Endometrial cancer differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monalisa Dmello, M.B,B.S., M.D. [2]Roukoz A. Karam, M.D.[3]

Overview

In early stages endometrial cancer must be differentiated from diseases that cause abnormal uterine bleeding and endometrial thickening on ultrasound, such as endometrial hyperplasia, endometrial polyp and submucosal uterine leiomyoma. In advanced stages endometrial cancer must be differentiated from uterine sarcoma and uterine lymphoma.

Differentiating Endometrial Cancer From Other Diseases

  • In early stages endometrial cancer must be differentiated from diseases that cause abnormal uterine bleeding and endometrial thickening on ultrasound, such as endometrial hyperplasia, endometrial polyp and submucosal uterine leiomyoma. In advanced stages endometrial cancer must be differentiated from uterine sarcoma and uterine lymphoma.[1]
Diseases Clinical manifestations Para-clinical findings Gold standard
Symptoms Physical examination
Lab Findings Imaging Pap Smear Histopathology
Bleeding Pelvic Pain/pressure/

discomfort

Other Pelvic examination Abdominal examination Hb B-HCG CA-125 Ultrasound MRI
Endometrial cancer[2][3][4][5]
  • Menorrhagia
  • Metrorrhagia in premenopausal women
  • Postcoital bleeding
  • Intermenstrual bleeding
 ±
  • Enlarged uterus
  • Vaginal bleeding
  • Vaginal discharge
  • Lymphadenopathy
  • Mesenteric nodules(metastasis)
  • Enlarged fixed uterus
 ↓ – +
  • A thickened endometrial lining >4mm
  • Endometrial thickening
  • Lymph node involvement
  • Pelvic metastasis
 Atypical glandular cells Endometrial malignant cells:
  • Low grade Type I
  • High grade Type II
 Histologic diagnosis
Uterine

leiomyosarcoma[6]

[7][8][9]

  • May have menorrhagia
  • Intermenstrual bleeding
 ±
  • Abdominal pain
  • Urinary symptoms
  • Abdominal distension
  • Asymptomatic
  • Enlarged or normal sized uterus
 ↓ – +
  • Uterine mass
  • Lymph node metastases
 Shows details of uterine mass boundaries, extent and spread Negative Epithiloid shaped smooth muscle cells showing:

Two variants of leiomyosarcoma:

Histologic diagnosis
Diseases Bleeding Pelvic Pain/pressure/

discomfort

Other Pelvic examination Abdominal examination Hb B-HCG CA-125 Ultrasound MRI Pap Smear Histopathology Gold standard
Uterine leiomyoma[10]

[11][12]

  • May have menorrhagia
  • May have intermenstrual bleeding
 +
  • Asymptomatic
  • Obstetric complications
  • Dysmenorrhea (most common symptoms)
  • Obstructive symptoms(due to urinary bladder and bowel compression)
  • Dyspareunia
  • Torsion or degeneration
  • Enlarged mobile uterus
  • Irregular contour
  • Usually normal
  • Large fibroid uteri may cause abdominal distention
 ↓

or

N

– – US shows:
  • Hypoechoic,
  • Well-circumscribed
  • Round masses

US determines location of fibroid:

  • Determines:
    • Size
    • Location
    • Numbers
  • Shows "popcorn" calcification in the fibroid (degeneration)
  • Differentiaites between leiomyomas, adenomyosisand adenomyomas
 Normal Normal appearing bundle of epithiloid shape smooth muscle cells with normal mitotic index Imaging

and

Histologic analysis

Uterine carcinosarcomas

(Malignant mixed mullerian tumour (MMMT) of the uterus)[13][14][15][16]

  • May have menorrhagia
  • May have intermenstrual bleeding
 ±
  • Classical triad:
    • Pain
    • Bleeding
    • Rapidly enlarging uterus
  • Enlarged uterus
  • pelvic mass
  • Mass protruding through the cervical os
  • Involvement of the cervix
  • Normal
  • May show distention if tumor size is large
 – +
  • Enlarged uterine cavity
  • Hyperechoic mass in uterus and cervix
 Heterogenous bulky polypoid mass

with intense enhancement

Biphasic (carcinoma/sarcoma combination) and contains:
  • High grade carcinomatous (epithelial) contents
  • Stromal sarcomatous (connective tissue)
 Histologic diagnosis
Cervical cancer

with

uterine

invasion[17]

