolation of granulosa cells can occur due to inhibi- normal.
tion of steroid synthesis leading to lipid accumulation within Hypertrophy, interstitial cell:
the cells. Other steroid producing cells, such as the adrenal • Interstitial cells, arranged in cords or nests, are enlarged
gland, may also be affected. and polyhedral with ample clear to pale-eosinophilic,
sometimes vacuolated cytoplasm.
Diagnostic Features • Decreased nuclear: cytoplasmic ratio.
• Granulosa cells have a normal fine vacuolation related to
steroid synthesis. Increased and decreased vacuolation Comment
should be more or less, respectively, than that normally Increased or decreased vacuolation may be associated
present. with alterations of steroid synthesis or phospholipidosis. Cat-
• Cells with increased vacuolation may appear larger than ionic amphiphilic compounds can induce phospholipidosis.
normal. On ultrastructural examination, the vacuoles contain abnor-
mal lamellated inclusions.
Differential Diagnoses
None. References
Greaves (2012), Lúllmann-Rauch and Reil (1974), Long et
Comment al. (2001)
Increased or decreased vacuolation may be associated
with alterations of steroid synthesis or phospholipidosis. Cat- Vacuolation, corpora lutea (N) Ovary (Figures 48 and 49)
ionic amphiphilic compounds can induce phospholipidosis. Species
On ultrastructural examination, the vacuoles contain abnor- Mouse; Rat.
mal lamellated inclusions.
Pathogenesis/cell of origin
References Vacuolation of luteal cells can occur due to inhibition of
Lúllmann-Rauch and Reil (1974) steroid synthesis leading to lipid accumulation within the
cells. Luteal cells can also be affected in cases of phospho-
Vacuolation, interstitial cell (N) Ovary (Figure 47) lipidosis.
Species
Mouse; Rat. Diagnostic Features
• Microvesicular or macrovesicular cytoplasmic vacuola-
tion of luteal cells in CL other than the CL of the most
Lesions of the Female Reproductive System 13S
recent ovulation at diestrus/proestrus. Infiltrate, inflammatory cell (N) Ovary (Figure 52)
• Luteal cells may appear enlarged. Species
• Lack of significant luteolysis in the affected CL. Mouse; Rat.
• Overall size of the CL may be increased.
Modifier
Differential Diagnoses Eosinophilic; Histiocytic; Neutrophilic; Lymphocytic;
Hypertrophy, corpora lutea Mononuclear; Mixed.
Normal vacuolation:
• Microvesicular vacuolation is normal in CL of the most Pathogenesis/cell of origin
recent ovulation during diestrus and early proestrus; Movement of inflammatory cells from the blood, bone
macrovesicular vacuolation with luteolysis is normal in marrow or hemo-lymphatic organs into tissue as a result of
the CL of the most recent ovulation during mid to late increased secretion of interleukins and/or specific cell che-
proestrus. moattractants.
Comment References
Mineralization of oocytes and interstitial cells of the ova- Alison et al. (1990), Davis et al. (1999), Montgomery and
ry may become more prominent with advanced age. Alison (1987)
References
Greaves (2012)
14S DIXON ET AL.
Inflammation, ovary (N) Ovary (Figure 53) rophages, lymphocytes, plasma cells, mixed), but other
Species inflammatory changes (congestion, edema, hemorrhage,
Mouse; Rat. exudate, necrosis, fibrosis, etc.) are absent or of limited
severity.
Synonym(s)
Oophoritis. Comment
Rare in rats and mice. May be seen with systemic infec-
Modifier tions caused by Mycoplasma pulmonis, Streptococcus pneu-
Neutrophilic; Lymphocytic; Mononuclear; Mixed. Other moniae, Pasteurella pneumotropica, Pseudomonas aerugi-
modifiers include suppurative, granulomatous. nosa and Corynebacterium kutscheri.
Comment Immaturity:
The morphological patterns of age-related ovarian atro- • Key histomorphologic features in ovarian development
phy are varied and influenced by many factors. The vagi- as described during PND 22-32 can be used to distin-
nal or uterine morphology is often influenced by the ovarian guish the normal developing ovary, such as numerous
changes. If the ovary has prominent atretic or cystic follicles primordial and primary follicles that can be readily visu-
and lacks corpora lutea, the vagina may show cornification alized at PND 20 to PND 25 in the immature rat ovary,
indicating an increase in the 17 beta-estradiol/progesterone that are typically found in dense clusters scattered along
ratio (persistent estrus). Alternatively, animals with promi- the cortical periphery at the ovarian hilus, which are less
nent CL sometimes have vaginal mucification, indicating commonly observed in the mature or senescent ovary.
a decrease in the 17 beta-estradiol/progesterone ratio (i.e.,
persistent diestrus). Age-related atrophy of the ovary is also Comment
heavily influenced by multiple factors including species, Destruction of oocytes in primordial follicles by radiation
strain and housing conditions. Age-related ovarian atrophy or ovotoxic agents such as 4-vinylcyclohexene diepoxide or
is often not diagnosed in carcinogenicity studies and its inci- maternal treatment with busulfan results in ovarian atrophy
dence in aged animals is likely underappreciated. within a short period of time. Lesions in the pituitary gland
causing a decrease in FSH release (i.e., space occupying neo-
References plasia) also can cause ovarian atrophy. The immature ovary
Alison et al. (1990), Davis et al. (1999), Maekawa et al. may resemble atrophy.
(1996), Peluso and Gordon (1992).
References
Atrophy (N) Ovary (Figure 55) Alison et al. (1990), Davis et al. (1999), Hoyer (2004), Picut
Species et al. (2014), Yoshida et al. (2005)
Mouse; Rat.
Atrophy, corpora lutea (N) Ovary (Figure 56)
Pathogenesis/cell of origin Species
Cessation of the normal estrous cycle caused by toxicant- Mouse; Rat.
induced reduction of oocytes or sex cord/stromal cells, or
alteration of hypothalamic-pituitary-ovarian axis that ulti- Synonym(s)
mately results in decreased gonadotropin-releasing hormone Small corpora lutea.
(GnRH), luteinizing hormone (LH) and/or follicle stimulat-
ing hormone (FSH). Diagnostic Features
• Decreased size of new or recently formed corpora lutea.
Diagnostic Features
• Small ovary. Differential Diagnoses
• Decreased number or absence of oocytes, follicles and Abnormal estrous cycling/anovulation:
corpora lutea. • The ovary has old corpora lutea (CL) but lacks new or re-
• No patterns indicating normal estrous cycling. cently formed CL. The CL are smaller than similar types
• The morphologic appearance of the ovary depends on of corpora lutea in normal cycling rats.
the length of time the toxicant has been administered
and the target of the toxic agent; the earliest change is Comment
often a decrease in healthy antral follicles, but corpora The sizes of the CL are smaller but the number of CL is
lutea may be normal or only slightly reduced in number. normal if the estrous cycle is normal. This change might be
In later stages, no new corpora lutea are observed, but induced by chemicals that inhibit angiogenesis in CL.
early follicular development may still be seen if primor-
dial follicles are present. References
• Interstitial cells may be small and spindle-shaped or en- Sato et al. (2009a)
larged and vacuolated.
Increased number, corpora lutea (H) Ovary
Differential Diagnoses (Figures 57 and 58)
Age-related atrophy: Species
• Difficult to distinguish morphologically from a test arti- Mouse; Rat.
cle-related change, particularly at the end of longer term
studies (>90 days); short-term studies are often needed Synonym(s)
to determine if there is a test article-related effect. Care- Retained corpora lutea.
ful comparison with controls is essential.
16S DIXON ET AL.
Comment References
A decrease in large follicles as a result of increased fol- Alison et al. (1990)
licular atresia is observed with a number of cytotoxic drugs,
for example cisplatin. The sensitivity of primordial, primary, Atretic follicles, increased number (N) Ovary (Figure 63)
secondary vesicular or tertiary follicles to this toxicity can Species
vary according to the particular xenobiotic. Degeneration of Mouse; Rat.
oogonia in utero or in the immediate postnatal period may
cause significant depletion of primordial follicles. CYP1B1 Synonym(s)
or PCNA immunostaining can be used to highlight oocytes Follicular degeneration.
within primordial follicles in rats for the purposes of evalu-
ation and/or counting. The Society of Toxicologic Pathology Modifier
recommends that follicle counting can be used to further Primordial; Primary; Secondary; Vesicular; Tertiary;
characterize suspected or demonstrated ovarian toxicants Atretic.
and therefore should be considered a second tier technique in
rodent toxicology studies. If the loss of primordial follicles is Diagnostic Features
complete or nearly complete, ovarian atrophy (characterized • Any or all of the following features may be present and
by an absence of follicles in all phases of maturation) as well indicate follicular atresia:
as secondary atrophy of the uterus and vagina and changes • Pyknotic granulosa and/or theca cell nuclei.
in mammary tissue will be observed in the qualitative as- • Apoptotic bodies at the periphery of the antrum.
sessment. • Cell debris in the antrum.
• Detachment of granulosa cells from follicular base-
References ment membrane.
Bolon et al. (1997), Hoyer (2004), Ito et al. (2009), Kao et • In addition, the following features may be present in
al. (1999), Kodama et al. (2009), Nozaki et al. (2009), Re- atretic follicles:
gan et al. (2005), Sakurada et al. (2009) • Reduced thickness of the granulosa cell layer.
• Macrophages present in the antrum in late stage.
Degeneration, corpora lutea (N) Ovary (Figures 61 and 62) • Hypertrophy of the theca cell layer.
Species • Dissolution of the corona radiata.
Mouse; Rat. • Degeneration of the ovum.
• Careful comparison to controls is essential for diagnosis.
Pathogenesis/cell of origin • The type(s) of atretic follicles (primordial, primary, sec-
Interruption of circulation such as thrombus formation or ondary, vesicular, tertiary) that are increased should be
disturbance of normal angiogenesis. specified if possible.
amalgam of tissues derived from all three germ layers Diagnostic Features
(endoderm, mesoderm, ectoderm). • Interstitial cells, arranged in cords or nests, are enlarged
Metastases and polyhedral with ample clear to pale-eosinophilic,
sometimes vacuolated cytoplasm.
Comment • Decreased nuclear: cytoplasmic ratio.
Ectopic tissue within the ovary is rarely reported in rat
and mouse. In humans, rare congenital lesions consistent Differential Diagnoses
with ectopic tissue in the ovary include splenic-ovarian fu- Hyperplasia, interstitial cell:
sion (ovarian splenosis), adrenal cortical rests, and uterus- • Hyperplastic cells are increased in proportion to other
like ovarian masses. ovarian structures.
Vacuolation, interstitial cell:
References • Vacuolated cells may appear to be enlarged due to ac-
Clement (2002) cumulation of cytoplasmic vacuoles.
• May be difficult to discern from true hypertrophy.
Immaturity (N) Ovary (Figure 72)
Species Comment
Mouse; Rat. Interstitial cell hypertrophy is a common change ob-
served in ovarian aging and atrophy, and often occurs in
Pathogenesis/cell of origin combination with interstitial cell hyperplasia. Hypertrophy
Age related development of ovary. in non-atrophied ovaries of adult rodents has been report-
ed in association with the administration of gonadotropins
Diagnostic Features as well as some organophosphate and thiocarbamate com-
• Morphologic features of ovarian development prior to pounds. Interstitial cells are steroidogenically active and, in
the onset of estrous cycling and/or ovulation.. some cases, hypertrophied cells contain oil-red-O-positive-
staining neutral lipid.
Comment
The developing ovary is important in reproductive toxic- References
ity studies. There are key histomorphologic features in ovar- Alison et al. (1990), Davis et al. (1999), Yuan and Foley
ian development as described during PND 22-32 that can be (2002)
used to distinguish the normal developing ovary, such as nu-
merous primordial and primary follicles that can be readily Hypertrophy, corpora lutea (N) Ovary (Figures 75 and 76)
visualized at PND 20 to PND 25 in the immature rat ovary, Species
that are typically found in dense clusters scattered along the Mouse; Rat.
cortical periphery at the ovarian hilus. Clusters of primordial
and primary follicles are less commonly observed in the ma- Synonym(s)
ture ovary. Histologically, the presence of one or more cor- Enlarged corpora lutea; Activated corpora lutea; Pseudo-
pora lutea would be consistent with a mature ovary. Imma- pregnancy.
turity of the ovary relative to animal age may occasionally
be encountered secondary to test article administration as Pathogenesis/cell of origin
demonstrated in immature mice administered chlorproma- Increased activity of steroidogenesis in corpora lutea.
zine or perphenazine. Increased prolactin secretion with preservation of func-
tional corpora lutea.
References
Jarrett (1963), Peluso (1992), Picut et al. (2014). Diagnostic Features
• Large corpora lutea compared with the CL of the most
Hypertrophy, interstitial cell (N) Ovary (Figures 73 and recent diestrus.
74) • Enlarged luteal cells with lightly basophilic or eosino-
Species philic cytoplasm.
Mouse; Rat. • Few degenerative luteal cells present in affected CL.
• Not all CL are affected.
Pathogenesis/cell of origin • May be accompanied by changes in other reproductive
May occur as a physiological response to increases in organs such as mammary gland lobuloalveolar hyper-
luteinizing hormone secretion or in response to xenobiotic plasia and lactogenic secretion due to the increased pro-
administration. lactin, and mucification of the vagina from increased
progesterone.
Lesions of the Female Reproductive System 21S
Comment Comment
Common lesion in some mouse strains; uncommon in Common lesion in some mouse strains; uncommon in
rats. Differentiating cystadenoma from adenoma of the rete rats. Difficult to distinguish from mesothelioma, malignant.
ovarii is difficult and arbitrary if evidence of intratubular
origin isn’t observed. References
Alison and Morgan (1987a), Alison and Morgan (1987b),
References Davis et al. (1999), Dixon et al. (1999), Greaves (2012),
Alison and Morgan (1987a), Alison et al. (1987b), Alison et Gregson et al. (1984)
al. (1990), Gregson et al. (1984), Lewis (1987), Long (2002)
Adenoma, tubulostromal (B) Ovary (Figure 93)
Cystadenocarcinoma (M) Ovary (Figures 91 and 92) Species
Species Mouse; Rat.
Mouse; Rat.
Synonym(s)
Pathogenesis/cell of origin Tubular adenoma.
Surface epithelium of the ovary.
Pathogenesis/cell of origin
Diagnostic Features Surface epithelium of the ovary.
• Solid or cystic mass lined by cuboidal or low columnar
pleomorphic epithelium that may be ciliated. Diagnostic Features
• Mitotic figures are frequent. • Nodular structure which shows compression or replace-
• Folds or papillary projections may be present. ment of tissue.
• Stromal compartment is delicate and not an inherent part • Delicate tubules lined by cuboidal epithelium that re-
of the tumor semble or are continuous with surface epithelium of the
• Infiltration of adjacent tissue is present. ovary.
