BREAST AND FEMALE GENITAL TRACT PATHOLOGY

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CHAPTER 5 BREAST AND FEMALE GENITAL TRACT PATHOLOGY

Pediatric breast pathology

Breast carcinoma
Li–fraumeni syndrome
Juvenile papillomatosis
Fibrocystic change
Fibrous mastopathy / diabetic mastopathy
Fibroadenoma
Phyllodes tumor
Gynecomastia
Virginal hypertrophy of the breast (macromastia)
Supernumerary nipple
Accessory breast tissue

Genital tract pathology

Ovarian germ cell tumors
Mixed germ cell–stromal tumors
Gonadoblastoma
Small cell carcinoma of hypercalcemic type
Ovarian sex-cord stromal tumors
Ovarian cysts
Streak ovary
Massive ovarian edema
Vulval lesions
Clear cell adenocarcinoma of vagina/cervix
Vaginal adenosis

PEDIATRIC BREAST PATHOLOGY

• Malignant disease is rare

image when present more likely to be secondary

– especially ARMS

• Mesenchymal tumors relatively much more common than in adulthood

image vascular lesions
image pseudoangiomatoid stromal hyperplasia

– anastomosing slit-like spaces
– CD34+ spindle cells, CD31−

image fibromatosis

BREAST CARCINOMA

• Rare in childhood
• May affect both females and males

image very rare but reported in boys (Bhagwandeen et al 1999)

• Secretory subtype most common (Longo et al 1999)

image ETV6-NTRK3 associated, same as IFS / CMN (Tognon et al 2002)
image low grade
image histological patterns

– honeycomb / microcystic
– solid
– tubular

image ovoid cells with pale eosinophilic granular cytoplasm
image intracytoplasmic lumina
• DPAS+ and AB+ mucin present
• EMA+
• Good prognosis in children

LI–FRAUMENI SYNDROME

• Predisposition to multiple malignant tumors

image including sarcomas and carcinomas

– occurring in children and adulthood

· soft tissue sarcomas, adrenal cortical carcinoma and brain tumors in childhood
· breast carcinoma in adulthood

• Due to TP53 mutations

JUVENILE PAPILLOMATOSIS

• Mass lesion in breast
• Usually young adults but reported in children

image including rarely infant boys

• Increased risk of familial breast cancer
• Unencapsulated macrocystic lesion with fibrous stroma (Figs 5.1, 5.2)

image multiple cysts
image dilated ducts with apocrine metaplasia
image duct ectasia
image sclerosing adenosis-like changes
image epithelial hyperplasia
image microcalcifications
image

Fig. 5.1

image

Figs 5.1–5.2 Photomicrographs of child with juvenile papillomatosis, demonstrating duct ectasia with apocrine metaplasia and stromal sclerosis.

FIBROCYSTIC CHANGE

• Focal mass lesion in breast
• Cystic change
• Epithelial hyperplasia / metaplasia

image if atypical hyperplasia may be associated with increased risk of breast carcinoma

FIBROUS MASTOPATHY / DIABETIC MASTOPATHY

• Firm breast mass
• Variably cellular spindle cells in collagenous stroma
• Entrapped ducts / lobules
• Lymphocytic infiltration with DM

FIBROADENOMA (Figs 5.3, 5.4)

• Painless firm breast nodule
• May grow very large in adolescents (giant fibroadenoma)
• Epithelial and mesenchymal components
• Pericanalicular pattern

image stromal cells circumferentially surrounding ducts

• Intracanalicular pattern

image ducts compressed into slit-like spaces

• Variably cellular stromal component

image pediatric cases often more cellular
image myxoid or hyaline stromal change

• Epithelial component

image variable hyperplastic and metaplastic changes
image pediatric cases often show epithelial proliferation

• Note: Intramammary hamartoma may show similar clinical and macroscopic features

image circumscribed lesion
image admixture of all components of normal breast tissue

– with or without superimposed secondary changes

image

Fig. 5.3

image

Figs 5.3–5.4 Photomicrographs of child with a juvenile (giant) fibroadenoma, demonstrating cellular stroma which circumferentially surrounds ducts which show epithelial proliferation.

