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					Novak 33. Ovarian ca

Nonepithelial Ovarian Cancers

       부산백병원 산부인과
         R2 박영미
    Nonepithelial Ovarian Cancers

   Compared with epithelial ovarian cancers,
     other malignant tumors of the ovary are
        about 10% of all ovarian cancers

        1. malinancies of germ cell origin,
            sex cord-stromal cell origin,
        2. metastatic carcinoma to ovary
        3. extremely rare ovarian cancers
           (sarcoma, lipoid cell tumors)
Germ-Cell Malignancies
Germ-Cell Malignancies
           Germ-Cell Malignancies
◆ Serum tumor markers in malignant germ cell tumors
    : can be clinically useful in the diagnosis of a pelvic mass and
      in monitoring course of patient after surgery

   α-fetoprotein(AFP), human chorionic
     : secreted by germ cell malignancy

   Placental alkaline phosphatase (PLAP),
    lactate dehydrogenase(LDH)
      : produced by dysgerminoma
         Germ-Cell Malignancies
◆ Symptoms

   Germ-cell malignancies grow rapidly,
    in contrast to the relatively slow growing epithelial
    ovarian tumors

    : often are characterized by subacute pelvic pain
      related to capsular distension, hemorrhage, or
    : may produce pressure symptoms on the bladder or
           Germ-Cell Malignancies
   In menarchal patients,
    menstrual irregularities may also occur
       Some young patients may misinterpret the early symptoms of
        a neoplasm as pregnancy
         --> This can lead to a delay in the diagnosis

   Acute symptoms associated with torsion or rupture of
    the adnexa

   In more advanced cases,
       ascites and abdominal distension may develop
          Germ-Cell Malignancies
◆ Diagnosis

   Adnexal masses will usually require surgical
       2 cm or larger in premenarchal patient
       8 cm or larger in other premennopausal patient

   Predominantly cystic lesions up to 8cm in
    diameters in postmenarcheal patients
    : may be observed or given oral contraceptives for
      two menstrual cycles
          Germ-Cell Malignancies
   For young patient
       Blood test - serum hCG and AFP titers, CBC, LFT
       Chest x-ray - evaluation for metastasis to the
                       lung or mediastinum
       Karyotype - preoperatively for all premenarcheal
                    girl because of the propensity of these
                    tumors to arise in dysgenetic gonads
       CT or MRI - may document retroperitoneal
                     lymphadenopathy or liver metastases
         but, such expensive and time- consuming
         evaluation is unnecessary because the patients
         require surgical exploration
◆ Clinical Characteristics

   The most common malignant germ-cell tumor
       1-3% of all ovarian cancer
       5-10% of ovarian cancers in patients younger than
        20 years of age

    * 5% : before the age of 10 years,
    * 75% : between the ages of 10 and 30 years
    * rarely occur after 50 years of age
   20-30% of ovarian malignancies associated with
    pregnancy are dysgerminomas

   Found in both sexes and may arise in gonadal or
    extragonadal sites

   Size varies widely, but usually 5-15cm in diameter

   Capsule is slightly bosselated, the cut surface
    consistency is spongy, the color is gray-brown
   The histologic

       The large round,
        ovoid, or polygonal

       abundant, clear, very
        pale staining
        cytoplasm, large and
        irregular nuclei, and
        prominent nucleoli
   Approximately 5% of dysgerminomas are
    discovered in phenotypic females with
    abnormal gonads.

       pure gonadal dysgenesis (46XY, bilateral streak
       mixed gonadal dysgenesis (45X/46XY, unilateral
        streak gonad, contralateral testis),
       androgen insensitivity syndrome (46XY, testicular

    ∴ the karyotype should be determined in
         premenarcheal patients with a pelvic mass
   About 75% of dysgerminomas are stage I at
    : 85-90 % are confined to one ovary
    : 10-15% are bilateral

    -     Dysgerminoama is the only germ-cell malignancy
          that has this significant rate of bilaterality
    -     Other germ-cell tumor are rarely bilateral

   Contralateral ovary has been preserved
        : diseases can develop in 5-10% of the retained
          gonads over next 2 years
   In the 25% of patients who present with
    metastatic disease

       the tumor most commonly spreads via lymphatic
       Metastases to the lungs, liver, brain
         : with long standing or recurrent disease
       Metastasis to the mediastinum and supraclavicular
        lymph nodes
         : a late manifestation of disease
◆ Treatment

