Diagnostic Accuracy of Transvaginal Ultrasound Versus Hysteroscopy in Evaluation of Endometrial Pathology in Breast Cancer Women Receiving Tamoxifen: Correlation with Histopathological Examination

 

 

 

Parameters	Symptomatic (n=5)		Asymptomatic (n=22)		p-value
	No.	%	No.	%
US findings
Regular endometrium	2	40.0%	9	40.9%	0.641
Irregular endometrium	3	60.0%	13	59.1%
Averagethickness	0	0.0%	6	27.3%	0.153
Diffusethickendometriumwithoutcysticchanges	2	40.0%	9	40.9%
Diffusethick endometrium with cystic changes	2	40.0%	5	22.7%
Polyp	1	20.0%	0	0.0%
Endometrialatrophy	0	0.0%	2	9.1%
hysteroscopic findings
Normal finding	0	0.0%	7	31.8%	0.370
Endometrial hyperplasis	4	80.0%	11	50.0%
Polyp	1	20.0%	2	9.1%
Endometrial atrophy	0	0.0%	2	9.1%
histopathological Findings
Normal findings	0	0.0%	10	45.4%	0.284
Typical simple hyperplasia	1	20.0%	2	9.1%
Typical complex hyperplasia	1	20.0%	4	18.2%
Atypical hyperplasia	2	40.0%	2	9.1%
Polyp	1	20.0%	2	9.1%
Atrophy Suspicious lesion	0 0	0.0% 0.0%	2 0	9.1% 0.0%

Table 3: Comparison between asymptomatic and symptomatic participants regarding the US, hysteroscopic and histopathological findings.

Findings	Histopathology		Sensitivity	Specificity	PPV	NPV	Accuracy
	Abnormal (n=17) (62.9%)	Normal (n=10) (37.1%)
US
Endometrial change			82.4%	30.0%	66.7%	50.0%	63.0%
Abnormal (n=21)	TP=14(82.3)	FP=7(70)
Normal (n=6)	FN=3(17.7)	TN=3(30)
Hysteroscopy
Abnormal (n=20)	TP=16(94.1)	FP=4(40)	94.1%	60.0%	80.0%	85.7%	81.5%
Normal (n=7)	FN=1(5.9)	TN=6(60)

Table 4: Diagnostic performance of U/S versus hysteroscopy in detection of endomtrial disease

Fig 1: Gray scale transvaginal ultrasound image (A) demonstrating diffuse endometrial thickening with multiple variable sized cystic changes. Gray scale transverse ultrasound image (B) of the same endometrium showing the cystic changes in thickened endometrium. Color Doppler image of the endometrium (C) demonstrating color flow in the central portion of the complex cystic endometrial lesion.Ultrasound diagnosis: endometrial hyperplasia with cystic changes. histopathological diagnosis: complex cystic hyperplasia without atypia: true positive result.

 

Fig 2: Grayscale (A) and color Doppler (B) sagittal view by transvaginal ultrasound showing a thickened homogenous echogenic endometrium, measuring about (12.3 mm) in maximal anteroposterior diameter (A), with irregular borders, preserving subendometrial halo. Ultrasound diagnosis, simple endometrial hyperplasia while histopathological result revealed endometrial hyperplasia wirh polyp: true negative result.

 

Fig 3: Gray scale transverse (A) and sagittal (B) TVUS images showing well defined echogenic lesion in the endometrial cavity. A thin fluid rim is noted separating the lesion from the endometrial lining at a few places. Cystic changes are noted within this echogenic lesion. Uterine myometrium shows normal echopattern. The sonographic findings suggest endometrial polyp. Ultrasound diagnosis: endometrial polyp which matched with histopathology result, endometrial polyp with no malignant cells.: true positive result.

 

DISCUSSION

This reseach was included  27 women aged between 32 - 65 years with a mean age of  52.8 ±9.3 years.There were  11 premenopausal, (40.7 %) and 16 (59.3%) post-menopausal women with two of them being under 40 years, they experienced early menopause,as a result of the drug's influence. The mean duration of TAM therapy was 2.72±1.34.

Abnormal vaginal bleeding was experienced by 5 patients (18%) who were symptomatic VS 22 patients (82%)  who were asymptomatic with  TAM use ranging1-4 years in both groups. The incidence of symptomatic patients in our study was close to that found in Hetta et al. ¹². Also Jindal et al.¹³conducted study  in line with our study, in which 88 % of  the partcipants  were asymptomatic and only 12 % were symptomatic.

Endometrial thickening on TVUS is a strong signal that is also suggestive of endometrial pathology¹⁴. There is no precise definition of an abnormal ET for pre- or postmenopausal women receiving TAM due to its estrogenic effect on subenendometrial gland which leading to increase ET¹⁵. Various cutoff values for detection of the endometrial disease in asymptomatic postmenopausal women under TAM were reported, 5, 9, 10mm ^{14, 15, 16}, however the findings of the previous studies are hampered by verifying bias and a small sample size. There is consensus about if postmenopausal and premenopausal women experience bleeding and their ET is >5 mm, >8mm respectively, further investigation is neede^8,9,10.