• Optional modifiers are papillary, cystic, serous and mu- • Tubules are separated by packets of cells of probable sex
cinous; however these are not generally used in toxicol- cord stromal origin, which may show varying degrees of
ogy studies. luteinization.
• Sertoliform tubules and/or glomerular-like structures
Differential Diagnoses may be present but do not predominate.
Carcinoma, yolk sac: • Ratio of tubular to non-tubular components, degree of
• Visceral and parietal patterns present. tubular dilation and amount of vacuolation/luteinization
• Contains PAS-positive, eosinophilic matrix. highly variable, but tubular structures with cuboidal epi-
Cystadenoma: thelium predominate.
• Cellular atypia is minimal or absent. • Diameter of proliferative lesion is larger than that of a
• Mitotic figures are infrequent. corpus luteum.
• Lacks invasive growth pattern. • May have areas with cystic dilation of the tubular struc-
Carcinoma, tubulostromal: tures.
• Frequently has a stromal component containing variably • Slight cellular pleomorphism/atypia may be seen.
luteinized cells. • Some extension into the ovarian bursa, especially near
Choriocarcinoma: the hilus, may be present.
• Contains both visceral and parietal patterns.
• Hematocysts, hemorrhage and necrosis are frequent. Differential Diagnoses
Mesothelioma, malignant: Hyperplasia, tubulostromal:
• Extra-ovarian location; often in ovarian bursa. • No distinct compression or displacement of adjacent tis-
• May be present on peritoneal surface of other tissues. sue.
• Stroma may be prominent and have hyaline appearance. • Size is smaller than or equal to a corpus luteum.
• Cells may have a ‘hobnail’ appearance. • Lack of cellular atypia.
Lesions of the Female Reproductive System 27S
Tumor, Sertoli cell, benign: highly variable, but tubular structures predominate.
• Sertoli cells and tubules predominate. • High degree of pleomorphism and atypia.
• Cells can vary from tall columnar with basal nuclei and • Diameter of proliferative lesion is larger than that of a
vertically oriented cytoplasm lining well-differentiated corpus luteum.
tubules to nests of vacuolated cells without basal nuclear • Mitotic figures may be numerous.
orientation (most frequently observed in Sprague-Daw- • Infiltration of adjacent tissues beyond the ovarian bursa
ley rats). is present.
• Fibrovascular stroma present. • Metastases may be present.
• No evidence of connection to ovarian surface epithe-
lium. Differential Diagnoses
Tumor, sex cord stromal, benign (Tumor, granulosa cell, Adenoma, tubulostromal:
benign, Thecoma, benign, Luteoma, benign, or Tumor, sex • Slight or no pleomorphism/atypia.
cord stromal, mixed, benign): • Invasion, if present, limited to ovarian bursa.
• Sex cord-stromal cells predominate (differentiation be- Cystadenocarcinoma:
tween luteoma, thecoma, granulosa cell, or mixed tumor • Absence of interstitial cell component.
is made upon the predominant cell type in the tumor). • Neoplastic epithelial cells generally taller than those in
• No evidence of connection to ovarian surface epithe- tubulostromal tumors.
lium. • Presence of cystic spaces and papillary structures.
Carcinoma, tubulostromal:
• Cellular atypia present. Comment
• Increased mitotic figures are observed. Rare tumor in rats and mice.
• Local invasion beyond the ovarian bursa may be present.
• Metastases may be observed. References
Cystadenoma / Cystadenocarcinoma: Alison and Morgan (1987a), Alison et al. (1987b), Alison et
• Absence of interstitial cell component. al. (1990), Davis et al. (1999), Dixon et al. (1999), Greaves
• Neoplastic epithelial cells generally taller than in tubulo- (2012), Gregson et al. (1984), Lewis (1987), Maekawa
stromal tumors. (1990), Maekawa et al. (1996), Morgan and Alison (1987)
• Frequently forms cystic spaces and/or papillary struc-
tures. Carcinoma, yolk sac (M) Ovary; Uterus
(Figures 95 and 96)
Comment Species
Alcian blue stain highlights acid mucopolysaccharides Mouse; Rat.
sometimes present in tubular epithelium. Common tumors
in some strains of mice; rare in rats. Synonym(s)
Tumor, endodermal sinus, malignant; Tumor, yolk sac,
References malignant.
Alison et al. (1990), Davis et al. (1999), Dixon et al. (1999),
Greaves (2012), Gregson et al. (1984), Lewis (1987), Pathogenesis/cell of origin
Maekawa (1990), Morgan and Alison (1987) Probable variant of germ cell tumor
• Do not contain PAS-positive droplets. Choriocarcinoma (M) Ovary; Uterus (Figures 97 and 98)
• May form papillary pattern composed of a central capil- Species
lary embedded in mesenchymal tissue and surrounded Mouse; Rat.
by visceral endoderm.
• Large cells with weakly staining cytoplasm and large Synonym(s)
nuclei, or giant cells surrounding blood-filled spaces Chorioepithelioma, malignant.
may be present.
• Metastases often composed of both parietal and visceral Pathogenesis/cell of origin
components; lymph nodes, kidneys, liver and spleen Trophoblasts.
commonly involved.
Diagnostic Features
Differential Diagnoses • Composed of 2 cell types: small, round amphophilic to
Cystadenocarcinoma: basophilic cells similar to placental cytotrophoblasts,
• Composed of pleomorphic often cuboidal epithelium. and giant cells with single large nuclei (trophoblastic
• Epithelium may be ciliated. giant cells) or multiple pleomorphic nuclei (syncytiotro-
• Lack of PAS-positive matrix. phoblasts) and prominent nucleoli.
• Lack of intracytoplasmic PAS-positive droplets/gran- • Erythrophagocytosis and/or intracellular PAS-positive
ules. material sometimes present in giant or syncytial cells.
Adenocarcinoma, endometrial (uterus, primary site; ovary, • Highly infiltrative growth by both types of cells.
invasive from uterus): • Hemorrhage and necrosis often present.
• Cells can form glandular structures.
• Lack of PAS-positive matrix. Differential Diagnoses
• Lack of intracytoplasmic PAS-positive droplets/gran- Carcinoma, yolk sac:
ules. • Contains PAS-positive eosinophilic matrix.
Choriocarcinoma: • Visceral and parietal patterns present.
• Areas of necrosis and hemorrhage are frequent. Cystadenoma:
• Lack of PAS-positive matrix. • Cysts and papillary structures often present.
• Lack of intracytoplasmic PAS-positive droplets/gran- • Composed of pleomorphic often cuboidal epithelium.
ules and • Epithelium may be ciliated.
• Composed of 2 cell types- small basophilic cells (pla- • Lack of intracytoplasmic PAS-positive droplets/gran-
cental cytotrophoblasts) and large giant cells (syncytio- ules.
trophoblasts). Carcinoma, embryonal:
Carcinoma, embryonal: • Composed of poorly differentiated fusiform cells with
• Differentiation of yolk sac carcinoma from embryonal large nuclei.
carcinoma is sometimes difficult. • May have areas of yolk sac carcinoma and/or areas of
• Embryonal carcinoma composed of fusiform, poorly well differentiated tissues from 1 or 2 but not all 3 germ
differentiated cells with large nuclei and prominent nu- cell layers.
cleoli. Hemangiosarcoma:
• May have areas of yolk sac carcinoma and/or areas of • Composed of 1 cell type.
well-differentiated tissues from 1 or 2 but not all 3 germ • Tumor forms true vascular spaces lined by malignant
cell layers. endothelial cells.
Comment Comment
Rare tumor in rats and mice. Spontaneous yolk sac carci- Rare tumor in mice and rats. Choriocarcinoma is usually
nomas may be more commonly seen in BDII/Han rats. Yolk associated with pregnancy or induced by displacement of the
sac carcinoma with trophoblastic differentiation develops visceral yolk sac after fetectomy.
spontaneously after pregnancy. Tumor stains positive for
laminin by immunohistochemistry. References
Alison et al. (1987a), Alison and Morgan (1987a), Alison et
References al. (1987b), Alison et al. (1990), Davis et al. (1999), Dixon
Alison et al. (1987b), Alison et al. (1990), Davis et al. et al. (1999), Leininger and Jokinen (1990), Lewis (1987),
(1999), Dixon et al. (1999), Greaves (2012), Leininger and Maekawa (1990), Maekawa et al. (1996), Sobis (1987a) ,
Jokinen (1990), Lewis (1987), Maekawa (1990), Maekawa Yoshida et al. (1997)
et al. (1996), Majeed et al. (1986), Mitsuhashi et al. (1993),
Sobis (1987)
Lesions of the Female Reproductive System 29S
• Occasionally granulosa cell tumors show areas or are • Fibrous capsule usually present.
partially composed of fusiform theca-like cells. • Characterized by seminiferous-like tubules separated
• Mitotic figures may be numerous. by fibrovascular stroma and lined by cells with basally
• Focal areas of necrosis and hemorrhage are frequently located nuclei and abundant faintly eosinophilic, vacu-
present. olated cytoplasm extending into the lumen.
• Local invasion is present. • Frequently have areas with nests of vacuolated cells/Ser-
• Tumor may show distant metastases to kidneys, lungs toli cells without obvious tubular structures.
and lymph nodes. • A variation of the Sertoli cell tumor is composed of ir-
regular tubules lined by vacuolated cells without basal
Differential Diagnoses nuclei (see comment).
Tumor, granulosa cell, benign: • If differentiation between focal hyperplasia and benign
• No significant atypia. Sertoli cell tumor cannot be made on the basis of criteria
• No invasion or infiltrative growth pattern. listed above, a proliferative lesion with a diameter larger
• Minimal areas of necrosis or hemorrhage may occasion- than the size of a corpus luteum is interpreted to be a
ally be present, but only in very large tumors. tumor.
• Occasional mitotic figures may be present.
• No metastases. Differential Diagnoses
Tumor, Sertoli cell, malignant: Hyperplasia, Sertoli cell:
• Predominant cell type (>70%) is Sertoli cell. • Diameter of lesion is smaller than or equal to the size of
• Composed of tubular structures and/or areas with nests a corpus luteum and
of vacuolated cells without obvious tubular structures. • Minimal or no compression.
• Metastases to peritoneal cavity may be present. Tumor, Sertoli cell, malignant:
Thecoma, malignant: • Cellular pleomorphism is present.
• Composed of >70% theca cells. • Areas of hemorrhage and necrosis are present.
• Infiltrative growth pattern or disruption of ovarian cap-
Comment sule is present.
The distinction between benign and malignant granu- • Metastases are present.
losa cell tumor is based on the degree of atypia, infiltrative Tumor, granulosa cell, benign:
growth pattern, presence of metastasis, and areas of necrosis • Cells comprising tumor are predominantly granulosa
and hemorrhage indicative of a high growth rate. cells (>70%), with coarsely stippled chromatin, variable
luteinization and lack of tubular growth pattern.
References • Cells have stippled chromatin.
Alison and Morgan (1987a), Alison and Morgan (1987b), Thecoma, benign:
Alison et al. (1987b), Alison et al. (1990), Gregson et al. • Cells comprising tumor are predominantly theca cells.
(1984), Lewis (1987), Maekawa and Hayashi (1987)
Comment
Tumor, Sertoli cell, benign (B) Ovary (Figures 110 and 111) In rats these tumors are lobulated, solid, white-yellow
Species masses with occasional cysts. This category includes ser-
Mouse; Rat. toliform tubular adenomas which have been previously
described as occurring primarily in Sprague-Dawley rats.
Synonym(s) These tumors are composed of irregular tubules of pale vac-
Tumor, gonadal stromal, benign; Tumor, sex cord stro- uolated cells with indistinct cell boundaries which may give
mal, benign; Tumor, sex cord stromal, benign, Sertoli type; a syncytial appearance. These cells often have intracytoplas-
Tumor, sustentacular, benign; Sertoliform tubular adenoma. mic hyaline-like PAS-positive inclusions. This variant dif-
fers from the other Sertoli cell type tumors in that the tubular
Pathogenesis/cell of origin cells lack basal nuclei and vertically oriented cytoplasm.
Sex cord/stromal cells.
References
Diagnostic Features Alison et al. (1987b), Alison et al. (1990), Gregson et al.
• Tumor composed predominantly (>70%) Sertoli cells, (1984), Stoica et al. (1987)
although other types of sex cord/stromal cells may be
present. Tumor, Sertoli cell, malignant (M) Ovary
• Sertoli cell tumors resemble their testicular counterpart (Figures 112 and 113)
histologically. Species
• Often arise in the hilus. Mouse; Rat.
• Compression is present.
32S DIXON ET AL.
Tumor, sex cord stromal, mixed, benign (B) Ovary Tumor, sex cord stromal, mixed, malignant (M) Ovary
(Figures 114 and 115) Species
Species Mouse; Rat.
Mouse; Rat.
Synonym(s)
Pathogenesis/cell of origin Gonadal stromal tumor, malignant; Granulosa-thecal cell
Sex cord/stromal cells. tumor, malignant; Mixed tumor, malignant.
• Discrete, well-demarcated focal lesions, which are big- • Collagen is present and is arranged around individual
ger than one large corpus luteum. cells rather than around bundles of cells.
• Included in this category are also extremely large dif- • Cellular pleomorphism often present and may include
fuse mixed-type lesions, which encompass the whole giant cells and multinucleated cells.
ovary and are in size/diameter markedly larger than a • Mitotic figures may be numerous.
normal ovary (old age type sex cord stromal hyperpla- Hyperplasia, sex cord stromal, mixed:
sia). • Composed of a mixture of sex cord stromal cells (theca,
• Necrosis, high mitotic rate and invasion. luteal, granulosa, Sertoli and/or stromal) in which no
one cell type predominates (present in >70% of lesion).
Differential Diagnoses • Focal lesion smaller in size than a large corpus luteum.
Tumor, granulosa cell, malignant: • Diffuse lesion replaces much of ovarian tissue-rat.
• Predominant cell type (>70%) is the granulosa cell. • Minimal or no compression.
Tumor, Sertoli cell, malignant: Tumor, granulosa cell, benign
• Predominant cell type (>70%) is the sertoli cell. Tumor, Sertoli cell, benign
Thecoma, malignant: Luteoma, benign:
• Predominant cell type (>70%) is fusiform theca cells. • Differentiation between thecomas and the other sex cord
stromal tumors is made on the predominant cell type
Comment present. In thecoma the major cell type is spindle-shaped
This is a rare tumor in rats and a very rare tumor in mice. theca cell.
Thecoma, malignant:
References • Cellular pleomorphism/atypia is present.
Alison and Morgan (1987a), Alison et al. (1990) • Prominent mitotic figures are present.
• Areas of necrosis may be present.
Thecoma, benign (B) Ovary (Figure 116) • Invasion of periovarian tissue is present.
Species • Metastases are present.
Mouse; Rat.
Comment
Synonym(s) Reticulin stain may help determine the arrangement of
Tumor, sex cord stromal, benign, thecoma type; Tumor, collagen to differentiate between thecoma and fibroma.
theca cell, benign.