PHYLLODES TUMOR

• Biphasic lesion similar to fibroadenoma
• Most are benign

image local recurrence and metastases reported in minority
image 2% mortality overall
image 10–20% local recurrence (Rajan et al 1998)

• Mainly adults

image well-reported in childhood

• Epithelial structures with surrounding stromal overgrowth

image stroma more cellular than fibroadenoma

– especially hypercellular beneath epithelium
– frankly malignant mesenchymal change may occur

image epithelium forms leaf-like areas

– epithelial hyperplasia / metaplasia

• Predictors of malignant behavior based on:

image degree of hypercellularity
image pleomorphism
image mitotic count
image stromal overgrowth

– poor prediction of behavior in individual cases

image local relapse associated with

– positive margins
– fibroproliferation in surrounding tissue
– necrosis (Barrio et al 2007)

GYNECOMASTIA

• Enlargement of the male breast ductular system

Epidemiology

• Males
• In childhood may occur in neonates and adolescents

Clinical features

• Bilateral but often asymmetric breast enlargement

Histopathological features (Figs 5.5, 5.6)

• Circumscribed area of ducts with surrounding stroma
• Stroma may be myxoid, with scattered inflammatory cells

image hyalinization with progression

• Epithelium usually bland

image ectasia, metaplasia and hyperplasia may occur

image

Fig. 5.5

image

Figs 5.5–5.6 Photomicrographs of breast lesions from a boy with gynecomastia, demonstrating ductular structures within a bland hyalinized stroma.

Differential diagnoses and pitfalls

• Always consider possible underlying endocrinopathies

VIRGINAL HYPERTROPHY OF THE BREAST (MACROMASTIA)

• Gynecomastia-like changes but in female breast around puberty
• Proliferation of ducts within hypocellular stroma

image may show pseudoangiomatous hyperplasia-like stromal changes
image stroma less cellular than fibroadenoma

SUPERNUMERARY NIPPLE

• Pigmented macule on milk line

image rarely more ‘ectopic’ position

• Histologically features of normal nipple
• Wide range of tumor may develop

image usually in adults

ACCESSORY BREAST TISSUE

• Mass in axilla or vulva

image range of breast pathologies

Other soft tissue lesions may also affect the breast

• See tumor and skin sections (Fig 5.7)
image

Fig 5.7 Photomicrograph of a case of fibromatosis involving the breast in a child.

GENITAL TRACT PATHOLOGY

OVARIAN GERM CELL TUMORS

Epidemiology

• Median age adolescent / young adult

image commonest malignant ovarian tumor of childhood

Clinical features

• Mass effect
• With or without torsion or rupture

Histopathological features (Figs 5.8–5.13)

• Two main groups

image teratoma
image malignant germ cell tumors

image

Fig. 5.8

image

Figs 5.8–5.9 Photographs of an ovarian teratoma in a child, showing a mixed solid and cystic pattern.

image

Fig. 5.10

image

Fig. 5.11

image

Fig. 5.12

image

Figs 5.10–5.13 Photomicrographs of ovarian teratomas, demonstrating a variety of mature elements. In immature teratomas, neuroepithelial tubular structures are also seen.

TERATOMA

• Mature teratoma

image contains only mature tissue elements
image from two or three embryonic layers
image cystic and solid
image monodermal teratomas

– predominantly one type of tissue

image malignancies may develop within a teratoma

– including carcinoid and PNET
– carcinoma development in teratoma occurs in adults

• Immature teratoma

image pure or part of mixed germ cell tumors
image contains immature neuroepithelial elements admixed with mature elements

– rosettes and tubules

image immature mesenchyme may also be present

– chondroid, osteoid, rhabdomyoblasts

image grading based on predominantly adult ovarian teratomas

– not directly applicable to teratomas at other sites and ages
– in childhood, surgery alone is curative for stage 1 regardless of grade provided that no yolk sac elements are present

image grading requires sampling of at least 1cm diameter

– Grade 1 <1 lpf (×40) on any slide
– Grade 2 1–3 lpf (×40) on any slide
– Grade 3 >3 lpf (×40) on any slide

• Gliomatosis peritonei

image multiple glial peritoneal nodules
image usually histologically mature
image occasionally immature
image initially thought to be secondary to tumor rupture / spillage and seeding

– recent genetic evidence suggests possible multifocal metaplasia / formation from peritoneal germ cells

