Occult Lymph Node Metastases Detected by Cytokeratin Immunohistochemistry Predict Recurrence in Node-Negative Endometrial Cancer

doi:10.1006/gyno.2000.6067

Gynecologic Oncology

Volume 80, Issue 2, February 2001, Pages 139-144

https://doi.org/10.1006/gyno.2000.6067 Get rights and content

Abstract

Objective. Even after curative resection of early endometrial cancer, some patients die as a result of recurrence. We believe that these patients likely had occult lymph node metastases at the time of diagnosis. In an attempt to identify the responsible occult metastases, the clinicopathological significance of cytokeratin expression in lymph nodes with unconfirmed metastasis was evaluated retrospectively in patients with endometrial carcinoma.

Methods. We examined 304 pelvic lymph nodes and 46 primary tumors excised from 46 patients with endometrial cancer, including 36 with Stage I disease and 10 with Stage IIIc disease. Formalin-fixed paraffin-embedded tissue sections were stained immunohistochemically using antibodies against cytokeratin, CA125, and macrophage-related antigen. Sections were also stained with hematoxylin and eosin.

Results. In 10 patients with Stage IIIc disease, cytokeratin expression was detected in cells other than the tumor cells in all 13 lymph nodes with metastasis and also in 20 (30.3%) of 66 lymph nodes without metastasis. Cytokeratin expression was observed in 37 (16.4%) of 225 lymph nodes with unconfirmed metastasis, which were obtained from 14 of 36 patients with Stage I disease. Five of fourteen patients with lymph nodes expressing cytokeratin had recurrent disease in the pelvic cavity, while all 22 patients with unconfirmed cytokeratin expression in their lymph nodes showed no recurrence. Cytokeratin and CA125 were detected simultaneously on macrophages in lymph nodes. Cytokeratin expression in lymph nodes was closely related to lymph-vascular space involvement of the primary tumor, but was not related to either histological grade or depth of myometrial invasion. Multivariate analysis identified cytokeratin expression as an independent risk factor for recurrence in Stage I endometrial cancer.

Conclusions. The immunohistochemical expression of cytokeratin in lymph nodes with undetected metastases predicts occult metastasis to these nodes and is a risk factor for recurrence in early-stage endometrial cancer.

References (21)

DS Mohan et al.
Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma
Gynecol Oncol
(1998)
DM Larson et al.
Surgery without radiotherapy for primary treatment of endometrial cancer
Obstet Gynecol
(1998)
CP Morrow et al.
Relationship between surgical–pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study
Gynecol Oncol
(1991)
P Descamps et al.
Predictors of distant recurrence in clinical stage I or II endometrial carcinoma treated by combination surgical and radiation therapy
Gynecol Oncol
(1997)
R Moll et al.
The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells
Cell
(1982)
F Lindemann et al.
Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients
Lancet
(1992)
Y Maehara et al.
Clinical significance of occult micrometastasis in lymph nodes from patients with early gastric cancer who died of recurrence
Surgery
(1996)
WT Creasman et al.
Surgical pathologic spread patterns of endometrial cancer
Cancer
(1987)
J DiSaia et al.
Risk factors and recurrent patterns in Stage I endometrial cancer
Am J Obstet Gynecol
(1985)
G Berclaz et al.
Lymphadenectomy in high risk endometrial carcinoma stage I and II: No more morbidity and no need for external pelvic radiation
Int J Gynecol Cancer
(1999)

There are more references available in the full text version of this article.

Cited by (119)

