The Prognostic Impact of Grading in FIGO IB and IIB Squamous Cell Cervical Carcinomas.

Background Tumor grade is one of the more controversial factors, and the data regarding its prognostic impact in squamous cell carcinoma (SCC) of the uterine cervix are controversial. Methods The histological slides of 467 surgically treated FIGO stage IB1 to IIB cervical SCC were re-examined regarding the prognostic impact of the histological tumor grade based on the degree of keratinization (conventional tumor grade) according to the WHO recommendation on recurrence-free and overall survival as well as on the prediction of pelvic lymph node involvement. Results 46.0% presented with well-differentiated tumors (G1, n = 215), 30.6% with moderate (G2, n = 143) and 23.3% with poor differentiation (G3, n = 109). The recurrence-free survival was significantly reduced in patients with poorly differentiated tumors (G1: 81.4%, G2: 70.6%, G3: 64.2%; p = 0.008). There was no impact on overall survival. Because of the lack of survival differences between G1- and G2-tumors, they were merged into low-grade tumors, and their prognostic outcome was compared to the high-grade group (G3-tumors). Based on this binary conventional grading system there was a significantly longer recurrence-free (low-grade: 77.1% vs. high-grade: 64.2%; p = 0.008) and overall survival (low-grade: 76.0% vs. high-grade: 65.1%; p = 0.031) in the low-grade group. However, both the conventional three-tiered and the binary grading systems (separating tumors into a low- and high-grade group) failed to predict pelvic lymph node involvement (p = 0.9 and 0.76, respectively). Conclusion A binary grading model for the conventional tumor grade (based on the degree of keratinization) in SCC of the uterine cervix may be suitable for the prognostic survival evaluation but failed to predict pelvic lymph node involvement.

Prognostic relevance of low-grade versus high-grade FIGO IB1 squamous cell uterine cervical carcinomas.

PURPOSE: Tumor grade is one of the more controversial factors with limited prognostic information in squamous cell carcinomas (SCC) of the uterine cervix. METHODS: Histologic slides of 233 surgically treated cervical SCC (FIGO IB1) were re-examined regarding the prognostic impact of the WHO-based grading system, using the different degree of keratinization, categorizing the tumors in G1, G2 and G3 (conventional tumor grade). RESULTS: 45.1% presented with well-differentiated tumors (G1), 29.2% with moderate (G2) and 25.8% with poor differentiation (G3). Tumor grade significantly correlated with decreased recurrence-free and overall survival. However, detailed analyses between G1- and G2-tumors failed to show any correlation with either recurrence-free or overall survival. G1- and G2-tumors were therefore merged into low-grade tumors and were compared to the high-grade group (G3-tumors). This binary conventional grading system showed an improved 5-years recurrence-free (low-grade: 90.2% vs. high-grade: 71.6%; p = 0.001) and overall survival rates (low-grade: 89.9% vs. high-grade: 71.1%; p = 0.001) for low-grade tumors. On multivariate analysis adjusted for lymph node metastasis, high-grade tumors represented a hazard ratio of 2.4 (95% CI 1.3-4.7) for reduced recurrence-free and 2.4 (95% CI 1.2-4.6) for overall survival. High-grade tumors showed a significantly higher risk for pelvic lymph node involvement [OR 2.7 (95% CI 1.4-5.5); p = 0.003]. The traditional three-tiered grading system failed to predict pelvic lymph node metastases. CONCLUSION: A binary grading model for the conventional tumor grade (based on the degree of keratinization) in SCC of the uterine cervix may allow a better prognostic discrimination than the traditionally used three-tiered system.

A cut-off value of 2 cm in tumor size is of prognostic value in surgically treated FIGO stage IB cervical cancer.