Malignant germ cell tumors

• Dysgerminoma

image sheets of monotonous polygonal primitive germ cells

– uniform nuclei

image lymphocytic infiltrate
image may show nested architecture
image 5% demonstrate syncytiotrophoblastic differentiation
image PLAP+
image CD117+
image patchy CK+
image CD30−

• Yolk sac tumor

image many histological patterns of epithelial differentiation

– reticular
– polyvesicular vitelline
– solid
– glandular
– hepatoid

image mesh-like epithelium in myxoid stroma
image clear cytoplasm

– DPAS+ cytoplasmic globules

image hyaline basement membrane-like material
image Schiller–Duval bodies in 30%

– papillary structures

image cytokeratin+
image aFP focal cytoplasmic+

• Embryonal carcinoma

image disorganized sheets of large pleomorphic primitive germ cells
image focal organoid differentiation
image CD30+
image focal aFP+

• Non-gestational choriocarcinoma

image trophoblastic differentiation

• Mixed malignant germ cell tumor

image mixture of above patterns

MIXED GERM CELL–STROMAL TUMORS

GONADOBLASTOMA

• Y chromosome present in almost all cases

image usually phenotypic females

• Local excision adequate treatment if no frankly malignant elements are present

Histopathological features

• May be bilateral
• Cellular nests of germ cells (seminoma / dysgerminoma like) mixed with sex cord cells surrounded by stroma
• Sex cord cells surround periphery of germ cell nests and globules of hyaline material
• Secondary hyalinization, calcification and development of malignant germ cell tumors

image especially dysgerminoma

Mixed germ cell–sex cord–stromal tumor

• Occurs in genetically normal females

image cf gonadoblastoma

• Mass and precocious puberty in 25%

Histopathological features

• Unilateral solid and cystic
• Mixed sex cord and germ cell elements

image without the characteristic pattern of gonadoblastoma

• Variable patterns:

image trabecular
image tubular
image haphazard
image mixed

• 10% associated with malignant germ cell tumors such as dysgerminoma

image less than with gonadoblastoma

SMALL CELL CARCINOMA OF HYPERCALCEMIC TYPE

Epidemiology

• Rare

image mainly sporadic but some familial cases reported

• Older children / young adults
• Hypercalcemia

Histopathological features

• Solid unilateral ovarian mass
• Sheets, trabeculae, cords, follicles
• Small ovoid to spindled cells

image little cytoplasm
image overlapping nuclei

Immunohistochemical staining

• Cytokeratin+
• CD56+
• Chromogranin+
• CD99 negative

image cf PNET

• Inhibin negative

image cf granulosa cell tumor

OVARIAN SEX-CORD STROMAL TUMORS

GRANULOSA CELL TUMOR

Epidemiology

• Mainly adults

image 5% of all ovarian granulosa cell tumors in childhood

• Mostly sporadic

image may be associated with Ollier, Mafucci and Goldenhar syndromes

– especially if bilateral

Clinical features

• Mass effect
• Steroid hormone effects

image usually estrogen

– precocious puberty

image 5% aggressive behavior

• Stage >I important for adverse outcome

Histopathological features (Figs 5.14–5.18)

• Two main types: adult and juvenile
• Adult type

image occurs only very rarely in children
image bland ovoid granulosa cells

– grooved nuclei

image fibrothecomatous stroma
image several patterns

– including Call–Exner body formation

image inhibin and CD99+

• Juvenile type

image nodular or diffuse growth of granulosa cells

– prominent cyst / follicle formation
– no classical Call–Exner bodies

image granulosa cells

– bland
– ovoid
– eosinophilic cytoplasm
– no nuclear grooves
– mitoses common

image inhibin and CD99+

image

Fig. 5.14

image

Figs 5.14–5.15 Photographs of an ovarian juvenile granulosa cell tumor, showing a mixed solid and cystic pattern.

image

Fig. 5.16

image

Fig. 5.17

image

Figs 5.16–5.18 Photomicrographs of an ovarian juvenile granulosa cell tumor, demonstrating cystic areas surrounded by granulosa type cells and solid areas composed of bland ovoid granulosa cells with eosinophilic cytoplasm.