   The treatment of early dysgerminoma
    : primarily surgical, including resection of the
      primary lesion and proper surgical staging

   Chemotherapy or radiation is administered to
    patients with metastatic disease
    -   Special consideration must be given to the
        preservation of fertility
    -   because the disease principally affects girls and
        young women
   Surgery

       Minimum operation : unilateral oophorectomy

       If there is a desire to preserve fertility,
        even in the presence of metastatic disease
         : contralateral ovary, fallopian tube, and
           uterus should be left in situ
         : because of the sensitivity of the tumor to

       If fertility need not be preserved
         : TAH and BSO with advanced disease

   Karyotype analysis reveals a Y chromosome
     --> both ovaries should be removed

   Dysgerminoma is the only germ-cell tumor that
    tends to be bilateral
     --> bisection of the contralateral ovary and
         excisional biopsy of any suspicious lesion

   If a small contralateral tumor is found
     --> resect it and preserve some normal ovay

   Radiation

       Dysgerminoma are very sensitive to radiation

       Doses of 2500-3500cGy may be curative

       Loss of fertility is a problem
         • radiation should rarely be used as first-line treatment
   Chemotherapy

       Metastatic dysgerminomas with systemic
         • the treatment of choice
         • preservation of fertility

       The most frequently used regimens
         • BEP (bleomycin, etoposide, cisplatin)
         • VBP (vinblastine, bleomycin, cisplatin)
         • VAC (vincristine, actinomycin, cyclophosphamide)
   Cysplatin-based combination chemoTx
     • Advanced stage, incompletely resected dysgerminoma
       have an excellent prognosis
     • The best regimen : Four cycles of BEP

   Macroscopic disease has all been resected at the
    primary operation
    -> No need to perform a second-look laparotomy

   Extensive macorscopic residual disease at the
    start of chemotherapy
    -> a second-look operation could be used
     • effective second-line therapy is available
     • the earlier persistent disease is identified, the better the
◆ Recurrent Disease

   About 75% of recurrences occur within the
    first year after initial treatment

   most common site
    : peritoneal cavity, retroperitoneal LN

   Patients with recurrent disease who have had
    no therapy other than surgery
    -> should be treated with chemotherapy
   If prior chemotharapy with BEP regimen

       POMB-ACE may used
         • Vincristine, bleomycin, cisplatin, etoposide, actinomycin D,

       The use of high-dose chemotherapy
         • Carboplatin, etoposide

       Radiation therapy is effective for this disease ;
        major disadvantage is loss of fertility
◆ Pregnancy

   Dysgerminomas tend to occur in young patient
    -> may coexist with pregnancy

   Stage Ia
       the tumor can be removed intact & the pregnancy continued

   More advanced diseases
       continuation of the pregnancy depend on gestational age

   Chemotherapy
       in 2nd & 3rd trimester
       in the same dosages as given for the nonpregnant patients
       without apparent detriment to the fetus
◆ Prognosis

   Stage Ia (unilateral encapsulated dysgerminoma)
    -> unilateral oophorectomy alone
      : 5yr disease-free survival rate of greater than 95%

   Higher tendency to recurrence
      lesions larger than 10-15 cm in diameter

      age younger than 20 years

      a microscopic pattern that includes numerous

       mitoses, anaplasia, medullary pattern

   In the past,
    Surgery for advanced disease followed by pelvic and
    abdominal radiation
      resulted in a 5-year survival rate of 63-83%,

   Now
    With the use of VBP or BEP combination
      cure rates of 85-90% for this same group
            Immature teratomas
   Fewer than 1% of all ovarian cancer

   2nd most common germ-cell malignancy

   10-20% of all ovarian malignancy in younger than 20
    years ago of age

   30% of deaths from ovarian cancer in younger than
    20 years ago of age

   About 50% of pure immature teratoma in women
    between 10 and 20 years

   Rarely occur postmenopausal women
               Immature teratomas
                         - Pathology –
-   Neural tissues : demonstrate most clearly the
    importance of the ability to mature

   Immature teratomas are classified
     : according to a grading system based on
       the degree of differentiation and the
       quantity of immature neural tissue
       Grade 1 tumor
         : <1 LPF contains immature neural elements
       Grade 2 tumor
         : 1-3 LPFs with immature elements
       Grade 3 tumor
         : >3 LPFs with these elements
           Immature teratomas
   The prognosis can be correlated with the grade of
    these immature neural elements