OBJECTIVES: Limited knowledge exists about the value of tumor size in surgically treated cervical cancer (CX) using a tumor size of 2 cm as cut-off value. METHODS: A total of 366 cases of CX FIGO stage IB who received upfront surgery were evaluated regarding tumor size, the prediction of pelvic lymph node involvement, and recurrence-free and overall survival during a median follow-up time of 94 months. Tumors ≤2.0 cm were defined as small, tumors 2.1-4.0 cm as medium sized and those larger than 4 cm as bulky disease. RESULTS: Small tumors were seen in 28.7%, medium sized in 52.5% and bulky tumors in 18.9%. There was a significant higher frequency of pelvic lymph node involvement with increasing tumor size (13.3% vs. 23.4% vs. 43.5%, respectively; p<0.001) and an increase of recurrent disease (6.7% vs. 18.8% vs. 29.4%, respectively; p<0.001). The 5-year overall survival rate was significantly reduced with increasing tumor size (94.0% vs. 85.1% vs. 69.9%, respectively; p<0.001). Pelvic lymph node involvement and maximal tumor size were independent prognostic factors for both recurrence-free and overall survival in multivariate analysis. CONCLUSIONS: The results support that tumor size is of prognostic impact in FIGO stage IB cervical carcinomas. A further substaging is suggested for tumors up to 4.0 cm maximum dimension using a cut-off value of 2.0 cm as discriminator. Patients with tumors ≤2.0 cm may represent low risk disease.

Morphological parameters associated with perineural invasion (PNI) in carcinoma of the cervix uteri.

The study determines morphological features that are associated with perineural invasion (PNI) in patients with cervical carcinoma (CX). Histological slides from 194 patients from surgically treated squamous cell carcinoma were re-examined for PNI and correlated to morphological factors of tumor growth. Material from 68 patients (35.1%) represented PNI. PNI was significantly correlated with advanced tumor stage (P < .001). Patients with deep cervical stromal invasion (>66%) showed more PNI than those with more superficial invasion (41% vs 16.9%; P = .001). Tumors with spray-like PI showed significantly more PNI (48.4%) when compared with finger-like PI (26.7%) and those with pushing borders (18.8%; P = .007). Strong peritumoral desmoplastic stromal reaction and absence of peritumoral inflammation were associated with a higher frequency of PNI (P < .001). PNI is associated with advanced tumor stage, deep cervical stromal invasion (>66%), high grade of tumor cell dissociation (ie, spray-like pattern of invasion), strong peritumoral desmoplastic stromal reaction, and reduced peritumoral inflammation.

Perineural invasion in carcinoma of the cervix uteri--prognostic impact.

PURPOSE: Limited information exists about the occurrence and the impact of perineural invasion (PNI) in patients with cervical carcinoma (CX). METHODS: The original histologic slides from patients primarily treated by radical hysterectomy and systematic pelvic lymphadenectomy were re-examined regarding the occurrence of PNI. PNI was correlated to recurrence free (RFS) and overall survival (OS). RESULTS: 35.1% of all patients (68/194) represented perineural invasion (=PNI). The 5-year-overall-survival-rate was significantly decreased in patients representing PNI, when they were compared with those without PNI (51.1% [95% CI 38.0-64.2] vs. 75.6% [95% CI 67.8-83.4]; p = 0.001). In a separate analysis the prognostic impact persisted in the node negative, but disappeared in the node-positive cases. In multivariate analysis, pelvic lymph node involvement and PNI were independent prognostic factors for overall survival. CONCLUSIONS: Perineural invasion is seen in about one-third of patients with cervical carcinoma. Patients affected by PNI represented a decreased overall survival. Further studies are required to get a deeper insight into the clinical impact and the pathogenetic mechanisms of PNI in CX.

Detection of micrometastases in pelvic lymph nodes in patients with carcinoma of the cervix uteri using step sectioning: Frequency, topographic distribution and prognostic impact.