THECOMA / FIBROMAS

• Rare in childhood
• Plump ovoid to spindle cells
• Thecomas are inhibin+

STROMAL TUMOR WITH MINOR (<10%) SEX CORD ELEMENTS

• Mainly adults

SCLEROSING STROMAL TUMOR

• Mainly adults

image occasional adolescents

• Cellular pseudolobules of round and spindle cells

image patchy sclerosis

• Separated by hypocellular edematous stroma
• Inhibin, vimentin, SMA and desmin+

SERTOLI–LEYDIG CELL TUMORS

• Mainly adults
• Androgen or estrogen production
• Sertoli cell tubules and Leydig cell clusters
• Varying degrees of differentiation from above to sarcomatoid appearance based on Sertoli cell appearance
• Higher grade associated with relative reduction in Leydig cell component
• Vimentin, keratin and inhibin+
• Minority (20%) may also have heterologous elements

image retiform variant has >90% slit-like spaces resembling rete testis
image may have more aggressive course

• Pure Sertoli cell tumors have no Leydig cell component
• Variant in Peutz–Jeghers syndrome

image Sex cord tumor with annular tubules (SCTAT)

– usually adults

· even in PJS

– Sertoli cell tubules surrounding hyaline bodies

• Charcot–Bottcher intracytoplasmic filaments
• Complex mixed sex-cord stromal tumors may also occur with combinations of the above

GYNANDROBLASTOMA

• Mixed well-differentiated Sertoli cell and granulosa cell components
• Pure steroid or Leydig cell tumors may also occur

image usually associated with steroid production effects

OVARIAN CYSTS

• Epithelial neoplastic cysts rare in childhood
• Most cystic neoplasms are teratomas (see above)
• Most cystic structures are non-neoplastic cysts (Figs 5.19, 5.20)

image follicular cysts

– includes theca-lutein and corpus luteum

image endometriosis

– stroma also present

image simple epithelial / unclassified

– simple cuboidal epithelium

image

Fig. 5.19

image

Figs 5.19–5.20 Photomicrographs of simple ovarian follicular cysts in infants, which may be nondescript, show definite follicular features and even luteinization.

STREAK OVARY

• Flattened, tubular structure
• Cellular, fibrous stroma (Fig 5.21)

image similar to normal ovarian stroma
• Absent follicles
• No germ cells

image may occasionally be present in fetal cases cf surgical specimens

image

Fig 5.21 Photomicrograph of streak ovary, demonstrating a nodule / plaque of ovarian type stroma but no oocytes.

MASSIVE OVARIAN EDEMA

• Non-neoplastic unilateral ovarian enlargement

image may be complicated by frank torsion
image presents as abdominal mass
image may be associated with precocious puberty

– possible response to torsion / ischemia (Nogales et al 1996)

• Smooth surface
• Thickened capsule
• Edematous stroma

image most marked centrally

• Stromal edema with scattered follicles
• Focal hemorrhage
• Scattered luteinized cells
• Note:

image may be overlap with ovarian fibromatosis

– more bilateral involvement
– more dense collagen
– less edema (Young & Scully 1984)

VULVAL LESIONS

• All vulval tumors are rare in childhood
• Wide range of cutaneous and soft tissue pathologies may affect the vulval region

image see skin and soft tissue sections

• Mesenchymal tumors most common

image eRMS (see tumor section)
image specific vulval fibromatous / angiofibromatous lesions (see below)

Deep angiomyxoma

• Mainly adults
• Deep infiltrative lesion of perineum
• Unencapsulated
• Composed of uniform spindle to stellate cells

image no significant nuclear atypia

• Admixed vessels with thickened and hyalinized walls
• Desmin and SMA+

Superficial angiomyxoma

• Mainly adults
• Dermal / subcutaneous mass lesion
• Fibroblastic lesion in myxoid matrix
• Thin walled vessels
• Minimal atypia
• Scattered neutrophils

Prepubertal vulval fibroma

• Distinctive lesion of prepubertal girls (Iwasa & Fletcher 2004)

image median age 8 years
• Unilateral labial mass
• Poorly circumscribed hypocellular lesion

image bland spindle cells
image variably collagenous / edematous / myxoid stroma

• Infiltrates between normal structures
• No cytologic atypia
• Immunoreactive for CD34

image SMA, desmin, S-100−

CLEAR CELL ADENOCARCINOMA OF VAGINA/CERVIX

• Many cases reported in children and young women in 1970s

image due to in-utero DES use
image now no longer used so much less common

• Adenosis adjacent to these tumors in >90%
• Clear cell adenocarcinoma
• Tubulocystic, solid, mixed and papillary patterns
• Clear cells and hobnail cells
• Most common malignancy of vagina in children is eRMS not carcinoma (see RMS section)