Retroperitoneal para-aortic ectopic pregnancies: A review of reported cases
2023, Gynecology and Obstetrics Clinical Medicine
To gain insights into the diagnosis and treatment of retroperitoneal para-aortic ectopic pregnancies (RPEP).
We conducted a review of the existing literature from the web of science, PubMed, and CNKI using the search terms "ectopic pregnancy" and "retroperitoneal." The present review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.
After applying the inclusion and exclusion criteria, we included a total of 54 relevant works, encompassing 55 cases. The studies have revealed that a history of artificial abortion, embryo transfer, salpingectomy, and uterine cavity operation, accounted for 65.5 % (36/55) of the cases. Typical symptoms of RPEP include abdominal pain (43.6 %, 24/55) and vaginal bleeding (36.4 %, 20/55), with only 32.7 % (18/55) of cases being asymptomatic. The most common sites of RPEP are the abdominal aorta and the inferior vena cava (74.5 %, 41/55). There were no statistically significant differences in the incidence of acute abdomen, diameter of the pregnancy sac, number of surgeries, and the time for postoperative hCG to normalize in different pregnant site. The most effective imaging examination for RPEP was found to be abdominal ultrasound (72.7 %, 40/55), and the most commonly used treatment method was laparoscopy surgery (55.3 % ,21/38).
It is crucial to consider the possibility of RPEP when a pregnancy mass cannot be located during routine examinations. Expanding the scope of the scan may significantly expedite diagnosis and treatment.
Ratiometric Raman nanotags enable intraoperative detection of metastatic sentinel lymph node
2021, Biomaterials
Sentinel lymph node (SLN) imaging and biopsy has been advocated as an important technique to evaluate the metastatic status of regional lymph nodes and determine subsequent surgical procedure for many cancers, yet there is no reliable means to provide accurate and rapid diagnosis of metastatic SLN during surgery. Here we develop a new approach, named “Ratiometric Raman dual-nanotag strategy”, that using folic acid functionalized targeted and nontargeted gap-enhanced Raman tags (FA-GERTs and Nt-GERTs) to detect metastatic SLN based on Raman imaging combined with classical least square data processing methods. By using this strategy, with built-in self-calibration for signal correction, rather than absolute intensity-dependent signal readout, we realize the visualization and prompt intraoperative diagnosis of metastatic SLN with a high accuracy of 87.5 % when the cut-off value of ratio (FA-GERTs/Nt-GERTs) set at 1.255. This approach may outperform the existing histopathological assessment in diagnosing SLN metastasis and is promising for guiding surgical procedure in the future.
Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study
2021, Gynecologic Oncology
Citation Excerpt :
Similar to our study, Aloisi et al. [21] retrospectively examined risk factors for recurrence among 79 LVM patients with a 97.2% ATx rate. In that study, grade, NE, myometrial invasion, positive cytology, and MM were significant risk factors for recurrence on univariate analysis, and histology alone was an independent risk factor on multivariate analysis; 10 of 12 reported recurrences exhibited high-risk uterine criteria [20]. The beneficial role of ATx in stage III EC has become established by an amassing body of evidence, including PORTEC-3 [17,22] and GOG 258 trials [17,22], but it is not clear whether this benefit applies to patients with LVM, or whether certain patients with LVM will benefit more than others.
To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs).
Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded.
Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%–85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2–41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50–9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45–7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44–9.54; P = .007) were independent predictors of recurrence.
Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months).
In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.
Sentinel lymph node (SLN) isolated tumor cells (ITCs) in otherwise stage I/II endometrioid endometrial cancer: To treat or not to treat?
2021, Gynecologic Oncology
To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC).
A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS.
175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/− radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11–3.52, and HR = 0.90, 95%CI 0.22–3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS.
Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.
IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway
2020, Cancer Letters
Citation Excerpt :