[18]

  • Menorrhagia
  • Intermenstrual bleeding
  • Postcoital bleeding
  • Vaginal passage of bleeding
 ±
  • Copious malodorous vaginal discharge
  • Pressure-related bowel and bladder symptoms
  • Hematuria
  • Enlarged uterus
  • Concomitant cervical lesions
  • Abdominal distention
 ↓ – ± For cervical cancer diagnoses, imaging is not usually done rather it is used to see the metastasis. Ultrasound may be used to see tumor size, extent and parametrial invasion. To evaluate tumor size and local extent and for its staging.

Pap test is done simultaneously with HPV testing, if cervical cancer is suspected.

Abnormal pap test may show two type of abnormal cells:

  • Squamous cell carcinoma
    • Low-grade squamous intraepithelial lesions (LSILs)
    • High-grade squamous intraepithelial lesions (HSILs)
  • Adenocarcinoma
    • Atypical glandular cells (AGC)
    • Endocervical adenocarcinoma in situ (AIS)
 If pap test shows abnormal results. Colposcopy and biopsy is done. Histologic types are Histologic diagnosis
Diseases Bleeding Pelvic Pain/pressure/

discomfort

Other Pelvic examination Abdominal examination Hb B-HCG CA-125 Ultrasound MRI Pap Smear Histopathology Gold standard
Metastasis
  • Menorrhagia
  • Intermenstrual bleeding
 ±
  • Asymptomatic
  • Obstetric complications
  • Dysmenorrhea (most common symptoms)
  • Obstructive symptoms (due to urinary bladder and bowel compression)
  • Dyspareunia
  • Enlarged uterus
  • Abdominal distention
 ↓ – –
  • Enlarged uterine cavity
  • Hyperechoic mass in uterus and cervix
 Shows involvement of uterus, lymph nodes, parmetrial area and surrounding area. Is normal or may show malignant metastatic cells. Although biopsy of the metastatic lesions to the uterus is not recommended however, it shows the malignant cells of the primary site. Biopsy and histology of the primary site of the tumor
Endometrial

polyp[19]

[20]

  • Menorrhagia
  • Intermenstrual bleeding
  • Postmenopausal bleeding
 –
  • Asymptomatic
  • Endometrial polyp prolapses (will be visible on speculum examination protruding through cervical os)
  • Normal sized uterus with smooth surface
  • Normal
 ↓ – +

or

N

Incidentally on pelvic ultrasound (most common) MRI will show polyp size and dimension in detail but it is usually is not required for its diagnoses. Normal Biopsy and histopathology analysis will show localized hyperplastic growth of endometrial glands and stroma around a vessel.
  • Imaging
  • Histologic evaluation
Endometrial

hyperpalsia[21]

[22][23][24]

  • Menorrhagia
  • Intermenstrual bleeding
  • Postmenopausal bleeding
 –
  • Asymptomatic
  • Normal sized uterus with smooth surface
  • Normal
 ↓ – +
  • Determines endometrial thickness
  • Rules out other abnormalities
 Thick endometrial lining Abnormal glandular or endometrial cells on pap smear
  • Endometrial sampling is used (gold standard) for the diagnosis of endometrial hyperplasia.
  • Biopsy and histology may show two types:
    • Non-neoplastic changes:
      • Disordered endometrial growth
      • Benign hyperplasia
      • Simple hyperplasia
      • Complex hyperplasias without atypia
  • Precancerous changes:
    • Endometrial intraepithelial neoplasms
    • Atypical complex hyperplasia

Histologic

diagnosis

Uterine

adenomyoma

[25][26]

[27]