References
Pathogenesis/cell of origin Alison and Morgan (1987a), Alison et al. (1990), Dixon et
Sex cord/stromal cells. al. (1999)
• Mitotic figures are often seen within this hypertrophied Cyst, NOS (N) Uterus; Uterine Cervix; Vagina; Ovary
epithelium. (See Ovary Section)
Comment References
Gland necks can become obstructed causing dilation of Faccini et al. (1990), Greaves (2012), Heywood and Wad-
the more basal parts of the glands. This dilation in most cas- sworth (1981), Leininger and Jokinen (1990), Maekawa
es is a purely mechanical change, not to be confused with and Maita (1996)
true cystic endometrial hyperplasia, which is a proliferative
lesion. The change is found in 6% of rats in 2-year studies. Angiectasis (N) Uterus (Figure 133)
The modifier “cystic” should be used to differentiate the Species
more severe form of the lesion rather than using a separate Mouse; Rat.
diagnostic term.
Pathogenesis/cell of origin
References Vascular tissue.
Brown and Leininger (1992), Faccini et al. (1990), Greaves
et al. (1992), Tucker (1997) Diagnostic Features
• Presence of multiple dilated/cystic small (thin-walled)
Adenomyosis (N) Uterus (Figure 132) blood vessels, usually within the myometrium, possibly
Species distorting the normal architecture.
Mouse; Rat. • Enlarged capillary channels lined by normal endothelial
cells.
Pathogenesis/cell of origin • May be associated with thrombosis, hemorrhage or in-
Endometrium. flammation.
resistant to this effect, while Wistar and Brown Norway rats Nuclei are small, dark and centrally located. There is
are more sensitive. limited connective tissue.
Sarcoma, endometrial stromal: • Mitotic figures can be found within this change.
• Malignant tumor composed primarily of spindle shaped
mesenchymal cells. In general the PAS reaction is nega- Differential Diagnoses
tive in the tumor cells. Hyperplasia, endometrial stromal:
Mesenchymal proliferative lesion: • Increased stromal component, characterized by prolif-
• Proliferative lesion of the genitourinary tract of mice, eration of slender spindle or stellated stromal cells with
usually occurring in the submucosa of the urinary blad- a variable amount of intercellular collagen dependent on
der. Composed of large eosinophilic epithelioid and the age of the lesion. In general the spindle cells do not
spindle cells. contain abundant intracytoplasmic PAS+ material.
Pregnancy: Decidual reaction:
• Decidual reaction in the pseudopregnant state may re- • Nodular proliferation of large eosinophilic stromal or
semble the decidual reaction during pregnancy; however, mesenchymal cells (decidual tissue) with a high level
it lacks a fetus, placental labyrinth, spongiotrophoblast of structural organization and regional variation. When
layer, giant cells, yolk sac, nucleated fetal erythrocytes, fully developed, the decidual reaction has two distinct
etc. areas: antimesometrial region containing closely packed
mesencymal cells with small capillary channels; meso-
Comment metrial region containing spiny mesometrial cells with
Decidual reaction is a rare spontaneous condition in most long cytoplasmic processes and abundant glycogen,
strains of rats and mice. The change mimics the true “decidu- which are commonly binucleated, and granulated me-
oma of pregnancy” related to early pregnancy. The change is trial gland cells with extensive cytoplasm containing
not a neoplastic lesion, but rather a response to implantation PAS-positive cytoplasmic granules.
or a mechanical stimulus (such as intrauterine contraceptive
devices). The reaction occurs on day 3 and 4 of pseudopreg- Comment
nancy and depends on exposure to progesterone for at least Focal stromal decidualization is an uncommon stromal
48 hours followed by a minute amount of estrogen at the end change. The hypertrophied stromal cells in the lesion resem-
of this period. The normal life span of the nodular decidual ble the true decidualized stromal cells in the decidual reac-
reaction is from day 4 to 16 of pseudopregnancy. Decidual tion, but the lesion does not show the structural organization
reactions can be induced by various compounds given at the as seen in the “decidual reaction”. Also in polyps and tumors
proper time in the estrous cycle or after progesterone treat- focal areas of decidualized stroma can be observed.
ment. Also various forms of mechanical irritation or trauma, Decidualization of the endometrial stroma as well as
as well as electric stimulation or instillation of agents into deciduomas can be induced by various substances, such as
the uterus can induce a decidual reaction. These lesions may prostaglandins, growth hormone or prolactin given at the
occur rarely in young animals. proper time in the estrous cycle or after progesterone treat-
ment. Intrauterine contraceptive devices or other intrauter-
References ine inserted materials or substances can cause stromal de-
Davis et al. (2001), Dixon et al. (1999), Hart-Elcock et al. cidualization. It is also believed that uterine intraluminal
(1987), Leininger and Jokinen (1990) polyps can cause the induction of stromal decidualization,
since areas of decidualized stroma can be found within pol-
Decidualization, focal (N) Uterus (Figure 149) yps or other tumors.
Species
Mouse; Rat. References
Leininger and Jokinen (1990)
Synonym(s)
Stromal pseudodecidualization, focal; Decidual altera- Mesonephric duct remnants (N) Uterus
tion. Species
Mouse; Rat.
Pathogenesis/cell of origin
Uterine decidualized stromal cells. Pathogenesis/cell of origin
Mesonephric ducts, Wolffian duct remnants
Diagnostic Features
• In focal stromal decidualization, stromal cells form nod- Synonym(s)
ular lesions within the endometrial stroma. Persistent Mesonephric ducts
• The stromal cells are strongly hypertrophied with prom-
inent nuclei. Diagnostic Features
• Within the cytoplasm of these hypertrophied cells, PAS+ • Tubular or cystic structure(s) lined by epithelial cells and
material (glycogen) can be demonstrated. smooth muscle, resembling poorly developed vas defer-
Lesions of the Female Reproductive System 45S
are given to rodents. Such drugs can cause intralysosomal Diagnostic Features
storage of polar phospholipids in various organs, including • Grossly, serosa of uterine tube is irregular or nodular.
the uterus. The anorectic drug chlorphentermine and the • May involve the entire uterine tube or can be focal.
tricyclic antidepressant imipramine, as well as tamoxifen, • The oviductal muscular wall becomes thickened and epi-
can cause vacuolar changes within the epithelial and smooth thelium form channels that show short projections into
muscle cells of the rat uterus. Electron microscopically, the the lumen.
vacuolated structures proved to be lysosomes filled with • The oviductal epithelium can also form extensive folds
typical whorled, lamellated membranous structures typical that extend into the muscularis dissecting the muscle
of phospholipidosis. bundles.
• The oviductal epithelium forms glandular structures that
References may or may not connect to the oviductal lumen.
Geist and Lüllmann-Rauch (1994), Ioannidis (1998) • Glandular structures may become cystic diverticulae
and lose their connection with the lumen.
Inflammation, oviduct (N) Oviduct (Figure 153) • With time there may be involvement of the entire ovi-
Species ductal serosa.
Mouse; Rat. • Inflammation may or may not be present.
B. Nonneoplastic Proliferative Lesions and eventually neoplasia in rats and mice. “Cystic endome-
trial hyperplasia” is occasionally observed in adult rats and
it is a very common lesion in old mice. Ward et al. (1979)
Hyperplasia, glandular, cystic (H) Uterus found an incidence of 35% of cystic endometrial hyperplasia
(Figures 156 and 157) in B6C3F1 mice.
Species
Mouse; Rat. References
Greaves (2012), Greaves and Faccini (1984), Jones et al.
Synonym(s) (1997), Ward et al. (1979)
Cystic endometrial hyperplasia; CEH.
Hyperplasia, glandular, focal (H) Uterus (Figure 158)
Modifier Species
Cystic; Endometrial. Mouse; Rat.
• Metastasis is rare. sinophilic and giant cells are absent. Lymph nodes are
• May be positive for S-100 and vimentin, negative for also involved.
desmin and actin. Decidual reaction:
• The large round or polygonal cells with eosinophilic
Differential Diagnoses cytoplasm in the decidual alteration of old rats mimic
Leiomyosarcoma or Fibrosarcoma or Schwannoma, malig- histiocytic sarcoma, and may form a polypoid mass;
nant: however, the nuclei are large and pale. These are not
• Diagnosis should be made by process of elimination of multicentric lesions and the liver is not involved.
the different morphological characteristics and growth
pattern in which special stains may be useful. Should Comment
be distinguished from other mesenchymal tumors by Lysozyme, MAC-2, and F4/80 are reliable and specific
means of special stains. Diagnosis can be easily made if markers in mice.
the malignant lesion originates from within an endome-
trial stromal polyp. References
Polyp, endometrial stromal: Davis et al. (1999), Frith et al. (2001), Hao et al. (2010)
• Endometrial stromal polyp distinguished by polypoid
projection into the lumen and by maturity of supporting Papilloma, squamous cell (B) Uterus; Uterine Cervix;
stroma and lack of infiltration. Vagina (See Uterine Cervix and Vagina Section)
Sarcoma, histiocytic (M) Uterus (Figures 171 and 172) Pathogenesis/cell of origin
Species Endometrial epithelium.
Mouse; Rat.
Diagnostic Features
Synonym(s) • Primarily uterine tumor, but may arise from uterine cer-
Reticulum cell sarcoma. vix or appear in vagina by extension.
• Arises from surface epithelium and may have either a
Pathogenesis/cell of origin broad base or a delicate stalk.
Cells of the mononuclear phagocyte system. • Epithelium is well-differentiated and arranged in papil-
lary, glandular or tubular structures which are lined by
Diagnostic Features cuboidal to columnar cells one to two cell layers thick.
• Uniform population of histiocytic cells with abundant • Some glandular structures may contain cysts filled with
eosinophilic cytoplasm. exudate.
• Nuclei are dark, pleomorphic, slightly elongated, and • Focal squamous metaplasia may be present especially
curved or folded. near cervix.
• Focal necrosis surrounded by palisaded cells is charac- • Form well-delineated solitary masses that may com-
teristic. press, but not invade the surrounding endometrium or
• Multinucleate giant cells and phagocytosis may be pres- adjacent myometrium, or protrude into the uterine lu-
ent. men.
• Liver is almost always also involved. • The modifier papillary is used if the predominant growth
pattern of the tumor is papillary.
Differential Diagnoses
Schwannoma, malignant: Differential Diagnoses
• Poorly differentiated malignant schwannomas may re- Polyp, glandular:
semble histiocytic sarcoma; however, they lack giant • May be confused with endometrial glandular polyp.
cells and abundant eosinophilic cytoplasm, and they Well differentiated endometrial stroma is generally a
stain positively with S-100. constant feature of the endometrial glandular polyp, but
Leiomyosarcoma: in papillary adenoma, there is little or no stromal prolif-
• Poorly differentiated leiomyosarcomas may also resem- eration.
ble histiocytic sarcoma; however, they are not multicen- Hyperplasia, glandular, focal:
tric lesions and the liver is not involved. • This type of hyperplasia is characterized by an increase
Lymphoma, malignant, pleomorphic: of the epithelial component within the normal morpho-
• Cells may be similar; however, the cytoplasm is less eo- logical boundaries.
52S DIXON ET AL.
References Comment
Kaspareit-Rittinghausen and Deerberg (1990), van den Tumors derived from the anlage of the Müllerian ducts
Brink-Knol and van Esch (2010) show a biphasic pattern and can exhibit both epithelial and
mesenchymal characteristics. The sarcomatous part may dif-
Tumor, mixed Müllerian, malignant (M) ferentiate into recognizable smooth or striated muscle, car-
Uterus; Uterine Cervix (Figure 180) tilage, and adipose tissue (heterologous mixed tumor). The
Species term homologous mixed tumor is used if the tumor consists
Mouse; Rat. simply of glands and malignant mesenchyme. Immunohis-
tochemical characteristics, such as the expression of epithe-
Synonym(s) lial markers in tumorous mesenchymal structures, point to
Malignant mixed mesodermal tumor; Carcinosarcoma. a common progenitor cell origin. Metastases in general are
epithelial rather than mesenchymal or combinations.
Modifier
Homologous; Heterologous. References
Kaspareit-Rittinghausen and Deerberg (1990), van den
Pathogenesis/cell of origin Brink-Knol and van Esch (2010)
Pluripotent mesodermal cells of the Müllerian ducts.
Teratoma, benign (B) Uterus; Ovary (See Ovary Section)
Diagnostic Features
• Tumor primarily can occur in ovary, uterus (cervix, va- Teratoma, malignant (M) Uterus; Ovary
gina). (See Ovary Section)
• The tumor often is polypoid and protrudes into the lu-
men of the tissue involved. Local invasion of surround- Leiomyoma (B) Uterus; Uterine Cervix; Vagina (Figures
ing tissues can be seen. 181 and 182)
• Infiltratively growing, highly malignant tumor com- Species
posed of epithelial and mesenchymal elements. Mouse; Rat.
• Both the epithelial and mesenchymal components of
the tumor can range from benign, well differentiated to Modifier
poorly differentiated or anaplastic cellular elements. Myometrium; Mesovarium; Uterus.
• In the less differentiated areas, nuclei can be very pleo-
morphic and bizarre. Pathogenesis/cell of origin
• Mitotic figures are frequent in all malignant elements. Smooth muscle cell.
• Two types can be differentiated:
• Homologous: The mesenchymal elements are derived Diagnostic Features
from cell-types that are a normal constituent of the tis- • Tumor primarily occurs in uterus and mesovarium, but
sue involved and can be differentiated towards fibrous may occur in uterine cervix and vagina.
tissue, smooth muscle and/or endometrial stroma-like • Typically, well-circumscribed masses that may be soli-
tissue. tary or multiple and compress adjacent structures.
• Heterologous: The heterologous type contains mesen- • Tumor cells form interlacing bundles and whorls remi-
chymal elements that normally are not found in the niscent of normal smooth muscle cells.
uterus such as striated muscle, cartilage, bone and/or • Varying amounts of collagenous tissue and vascularity.
adipose tissue. Areas with cartilaginous and rhabdo- • Tumor cells are spindle-shaped, have abundant eosino-
myosarcomatous differentiation are often present.
Lesions of the Female Reproductive System 55S
philic cytoplasm, distinct borders and “cigar-shaped” or • Focal areas of hemorrhage, necrosis or cysts may be
blunt-ended nuclei. present.
• There is minimal nuclear pleomorphism and mitotic fig-
ures are rare. Differential Diagnoses
Leiomyoma:
Differential Diagnoses • Typically lacks cellular pleomorphism and atypia, mito-
Leiomyosarcoma: sis and local invasion.