OBJECTIVES: Limited information exist about the frequency of micrometastases, their topographic distribution and prognostic impact in patients with cervical carcinoma (CX). METHODS: Lymph nodes of patients with surgically treated CX, FIGO IB to IIB, with pelvic lymph node involvement, were re-examined regarding the size of metastatic deposits, their topographic distribution within the pelvis. Lymph node status (pN0 vs. pN1mic=metastasis<0.2 cm vs. pN1=metastasis>0.2 cm) was correlated to recurrence free (RFS) and overall survival (OS). RESULTS: 31.4% of all patients (281/894) represented pelvic lymph node involvement. 22.2.% of the node positive ones showed micrometastases (pN1mic). Most commonly, obturator and internal nodes were affected by pN1mic, without any side differences. Patients with macrometastases (pN1) and micrometastases (pN1mic) represented significant reduced RFS-rate at 5-years (62% [95% CI: 54.2 to 69.8] for pN1 and 68.9% [95% CI: 55.5 to 82.4] for pN1mic) when compared to patients without metastatic disease (91.4% [95% CI: 89.0 to 93.8]; p<0.001) The 5-years OS-rate was decreased in patients with metastatic disease (pN0: 86.6% [95% CI: 83.7 to 89.5], pN1mic: 63.8% [95% CI: 50.9 to 76.7], pN1: 48.2% [95% CI: 40.4 to 56.0]; p<0.0001). These differences persisted in detailed analysis within these subgroups. In multivariate analysis, tumor stage, pelvic lymph node involvement and micrometastases were independent prognostic factors. CONCLUSIONS: A remarkable number of patients with CX show micrometastases within pelvic nodes. Micrometastatic disease represents an independent prognostic factor. So, all patients with pelvic lymph node involvement, including micrometastatic deposits, might be candidates for adjuvant treatment.

Extracapsular extension of pelvic lymph node metastases is of prognostic value in carcinoma of the cervix uteri.

OBJECTIVES: Pelvic lymph node involvement is a well-recognized prognostic factor in cervical carcinoma (CX). Limited knowledge exists about extranodal extension of the tumor outside the lymph node capsule, i.e. extracapsular spread (ECS). METHODS: Two hundred fifty-six cases of surgically treated CX (FIGO stage IB1 to IIB) with pelvic lymph node involvement were evaluated regarding the occurrence of extranodal spread of the metastatic deposits outside the lymph node capsule (ECS), determined on standardized handled lymphadenectomy specimens, regarding their impact of recurrent disease and overall survival during a median follow-up time of 62 months (95% CI 51-73 months). RESULTS: ECS was seen in 30.9% (79/256) of the cases. The occurrence of ECS showed a significant correlation to advanced stage disease (p=0.02), the number of involved nodes (p<0.001) and the size of metastatic deposits (p<0.01). The 5-year recurrence-free survival rate in patients with ECS was significant lower compared to patients without ECS (59.7% [95% CI: 46.3%-73.2%] versus 67.2% [95% CI: 58.9%-75.5%]; (p=0.04). The 5-year overall survival rate was significant lower in patients with ECS (33.5% [95% CI: 20.6%-46.3%] vs. 60.5% [95% CI: 52.3%-68.6%]; p<0.001). In multivariate analysis, tumor stage, number of involved pelvic nodes, tumor differentiation and ECS were independent prognostic factors. CONCLUSIONS: The results indicate that extracapsular spread (ECS) of pelvic lymph node metastases is of prognostic impact in cervical carcinomas. A revised FIGO/TNM classification system for pelvic lymph node disease is recommended: ECS 0 = lymph node involvement without extranodal spread of the metastatic deposits and ECS 1 = lymph node involvement with extranodal spread of the metastatic deposits.

COX-2 and Her-2/neu are overexpressed in Paget's disease of the vulva and the breast: results of a preliminary study.

PURPOSE: Paget's disease (PD) of the breast as well as the vulva is a rare condition that accounts for about 4% of breast neoplasms and 1% of vulvar malignancies. Recurrent disease after breast and vulvar surgery might be a challenge. To evaluate relevant molecules therapeutically, tissue from mammary and vulvar PD lesions was investigated immunohistochemically. METHODS: Histopathologic samples from 11 patients with mammary PD and eight patients with vulvar PD were stained with antibodies against estrogen and progesterone receptors, HER-2/neu and COX-2 followed by semiquantitative evaluation of the staining results. RESULTS: All tested mammary lesions as well as seven out of eight vulvar PD were negative for estrogen and progesterone receptors. Strong membranous staining for HER-2/neu (Score 3) was seen in all cases. Six out of 8 vulvar and 10 out of 11 mammary PD showed COX-2 overexpression. CONCLUSIONS: PD of the breast and vulva are negative for estrogens and progesterons, therefore, anti-hormonal therapy is not indicated. The high frequency of Her-2/neu and COX-2 overexpression, however, suggests that these molecules could be therapeutically relevant in patients with PD. These results require further investigation.