- ±
  • Subfertility
  • Diffusely enlarged tender boggy uterus with smooth surface
  • Uterus may develop masses
  • Normal
 ↓ – +
  • Snow storm appearance in diffuse adenomyosis
  • Shows a uterine mass in case of adenomas
 Identifies diffuse or focal adenomyosis from leiomyoma Mostly normal may show glandular cells in cervical cytology Endometrial glands in myometrium of uterus
  • Imaging
  • Histologic

diagnosis

Diseases Bleeding Pelvic Pain/pressure/

discomfort

Other Pelvic examination Abdominal examination Hb B-HCG CA-125 Ultrasound MRI Pap Smear Histopathology Gold standard
Hematometra

(blood within the

uterine cavity)

[28][29]

- +
  • Acute pain abdomen
  • Cramping in pelvis
  • Cyclic pain
  • Dysmenorrhea
  • Amenorrhea
  • Hypotension
  • Vasovagal syncopy
  • Firm and enlarged uterus
  • Adenaxal tenderness
  • Pelvic examination may be restricted by pain
  • Normal
 ↓ – – Echogenic fluid in the uterine cavity occluding cervical os MRI is not required for the diagnoses Normal Biopsy is not required for the diagnoses Ultrasound
Gestational trophoblastic disease

[30][31]

  • May have menorrhagia
  • May have intermenstrual bleeding
 + Metastatic symptoms in case of cancer:
  • Pulmonary symptoms
    • Dyspnea
    • Chest pain
    • Cough
    • Hemoptysis
  • Vaginal metastases
    • Vaginal bleeding
    • Purulent vaginal discharge
  • Central nervous system metastases
    • Asymptomatic
    • Neurologic signs
  • Irregularly sized boggy enlarged uterus
  • Adnexal fullness
  • Abdominal distention
 ↓ ± +
  • US shows dilated grape like structures
  • Diffuse hydropic swelling
  • Multiples echoes
  • Cystic spaces invading edometrium and myometrium (in case of invasive disease)
 MRI defines the extent of primary lesion, invasion and distant metastasis Pap smear shows trophoblasric cells Biopsy and histologic analysis confirms the diagnoses depending on the type of lesion benign or malignant it may sow dilated grape like villous structures or invasive malignant lesions
  • Imaging
  • Histologic

diagnosis

Incomplete abortion
  • Intermenstrual bleeding
  • Vaginal bleeding
 +
  • Abdominal pain/ cramps
  • Enlarges uterus
  • Abdominal distention
 N/↓ ± +↓ Uterus shows fetus with absent cardiac activity in lower part of uterus MRI is not required for the diagnoses Pap smear is not done for the diagnoses Suction biopsy and histology shows fetal and placental tissues
  • Imaging
  • Histologic

diagnosis

Pregnancy
  • Absent menstrual cycle
  • May have intermenstrual bleeding
 +
  • Nausea
  • Fatigue
  • Enlarged gravid uterus
  • Abdominal distention
 – + – Fetus inside uterine cavity Not needed once ultrasound determines pregnancy Normal or may show cervical cells
  • Not needed once ultrasound
  • May show Fetal tissues

amniotic fluid

Imaging (Transvaginal ultrasound)
Diseases Bleeding Pelvic Pain/pressure/

discomfort

Other Pelvic examination Abdominal examination Hb B-HCG CA-125 Ultrasound MRI Pap Smear Histopathology Gold standard