• Cellular and nuclear pleomorphism, poorly circum- Fibrosarcoma:
scribed and invasive tumor with spindled tumor cells • Usually has increased amounts of collagen and is nega-
having prominent nucleoli and mitotic activity. tive for alpha smooth muscle actin and desmin immu-
Fibroma: noreactivity. Lack characteristic “cigar shaped or blunt
• Has extensive collagen formation that can be shown by ended nuclei of smooth muscle cells.
special stains, such as van Gieson’s or Masson’s Tri- Fibrosarcoma, pleomorphic:
chrome stain. • They show several patterns of growth characterized as
storiform, fascicular, myxoid, and pleomorphic with
Comment pleomorphic and myxoid being the most common. Gi-
Longitudinal myofibrils have been reported in leiomyoma ant multinucleated cells, erythrophagocytic cells, and
cells using the phosphotungstic acid-hematoxylin (PTAH) foamy cells have all been described to occur within this
stain and can be used to differentiate these cells from fibro- tumor.
blasts or fibrocytes. Most leiomyoma cells are immunoreac- Sarcoma, histiocytic:
tive for desmin and alpha smooth muscle actin. Diethylstil- • Composed of spindle to rounded cells with dark nuclei
bestrol (DES) has been shown to induce uterine leiomyomas and adequate amounts of eosinophilic cytoplasm. The
in CD-1 mice following developmental exposures. Uterine tumor cells may be haphazardly arranged or may take on
smooth muscle cells express estrogen receptors and appear a whorling pattern. Tumor cells may take on a fusiform
to be hormonally responsive. shape resembling connective tissue cells or fibroblasts
and giant cells may be present throughout the tumors.
References
Davis et al. (1999), Dixon et al. (1999), Ernst et al. (2001a), Comment
Newbold et al. (2002) Longitudinal myofibrils have been reported in leiomyoma
cells using the phosphotungstic acid-hematoxylin (PTAH)
Leiomyosarcoma (M) Uterus; Uterine Cervix; Vagina stain and can be used to differentiate these cells from fibro-
(Figures 183 and 184) blasts or fibrocytes. Most leiomyosarcoma cells are immuno-
Species reactive for desmin and alpha smooth muscle actin, TGF-al-
Mouse; Rat. pha and EGF receptor. Uterine smooth muscle cells express
estrogen receptors and appear to be hormonally responsive.
Modifier
Uterus. References
Davis et al. (1999), Dixon et al. (1999), Ernst et al. (2001a),
Pathogenesis/cell of origin Moore et al. (2000)
Pluripotential mesenchymal stem cells, smooth muscle
cells. Schwannoma, benign (B) Uterus; Uterine Cervix; Vagina
(Figures 185 and 186)
Diagnostic Features Species
• Tumor primarily occurs in uterus and mesovarium, but Mouse; Rat.
may occur in uterine cervix and vagina.
• Poorly delineated mass with disorganized and invasive Synonym(s)
growth patterns, although metastasis is not common. Neurilemmoma, benign; Neurinoma, benign.
• Appear hypercellular due to decrease in amount of cyto-
plasm of anaplastic cells. Pathogenesis/cell of origin
• Tumor cells are spindled to pleomorphic and have blunt Schwann cell, considered to be neuroectodermal with
ended to oval nuclei. facultative mesenchymal features.
• Nuclei may be pleomorphic and have high mitotic activ-
ity, prominent nucleoli and hyperchromasia. Diagnostic Features
• Multinucleated tumor cells may be present. • Expansile, compressive and usually encapsulated.
• Some collagenous stroma and varying degrees of vascu- • Elongated cells with indistinct borders arranged in an in-
larity may be present. terlacing or whorling pattern, or more loosely arranged
56S DIXON ET AL.
cells within a clear matrix. • Elongated cells with indistinct borders arranged in an
• Two different growth-patterns can be recognized: interlacing or whorling pattern or more loosely arranged
• Antoni type A pattern shows nuclear palisading, cells within a clear matrix.
sometimes forming “Verocay bodies” (palisading nu- • Two growth-patterns can be recognized:
clei surrounding homogeneous, eosinophilic intercel- • Antoni type A pattern shows nuclear palisading,
lular material). sometimes forming “Verocay bodies” (palisading nu-
• Antoni type B pattern shows a more loose arrange- clei surrounding homogeneous, eosinophilic intercel-
ment of cells, often containing cystic spaces contain- lular material).
ing eosinophilic/proteinaceous fluid and blood cells • Antoni type B pattern shows a more loose arrange-
and lined by more cuboidal cells. ment of cells, often containing cystic spaces contain-
• Both patterns may or may not be present within the same ing eosinophilic/proteinaceous fluid and blood cells
neoplasm. and lined by more cuboidal cells. Large, dilated blood
• S-100 protein immunoreactivity and the presence of vessels may also be seen.
basement membrane in electron micrographs support • Both patterns may or may not be present within the same
the diagnosis of Schwannoma. neoplasm.
• Generally infiltrative growth pattern into the adjacent
Differential Diagnoses tissues.
Schwannoma, malignant: • High mitotic activity, mitotic or cellular atypia, necrosis
• Cellular atypia, invasion or distant metastases are pres- and/or distant metastases are all indicative of malignan-
ent and/or increased mitotic activity. cy.
Polyp, endometrial stromal: • S-100 protein immunoreactivity and the presence of
• Polypoid mass protruding into lumen covered by endo- basement membrane in electron micrographs support
metrial epithelium composed of spindle or stellate cells, the diagnosis of Schwannoma.
variable amounts of collagen, blood vessels and/or glan-
dular tissue. Differential Diagnoses
Fibroma: Schwannoma, benign:
• Prominent bundles of collagen with low cellularity; neg- • No cellular atypia, invasion or distant metastases are
ative S-100 immunoreactivity. present and very low mitotic rate.
Leiomyoma: Sarcoma, endometrial stromal:
• Eosinophilic, spindle-shaped cells with blunt-ended nu- • Absence of cystic cavities or “Verocay bodies”; negative
clei; negative S-100 immunoreactivity but positive for S-100 immunoreactivity.
desmin and smooth muscle actin. Often bundles of cells Fibrosarcoma:
align perpendicular to one another (“herringbone” pat- • No basal lamina present; negative S-100 protein immu-
tern). noreactivity. Variable amounts of collagen.
Leiomyosarcoma:
References • Eosinophilic, spindle-shaped cells with blunt-ended nu-
Cardesa et al. (1990), Ernst et al. (2001a), Ernst et al. clei; negative S-100 immunoreactivity but positive for
(2001b), Greaves et al. (2004), Greaves et al. (1992), Lan- desmin and smooth muscle actin.
des et al. (1990), Maekawa and Mitsumori (1990), Stewart Sarcoma, histiocytic:
et al. (1974), Walker et al. (1994) • Composed of spindle to rounded cells with dark nuclei
and adequate amounts of eosinophilic cytoplasm. The
Schwannoma, malignant (M) tumor cells may be haphazardly arranged or may take on
Uterus; Uterine Cervix; Vagina (Figures 187 and 188) a whorling pattern. Tumor cells may take on a fusiform
Species shape resembling connective tissue cells or fibroblasts
Mouse; Rat. and giant cells may be present throughout the tumors.
Synonym(s) Comment
Neurilemmoma, malignant; Neurinoma, malignant. Malignant schwannoma is occasionally observed in the
uterus/cervix of rats. Rare tumor in most strains of mice;
Pathogenesis/cell of origin however, in the NHO strain schwannoma is seen in the uterus
Schwann cell, considered to be neuroectodermal with and other organs. Malignant schwannoma has been induced
facultative mesenchymal features. by direct-acting alkylating agents such as N-nitrosoethyl-
urea or methylmethane-sulfonate acting as transplacental
Diagnostic Features carcinogens in rats. Schwannomas were also induced follow-
• Expansile, poorly delineated mass with invasive growth ing postnatal exposure of rats with 7,12-dimethylbenz[α]an-
pattern. thracene, or N-nitrosomethylurea. Malignant Schwannomas
Lesions of the Female Reproductive System 57S
estrous cycle. Inflammation of the vagina and cervix, and Diagnostic Features
transmural involvement of the uterine wall are less common • Presence of inverted uterine tissue within the cervix
than inflammation of the oviduct, myometrium and endome- and/or vagina.
trium occuring independently. May be seen in conjunction • Endometrial glands and epithelium present on both in-
with degeneration and/or necrosis or can also occur as part ternal and external aspects of the uterine tissue.
of an infectious disease (Mycoplasma pulmonalis). In addi- • Myometrium present between the two layers of endome-
tion, inflammation may be observed secondary to intravagi- trium.
nal administration of xenobiotics, irritating vehicles, and/or
intravaginal devices (pessaries). Differential Diagnoses
Polyp, endometrial stromal:
References • Pedunculated mass that protrudes into uterine lumen
Greaves (2012), Leininger and Jokinen (1990), Yuan and and may extend through cervix into vagina, lined ex-
Foley (2002) ternally by epithelium and with prominent loose stroma.
Frequently contains glandular elements within the stro-
Necrosis, epithelial (N) Uterine Cervix; Vagina ma. Myometrium is not present.
(Figure 195)
Species Comment
Mouse; Rat. Gross examination and careful histological trimming are
important to enable accurate differentiation between pro-
Pathogenesis/cell of origin lapse and stromal polyp. In aged mice, prolapse is often as-
Epithelial origin. sociated with other uterine lesions, in particular severe cystic
changes and/or tumors.
Diagnostic Features
• Nuclear pyknosis and/or karyorrhexis. References
• Cytoplasmic eosinophilia. Davis et al. (1999), Leininger and Jokinen (1990), Maeka-
• Cellular swelling or shrinkage. wa and Maita (1996)
• Exfoliated cells and/or intraluminal cellular debris.
• Often associated with acute inflammation. Prostatic rudiment (N) Vagina (Figures 197 and 198)
• May result in erosion/ulcer. Species
Mouse; Rat.
Differential Diagnoses
Autolysis: Synonym(s)
• Uniform dissolution of tissue. Skene’s glands; Skene’s paraurethral glands; Female
Degeneration, epithelial: prostate.
• Displays cellular features of degeneration and lacks an
inflammatory response. May represent a continuum Pathogenesis/cell of origin
with necrosis. Urogenital sinus.
Prolapse (N) Uterus; Uterine Cervix; Vagina (Figure 196) Differential Diagnoses
Species Adenoma, endometrial:
Mouse; Rat. • Adenoma is more densely cellular, contains mitotic fig-
ures, and lacks a distinct fibromuscular stroma.
Pathogenesis/cell of origin
Uterus. Comment
Presence or absence of prostatic rudiment may be en-
countered in sections of the vagina depending on the location
and plane of the section.
Lesions of the Female Reproductive System 61S
References Comment
Santos et al. (2006) Extremely rare spontaneous lesion. Developmental ab-
normality associated with exposure to certain estrogenic
Vacuolation, epithelial (N) Uterine Cervix; Vagina compounds perinatally or neonatally. In mice exposed to
Species DES neonatally transformation from the Müllerian epithe-
Mouse; Rat. lium to a two-cell layered vaginal epithelium does not oc-
cur. This persistent primitive epithelium can form glands in
Pathogenesis/cell of origin the underlying stroma following puberty. Also in humans,
Epithelial origin. this phenomenon is known as adenosis. Severity and extent
of change varies with strain, compound, dose, and time of
Diagnostic Features exposure.
• Presence of multiple small intracytoplasmic vacuoles
(negative for PAS and/or Alcian blue). References
Chamness et al. (1979), Ennis and Davies (1982), Forsberg
Differential Diagnoses and Kalland (1981), Iguchi et al. (1986), Johnson (1987),
Mucification, increased: Ketani et al. (2002), Newbold and McLachlan (1982)
• Superficial epithelial cells contain a large cytoplasmic
mucus vacuole, which may form a distinct “mucified” Hyperplasia, epithelial (H) Vagina (Figure 201)
layer. The mucus can be stained using PAS and/or Al- Species
cian blue. Mouse; Rat.
Proestrus:
• Superficial mucoid layer (also called stratum mucifica- Modifier
tion) characterized by layers of cuboidal to ovoid cells Basal cell; Squamous cell.
with intracytoplasmic mucin vacuoles overlays stratum
granulosum (early proestrus) or keratinized stratum cor- Pathogenesis/cell of origin
neum (late proestrus). In these cases, it is recommended Vaginal epithelium.
not to record, if part of the normal cyclic activity.
Diagnostic Features
• Increased thickness of the vaginal epithelium (when
B. Nonneoplastic Proliferative Lesions compared to normal estrus).
• Cells are well differentiated with no atypia or invasion of
Adenosis (N) Uterine Cervix; Vagina (Figures 199 and 200) the underlying stroma.
Species • May form downward projections into the underlying
Mouse. stroma.
• May have overlying keratinization.
Synonym(s) • Few mitotic figures present.
Adenomatous differentiation; Adenomatous hyperplasia.
Differential Diagnoses
Pathogenesis/cell of origin Estrus:
Epithelium of Müllerian ducts. • Vaginal epithelium composed of approximately 8 to
10 cell layers, with overlying keratinization, which is
Diagnostic Features in conjunction with the presence of basophilic corpora
• Presence of columnar to cuboidal epithelium on the sur- lutea indicating recent ovulation. In these cases, it is
face and formation of glands in the cervix and vagina. recommended not to record, if part of the normal cyclic
• Primarily appears in anterior vagina and fornices, but activity.
may extend to mid-vagina. Papilloma, squamous cell:
• Heterotopic (columnar) epithelium observed in prepu- • Papillary proliferation of the mucosa with squamous dif-
beral mice with formation of glands at puberty. ferentiation.
Carcinoma, squamous cell:
Differential Diagnoses • Squamous cell carcinomas may be well differentiated,
Adenocarcinoma, endometrial: but cells have varying degrees of atypia and often infil-
• Glandular structures in stroma show cellular atypia and/ trate into submucosa and muscularis, and serosa. Differ-
or invasion. entiation from basal to squamous cells – if detectable - is
often less organized.
Polyp, vaginal:
62S DIXON ET AL.
• Lesion is comprised predominantly of a fibromuscular Hyperplasia, stroma (H) Uterine Cervix (Figure 204)
core covered by normal or slightly hyperkeratinized epi- Species
thelium. Mouse; Rat.
• Tumor cells form interlacing bundles and whorls remi- Differential Diagnoses
niscent of normal smooth muscle cells. Hyperplasia, epithelial, squamous cell:
• Varying amounts of collagenous tissue and vascularity. • Restricted to the normal mucosal surface and does not
• Tumor cells are spindle-shaped, have abundant eosino- form a mass with a cavity filled with laminated keratin
philic cytoplasm, distinct borders and “cigar-shaped” or or homogeneous material.
blunt-ended nuclei. Carcinoma, squamous cell:
Fibroma: • Squamous cell carcinomas may be well differentiated
• Tumors cause compression of surrounding tissues and but cells have varying degrees of atypia and often infil-
usually are moderately to poorly cellular depending on trate into submucosa and muscularis, and serosa.
extent of mature collagen present.
• Cells are spindled or fusiform and contain elongated nu- Reference
clei with observable nuclei. Davis et al. (2001)
• Varying amounts of mature collagen forming interwo-
ven bands. Papilloma, squamous cell (B) Vagina; Uterine cervix;
Hyperplasia, stroma: Uterus (Figures 206 and 207)
• Focal to diffuse increased proliferation of primarily Species
stromal cells within a fibrovascular stroma. More stro- Mouse; Rat.
mal cell nuclei are typically present.
