Knowing the difference

Diagnosing LGSOC

~90% of patients are diagnosed with LGSOC in an advanced stage.1,2 Nonspecific symptoms and prevalence in a younger patient population may contribute to a delayed diagnosis of LGSOC.3,4 Due to its differences from HGSOC, accurate diagnosis is critical for tailoring appropriate low-grade serous ovarian cancer management.5,6
On this page:
LGSOC vs. HGSOC
Key LGSOC Characteristics
Guidelines for Diagnosis

Nonspecific signs and symptoms of LGSOC

LGSOC symptoms generally overlap with other ovarian cancers, other gynecologic and GI cancers, and several benign conditions.3,7 LGSOC symptoms include3,8:
  • Bloating
  • Pelvic or abdominal pain
  • Trouble eating or feeling full quickly
  • Urinary symptoms of frequency or constant sense of having to urinate
  • Fatigue
  • Upset stomach
  • Back pain
  • Changes in period patterns such as heavier bleeding or irregular bleeding

Distinct ovarian cancers

How does LGSOC differ from HGSOC?

  • The World Health Organization (WHO) Classification of Tumours (5th ed) defines LGSOC as an invasive serous neoplasm with low-grade malignant features.9
  • Initially, it was thought that LGSOC was on a continuum with high-grade serous ovarian cancer, but more recently, LGSOC has been established as a distinct and different ovarian cancer.10
  • The complex biology and signaling pathways of LGSOC distinguish it from HGSOC and underlie the differences in their clinical course and overall prognosis.11
  • Consultation with a pathologist experienced in evaluating LGSOC is recommended for accurate diagnostic classification.6

~70% of LGSOC patients have RAS/MAPK pathway-associated mutations.12-15

Differentiating LGSOC from HGSOC

LGSOC is characterized by low mutational burden, lack of TP53 mutations, no clear germline association, and frequent MAPK-pathway alterations.12,16

Histopathological and molecular characteristics between LGSOC and HGSOC.

Managing LGSOC depends on distinguishing it from HGSOC.

LGSOC

Histopathological characteristics5

Mild to moderate nuclear atypia

Low mitotic index (12 mitoses per 10 high-power fields)

Molecular characteristics

TP53 wild type17

KRAS, BRAF, NRAS, and PIK3CA mutations12,1812,18

HGSOC

Histopathological characteristics5

Tumors are pleomorphic with marked nuclear pleomorphism (>3:1 size variation)

High mitotic index (≥12 mitoses per 10 high-powered fields)

Molecular characteristics

TP53 mutation and BRCA1/2 mutations12

Distinguishing histopathologic features of LGSOC and HGSOC19

LGSOC is defined by stromal invasion by tumor cells, arranged in nests and micropapillae. The nuclei are small, round, and monotonous.
LGSOC
In contrast, HGSOC shows marked nuclear pleomorphism, including tumor giant cells, and abundant mitotic figures.
HGSOC
Immunohistochemistry for p53 shows a wild‐type (heterogeneous) expression pattern in LGSOC and aberrant (diffuse) overexpression in a representative case of HGSOC.
p53 Immunohistochemistry

Hear from experts

Low-grade vs high-grade serous ovarian cancer

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend both germline mutation testing and somatic tumor testing for all patients with ovarian cancer, including LGSOC, at both diagnosis and recurrence.20

Germline testing

BRCA mutations rare in LGSOC (approximately 5%)21

Somatic testing

Can be helpful to determine prognosis and response to certain therapies22

Activating mutations in RAS/MAPK pathway promote tumorigenesis in LGSOC21

  • KRAS mutations common (~1/3 patients)12
  • NRAS12
  • BRAF12
  • NF112
  • RAF123

Less common mutations found in LGSOC tumors: ERBB2 and PIK3CA13,23

Somatic tumor testing may identify patients for novel and emerging treatment options or clinical trials22

~90% of patients are diagnosed with LGSOC in an advanced stage, demonstrating the need for an accurate diagnosis.1,2

Healthcare provider guidelines for diagnosis

Diagnostic workup

The diagnostic workup for LGSOC typically includes clinical examination including pelvic examination, obtaining tumor markers (CA125), and imaging techniques.6

Imaging in LGSOC

  • NCCN Guidelines® recommend imaging in LGSOC, including chest/abdominal/pelvic computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography PET-CT (skull base to mid-thigh), or PET as indicated, and/or ultrasound (US). All imaging should be performed with contrast unless contraindicated.20 There is not one optimal imaging technique for low-grade serous cancer; however, a majority of panelists prefer CT to PET-CT6

Histopathology diagnosis

  • LGSOC and HGSOC are distinguished using a two-tiered pathology grading system based primarily on nuclear atypia and mitotic index as a secondary feature5