   With a higher grade, there is a poorer prognosis

   Malignant change in benign cystic teratomas
     occuring in 1-2% of cases

     usually after the 40 years of age
           Immature teratomas

                      - Diagnosis -

   Some of these lesions will contain calcification
    similar to mature teratomas

   Calcification can be detected by an x-ray of the
    abdomen or by ultrasonography

   Tumor markers are negative unless a mixed germ-
    cell tumor is present
             Immature teratomas
                      - Treatment -
   Surgery

       For premenopausal patient, confined to a single
         : unilateral ooporectomy and surgical staging

       For postmenopausal patients
         : TAH and BSO

       Contralateral involvement is rare and routine
        resection or wedge biopsy of the contralateral
        ovary is unnecessary
             Immature teratomas
   Chemotharapy

       Stage Ia, grade 1
        : an excellent prognosis
        : no adjuvant therapy is required

       Stage Ia, grade 2 or 3
        : adjuvant chemotherapy should be used

       Ascites
        : Chemotherapy is also indicated regardless of
          tumor grade
         Immature teratomas
   Regimen
    : VAC (most frequently used in the past)
    : BEP, VBP (the newer approach)
     • the BEP regimen is superior to the VAC regimen in the
       treatment of completely resected nondysgerminomatous
       germ cells tumors of the ovary

   The switch from VBP to BEP
     • replacement of vinblastine with etoposide
     • a better therapeutic index, especially less neurologic and
       gastrointestinal toxicity
             Immature teratomas
   Radiation therapy

       Generally not used in the primary treatment

       No evidence that the combination of
        chemotherapy and radiation has a higher rate of
        disease control than chemotherapy alone

       For patients with localized persistent disease after
               Immature teratomas
              - Second-Look Laparotomy -

   The need for second-look operation has been

   It seems not to be justified in patient who have
    received chemotherapy in an adjuvant setting,
    because chemotherapy in these patients is so

   Sampling of any peritoneal lesions and the
    retroperitoneal lymph nodes
       Only mature elements : chemoTx should be discontinued
       Persistent immature elements : alternative chemoTx
                Immature teratomas
                          - Prognosis -

   The most important prognostic feature
    : the grade of the lesion

   the stage of disease and the extent of tumor at the
    initiation of treatment
     -> have an impact on the curability

   the 5-year survival rate
       all stage : 70-80%
       surgical stage I : 90-95 %

   The 5yr survival rates for all stages with grade 1, 2, 3
     : 82%, 62%, 30%
          Endodermal Sinus Tumor
   Yolk sac carcinoma

   3rd most frequent malignant germ-cell tumor

   Median age ; 16-18 year

   Abdominal or pelvic pain
       The most frequent initial symptom
       about 75%

   Asymptomatic pelvic mass
       In 10%
         Endodermal Sinus Tumor
                     - Pathology -

   The gross : soft grayish-brown

   Cystic areas : degeneration of the rapidly
    growing lesions

   The capsule is intact

   Unilateral in 100%
       Biopsy of the opposite ovary in such young
        patients is contraindicated
        Endodermal Sinus Tumor
   Schill-Duval body

       Microscopically, the
        characteristic feature
       The cystic space is
        lined with a layer of
        flattened or irregular
       into which projects a
        glomerulus-like tuft
        with a central
        vascular core
        Endodermal Sinus Tumor

   Most EST secrete AFP

       There is a good correlation between the
        extent of disease and the level of AFP

       AFP is useful in monitoring the patient's
        response to treatment
      Endodermal Sinus Tumor
                   - Treatment -
 Surgery

     Unilateral salpingo-oophorectomy and a
      frozen section for diagnosis

     Any gross metastases should be removed

     Surgical staging is not indicated
       • All patients need chemotherapy
    Endodermal Sinus Tumor

   The tumors tend to be solid and large
     • In size from 7 to 28 cm (median 15 cm)

   Bilaterality is not seen

   Most patients have early stage disease
     • Stage I : 71%
     • Stage II : 6%
     • Stage III : 23%
        Endodermal Sinus Tumor
   Chemotherapy

       All patients with EST are treated with either
        adjuvant or therapeutic chemotherapy

       VBP regimen
         • more effective regimen in the treatment of measurable of
           incompletely resected tumor