Modifier
Comment Keratinizing; Non-keratinizing.
This lesion is often observed in aged Fisher 344 rats. It
has also been observed in mice following transplacental ex- Pathogenesis/cell of origin
posure to DES. Surface epithelium of vagina, uterine cervix or uterus.
Carcinoma, squamous cell (M) Vagina; Uterine Cervix; • Moderate mitotic activity.
Uterus (See Uterus and Oviduct Section) • Increased numbers of cells with small, basophilic nuclei.
• Necrotic areas may be present.
Polyp, vaginal (B) Vagina (Figure 208) • Focal areas of hemorrhage, numerous dilated and con-
Species gested blood vessels.
Mouse; Rat. • May infiltrate the vagina and uterus.
• May metastasize to distant sites.
Synonym(s)
Polyp, squamous. Differential Diagnoses
Hyperplasia, stroma:
Pathogenesis/cell of origin • Focal to diffuse increased proliferation of primarily typ-
Vaginal epithelium and submucosal stroma. ical stromal cells within the dense fibromuscular stroma.
• No atypia or cellular pleomorphism is present.
Diagnostic Features Leiomyosarcoma:
• Polyp covered by normal to hyperplastic squamous epi- • Poorly delineated mass with disorganized and invasive
thelium. growth patterns, although metastasis is not common.
• Epithelium may have areas of hyperkeratosis. • Appear hypercellular due to decrease in amount of cyto-
• Epithelium may have mitotic figures, but is not infiltra- plasm of anaplastic cells.
tive into the stroma. • Tumor cells are spindled to pleomorphic and have blunt
• Bulk of the lesion is generally a dense fibrous or fibro- ended to oval nuclei.
muscular core, less commonly loose more highly vascu- • Nuclei may be pleomorphic and have high mitotic activ-
larized connective tissue. ity, prominent nucleoli and hyperchromasia.
• The lesion may be solitary or multiple. • Typically, well-circumscribed masses that may be soli-
• Lesion may be edematous or infarcted. tary or multiple and infiltrate into adjacent structures.
• Varying amounts of collagenous tissue, vascularity,
Differential Diagnoses hemorrhage and necrosis may be present.
Polyp, endometrial stromal: Fibrosarcoma:
• Presence of endometrial epithelium on or covering the • Tumor consists of pleomorphic spindle-shaped cells that
polyp. often form interlacing bundles or a “herring bone” cel-
• Evidence of origin in uterus, projection into vagina. lular pattern.
Polyp, glandular: • Varying amounts of collagen can be seen between tumor
• Presence of prominent and often hyperplastic glandular cells depending on the degree of differentiation.
structures throughout a major part of the polyp. • Numerous mitotic figures are typically present.
• Areas of necrosis and hemorrhage can be seen.
Comment • Local invasion and extension into adjacent structures.
Endometrial stromal polyps commonly project through
the cervix and appear in the vagina. Key determinants of Comment
a vaginal polyp are evidence of the stalk arising from the There is a report of a CD-1 mouse exposed to DES that
vaginal stroma and characteristic vaginal epithelium on the had a stromal sarcoma that infiltrated the uterus and vagina
surface. and metastasized to the liver, spleen, ovary, and oviduct.
References References
Dixon et al. (1999), Greaves and Faccini (1984), Leininger Johnson (1987), McLachlan et al. (1980)
and Jokinen (1990)
Leiomyoma (B) Uterine Cervix; Vagina; Uterus
Sarcoma, stromal (M) Uterine Cervix (See Uterus and Oviduct Section)
(Figures 209 and 210)
Species Leiomyosarcoma (M) Uterine Cervix; Vagina; Uterus
Mouse; Rat. (See Uterus and Oviduct Section)
FigUre 85––– Sex Cord Stromal Hyperplasia, Diffuse, Mixed, Ovary, rat.
FigUre 86––– Hyperplasia, Smooth Muscle, Mesovarium, rat.
FigUre 87––– Hyperplasia, Rete Ovarii, Ovary, rat.
FigUre 88––– Rete Ovarii Adenoma, Ovary, rat.
FigUre 89––– Cystadenoma, Ovary, mouse.
FigUre 90––– Cystadenoma, Ovary, mouse.
Lesions of the Female Reproductive System 81S
FigUre 115 –– Sex Cord Stromal Tumor, Mixed, Benign, Ovary, rat.
FigUre 116 –– Thecoma, Benign, Ovary, mouse.
FigUre 117 –– Thecoma, Malignant, Ovary, rat.
FigUre 118 –– Luteoma. Ovary, rat.
FigUre 119 –– Luteoma, Ovary, rat.
FigUre 120–– Luteoma, Ovary, rat.
86S DIXON ET AL.
[CrossRef]
r eFerenCes Chen Y, Jefferson WN, Newbold RR, Padilla-Banks E, and Pepling ME. Es-
Alison RH, Lewis DJ, and Montgomery CA. Ovarian choriocarcinoma in the tradiol, progesterone, and genistein inhibit oocyte nest breakdown and
mouse. Vet Pathol. 24: 226–230. 1987a. [Medline] primordial follicle assembly in the neonatal mouse ovary in vitro and in
Alison RH, and Morgan KT. Ovarian neoplasms in F344 rats and B6C3F1 vivo. Endocrinology. 148: 3580–3590. 2007. [Medline] [CrossRef]
mice. Environ Health Perspect. 73: 91–106. 1987a. [Medline] [CrossRef] Ciaccio LA, Hill JL, and Kincl FA. Observation on toxic effects of quinacrine
Alison RH, and Morgan KT. Granulosa cell tumor, ovary, mouse. In: Mono- hydrochloride (in rodents). Contraception. 17: 231–236. 1978. [Medline]
graphs on pathology of laboratory animals. Genital System. Jones TC, [CrossRef]
Mohr U, and Hunt RD (eds). Springer-Verlag, Berlin, Heidelberg, New Clement PB. Non-neoplastic lesions of the ovary. In: Blaustein’s Pathology of
York. 22–30. 1987b. the Female Genital Tract. Kurman RJ (ed). Springer-Verlag, New York.
Alison RH, Morgan KT, Haseman JK, and Boorman GA. Morphology and 676–677. 2002.
classification of ovarian neoplasms in F344 rats and (C57BL/6 X C3H)F1 Clow OL, Hurst PR, and Fleming JS. Changes in the mouse ovarian surface
mice. J Natl Cancer Inst. 78: 1229–1243. 1987b. [Medline] epithelium with age and ovulation number. Mol Cell Endocrinol. 191:
Alison RH, Morgan KT, and Montgomery CA. Ovary. In: Pathology of the 105–111. 2002. [Medline] [CrossRef]
Fischer rat. Reference and atlas. Boorman GA, Eustis SL, Elwell MR, Comereski CR, Peden WM, Davidson TJ, Warner GL, Hirth RS, and Frantz
Montgomery CA, Jr, and MacKenzie WF (eds). Academic Press, San Di- JD. BR96-doxorubicin conjugate (BMS-182248) versus doxorubicin:
ego, New York, London. 429–442. 1990. a comparative toxicity assessment in rats. Toxicol Pathol. 22: 473–488.
Amadi K, Nwana EJ, and Otubu JA. Morphology and function of the rat ovi- 1994. [Medline] [CrossRef]
duct: effects of thyroidectomy and thyroxine administration. Afr J Med Corbeil LB, Chatterjee A, Foresman L, and Westfall JA. Ultrastructure of
Med Sci. 36: 353–358. 2007. [Medline] cyclic changes in the murine uterus, cervix, and vagina. Tissue Cell. 17:
Andrews P, Freyberger A, Hartmann E, Eiben R, Loof I, Schmidt U, Tem- 53–68. 1985. [Medline] [CrossRef]
erowski M, Folkerts A, Stahl B, and Kayser M. Sensitive detection of the Cornillie FJ, and Lauweryns JM. Phagocytotic and iron-storing capacities of
endocrine effects of the estrogen analogue ethinylestradiol using a modi- stromal cells in the rat endometrium. A histochemical and ultrastructural
fied enhanced subacute rat study protocol (OECD Test Guideline no. 407). study. Cell Tissue Res. 239: 467–476. 1985. [Medline] [CrossRef]
Arch Toxicol. 76: 194–202. 2002. [Medline] [CossRef] Coskun A, Coban YK, and Ciralik H. Critical ischemic time for the rat ovary:
Anisimov VN, and Nikonov AA. Tumours of the vagina, uterus and oviduct. experimental study evaluating early histopathologic changes. J Obstet
In: Pathology of tumours in laboratory animals. Vol I. Tumours of the rat, Gynaecol Res. 35: 330–334. 2009. [Medline] [CrossRef]
2nd edition. Turusov VS, and Mohr U (eds). IARC Scientific Publications Courtney CL, Hawkins KL, Meierhenry EF, and Graziano MJ. Immunohis-
No. 99, Lyon. 445–471. 1990. tochemical and ultrastructural characterization of granular cell tumors
Ashley DJB. Evan’s histological appearances of tumors. Churchill Living- of the female reproductive tract in two aged Wistar rats. Vet Pathol. 29:
stone, Edinburgh. 1990. 86–89. 1992. [Medline] [CrossRef]
Berger L, El-Alfy M, Martel C, and Labrie F. Effects of dehydroepiandros- Davis BJ, Almekinder JL, Flagler N, Travlos G, Wilson R, and Maronpot
terone, Premarin and Acolbifene on histomorphology and sex steroid re- RR. Ovarian luteal cell toxicity of ethylene glycol monomethyl ether and
ceptors in the rat vagina. J Steroid Biochem Mol Biol. 96: 201–215. 2005. methoxy acetic acid in vivo and in vitro. Toxicol Appl Pharmacol. 142:
[Medline] [CrossRef] 328–337. 1997. [Medline] [CrossRef]
Biegel LB, Flaws JA, Hirshfield AN, O’Connor JC, Elliott GS, Ladics GS, Davis BJ, Dixon D, and Herbert RA. Ovary, oviduct, uterus, cervix, and vagi-
Silbergeld EK, Van Pelt CS, Hurtt ME, Cook JC, and Frame SR. 90-day na. In: Pathology of the mouse. Reference and atlas. Maronpot RR, Boor-
feeding and one-generation reproduction study in Crl:CD BR rats with 17 man GA, and Gaul BW (eds). Cache River Press, Vienna. 409–443. 1999.
beta-estradiol. Toxicol Sci. 44: 116–142. 1998. [Medline] Davis BJ, Harleman JH, Heinrichs M, Maekawa A, McConnell RF, Reznik
Bolon B, Bucci TJ, Warbritton AR, Chen JJ, Mattison DR, and Heindel JJ. G, and Tucker M. Female genital system. In: International Classification
Differential follicle counts as a screen for chemically induced ovarian of Rodent Tumors: The Mouse. Mohr U (ed). Springer-Verlag, Heidelberg,
toxicity in mice: results from continuous breeding bioassays. Fundam Berlin, New York. 211–268. 2001.
Appl Toxicol. 39: 1–10. 1997. [Medline] [CrossRef] Davis JK, Gaertner DJ, Cox NR, Lindsey JR, Cassell GH, Davidson MK,
Branham WS, Zehr DR, Chen JJ, and Sheehan DM. Alterations in developing Kervin KC, and Rao GN. The role of Klebsiella oxytoca in utero-ovarian
rat uterine cell populations after neonatal exposure to estrogens and anti- infection of B6C3F1 mice. Lab Anim Sci. 37: 159–166. 1987. [Medline]
estrogens. Teratology. 38: 271–279. 1988. [Medline] [CrossRef] de la Maza LM, Pal S, Khamesipour A, and Peterson EM. Intravaginal inocu-
Brossia LJ, Roberts CS, Lopez JT, Bigsby RM, and Dynlacht JR. Interstrain lation of mice with the Chlamydia trachomatis mouse pneumonitis biovar
differences in the development of pyometra after estrogen treatment of results in infertility. Infect Immun. 62: 2094–2097. 1994. [Medline]
rats. J Am Assoc Lab Anim Sci. 48: 517–520. 2009. [Medline] Deerberg F, Pohlmeyer G, Lörcher K, and Petrow V. Total suppression of
Brown H, and Leininger JR. Alterations of the uterus. In: Pathobiology of spontaneous endometrial carcinoma in BDII/Han rats by melengestrol
the aging rat. Mohr U, Dungworth DL, and Capen CC (eds). ILSI Press, acetate. Oncology. 52: 319–325. 1995. [Medline] [CrossRef]
Washington DC. 377–388. 1992. Deerberg F, Rehm S, and Pittermann W. Uncommon frequency of adenocar-
Busch K, and Naglić T. Natural uterine Mycoplasma pulmonis infection in cinomas of the uterus in virgin Han:Wistar rats. Vet Pathol. 18: 707–713.
female rats. Vet Med (Praha). 40: 253–255. 1995. [Medline] 1981. [Medline] [CrossRef]
Campbell JS. Adenoacanthoma, uterus, rat. In: Monographs on pathology Diters RW, Funk KA, Fang H, Durham SK, and Mense MG. Hermaphrodit-
of laboratory animals. Genital system. Jones TC, Mohr U, and Hunt RD ism in a Sprague-Dawley rat. Vet Pathol. 44: 418–420. 2007. [Medline]
(eds). Springer, Berlin, Heidelberg, New York, Tokyo. 110–115. 1987. [CrossRef]
Cardesa A, Ribalta T, Vogeley KT, Reifenberger G, Wechsler W, and Turusov Dixon D, Couse JF, and Korach KS. Disruption of the estrogen receptor gene
VS. Tumours of the peripheral nervous system. In: Pathology of tumours in mice. Toxicol Pathol. 25: 518–520. 1997. [Medline] [CrossRef]
in laboratory animals. Vol I. Tumours of the rat, 2nd edition. Turusov VS, Dixon D, Leininger JR, Valerio MG, Johnson AN, Stabinski LG, and Frith
Mohr U (eds). IARC Scientific Publications No. 99, Lyon. 699–724. 1990. CH. Proliferative lesions of the ovary, uterus, vagina, cervix and oviduct
Carthew P, Edwards RE, Nolan BM, Martin EA, and Smith LL. Tamoxifen in rats. In Guides for Toxicologic Pathology. STP/ARP/AFIP, Washing-
associated uterine pathology in rodents: relevance to women. Carcino- ton, DC. 1999.
genesis. 17: 1577–1582. 1996. [Medline] [CrossRef] Dodo T, Taketa Y, Sugiyama M, Inomata A, Sonoda J, Okuda Y, Mineshima
Chamness GC, Bannayan GA, Landry LA Jr, Sheridan PJ, and McGuire WL. H, Hosokawa S, and Aoki T. Collaborative work on evaluation of ovarian
Abnormal reproductive development in rats after neonatally administered toxicity. 11) Two- or four-week repeated-dose studies and fertility study
antiestrogen (tamoxifen). Biol Reprod. 21: 1087–1090. 1979. [Medline] of ethylene glycol monomethyl ether in female rats. J Toxicol Sci. 34(Sup-
Lesions of the Female Reproductive System 103S
pl 1): SP121–SP128. 2009. [Medline] [CrossRef] TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New York,
Durlinger AL, Kramer P, Karels B, Grootegoed JA, Uilenbroek JT, and Tokyo. 78–80. 1987c.