VAGINAL ADENOSIS

• Persistence of mullerian epithelium in vaginal wall forming glandular structures

image endocervical or endometrial types

• May occur sporadically or with increased frequency after in-utero exposure of DES
• Increased risk of development of clear cell carcinoma
• Preceded by atypical adenosis
• Note: Gartner (mesonephric) duct remnants and Mullerian papillomas both also reported in vaginal wall
• Uterine surgical pathology is extremely rare in childhood

REFERENCES

Barrio AV, Clark BD, Goldberg JI, et al. Clinicopathologic features and long-term outcomes of 293 phyllodes tumors of the breast. Ann Surg Oncol. 2007;14:2961-2970.

Bhagwandeen BS, Fenton L. Secretory carcinoma of the breast in a nine year old boy. Pathology. 1999;31:166-168.

Iwasa Y, Fletcher CD. Distinctive prepubertal vulval fibroma: a hitherto unrecognized mesenchymal tumor of prepubertal girls: analysis of 11 cases. Am J Surg Pathol. 2004;28:1601-1608.

Longo OA, Mosto A, Moran JC, Mosto J, Rives LE, Sobral F. Breast carcinoma in childhood and adolescence: case report and review of the literature. Breast J. 1999;5:65-69.

Nogales FF, Martin-Sances L, Mendoza-Garcia E, Salamanca A, González-Nuñez A, Pardo Mindán FJ. Massive ovarian edema. Histopathol. 1996;28:229-234.

Rajan PB, Cranor ML, Rosen PP. Cystosarcoma phyllodes in adolescent girls and young women: a study of 45 patients. Am J Surg Pathol. 1998;22:64-69.

Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367-376.

Young RH, Scully RE. Fibromatosis and massive edema of the ovary, possibly related entities: a report of 14 cases of fibromatosis and 11 cases of massive edema. Int J Gynecol Pathol. 1984;3:153-178.

[/level-membership-for-pathology-category][not-level-membership-for-pathology-category]

CHAPTER 5 BREAST AND FEMALE GENITAL TRACT PATHOLOGY

Pediatric breast pathology

Breast carcinoma
Li–fraumeni syndrome
Juvenile papillomatosis
Fibrocystic change
Fibrous mastopathy / diabetic mastopathy
Fibroadenoma
Phyllodes tumor
Gynecomastia
Virginal hypertrophy of the breast (macromastia)
Supernumerary nipple
Accessory breast tissue

Genital tract pathology

Ovarian germ cell tumors
Mixed germ cell–stromal tumors
Gonadoblastoma
Small cell carcinoma of hypercalcemic type
Ovarian sex-cord stromal tumors
Ovarian cysts
Streak ovary
Massive ovarian edema
Vulval lesions
Clear cell adenocarcinoma of vagina/cervix
Vaginal adenosis

PEDIATRIC BREAST PATHOLOGY

• Malignant disease is rare

image when present more likely to be secondary

– especially ARMS

• Mesenchymal tumors relatively much more common than in adulthood

image vascular lesions
image pseudoangiomatoid stromal hyperplasia

– anastomosing slit-like spaces
– CD34+ spindle cells, CD31−

image fibromatosis

BREAST CARCINOMA

• Rare in childhood
• May affect both females and males

image very rare but reported in boys (Bhagwandeen et al 1999)

• Secretory subtype most common (Longo et al 1999)

image ETV6-NTRK3 associated, same as IFS / CMN (Tognon et al 2002)
image low grade
image histological patterns

– honeycomb / microcystic
– solid
– tubular

image ovoid cells with pale eosinophilic granular cytoplasm
image intracytoplasmic lumina
• DPAS+ and AB+ mucin present
• EMA+
• Good prognosis in children

LI–FRAUMENI SYNDROME

• Predisposition to multiple malignant tumors

image including sarcomas and carcinomas

– occurring in children and adulthood

· soft tissue sarcomas, adrenal cortical carcinoma and brain tumors in childhood
· breast carcinoma in adulthood