       POMB-ACE regimen
         • Primary therapy for patients with liver or brain metastases
         • Moderately myelosuppressive
         • the intervals between each course can be kept to a
           maximum of 14days (usually 9 to 11 days)
    Endodermal Sinus Tumor
   Cisplatin-containing combination chemotherapy,

     • primary chemotherapy for EST

     • 3 cycles
        : stage I & completely resected disease

     • 2 further cycles after negative tumor marker
        : macroscopic residual disease before
        Endodermal Sinus Tumor
           - Second-Look Laparotomy -

   The value of a second-look operation has yet
    to be established in patients with EST

   It seems reasonable to omit the operation
       Pure low stage lesions
       AFP values return to normal
       Remain normal for the balance of their treatment
            Embryonal Carcinoma
   Extremely rare tumor

   Distinguished from a choriocarcinoma
       By the absence of syncytiotrophoblastic and
        cytotrophoblastic cells

   The patients are very young
       Between 4 and 28 years (median 14yr)

   Estrogen secretion
       precocious pseudopuberty
       Irregular bleeding
            Embryonal Carcinoma

   The primary lesions tend to be large

   About two-thirds are confined to one ovary at
    the time of diagnosis

   The treatment of embryonal carcinoma is the
    same as for the EST
       Unilateral oophorectomy followed by combination
        chemotherapy with BEP
    Choriocarcinoma of the Ovary
   Extremely rare tumor

   The same appearance as gestational
    choriocarcinoma metastatic to the ovaries

   Most patients are younger than 20 years

   High hCG
       Isosexual precocity in about 50% of patients
        before menarche
    Choriocarcinoma of the Ovary

   MAC regimen
    : complete responses have been reported
       Methotrexate
       Actinomycin D
       Cyclophosphamide

   The prognosis has been poor
       Most patients having metastases to organ
        parenchyma at the time of diagnosis

   Extremely rare tumor

   Composed of embryoid bodies

   Very young & premenarcheal girls
       Pseudopuberty
       Elevated AFP & hCG

   VAC regimen : effective
          Mixed Germ Cell Tumors
   The most common component of a mixed
       Dysgerminoma in 80%
       EST in 70%
       Immature teratoma in 53%
       Choriocarcinoma in 20%
       Embryonal carcinoma in 16%

   The most frequent combination
       Dysgerminoma and EST

   Combination chemotherapy BEP
          Mixed Germ Cell Tumors
   Second look laparotomy
       Macroscopic desease was present at initiation of

   The most important prognostic features
       The size of the primary tumor
         • Stage IA, samller than 10cm : survival is 100%

       The relative size of most malignant component
         • Less than one-third EST, choriocarcinoma,
           grade 3 immature teratoma : excellent prognosis
Sex Cord-Stromal Tumors
       Sex Cord-Stromal Tumors
 5-8 % of all ovarian malignancies
 derived from the sex cords and the ovarian
  stroma or mesenchyme
     Granulosa-stromal cell tumor
            - granulosa cell tumor -

   low-grade malignancy

   secrete estrogen

   seen in womon of all ages

   bilateral in only 2% of patients
        Granulosa-stromal cell tumor
                     - Pathology -

   range from a few millimeters to 20cm or more
    in diameter

   Smooth, lobulated surface

   Solid portion
       granular, trabeculated
       Yelow or gray-yellow
        Granulosa-stromal cell tumor

   “Coffee bean”
    grooved nuclei

   Call-Exner bodies
       Small clusters or
        rosettes around a
        central cavity
        Granulosa-stromal cell tumor
                     - Diagnosis -

   Of the rare prepubertal patients
       75% are associated with sexual pseudoprecocity
       because of the estrogen secretion

   For women of reproductive age
       menstrual irregulartities or secondary amenorrhea
       cystic hyperplasia of the endometrium

   For postmenopausal women
       abnormal uterine bleeding
     Granulosa-stromal cell tumor

   Endometrial cancer in 5%

   Endometrial hyperplasia in 25-50%

   Ascites is present in about 10%

   Hemorrhagic
     : occasionally rupture and produce a
        Granulosa-stromal cell tumor

   Usually stage I at diagnosis
    but may recur 5-30 years after initial

   Hematogenously spread
       Lungs, liver, brain metastasis years after initial

   Recur -> progress rapidly

   Inhibin : useful marker
        Granulosa-stromal cell tumor

                     - Treatment -

   The treatment depends on the age of the
    patient and the extent of disease

   For most patients, surgery alone is sufficient
    primary therapy

   Radiation and chemotherapy
       recurrent or metastatic disease
  Granulosa-stromal cell tumor