Themmen AP. Apoptotic and proliferative changes during induced atresia Goodman DG, and Hildebrandt PK. Squamous cell carcinoma, endometrium/
of pre-ovulatory follicles in the rat. Hum Reprod. 15: 2504–2511. 2000. cervix, rat. In: Monographs on pathology of laboratory animals. Genital
[Medline] [CrossRef] system. Jones TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidel-
Elwell M, Mahler JF, and Ruecker FA. Proliferative and non-proliferative berg, New York, Tokyo. 82–83. 1987d.
lesions in the heart and vasculature in mice. In Guides for Toxicologic Goodman DG, and Hildebrandt PK. Stromal sarcoma, endometrium, rat. In:
Pathology. STP/ARP/AFIP, Washington, DC. 2004. Monographs on pathology of laboratory animals. Genital system. Jones
Engle ET. Tubular adenomas and testis-like tubules of the ovaries of aged rats. TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New York,
Cancer Res. 6: 578–582. 1946. [Medline] Tokyo. 70–72. 1987e.
Ennis BW, and Davies J. Reproductive tract abnormalities in rats treated neo- Gopinath C, and Gibson WA. Mesovarian leiomyomas in the rat. Environ
natally with DES. Am J Anat. 164: 145–154. 1982. [Medline] [CrossRef] Health Perspect. 73: 107–113. 1987. [Medline] [CrossRef]
Ernst H, Carlton WW, Courtney C, Rinke M, Greaves P, Isaacs KR, Krinke Gopinath C, Prentice DE, and Lewis DJ. The respiratory system. In: Atlas
G, Konishi Y, Mesfin GM, and Sandusky G. Soft tissue and skeletal mus- of experimental pathology. MTP Press, Lancaster, Boston, The Hague,
cle. In: International Classification of Rodent Tumors. The Mouse. Mohr Dordrecht. 1987.
U (ed). Springer, Heidelberg, Berlin, New York. WHO IARK 361–387. Graham CE. Cyclic changes in the squamo-columnar junction of the mouse
2001a. cervix uteri. Anat Rec. 155: 251–260. 1966. [Medline] [CrossRef]
Ernst H, Carlton WW, Courtney C, Rinke M, Greaves P, Isaacs KR, Krinke Greaves P. Female genital tract. In: Histopathology of Preclinical Toxicity
G, Konishi Y, Mesfin GM, and Sandusky G. Soft tissue and skeletal mus- Studies. 4th ed. Elsevier, Amsterdam. 667–723. 2012.
cle. In: International Classification of Rodent Tumors. The Mouse. Mohr Greaves P, Carlton WW, Courtney CL, Ernst H, Halm S, Isaacs KR, Konishi
U (ed). Springer, Heidelberg, Berlin, New York. WHO IARK. 2001b. Y, Krinke GJ, Mesfin GM, Rinke M, and Sandusky G. Non-proliferative
Faccini JM, Abbott DP, and Paulus GJJ. Mouse histopathology. A glossary and proliferative lesions of soft tissues and skeletal muscle in mice. In:
for use in toxicity and carcinogenicity studies. Elsevier, Amsterdam, New Guides for Toxicologic Pathology. STP/ARP/AFIP, Washington DC. 1–18.
York, Oxford. 1990. 2004.
Fleming JS, McQuillan HJ, Millier MJ, Beaugié CR, and Livingstone V. E- Greaves P, and Faccini JM. Rat histopathology. A glossary for use in toxic-
cadherin expression and bromodeoxyuridine incorporation during devel- ity and carcinogenicity studies. Elsevier, Amsterdam, New York, Oxford.
opment of ovarian inclusion cysts in age-matched breeder and incessantly 1984.
ovulated CD-1 mice. Reprod Biol Endocrinol. 5: 14. 2007. [Medline] Greaves P, Faccini JM, and Courtney CL. Proliferative lesions of soft tissues
[CrossRef] and skeletal muscle in rats. In: Guides for Toxicologic Pathology. STP/
Forsberg JG, and Kalland T. Neonatal estrogen treatment and epithelial ab- ARP/AFIP, Washington DC. 1–14. 1992.
normalities in the cervicovaginal epithelium of adult mice. Cancer Res. Greaves P, and Seely JC. Non-proliferative lesions of soft tissues and skel-
41: 721–734. 1981. [Medline] etal muscle in rats. In: Guides for Toxicologic Pathology. STP/ARP/AFIP.
Frith CH, and Chandra M. Incidence, distribution, and morphology of amy- MST-1. Washington DC. 292–299. 1996.
loidosis in Charles Rivers CD-1 mice. Toxicol Pathol. 19: 123–127. 1991. Gregson RL, Lewis DJ, and Abbott DP. Spontaneous ovarian neoplasms of
[Medline] [CrossRef] the laboratory rat. Vet Pathol. 21: 292–299. 1984. [Medline]
Frith CH, and Ward JM. Color atlas of neoplastic and non-neoplastic lesions Hao X, Fredrickson TN, Chattopadhyay SK, Han W, Qi CF, Wang Z, Ward
in aging mice. Elsevier, Amsterdam, New York, Tokyo. 1988. JM, Hartley JW, and Morse HC 3rd. The histopathologic and molecular
Frith CH, Ward JM, Harleman JH, Stromberg PC, Halm S, Inoue T, and basis for the diagnosis of histiocytic sarcoma and histiocyte-associated
Wright JA. Hematopoietic System. In: International classification of ro- lymphoma of mice. Vet Pathol. 47: 434–445. 2010. [Medline] [CrossRef]
dent tumors in the mouse. Mohr U (ed). Springer, Berlin. 417–451. 2001. Harada M, Kishimoto K, Hagiwara R, Nakashima Y, Kurisu K, and Kawagu-
Gaytán M, Bellido C, Morales C, Sánchez-Criado JE, and Gaytán F. Effects chi Y. Infertility observed in female rats treated with N-acetyl-L-cysteine:
of selective inhibition of cyclooxygenase and lipooxygenase pathways Histopathological examination of ovarian follicles and recovery of fertil-
in follicle rupture and ovulation in the rat. Reproduction. 132: 571–577. ity. Congenit Anom (Kyoto). 43: 168–176. 2003. [Medline] [CrossRef]
2006. [Medline] [CrossRef] Hart-Elcock L, Stuart BP, Mueller RE, and Hoss HE. Deciduoma, uterus,
Geist SH, and Lüllmann-Rauch R. Experimentally induced lipidosis in uter- rat. In: Monographs on pathology of laboratory animals. Genital system.
ine and vaginal epithelium of rats. Ann Anat. 176: 3–9. 1994. [Medline] Jones TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New
[CrossRef] York, Tokyo. 140–146. 1987.
Genadry R, Parmley T, and Woodruff JD. The origin and clinical behavior of Hendry WJ 3rd, Zheng X, Leavitt WW, Branham WS, and Sheehan DM.
the parovarian tumor. Am J Obstet Gynecol. 129: 873–880. 1977. [Med- Endometrial hyperplasia and apoptosis following neonatal diethylstil-
line] bestrol exposure and subsequent estrogen stimulation in both host and
Ginty I, and Hoogstraten-Miller S. Perineal swelling in a mouse. Diagno- transplanted hamster uteri. Cancer Res. 57: 1903–1908. 1997. [Medline]
sis: imperforate vagina with secondary mucometra. Lab Anim (NY). 37: Heywood R, and Wadsworth PF. The experimental toxicology of estrogens.
196–199. 2008. [Medline] [CrossRef] In: Pharmacology of Estrogens (International Encyclopedia of Pharma-
Goldman JM, Murr AS, and Cooper RL. The rodent estrous cycle: character- cology and Therapeutics). Chaudhury RR (ed). Pergamon Press, New
ization of vaginal cytology and its utility in toxicological studies. Birth York. Vol. Section 106, 68. 1981.
Defects Res B Dev Reprod Toxicol. 80: 84–97. 2007. [Medline] [Cross- Hirshfield AN, and Midgley AR Jr. Morphometric analysis of follicular devel-
Ref] opment in the rat. Biol Reprod. 19: 597–605. 1978. [Medline] [CrossRef]
Goodman DG, and Hildebrandt PK. Adenocarcinoma, endometrium, rat. In: Hollander CF, Burek JD, Boorman GA, Snell KC, and Laqueur GL. Granular
Monographs on pathology of laboratory animals. Genital system. Jones cell tumors of the central nervous system of rats. Arch Pathol Lab Med.
TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New York, 100: 445–447. 1976. [Medline]
Tokyo. 80–82. 1987a. Hoyer PB. Can the clock be turned back on ovarian aging? Sci SAGE KE.
Goodman DG, and Hildebrandt PK. Stromal polyp, endometrium, rat. In: 2004: pe11. 2004. [Medline]
Monographs on pathology of laboratory animals. Genital system. Jones Iguchi T, Hirokawa M, and Takasugi N. Occurrence of genital tract abnor-
TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New York, malities and bladder hernia in female mice exposed neonatally to tamoxi-
Tokyo. 146–148. 1987b. fen. Toxicology. 42: 1–11. 1986. [Medline] [CrossRef]
Goodman DG, and Hildebrandt PK. Papillary adenoma, endometrium, rat. In: Ioannidis N. Lipidosis induced in rat uteri by high doses of tamoxifen. Ann
Monographs on pathology of laboratory animals. Genital system. Jones Anat. 180: 315–319. 1998. [Medline] [CrossRef]
104S DIXON ET AL.
Ishii S, Ube M, Okada M, Adachi T, Sugimoto J, Inoue Y, Uno Y, and Mutai Krinke G, Naylor DC, Schmid S, Fröhlich E, and Schnider K. The incidence
M. Collaborative work on evaluation of ovarian toxicity. 17) Two- or four- of naturally-occurring primary brain tumours in the laboratory rat. J
week repeated-dose studies and fertility study of sulpiride in female rats. Comp Path. 95: 175–192.1985.
J Toxicol Sci. 34(Suppl 1): SP175–SP188. 2009. [Medline] Krinke GJ, Kaufmann W, Mahrous AT, and Schaetti P. Morphologic charac-
Ito A, Mafune N, and Kimura T. Collaborative work on evaluation of ovarian terization of spontaneous nervous system tumors in mice and rats. Toxicol
toxicity. 4) Two- or four-week repeated dose study of 4-vinylcyclohexene Pathol. 28: 178–192. 2000. [Medline] [CrossRef]
diepoxide in female rats. J Toxicol Sci. 34(Suppl 1): SP53–SP58. 2009. Kumazawa T, Nakajima A, Ishiguro T, Jiuxin Z, Tanaharu T, Nishitani H, In-
[Medline] [CrossRef] oue Y, Harada S, Hayasaka I, and Tagawa Y. Collaborative work on evalu-
Izumi Y, Watanabe T, Awasaki N, Hikawa K, Minagi T, and Chatani F. Col- ation of ovarian toxicity. 15) Two- or four-week repeated-dose studies and
laborative work on evaluation of ovarian toxicity. 16) Effects of 2 or 4 fertility study of bromocriptine in female rats. J Toxicol Sci. 34(Suppl 1):
weeks repeated dose studies and fertility study of Chlorpromazine hydro- SP157–SP165. 2009. [Medline] [CrossRef]
chloride in rats. J Toxicol Sci. 34(Suppl 1): SP167–SP174. 2009. [Medline] Löseke A, and Spanel-Borowski K. Simple or repeated induction of super-
[CrossRef] ovulation: a study on ovulation rates and microvessel corrosion casts in
Jarrett RJ. Some endocrine effects of two phenothiazine derivatives, chlor- ovaries of golden hamsters. Ann Anat. 178: 5–14. 1996. [Medline] [Cross-
promazine and perphenazine, in the female mouse. Br Pharmacol Che- Ref]
mother. 20: 497–506. 1963. [Medline] [CrossRef] Lúllmann-Rauch R, and Reil GH. Fenfluramine-induced ultrastructural al-
Johnson LD. Lesions of the female genital system caused by diethylstilbes- terations in tissues of rats and guinea pigs. Naunyn Schmiedebergs Arch
trol in humans, subhuman primates, mice. In: Monographs on pathology Pharmacol. 285: 175–184. 1974. [Medline] [CrossRef]
of laboratory animals. Genital system. Jones TC, Mohr U, and Hunt RD Landes C, Heider K, Krinke AL, Krinke GJ, Mahrous AT, and Hess R. Con-
(eds). Springer, Berlin, Heidelberg, New York, Tokyo. 84–109. 1987. tribution of immunohistochemistry toward the diagnosis of tumors of
Jones TC, Hunt RD, and King NW. Veterinary pathology. Williams and laboratory rats. Exp Pathol. 40: 239–250. 1990. [Medline] [CrossRef]
Wilkins, Baltimore. 1997. Lee S-H, Ichii O, Otsuka S, Elewa YH, Namiki Y, Hashimoto Y, and Kon Y.
Kai K, Satoh N, Watanabe A, Shiraiwa K, Sasano H, and Furuhama K. Case Ovarian cysts in MRL / MpJ mice are derived from the extraovarian rete:
report of rat true hermaphroditism: colocalization of oocytes and granu- a developmental study. J Anat. 219: 743–755. 2011. [Medline] [CrossRef]
losa and sertoli cells in the germinal cord. Toxicol Pathol. 31: 290–294. Leininger JR, and Jokinen MP. Oviduct, uterus and vagina. In: Pathology
2003. [Medline] of the Fischer rat. Reference and atlas. Boorman GA, Eustis SL, Elwell
Kaipia A, and Hsueh AJ. Regulation of ovarian follicle atresia. Annu Rev MR, Montgomery CA, Jr, and MacKenzie WF (eds). Academic Press, San
Physiol. 59: 349–363. 1997. [Medline] [CrossRef] Diego, New York, London. 443–459. 1990.
Kao SW, Sipes IG, and Hoyer PB. Early effects of ovotoxicity induced by Lemon PG, and Gubareva AV. Tumours of the ovary. In: Pathology of tu-
4-vinylcyclohexene diepoxide in rats and mice. Reprod Toxicol. 13: 67– mours in laboratory animals. Vol. II. Tumours of the mouse. Turusov VS
75. 1999. [Medline] [CrossRef] (ed). IARC Scientific Publications No. 23, Lyon. 385–409. 1979.