• Due to TP53 mutations

JUVENILE PAPILLOMATOSIS

• Mass lesion in breast
• Usually young adults but reported in children

image including rarely infant boys

• Increased risk of familial breast cancer
• Unencapsulated macrocystic lesion with fibrous stroma (Figs 5.1, 5.2)

image multiple cysts
image dilated ducts with apocrine metaplasia
image duct ectasia
image sclerosing adenosis-like changes
image epithelial hyperplasia
image microcalcifications
image

Fig. 5.1

image

Figs 5.1–5.2 Photomicrographs of child with juvenile papillomatosis, demonstrating duct ectasia with apocrine metaplasia and stromal sclerosis.

FIBROCYSTIC CHANGE

• Focal mass lesion in breast
• Cystic change
• Epithelial hyperplasia / metaplasia

image if atypical hyperplasia may be associated with increased risk of breast carcinoma

FIBROUS MASTOPATHY / DIABETIC MASTOPATHY

• Firm breast mass
• Variably cellular spindle cells in collagenous stroma
• Entrapped ducts / lobules
• Lymphocytic infiltration with DM

FIBROADENOMA (Figs 5.3, 5.4)

• Painless firm breast nodule
• May grow very large in adolescents (giant fibroadenoma)
• Epithelial and mesenchymal components
• Pericanalicular pattern

image stromal cells circumferentially surrounding ducts

• Intracanalicular pattern

image ducts compressed into slit-like spaces

• Variably cellular stromal component

image pediatric cases often more cellular
image myxoid or hyaline stromal change

• Epithelial component

image variable hyperplastic and metaplastic changes
image pediatric cases often show epithelial proliferation

• Note: Intramammary hamartoma may show similar clinical and macroscopic features

image circumscribed lesion
image admixture of all components of normal breast tissue

– with or without superimposed secondary changes

image

Fig. 5.3

image

Figs 5.3–5.4 Photomicrographs of child with a juvenile (giant) fibroadenoma, demonstrating cellular stroma which circumferentially surrounds ducts which show epithelial proliferation.

PHYLLODES TUMOR

• Biphasic lesion similar to fibroadenoma
• Most are benign

image local recurrence and metastases reported in minority
image 2% mortality overall
image 10–20% local recurrence (Rajan et al 1998)

• Mainly adults

image well-reported in childhood

• Epithelial structures with surrounding stromal overgrowth

image stroma more cellular than fibroadenoma

– especially hypercellular beneath epithelium
– frankly malignant mesenchymal change may occur

image epithelium forms leaf-like areas

– epithelial hyperplasia / metaplasia

• Predictors of malignant behavior based on:

image degree of hypercellularity
image pleomorphism
image mitotic count
image stromal overgrowth

– poor prediction of behavior in individual cases

image local relapse associated with

– positive margins
– fibroproliferation in surrounding tissue
– necrosis (Barrio et al 2007)

GYNECOMASTIA

• Enlargement of the male breast ductular system

Epidemiology

• Males
• In childhood may occur in neonates and adolescents

Clinical features

• Bilateral but often asymmetric breast enlargement

Histopathological features (Figs 5.5, 5.6)

• Circumscribed area of ducts with surrounding stroma
• Stroma may be myxoid, with scattered inflammatory cells

image hyalinization with progression

• Epithelium usually bland

image ectasia, metaplasia and hyperplasia may occur

image

Fig. 5.5

image

Figs 5.5–5.6 Photomicrographs of breast lesions from a boy with gynecomastia, demonstrating ductular structures within a bland hyalinized stroma.

Differential diagnoses and pitfalls

• Always consider possible underlying endocrinopathies

VIRGINAL HYPERTROPHY OF THE BREAST (MACROMASTIA)

• Gynecomastia-like changes but in female breast around puberty
• Proliferation of ducts within hypocellular stroma

image may show pseudoangiomatous hyperplasia-like stromal changes
image stroma less cellular than fibroadenoma

SUPERNUMERARY NIPPLE

• Pigmented macule on milk line

image rarely more ‘ectopic’ position

• Histologically features of normal nipple
• Wide range of tumor may develop

image usually in adults

ACCESSORY BREAST TISSUE

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