IMPAD1 knockdown resulted in reduced lung metastases compared with controls (shluc) (Fig. 2D). We also quantified the grade of lymph node invasion by scoring the levels of cytokeratin 18 (CK18) [21,22]. Compared with control (shluc), knockdown of IMPAD1 reduced CK18 expression in mouse lymph nodes (Fig. 2E).
The tumor microenvironment (TME) and metabolic reprogramming have been implicated in cancer development and progression. However, the link between TME, metabolism, and cancer progression in lung cancer is unclear. In the present study, we identified IMPAD1 from the conditioned medium of highly invasive CL1-5. High expression of IMPAD1 was associated with a poorer clinical phenotype in lung cancer patients, with reduced survival and increased lymph node metastasis. Knockdown of IMPAD1 significantly inhibited migration/invasion abilities and metastasis in vitro and in vivo. Upregulation of IMPAD1 and subsequent accumulation of AMP in cells increased the pAMPK, leading to Notch1 and HEY1 upregulation. As AMP is an ADORA1 agonist, treatment with ADORA1 inhibitor reduced the expression of pAMPK and HEY1 expression in IMPAD1-overexpressing cells. IMPAD1 caused mitochondria dysfunction by inhibiting mitochondrial Complex I activity, which reduced mitochondrial ROS levels and activated the AMPK-HEY1 pathway. Collectively this study supports the multipotent role of IMPAD1 in promotion of lung cancer metastasis by simultaneously increasing AMP levels, inhibition of Complex I activity to decrease ROS levels, thereby activating AMPK-Notch1-HEY1 signaling, and providing an alternative metabolic pathway in energy stress conditions.
Sentinel lymph nodes (SLN) in endometrial cancer: The relationship between primary tumor histology, SLN metastasis size, and non-sentinel node metastasis
2019, Gynecologic Oncology
Citation Excerpt :
Forty-percent of patients with SLN metastases were ITC, and approximately two-thirds were detected only by IHC staining. There are very few studies addressing the significance of H&E versus IHC identified ITCs [18]. Our study adds to the body of experience suggesting that ITCs, including IHC-detected metastases, may have clinical significance with associated risks for para-aortic metastasis.
To examine sentinel lymph node pathology and describe relationships to uterine pathology, non-sentinel pelvic lymph nodes, and para-aortic lymph nodes.
Patients with apparent uterine-confined endometrial cancer underwent robotic hysterectomy, SLN mapping, completion pelvic lymphadenectomy (LND), and para-aortic (PaLND) directed by frozen section. Patients were risk stratified by histology: low-risk (LR) endometrioid <50% depth-of-invasion (DOI), intermediate-risk (IR) endometrioid ≥50% DOI, and high-risk (HR) type II histology for comparison to other pelvic/aortic metastases.
414 patients were stratified: 275 LR, 80 IR, and 59 HR cases. PaLND was performed in 84.2% of IR/HR patients and 25.1% LR patients. Pelvic node metastasis was detected in 11.6% LR, 50.0% IR, and 39.0% HR patients. PaLN metastasis was detected in 2.9% LR, 11.3% IR, and 16.9% HR patients. Proportionally, isolated tumor cells (ITC) SLNs were more common in LR or IR vs. HR group (51.6% and 44.7% vs. 15.0%, p < 0.05). The SLN false negative rates (FNR) were 0% LR, 2.5% IR, and 5.1% HR. Non-sentinel pelvic node metastases were present in 28(31.5%) of all SLN+ cases, but only 3(8.3%) of SLN with ITC. PaLN metastasis was found in 18.8% LR, 11.8% IR, and 33.3% HR cases with ITC SLNs. After controlling for DOI, LVSI, and grade, ITC-positive SLNs had a significant association with non-sentinel pelvic and aortic metastasis (p = 0.03 and p = 0.008, respectively).
Patients with HR histology have more micro/macro-metastases in both SLNs and non-SLN metastases compared to LR/IR patients. SLN ITCs were associated with a clinically significant incidence of PaLN metastasis across all histology risk groups. There were no cases of isolated aortic node metastasis in this study. SLN mapping had an increased, although clinically acceptable FNR in the HR cohort compared to LR patients.

View all citing articles on Scopus

¹: To whom correspondence should be addressed. Fax: +81-561-62-2991. E-mail: [email protected].

View full text

Regular ArticleOccult Lymph Node Metastases Detected by Cytokeratin Immunohistochemistry Predict Recurrence in Node-Negative Endometrial Cancer

Abstract

Gynecol Oncol

Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Cell

Lancet

Surgery

Surgical pathologic spread patterns of endometrial cancer

Cancer

Risk factors and recurrent patterns in Stage I endometrial cancer

Am J Obstet Gynecol

Lymphadenectomy in high risk endometrial carcinoma stage I and II: No more morbidity and no need for external pelvic radiation

Int J Gynecol Cancer

Regular Article
Occult Lymph Node Metastases Detected by Cytokeratin Immunohistochemistry Predict Recurrence in Node-Negative Endometrial Cancer