Kaspareit-Rittinghausen J, and Deerberg F. Spontaneous malignant mixed Lerner LJ, Hilf R, Turkheimer AR, Michel I, and Engel SL. Effects of hor-
müllerian tumors and rhabdomyosarcoma of the uterus in rats. Toxicol mone antagonists on morphological and biochemical changes induced by
Pathol. 18: 417–422. 1990. [Medline] [CrossRef] hormonal steroids in the immature rat uterus. Endocrinology. 78: 111–
Kaufmann W, Bolon B, Bradley A, Butt M, Czasch S, Garman RH, George 124. 1966. [Medline] [CrossRef]
C, Gröters S, Krinke G, Little P, McKay J, Narama I, Rao D, Shibutani M, Lewis DJ. Ovarian neoplasia in the Sprague-Dawley rat. Environ Health Per-
and Sills R. Proliferative and nonproliferative lesions of the rat and mouse spect. 73: 77–90. 1987. [Medline] [CrossRef]
central and peripheral nervous systems. Toxicol Pathol. 40(Suppl): 87S– Li S, and Davis B. Evaluating rodent vaginal and uterine histology in toxic-
157S. 2012. [Medline] [CrossRef] ity studies. Birth Defects Res B Dev Reprod Toxicol. 80: 246–252. 2007.
Kaushic C, Frauendorf E, Rossoll RM, Richardson JM, and Wira CR. Influ- [Medline] [CrossRef]
ence of the estrous cycle on the presence and distribution of immune cells Long GG. Apparent mesonephric duct (rete anlage) origin for cysts and pro-
in the rat reproductive tract. Am J Reprod Immunol. 39: 209–216. 1998. liferative epithelial lesions in the mouse ovary. Toxicol Pathol. 30: 592–
[Medline] [CrossRef] 598. 2002. [Medline] [CrossRef]
Kelly WA, Marler RJ, and Weikel JH. Drug-induced mesovarial leiomyomas Long GG, Cohen IR, Gries CL, Young JK, Francis PC, and Capen CC. Prolif-
in the rat - a review and additional data. J Am Coll Toxicol. 12: 13–22. erative lesions of ovarian granulosa cells and reversible hormonal changes
1993. [CrossRef] induced in rats by a selective estrogen receptor modulator. Toxicol Pathol.
Kent Jr HA. Polyovular follicles and multinucleate ova in the ovaries of young 29: 719–726. 2001. [Medline] [CrossRef]
mice. Anat Rec. 137: 521–524. 1960. [Medline] [CrossRef] Maekawa A. Tumours of the ovary. In: Pathology of tumours in laboratory
Kent Jr HA. Polyovular follicles and multinucleate ova in the ovaries of young animals. Vol I. Tumours of the rat, 2nd edition. Turusov VS, and Mohr U
rats. Anat Rec. 142: 25–29. 1962. [Medline] [CrossRef] (eds). IARC Scientific Publications No. 99, Lyon. 473–497. 1990.
Ketani MA, Ketani S, Kaloğlu C, and Güney B. Effects of tamoxifen admin- Maekawa A. Genital tumors in female rats—influence of chemicals and/or
istration in rat vaginas: an ultrastructural and light microscopy study. Eur hormones and host factors on their occurrence. J Toxicol Sci. 19: 119–132.
J Gynaecol Oncol. 23: 557–560. 2002. [Medline] 1994. [Medline] [CrossRef]
Kim H, Nakajima T, Hayashi S, Chambon P, Watanabe H, Iguchi T, and Sato Maekawa A, and Hayashi Y. Granulosa/theca cell tumor, ovary, rat. In:
T. Effects of diethylstilbestrol on programmed oocyte death and induc- Monographs on pathology of laboratory animals. Genital system. Jones
tion of polyovular follicles in neonatal mouse ovaries. Biol Reprod. 81: TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New York,
1002–1009. 2009. [Medline] Tokyo. 15–22. 1987.
King A, Gardner L, and Loke YW. Evaluation of oestrogen and progesterone Maekawa A, and Maita K. Changes in the uterus and vagina. In: Pathobiol-
receptor expression in uterine mucosal lymphocytes. Hum Reprod. 11: ogy of the Aging Mouse. Mohr U, Dungworth DL, Capen CC, Carlton
1079–1082. 1996. [Medline] [CrossRef] WW, JP Sundberg JP, and Ward JM (eds). ILSI Press, Washington, DC.
Kodama T, Yoshida J, Miwa T, Hasegawa D, and Masuyama T. Collabora- 469–480. 1996.
tive work on evaluation of ovarian toxicity. 4) Effects of fertility study of Maekawa A, Maita K, and Harleman JH. Changes in the ovary. In: Pathobi-
4-vinylcyclohexene diepoxide in female rats. J Toxicol Sci. 34(Suppl 1): ology of the Aging Mouse. Vol 1. Mohr U, Dungworth DL, Capen CC,
SP59–SP63. 2009. [Medline] [CrossRef] Carlton WW, JP Sundberg JP, and Ward JM (eds). ILSI Press, Washing-
Kon Y, Konno A, Hashimoto Y, and Endoh D. Ovarian cysts in MRL/MpJ ton, DC. 466. 1996.
mice originate from rete ovarii. Anat Histol Embryol. 36: 172–178. 2007. Maekawa A, and Mitsumori K. Spontaneous occurrence and chemical induc-
[Medline] [CrossRef] tion of neurogenic tumors in rats—influence of host factors and specific-
Lesions of the Female Reproductive System 105S
ity of chemical structure. Crit Rev Toxicol. 20: 287–310. 1990. [Medline] 4328. 2001. [Medline]
[CrossRef] Newbold RR, Bullock BC, and McLachlan JA. Diverticulosis and salpingi-
Majeed SK, Alison RH, Boorman GA, and Gopinath C. Ovarian yolk sac tis isthmica nodosa (SIN) of the fallopian tube. Estrogen-induced diver-
carcinoma in mice. Vet Pathol. 23: 776–778. 1986. [Medline] ticulosis and SIN of the mouse oviduct. Am J Pathol. 117: 333–335. 1984.
Markovits JE, and Sahota PS. Aromatase inhibitors prevent spontaneous [Medline]
granular cell tumors in the distal female reproductive tract of Sprague- Newbold RR, Jefferson WN, and Padilla-Banks E. Long-term adverse effects
Dawley rats. Toxicol Pathol. 28: 799–801. 2000a. [Medline] [CrossRef] of neonatal exposure to bisphenol A on the murine female reproductive
Markovits JE, and Sahota PS. Granular cell lesions in the distal female re- tract. Reprod Toxicol. 24: 253–258. 2007. [Medline] [CrossRef]
productive tract of aged Sprague-Dawley rats. Vet Pathol. 37: 439–448. Newbold RR, Jefferson WN, and Padilla-Banks E. Prenatal exposure to bi-
2000b. [Medline] [CrossRef] sphenol a at environmentally relevant doses adversely affects the murine
Mattheij JA, and Swarts HJ. Induction of luteinized unruptured follicles in female reproductive tract later in life. Environ Health Perspect. 117: 879–
the rat after injection of luteinizing hormone early in pro-oestrus. Eur J 885. 2009. [Medline] [CrossRef]
Endocrinol. 132: 91–96. 1995. [Medline] [CrossRef] Newbold RR, and McLachlan JA. Vaginal adenosis and adenocarcinoma in
McIntyre A, and La Perle KM. Hermaphroditism in 3 chimeric mice. Vet mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res.
Pathol. 44: 249–252. 2007. [Medline] [CrossRef] 42: 2003–2011. 1982. [Medline]
McLachlan JA, Newbold RR, and Bullock BC. Long-term effects on the fe- Newbold RR, Moore AB, and Dixon D. Characterization of uterine leiomyo-
male mouse genital tract associated with prenatal exposure to diethylstil- mas in CD-1 mice following developmental exposure to diethylstilbestrol
bestrol. Cancer Res. 40: 3988–3999. 1980. [Medline] (DES). Toxicol Pathol. 30: 611–616. 2002. [Medline] [CrossRef]
Medlock KL, Branham WS, and Sheehan DM. Effects of toremifene on neo- Nielsen SW, Misdorp W, and McEntee K. Tumours of the ovary. Bull World
natal rat uterine growth and differentiation. Biol Reprod. 56: 1239–1244. Health Organ. 53: 203–215. 1976. [Medline]
1997. [Medline] [CrossRef] Nomura T, and Kanzaki T. Induction of urogenital anomalies and some tu-
Mirsky ML, Sivaraman L, Houle C, Potter DM, Chapin RE, and Cappon GD. mors in the progeny of mice receiving diethylstilbestrol during pregnan-
Histologic and cytologic detection of endocrine and reproductive tract cy. Cancer Res. 37: 1099–1104. 1977. [Medline]
effects of exemestane in female rats treated for up to twenty-eight days. Nozaki Y, Furubo E, Matsuno T, Fukui R, Kizawa K, Kozaki T, and Sanzen
Toxicol Pathol. 39: 589–605. 2011. [Medline] [CrossRef] T. Collaborative work on evaluation of ovarian toxicity. 6) Two- or four-
Mitsuhashi N, Takahashi T, Nozaki M, Matsumoto H, Sakurai H, Takahashi week repeated-dose studies and fertility study of cisplatin in female rats.
M, and Niibe H. Establishment and characterization of a rat yolk sac J Toxicol Sci. 34(Suppl 1): SP73–SP81. 2009. [Medline]
tumor cell line, NMT-1, producing alpha-fetoprotein, with potential for Nyska A, Pirak M, Shahar A, Scolnik M, and Waner T. Spontaneous uterine
lymphatic metastasis. Jpn J Cancer Res. 84: 1287–1291. 1993. [Medline] granular cell tumour in a Fischer 344 rat. Lab Anim. 25: 299–302. 1991.
[CrossRef] [Medline] [CrossRef]
Miwa M, Kojima M, Ohtani T, and Tsuji K. [A recessive mutant causing tes- Ohtake S, Fukui M, and Hisada S. Collaborative work on evaluation of ovar-
ticular/ovarian teratoma in rats (Tera strain)]. Jikken Dobutsu. 36: 205– ian toxicity. 1) Effects of 2- or 4-week repeated-dose administration and
208. 1987 (In Japanese). [Medline] fertility studies with medroxyprogesterone acetate in female rats. J Toxi-
Mobini Far HR, Agren G, Lindqvist AS, Marmendal M, Fahlke C, and Thib- col Sci. 34(Suppl 1): SP23–SP29. 2009. [Medline] [CrossRef]
lin I. Administration of the anabolic androgenic steroid nandrolone dec- Pears AGE. Histochemistry, Theoretical and Applied, Vol Two: Analytical
anoate to female rats causes alterations in the morphology of their uterus Technology. Churchill Livingstone, Edinburgh, London, Melbourne,
and a reduction in reproductive capacity. Eur J Obstet Gynecol Reprod New York. 1985.
Biol. 131: 189–197. 2007. [Medline] [CrossRef] Pedersen T, and Peters H. Proposal for a classification of oocytes and fol-
Montgomery CA, and Alison RH. Nonneoplastic lesions of the ovary in licles in the mouse ovary. J Reprod Fertil. 17: 555–557. 1968. [Medline]
Fischer 344 rats and B6C3F1 mice. Environ Health Perspect. 73: 53–75. [CrossRef]
1987. [Medline] [CrossRef] Peluso JJ. Morphologic and physiologic features of the ovary. In: Mohr U,
Moore AB, He H, Yoshida A, Rico PJ, Haseman JK, and Dixon D. Transform- Dungworth DL, and Capen CC (eds). Pathobiology of the Aging Rat. ILSI
ing growth factor-alpha, epidermal growth factor receptor, and PCNA im- Press, Washington DC. 337–349. 1992.
munoexpression in uterine leiomyosarcomas and leiomyomas in B6C3F1 Peluso JJ, and Gordon LR. Nonneoplastic and neoplastic changes in the ovary.
mice. Exp Toxicol Pathol. 52: 195–200. 2000. [Medline] [CrossRef] In: Pathobiology of the aging rat. Vol 1.Mohr U, Dungworth DL, and Cap-
Morgan KT, and Alison RH. Tubular adenoma, ovary, mouse. In: Mono- en CC (eds). ILSI Press, Washington DC. 351–364. 1992.
graphs on pathology of laboratory animals. Genital system. Jones TC, Picut CA, Aoyama H, Holder JW, Gold LS, Maronpot RR, and Dixon D. Bro-
Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg New York, To- moethane, chloroethane and ethylene oxide induced uterine neoplasms
kyo. 36–41. 1987. in B6C3F1 mice from 2-year NTP inhalation bioassays: pathology and
Myers RK, and McGavin MD. Cellular and tissue responses to injury. In: incidence data revisited. Exp Toxicol Pathol. 55: 1–9. 2003. [Medline]
Pathologic Basis of Veterinary Disease. Fourth Ed. McGavin MD, and [CrossRef]
Zachary JF (eds). Mosby Elsevier, St. Louis. 2007. Picut CA, Remick AK, Asakawa MG, Simons ML, and Parker GA. Histo-
Nagaoka T, Takeuchi M, Onodera H, Matsushima Y, Ando-Lu J, and Maeka- logic features of prepubertal and pubertal reproductive development in
wa A. Sequential observation of spontaneous endometrial adenocarci- female Sprague-Dawley rats. Toxicol Pathol. 42: 403–413. 2014. [Med-
noma development in Donryu rats. Toxicol Pathol. 22: 261–269. 1994. line] [CrossRef]
[Medline] [CrossRef] Picut CA, Swanson CL, Parker RF, Scully KL, and Parker GA. The metrial
National Toxicology Program Carcinogenesis Bioassay of Zearalenone (CAS gland in the rat and its similarities to granular cell tumors. Toxicol Pathol.
No. 17924-92-4) in F344/N Rats and B6C3F1 Mice (Feed Study). Natl 37: 474–480. 2009. [Medline] [CrossRef]
Toxicol Program Tech Rep Ser. 235: 1–155. 1982. [Medline] Plowchalk DR, Meadows MJ, and Mattison DR. Reproductive toxicity of cy-
National Toxicology Program. NTP Toxicology and Carcinogenesis Studies clophosphamide in the C57BL/6N mouse: 2. Effects on uterine structure
of Oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 Mice and function. Reprod Toxicol. 6: 423–429. 1992. [Medline] [CrossRef]
(Feed Studies). Natl Toxicol Program Tech Rep Ser. 443: 1–321.1993. Putti R, and Varano L. Histological and histochemical modifications of the
Nelson LW, Kelly WA, and Weikel JH Jr. Mesovarial leiomyomas in rats in a uterine and vaginal mucosa of the mouse during the oestrus cycle. Basic
chronic toxicity study of mesuprine hydrochloride. Toxicol Appl Pharma- Appl Histochem. 23: 25–37. 1979. [Medline]
col. 23: 731–737. 1972. [Medline] [CrossRef] Rao GN, Hickman RL, Seilkop SK, and Boorman GA. Utero-ovarian infec-
Newbold RR, Banks EP, Bullock B, and Jefferson WN. Uterine adenocarci- tion in aged B6C3F1 mice. Lab Anim Sci. 37: 153–158. 1987. [Medline]
noma in mice treated neonatally with genistein. Cancer Res. 61: 4325– Regan KS, Cline JM, Creasy D, Davis B, Foley GL, Lanning L, Latendresse
106S DIXON ET AL.