 Surgery

     A unilateral salpingo-oophorectomy
       • stage Ia tumors in children or in women
         of reproductive age
       • bilateral in only about 2% of patients

     If a granulosa-cell tumor is identified by
      frozen section
       • a staging operation is performed
       • assessment of the contralateral ovary - biopsy
  Granulosa-stromal cell tumor
     For premenopausal patients in whom the
      uterus is left in situ
       • Endometrial biopsys should be perfromed
       • the possibiltiy of coexistent adenocarcinoma of
         the endometrium

 Radiation
     No evidence to support the use of adjuvant
      radiation therapy for granulosa-cell tumors
  Granulosa-stromal cell tumor

 Chemotherapy

     No evidence that adjuvant chemotherapy
      will prevent recurrence of disease

     Metastatic lesions and recurrences have
      been treated

     The most effective regimen : BEP
        Granulosa-stromal cell tumor
                    - Prognosis -

   Prolonged natural history,
    tendency toward late relapse

   Survival rate
       10 YSR ; 90 %
       20 YSR ; 75 %

   The DNA ploidy -> correlated with survival
       Residual-negative DNA diploid tumors had a 10-
        year progression-free survival of 96 %
            Sertoli-Leydig Tumors

   Extremely rare : less than 0.2% of ovarian

   Most frequently in the third and fourth
    decades : 75% in younger than 40years

   Low grade malignancies

   Androgen : clinical virilization in 70%-85%
       Oligomenorrhea, amenorrhea, breast atrophy,
        acne, hirsutism, clitoromegaly, deepening of the
        voice, receding hairline
             Sertoli-Leydig Tumors
   Treatment
       In reproductive years
         • Unilateral salpingo-oophorectomy and evaluation of the
           contralateral ovary
         • Low-grade lesion are only rarely bilateral (<1%)
       Older patients
         • TAH c BSO

   Prognosis
       The 5-year survival rate : 70-90%
       Recurrences : uncommon
             Fallopian tube cancer
   0.3% of all female genital tract

   Similar to ovarian cancer
       The evaluation and treatment are the same

   Frequently involved secondarily from other
    primary sites
       ovaries, endometrium, GI tract, or breast

   Most frequently in the fifth and sixth decade
       mean age : 55-60 years
       Fallopian tube cancer

        - Symptoms and Signs -

 Classic   triad
  ① a prominent watery vaginal discharge
  ② pelvic pain
  ③ a pelvic mass
             Fallopian tube cancer
   Vaginal discharge or bleeding
       The most common symptom (more than 50%)
       For perimenopausal and postmenopausal women
        with an unusual, unexplained,or persistent vaginal
          -> the clinician should be concerned about the
              possibility of an occult tubal cancer
       Often found incidentally in asymptomatic women
        at the time of TAH and BSO

   Pelvic mass : about 60%

   Ascites : advanced disease
             Fallopian tube cancer

                     - Spread pattern -

   The same manner as epithelial ovarian
       by the transcoelomic exfoliation of cells
        -> implant throughout the peritoneal cavity

   Permeated with lymphatic channels
       spread to the para-aortic and pelvic lymph nodes
        is common(33%)
          Fallopian tube cancer

                    - Staging -

 Based on the surgical findings at

     stage   I : 20-25%
     stage   II : 20-25%
     stage   III : 40-45%
     stage   IV : 5-10%
            Fallopian tube cancer
                  - Treatment -
 Similar to epithelial ovarian cancer

   Exploratory laparotomy is necessary
       to remove the primary tumor (TAH c BSO)
       to stage the disease (No gross tumor spread)
       to resect metastases (as much as possible)

   the most frequently employed treatment
       combination chemotherapy (PC or PAC)

   radiation also used in selected cases
             Fallopian tube cancer
                      - Prognosis -

 Overall 5-year survival : about 40%
 higher than for patients with ovarian cancer
 higher proportion of early-stage disease

   5-year survival rate
       stage I - 65%
       stage II - 50-60%
       stage III and IV - 10-20%
                 Tubal Sarcomas
   Malignant mixed mesodermal tumors

   In the sixth decade

   Advanced at the time of diagnosis

   Platinum based combination chemotherapy
    (if all gross disease can be resected)

   Survival is generally poor

   Most patients die of their disease within 2 years

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