References

  1. ↑ Hippisley-Cox J, Coupland C (2011). "Identifying women with suspected ovarian cancer in primary care: derivation and validation of algorithm". BMJ. 344: d8009. doi:10.1136/bmj.d8009. PMC 3251328. PMID 22217630.
  2. ↑ "ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer". Obstet Gynecol. 106 (2): 413–25. August 2005. PMID 16055605.
  3. ↑ Boruta DM, Gehrig PA, Fader AN, Olawaiye AB (October 2009). "Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review". Gynecol. Oncol. 115 (1): 142–153. doi:10.1016/j.ygyno.2009.06.011. PMID 19592079.
  4. ↑ Bokhman JV (February 1983). "Two pathogenetic types of endometrial carcinoma". Gynecol. Oncol. 15 (1): 10–7. PMID 6822361.
  5. ↑ Felix AS, Weissfeld JL, Stone RA, Bowser R, Chivukula M, Edwards RP, Linkov F (November 2010). "Factors associated with Type I and Type II endometrial cancer". Cancer Causes Control. 21 (11): 1851–6. doi:10.1007/s10552-010-9612-8. PMC 2962676. PMID 20628804.
  6. ↑ Nordal RR, Thoresen SO (May 1997). "Uterine sarcomas in Norway 1956-1992: incidence, survival and mortality". Eur. J. Cancer. 33 (6): 907–11. PMID 9291814.
  7. ↑ Goto A, Takeuchi S, Sugimura K, Maruo T (2002). "Usefulness of Gd-DTPA contrast-enhanced dynamic MRI and serum determination of LDH and its isozymes in the differential diagnosis of leiomyosarcoma from degenerated leiomyoma of the uterus". Int. J. Gynecol. Cancer. 12 (4): 354–61. PMID 12144683.
  8. ↑ Bell SW, Kempson RL, Hendrickson MR (June 1994). "Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases". Am. J. Surg. Pathol. 18 (6): 535–58. PMID 8179071.
  9. ↑ Karpathiou G, Sivridis E, Giatromanolaki A (2010). "Myxoid leiomyosarcoma of the uterus: a diagnostic challenge". Eur. J. Gynaecol. Oncol. 31 (4): 446–8. PMID 20882892.
  10. ↑ Stewart EA (April 2015). "Clinical practice. Uterine fibroids". N. Engl. J. Med. 372 (17): 1646–55. doi:10.1056/NEJMcp1411029. PMID 25901428.
  11. ↑ Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F (March 2002). "Accuracy of magnetic resonance imaging and transvaginal ultrasonography in the diagnosis, mapping, and measurement of uterine myomas". Am. J. Obstet. Gynecol. 186 (3): 409–15. PMID 11904599.
  12. ↑ Omary RA, Vasireddy S, Chrisman HB, Ryu RK, Pereles FS, Carr JC, Resnick SA, Nemcek AA, Vogelzang RL (November 2002). "The effect of pelvic MR imaging on the diagnosis and treatment of women with presumed symptomatic uterine fibroids". J Vasc Interv Radiol. 13 (11): 1149–53. PMID 12427815.
  13. ↑ Chaffer CL, San Juan BP, Lim E, Weinberg RA (December 2016). "EMT, cell plasticity and metastasis". Cancer Metastasis Rev. 35 (4): 645–654. doi:10.1007/s10555-016-9648-7. PMID 27878502.
  14. ↑ Zhao S, Bellone S, Lopez S, Thakral D, Schwab C, English DP, Black J, Cocco E, Choi J, Zammataro L, Predolini F, Bonazzoli E, Bi M, Buza N, Hui P, Wong S, Abu-Khalaf M, Ravaggi A, Bignotti E, Bandiera E, Romani C, Todeschini P, Tassi R, Zanotti L, Odicino F, Pecorelli S, Donzelli C, Ardighieri L, Facchetti F, Falchetti M, Silasi DA, Ratner E, Azodi M, Schwartz PE, Mane S, Angioli R, Terranova C, Quick CM, Edraki B, Bilgüvar K, Lee M, Choi M, Stiegler AL, Boggon TJ, Schlessinger J, Lifton RP, Santin AD (October 2016). "Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition". Proc. Natl. Acad. Sci. U.S.A. 113 (43): 12238–12243. doi:10.1073/pnas.1614120113. PMC 5087050. PMID 27791010.