JR, Makris S, Morton D, Rehm S, Stebbins K. STP Ovary Evaluation (eds). Springer, Berlin, Heidelberg, New York, Tokyo. 134–138. 1987b.
Working Group STP position paper: ovarian follicular counting in the Sobis H. Teratoma, uterus, rat. In: Monographs on pathology of laboratory
assessment of rodent reproductive toxicity. Toxicol Pathol. 33: 409–412. animals. Genital system. Jones TC, Mohr U, and Hunt RD (eds). Springer,
2005. [Medline] [CrossRef] Berlin, Heidelberg, New York, Tokyo. 120–126. 1987c.
Rehm S, Dierksen D, and Deerberg F. Spontaneous ovarian tumors in Squire RA, Goodman DG, Valerio MG, Fredrickson T, Strandberg JD, Levitt
Han:NMRI mice: histologic classification, incidence, and influence of MH, Lingeman CH, Harshbarger JC, and Dawe CJ. Tumors. Female re-
food restriction. J Natl Cancer Inst. 72: 1383–1395. 1984. [Medline] productive system. In: Pathology of laboratory animals Vol II. Benirschke
Rehm S, Stanislaus DJ, and Wier PJ. Identification of drug-induced hyper- or K, Garner FM, and Jones TC (eds). Springer, Berlin, Heidelberg, New
hypoprolactinemia in the female rat based on general and reproductive York, Tokyo. 1172–1194. 1978.
toxicity study parameters. Birth Defects Res B Dev Reprod Toxicol. 80: Steinmetz R, Mitchner NA, Grant A, Allen DL, Bigsby RM, and Ben-Jona-
253–257. 2007. [Medline] [CrossRef] than N. The xenoestrogen bisphenol A induces growth, differentiation,
Ruben Z, Arceo RJ, Bishop SP, Elwell MR, Kerns WD, Mesfin GM, San- and c-fos gene expression in the female reproductive tract. Endocrinol-
dusky GE, and Van Vleet JF. Proliferative lesions of the heart and vascu- ogy. 139: 2741–2747. 1998. [Medline]
lature in rats. In: Guides for Toxicologic Pathology. STP/ARP/AFIP CV-1, Stewart HL, Deringer MK, Dunn TB, and Snell KC. Malignant schwannomas
Washington, DC. 1997. of nerve roots, uterus, and epididymis in mice. J Natl Cancer Inst. 53:
Sakurada Y, Kudo S, Iwasaki S, Miyata Y, Nishi M, and Masumoto Y. Col- 1749–1758. 1974. [Medline]
laborative work on evaluation of ovarian toxicity. 5) Two- or four-week Stoica G, Capen CC, and Koestner A. Sertoli’s cell tumor, ovary, rat. In:
repeated-dose studies and fertility study of busulfan in female rats. J Monographs on pathology of laboratory animals. Genital system. Jones
Toxicol Sci. 34(Suppl 1): SP65–SP72. 2009. [Medline] [CrossRef] TC, Mohr U, and Hunt RD (eds). Springer, Berlin, Heidelberg, New York,
Sanbuissho A, Yoshida M, Hisada S, Sagami F, Kudo S, Kumazawa T, Ube Tokyo. 30–36. 1987.
M, Komatsu S, and Ohno Y. Collaborative work on evaluation of ovarian Suckow M, Weisbroth SH, and Franklin CL. The Laboratory Rat. Elsevier
toxicity by repeated-dose and fertility studies in female rats. J Toxicol Sci. Academic Press, Burlington. 2006.
34(Suppl 1): SP1–SP22. 2009. [Medline] [CrossRef] Sundberg JP. Imperforate vagina and mucometra in mice. In: JAX NOTES
Santos FC, Leite RP, Custódio AM, Carvalho KP, Monteiro-Leal LH, San- Issue 441, Spring 1990. 1990.
tos AB, Góes RM, Carvalho HF, and Taboga SR. Testosterone stimulates Sundberg JP, and Brown KS. Imperforate vagina and mucometra in inbred
growth and secretory activity of the female prostate in the adult gerbil laboratory mice. Lab Anim Sci. 44: 380–382. 1994. [Medline]
(Meriones unguiculatus). Biol Reprod. 75: 370–379. 2006. [Medline] Taketa Y, Yoshida M, Inoue K, Takahashi M, Sakamoto Y, Watanabe G, Taya
[CrossRef] K, Yamate J, and Nishikawa A. Differential stimulation pathways of pro-
Sasahara K, Ando-Lu J, Nishiyama K, Takahashi M, Yoshida M, and Maeka- gesterone secretion from newly formed corpora lutea in rats treated with
wa A. Granular cell foci of the uterus in Donryu rats. J Comp Pathol. 119: ethylene glycol monomethyl ether, sulpiride, or atrazine. Toxicol Sci. 121:
195–199. 1998. [Medline] [CrossRef] 267–278. 2011. [Medline] [CrossRef]
Sass B, and Rehm S. Tumours of the ovary. In: Pathology of tumours in labo- Tamura T, Yokoi R, Okuhara Y, Harada C, Terashima Y, Hayashi M, Naga-
ratory animals. Vol 2. Tumours of the mouse, 2nd edition. Turusov VS, sawa T, Onozato T, Kobayashi K, Kuroda J, and Kusama H. Collaborative
and Mohr U (eds). IARC Scientific Publications No. 111, Lyon. 493–526. work on evaluation of ovarian toxicity. 2) Two- or four-week repeated
1994. dose studies and fertility study of mifepristone in female rats. J Toxicol
Sato M, Shiozawa K, Uesugi T, Hiromatsu R, Fukuda M, Kitaura K, Minami Sci. 34(Suppl 1): SP31–SP42. 2009. [Medline] [CrossRef]
T, and Matsumoto S. Collaborative work on evaluation of ovarian toxic- Tan OL, Hurst PR, and Fleming JS. Location of inclusion cysts in mouse
ity. 7) Effects of 2- or 4- week repeated dose studies and fertility study of ovaries in relation to age, pregnancy, and total ovulation number: im-
cyclophosphamide in female rats. J Toxicol Sci. 34(Suppl 1): SP83–SP89. plications for ovarian cancer? J Pathol. 205: 483–490. 2005. [Medline]
2009a. [Medline] [CrossRef]
Sato N, Uchida K, Nakajima M, Watanabe A, and Kohira T. Collaborative Telfer E, and Gosden RG. A quantitative cytological study of polyovular fol-
work on evaluation of ovarian toxicity. 13) Two- or four-week repeated licles in mammalian ovaries with particular reference to the domestic
dose studies and fertility study of PPAR alpha/gamma dual agonist in bitch (Canis familiaris). J Reprod Fertil. 81: 137–147. 1987. [Medline]
female rats. J Toxicol Sci. 34(Suppl 1): SP137–SP146. 2009b. [Medline] [CrossRef]
Seaman WJ. Postmortem change in the rat: A histologic characterization. Toaff ME, Abramovici A, Sporn J, and Liban E. Selective oocyte degenera-
Iowa State University Press, Ames. 1987. tion and impaired fertility in rats treated with the aliphatic monoterpene,
Serov SF, Scully RE, and Sobin LH. International histological classification Citral. J Reprod Fertil. 55: 347–352. 1979. [Medline] [CrossRef]
of tumours No 9. Histological typing of ovarian tumours. WHO, Geneva. Tryphonas L, and Buttar HS. Genital tract toxicity of nonoxynol-9 in female
1–56. 1973. rats: temporal development, reversibility and sequelae of the induced le-
Shibayama H, Kotera T, Shinoda Y, Hanada T, Kajihara T, Ueda M, Tamura sions. Fundam Appl Toxicol. 2: 211–219. 1982. [Medline] [CrossRef]
H, Ishibashi S, Yamashita Y, and Ochi S. Collaborative work on evalu- Tsubota K, Kushima K, Yamauchi K, Matsuo S, Saegusa T, Ito S, Fujiwara
ation of ovarian toxicity. 14) Two- or four-week repeated-dose studies M, Matsumoto M, Nakatsuji S, Seki J, and Oishi Y. Collaborative work on
and fertility study of atrazine in female rats. J Toxicol Sci. 34(Suppl 1): evaluation of ovarian toxicity. 12) Effects of 2- or 4-week repeated dose
SP147–SP155. 2009. [Medline] [CrossRef] studies and fertility study of indomethacin in female rats. J Toxicol Sci.
Shirai M, Sakurai K, Saitoh W, Matsuyama T, Teranishi M, Furukawa T, San- 34(Suppl 1): SP129–SP136. 2009. [Medline] [CrossRef]
buissho A, and Manabe S. Collaborative work on evaluation of ovarian Tsujioka S, Ban Y, Wise LD, Tsuchiya T, Sato T, Matsue K, Ikeda T, Sasaki
toxicity. 8) Two- or four-week repeated-dose studies and fertility study of M, and Nishikibe M. Collaborative work on evaluation of ovarian toxic-
Anastrozole in female rats. J Toxicol Sci. 34(Suppl 1): SP91–SP99. 2009. ity. 3) Effects of 2- or 4- week repeated-dose toxicity and fertility stud-
[Medline] [CrossRef] ies with tamoxifen in female rats. J Toxicol Sci. 34(Suppl 1): SP43–SP51.
Sobis H. Yolk sac carcinoma, rat. In: Monographs on pathology of laboratory 2009. [Medline] [CrossRef]
animals. Genital system. Jones TC, Mohr U, and Hunt RD (eds). Springer, Tucker MJ. Diseases of the Wistar Rat. Taylor & Francis, London, Bristol.
Berlin, Heidelberg, New York, Tokyo. 127–134. 1987. 1997.
Sobis H. Choriocarcinoma, uterus, rat. In: Monographs on pathology of labo- Turusov MS, Munoz N, and Dunn TB. Tumours of the vagina and uterus.
ratory animals. Genital system. Jones TC, Mohr U, and Hunt RD (eds). In: Pathology of Tumours in Laboratory Animals, Vol 2. Tumours of the
Springer, Berlin, Heidelberg, New York, Tokyo. 138–140. 1987a. Mouse. Turusov V, and Mohr U (eds). IARC Scientific Publications. 1994.
Sobis H. Embryonal carcinoma, uterus, rat. In: Monographs on pathology Usta U, Inan M, Erbas H, Aydogdu N, Oz Puyan F, and Altaner S. Tissue dam-
of laboratory animals. Genital system. Jones TC, Mohr U, and Hunt RD age in rat ovaries subjected to torsion and detorsion: effects of L-carnitine
Lesions of the Female Reproductive System 107S
and N-acetyl cysteine. Pediatr Surg Int. 24: 567–573. 2008. [Medline] mice. J Natl Cancer Inst. 63: 849–854. 1979. [Medline]
[CrossRef] Wenzel JG, and Odend’hal S. The mammalian rete ovarii: a literature review.
van den Brink-Knol H, and van Esch E. Spontaneous malignant mixed Mülle- Cornell Vet. 75: 411–425. 1985. [Medline]
rian tumor in a Wistar rat: a case report including immunohistochemistry. Westwood FR. The female rat reproductive cycle: a practical histological
Vet Pathol. 47: 1105–1110. 2010. [Medline] [CrossRef] guide to staging. Toxicol Pathol. 36: 375–384. 2008. [Medline] [Cross-
Veit AC, Painter JT, Miller RA, Hardisty JF, and Dixon D. Characterization Ref]
of uterine granular cell tumors in B6C3F1 mice: a histomorphologic, im- Yoshida M, Katsuda S, Tanimoto T, Asai S, Nakae D, Kurokawa Y, Taya K,
munohistochemical, and ultrastructural study. Vet Pathol. 45: 654–662. and Maekawa A. Induction of different types of uterine adenocarcinomas
2008. [Medline] [CrossRef] in Donryu rats due to neonatal exposure to high-dose p-t-octylphenol
Vidal JD, Mirsky ML, Colman K, Whitney KM, and Creasy DM. Reproduc- for different periods. Carcinogenesis. 23: 1745–1750. 2002. [Medline]
tive System and Mammary Gland. In: Toxicologic Pathology: Nonclinical [CrossRef]
Safety Assessment. Sahota P, Popp JA, Hardisty JF, and Gopinath C (eds). Yoshida M, Sanbuissyo A, Hisada S, Takahashi M, Ohno Y, and Nishikawa
CRC Press, Boca Raton. 717–830. 2013. A. Morphological characterization of the ovary under normal cycling
Vollmer G. Endometrial cancer: experimental models useful for studies on in rats and its viewpoints of ovarian toxicity detection. J Toxicol Sci.
molecular aspects of endometrial cancer and carcinogenesis. Endocr 34(Suppl 1): SP189–SP197. 2009. [Medline]
Relat Cancer. 10: 23–42. 2003. [Medline] [CrossRef] Yoshida M, Shiraki K, Kudoh K, Ando-Lu J, Takahashi M, and Maekawa
Vrcić H, Horvat B, and Damjanov I. Lectin histochemistry of mouse vagina A. A uterine choriocarcinoma in a virgin Donryu rat. Toxicol Pathol. 25:
during the estrous cycle. J Histochem Cytochem. 39: 1685–1692. 1991. 644–646. 1997. [Medline] [CrossRef]
[Medline] [CrossRef] Yoshida M, Watanabe G, Shirota M, Maekawa A, and Taya K. Reduction of
Walker VE, Morgan KT, Zimmerman HM, and Innes JRM. Tumours of the primordial follicles caused by maternal treatment with busulfan promotes
central and peripheral nervous system. In: Pathology of tumours in labo- endometrial adenocarcinoma development in donryu rats. J Reprod Dev.
ratory animals. Vol 2. Tumours of the mouse, 2nd edition. Turusov VS, 51: 707–714. 2005. [Medline] [CrossRef]
and Mohr U (eds). IARC Scientific Publications No. 111, Lyon. 731–776. Yuan Y. Structure, cyclic change, and function, vagina and vulva, rat. In:
1994. Monographs on Pathology of Laboratory Animals. Genital System.
Wang F, Yu B, Yang W, Liu J, Lu J, and Xia X. Polycystic ovary syndrome Springer-Verlag, Berlin, Heidelberg, New York. 161–168. 1987.
resembling histopathological alterations in ovaries from prenatal andro- Yuan Y, and Foley G. Female reproductive system. In: Handbook of Toxico-
genized female rats. J Ovarian Res. 5: 15. 2012. [Medline] [CrossRef] logic Pathology, Vol. 2. Hascheck WM, Rousseaux CG, and Wallig MA
Ward JM, Goodman DG, Squire RA, Chu KC, and Linhart MS. Neoplastic (eds). Academic Press, San Diego. 847–894. 2002.
and nonneoplastic lesions in aging (C57BL/6N x C3H/HeN)F1 (B6C3F1)