Mixed small cell carcinomas of the uterine cervix: prognostic impact of focal neuroendocrine differentiation but not of Ki-67 labeling index.

Small cell neuroendocrine carcinomas sometimes represent a non-small cell component. Because of infection with the high-risk human papillomavirus of small cell carcinomas (SmCCs), several host cell regulatory proteins are altered, thus causing altered proliferative activity. Knowledge regarding the prognostic impact of focal neuroendocrine differentiation in mixed SmCCs and the value of proliferative activity in these tumors is very limited. Small cell carcinomas were selected for immunohistochemical staining with neuroendocrine markers and Ki-67. In cases with mixed tumors, the percentage of the SmCC component was calculated and correlated with survival. Of 677 tumors, 9 (1.3%) were classified as SmCCs after Grimelius staining (8/9 positive tumors) and immunohistochemical reaction against neuron-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD56 (8/9 positive tumors); all specimens were positive for at least 2 of these. CD99 staining was completely negative. Two thirds of the SmCCs showed non-small cell differentiation. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months). Even an SmCC component of 17% was associated with a fatal course. Small cell carcinoma represented a significantly lower proliferation (Ki-67 labeling index) than did the non-small cell component in the same tumor (12.8% vs 70.8%; P < .001). Even a small SmCC component in mixed carcinomas of the uterine cervix was associated with adverse outcome. Proliferative activity, determined by Ki-67 labeling index, is of no prognostic value.

p16, p14, p53, and cyclin D1 expression and HPV analysis in small cell carcinomas of the uterine cervix.

Small cell carcinomas (SmCCs) of the uterine cervix are rare tumors. The knowledge regarding protein expression of several checkpoint candidates of cell cycle regulation is limited. Surgically treated SmCCs were selected from our files for immunohistochemical staining (neuroendocrine markers, p53, p16, p14, and cyclin D1). Polymerase chain reaction analysis, using general primers, was performed for human papillomavirus analysis. Nine of 677 tumors (1.3%) were classified as SmCCs after Grimelius staining (8/9 tumors positive) and immunohistochemical reaction against neurone-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD 56 (8/9 positive tumors). All specimens were positive for at least two of the above. Two SmCCs were p53 positive and one case was p14 positive. Cyclin D1 staining was completely negative. All cases showed strong nuclear and/or cytoplasmic p16-immunostaining. Seven tumors represented human papillomavirus positivity for high-risk types. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months), representing a 5-year survival rate of 56%. The results suggest that p16 is up-regulated or accumulated in the SmCCs of the uterine cervix, probably caused by infection with human papillomavirus. p14 inactivation is of high prevalence in SmCCs and detection rate of p53 is similar to other histologic types of cervical carcinomas.

Occult tumor cells in pelvic lymph nodes and parametrial tissue of small-sized FIGO IB1 squamous cell carcinomas of the uterine cervix--results of a pilot study.

Micrometastases (MM) and occult tumor cell deposits (OTCD) in pelvic tissue may cause recurrences, and immunohistochemistry may improve their detection. We used cytokeratine-immunohistochemistry to investigate 263 pelvic lymph nodes and parametrial tissue for MM and OTCD obtained from eight squamous cell carcinomas (maximum tumor size: 2.5 cm). These patients were treated with radical abdominal hysterectomy (Piver type III) with complete tumor resection without receiving any adjuvant therapy. The mean count of resected pelvic lymph nodes was 32.9 (range 24-47). All lymph nodes were completely embedded, and three step sections were performed for routine histopathologic evaluation. Three patients developed pelvic side wall and five central tumor recurrences within a median time of 25.9 (range 8-55) months. On immunohistochemistry, only one case (12.5%) showed OTCD in a venule in the parametrial tissue. In patients with small cervical carcinomas (< 2.5 cm in largest dimension), OTCD can only rarely be detected by immunohistochemistry after careful handling of resected lymph nodes using step sectioning for routine histologic examination and complete processing of parametrial pelvic tissue. Therefore, tumor recurrence in those patients appears to be due to occult residual tumor cells that were not resected during the classical Wertheim-Meigs-procedure or that were disseminated during the surgical procedure and persisted in situ.