  15. ↑ Callister M, Ramondetta LM, Jhingran A, Burke TW, Eifel PJ (March 2004). "Malignant mixed Müllerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome". Int. J. Radiat. Oncol. Biol. Phys. 58 (3): 786–96. doi:10.1016/S0360-3016(03)01561-X. PMID 14967435.
  16. ↑ Teo SY, Babagbemi KT, Peters HE, Mortele KJ (July 2008). "Primary malignant mixed mullerian tumor of the uterus: findings on sonography, CT, and gadolinium-enhanced MRI". AJR Am J Roentgenol. 191 (1): 278–83. doi:10.2214/AJR.07.3281. PMID 18562759.
  17. ↑ "Pap and HPV Testing - National Cancer Institute".
  18. ↑ Benedet JL, Bender H, Jones H, Ngan HY, Pecorelli S (August 2000). "FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology". Int J Gynaecol Obstet. 70 (2): 209–62. PMID 11041682.
  19. ↑ Kim KR, Peng R, Ro JY, Robboy SJ (August 2004). "A diagnostically useful histopathologic feature of endometrial polyp: the long axis of endometrial glands arranged parallel to surface epithelium". Am. J. Surg. Pathol. 28 (8): 1057–62. PMID 15252313.
  20. ↑ Salim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J (2011). "Diagnosis and management of endometrial polyps: a critical review of the literature". J Minim Invasive Gynecol. 18 (5): 569–81. doi:10.1016/j.jmig.2011.05.018. PMID 21783430.
  21. ↑ Emons G, Beckmann MW, Schmidt D, Mallmann P (February 2015). "New WHO Classification of Endometrial Hyperplasias". Geburtshilfe Frauenheilkd. 75 (2): 135–136. doi:10.1055/s-0034-1396256. PMC 4361167. PMID 25797956.
  22. ↑ Wright TC, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D (October 2007). "2006 consensus guidelines for the management of women with abnormal cervical screening tests". J Low Genit Tract Dis. 11 (4): 201–22. doi:10.1097/LGT.0b013e3181585870. PMID 17917566.
  23. ↑ Espindola D, Kennedy KA, Fischer EG (December 2007). "Management of abnormal uterine bleeding and the pathology of endometrial hyperplasia". Obstet. Gynecol. Clin. North Am. 34 (4): 717–37, ix. doi:10.1016/j.ogc.2007.09.001. PMID 18061866.
  24. ↑ Montgomery BE, Daum GS, Dunton CJ (May 2004). "Endometrial hyperplasia: a review". Obstet Gynecol Surv. 59 (5): 368–78. PMID 15097798.
  25. ↑ McElin TW, Bird CC (1974). "Adenomyosis of the uterus". Obstet Gynecol Annu. 3: 425–41. PMID 4608783.
  26. ↑ Maheshwari A, Gurunath S, Fatima F, Bhattacharya S (July 2012). "Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes". Hum. Reprod. Update. 18 (4): 374–92. doi:10.1093/humupd/dms006. PMID 22442261.
  27. ↑ Byun JY, Kim SE, Choi BG, Ko GY, Jung SE, Choi KH (October 1999). "Diffuse and focal adenomyosis: MR imaging findings". Radiographics. 19 Spec No: S161–70. doi:10.1148/radiographics.19.suppl_1.g99oc03s161. PMID 10517452.
  28. ↑ McCausland AM, McCausland VM (2007). "Long-term complications of endometrial ablation: cause, diagnosis, treatment, and prevention". J Minim Invasive Gynecol. 14 (4): 399–406. doi:10.1016/j.jmig.2007.04.004. PMID 17630156.
  29. ↑ U Nayak A, Swarup A, G S J, N S (April 2010). "Hematometra and acute abdomen". J Emerg Trauma Shock. 3 (2): 191–2. doi:10.4103/0974-2700.62117. PMC 2884455. PMID 20606801. Vancouver style error: name (help)
  30. ↑ Bakri YN, Berkowitz RS, Khan J, Goldstein DP, von Sinner W, Jabbar FA (March 1994). "Pulmonary metastases of gestational trophoblastic tumor. Risk factors for early respiratory failure". J Reprod Med. 39 (3): 175–8. PMID 8035373.
  31. ↑ Lurain JR (December 2010). "Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole". Am. J. Obstet. Gynecol. 203 (6): 531–9. doi:10.1016/j.ajog.2010.06.073. PMID 20728069.
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