Germline testing

  • Germline testing for all patients newly diagnosed with ovarian cancer will help to better define the prevalence of alterations in rare tumor populations such as LGSOC over time.19 Although BRCA mutations are rare in LGSOC, patients should still be offered germline testing25

Somatic tumor testing

  • At diagnosis, a somatic tumor testing panel should be conducted for LGSOC. The panel should test, at a minimum, KRAS, HRAS, NRAS, BRAF, NF1, and BRCA alterations.12,20 These tests can be helpful to determine prognosis and response to certain therapies22
  • Reasons to repeat somatic tumor testing may include unpredictable clinical behavior, clinical trial eligibility, prolonged disease course, and disease recurrence6
  • In the recurrent setting, tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit, including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI/MMR, TMB, BRAF, FRɑ (FOLR1), RET, and NTRK20
  • Somatic tumor testing may identify patients for novel and emerging treatment options or clinical trials21

Pathologist consultation

  • Consultation with a pathologist experienced in evaluating these lesions (LGSOC, SBT, etc.) is recommended for accurate diagnostic classification6

Accurate diagnosis and better understanding of what drives LGSOC may help patients who could suffer for years with poor quality of life.6 If not initially diagnosed as LGSOC, at first recurrence, reconfirm pathology.

Get the facts about LGSOC management
  1. De Decker K, Wenzel HHB, Bart J, et al. Stage, treatment and survival of low-grade serous ovarian carcinoma in the Netherlands: a nationwide study. Acta Obstet Gynecol Scand. 2023;102(3):246-256.
  2. Gershenson DM, Bodurka DC, Lu KH, et al. Impact of age and primary disease site on outcome in women with low-grade serous carcinoma of the ovary or peritoneum: results of a large single-institution registry of a rare tumor. J Clin Oncol. 2015;33(24):2675-2682.
  3. Harvard Health. Certain symptoms may be early signs of ovarian cancer. Accessed July 9, 2024. https://www.health.harvard.edu/cancer/certain-symptoms-may-be-early-signs-of-ovarian-cancer  
  4. Gockley A, Melamed A, Bregar AJ, et al. Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstet Gynecol. 2017;129(3):439-447.
  5. Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28(4):496-504.
  6. Grisham RN, Slomovitz BM, Andrews N, et al. Low-grade serous ovarian cancer: expert consensus report on the state of the science. Int J Gynecol Cancer. 2023;33(9):1331-1344.
  7. Ricciardi E, Baert T, Ataseven B, et al. Low-grade serous ovarian carcinoma. Geburtsh Frauenheilk. 2018;78(10):972-976.
  8. Ferrell B, Smith S, Cullinane C, et al. Symptom concerns of women with ovarian cancer. J Pain Symptom Manage. 2003;25(6):528-538.
  9. WHO Classification of Tumours Editorial Board. Female genital tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 4). https://tumourclassification.iarc.who.int/chapters/34
  10. Vang R, Shih IM, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol. 2009;16(5):267-282.
  11. Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol. 2008;198(4):459.e1-8.
  12. Manning-Geist B, Gordhandas S, Liu YL, et al. MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma. Clin Cancer Res. 2022;28(20):4456-4465.
  13. Gershenson DM, Sun CC, Westin SN, et al. The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes. Gynecol Oncol. 2022;165(3):560-567.
  14. ElNaggar A, Robins D, Baca Y, et al. Genomic profiling in low grade serous ovarian cancer: identification of novel markers for disease diagnosis and therapy. Gynecol Oncol. 2022;167(2):306-313.
  15. Thomson JP, Hollis RL, van Baal J, et al. Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome. Gynecol Oncol. 2023;174:157-166.
  16. Wong KK, Tsang YTM, Deavers MT, et al. BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol. 2010;177(4):1611-1617.
  17. Sallum LF, Andrade L, Ramalho S, et al. WT1, p53 and p16 expression in the diagnosis of low- and high-grade serous ovarian carcinomas and their relation to prognosis. Oncotarget. 2018;9(22):15818-15827.
  18. Dey P, Nakayama K, Razia S, et al. Development of low-grade serous ovarian carcinoma from benign ovarian serous cystadenoma cells. Cancers (Basel). 2022;14(6):1506.
  19. Grisham RN, Manning-Geist BL, Chui MH. The highs and lows of serous ovarian cancer. Cancer. 2023;129(17):2613-2620.
  20. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed July 17, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org
  21. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2(4):482-490.
  22. Grisham RN, Chui MH. Advancements in low-grade serous carcinoma of the ovary and peritoneum. Curr Oncol Rep. 2022;24(11):1549-1555.
  23. Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(10324):541-553.
  24. Jones S, Wang TL, Kurman RJ, et al. Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol. 2012;226(3):413-20.
  25. Konstantinopoulos PA, Norquist B, Lacchetti C, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO Guideline. J Clin Oncol. 2020;38(11):1222-1245.
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