The mean  ET  in  our patients was 9.52±4.32 with range 3-30mm. Six participants (22.2%) had average thickness and 21 women (77.8%) had endometrial changes, which manifested as, diffuse thickened endometrium without cystic changes in 7 patients(40.7), diffuse thickened endometrium with cystic changes in 11 patients(25.9%), polyp in one patient (3.7) and atrophic endometrium in 2 patients(7.4). No suspicious endometrial lesion was found. TVUS also revealed 2 patients had adenomyosis as associated lesion and that was expected with TAM. TVUS sometimes detects the polyp as a nonspecific thickening of the central endometrial complex, with or without cystic changes, but it may also skip the diagnosis⁹.

Our results were matched with Amer et al. ¹ and Le Donne et al. ¹⁷whoreported the same results regarding increased ET in patients receiving TAM after mastactomy. In term of endometrial regularity, we found, 12 patients (44.5%) had irregular endometrial line. Although, Irregular or poorly defined ET is usually indicative of malignancy. However, in women receiving TAM, because of underlying benign diseases as adenomyosis, or polyp, poor definition of ET is not a helpful for the diagnosis of endometrial carcinoma. Also our results were in accordance with the results of Le Donne et al. ¹⁷who found that cystic endometrial appearance was frequent in patients under TAM.

Regarding the hysteroscopic findings, we found that, 7 patients (25.9%) had normal endometrium but 20 patienrs (74.1%) had abnormal endometrium as follow, l5 participants (55.6%) had endometrial hyperplasia (EH), (Figure 4). Really inspite of some studies were demonstrated the hysteroscopic morphology for each type of EH as Butureanu et al. ^(18), but this was not practically established, we only suspected, EH when the endometrium appears thicker on hysteroscopy than standard proliferative endometrium, which has a glistening, mucoid, pink-gray look. It's also likely that it's polypoid in nature.Small cysts and dilated, clogged sinusoids can be visible underneath the surface ⁹, but it was difficult to distinguish between its types i,e typical and atypical forms. De Franiscis et al. ¹⁹ reported that uptill now, the EH morphological criteria that detected by hysteroscopy are based on the operator’s subjective assessment and, therefore, are not reliable. Three patients (11.1%) had polyps, 2 of which were missed by TVUS. It was found that women under TAM, either they experienced vaginal bleeding or not, the endometrial polyps usually are expected but they are common in asymptomatic women⁹. At hysteroscopy, the majority of polyps have smooth, glistening surfaces and are pink-gray to white in colour (Figure. 4). The polyps may be connected to a long or narrow stalk. Unlike endometrial carcinoma, they usually do not bleed readily when touched. Sometimes, the whole polyp or only the tip of the polyp may be hemorrhagic or infarcted ⁹. Our study revealed 2 participants (7.4%) had atrophic endometrium. A hysteroscopic diagnosis of atrophic endometrium is established when uterine cavity was regular and the uterine lining was smooth, thin, and pale white with clearly visible network vessels (Figure 4). Regarding the adenomyosis, the hysteroscope plays little role in its detection easpecially the diffused form, so TVUS is superior in detecting of adenomyosis over US.

Regarding the histopathological findings there was10 patients (37.1%). revealed normal reports while 17 patients (62.9%) revealed pathology. as follow, 3 patients(11.1%) had simple EH, 5 (18.5%) had mixed cystic hyperplasia, 4 (14.8%)had atypical hyperplsia that noticed in patients used TAM > 2 years, 3 patients (11.1%) had polyp. All polyps were detected by hysteroscopy versus only one polyp detected by TVUS. Two participants (7.4%) had endometrial atrophy which was easily detected by both US and hysteroscopy. Our result was in agreement with Amer et al ¹, who found that the most common histopathologic finding was EH. (31.3%).

In term of atypical EH., Hetta et al.¹² reported higher incidence with atypia in patients with TAM treatment. However Saccardi et al.²⁰reported less incidence of EH with atypia, This may be attributable to different sample size.

No cases of endometrial cancer was found in our study, several studies were reported a significant correlation between TAM. therapy and benign uterine pathologies and the majority of TAM's proliferative influences on endometrium are unlikely to progress to cancer ^17,21. On other hand some researchers found in their studies cases of endometrial cancer among TAM treated women¹².But we can attributed that to our small sample size and or short duration of drug treatment, most of our participants didn’t take TAM more than 4 years and most of researchers as Le Donne et al.^17,and Jones et al.²² inferred the increase the frequency of endometrial cancer to the long term use of TAM.

 Our study revealed that no difference was found between the symptomatic and asymptomatic participants in the incidence of endometrial changes, p>0.05 (Table 3).

Jindal et al¹³.in agreement with our result, they found that increased endometrial changes On TVUS in asymptomatic postmenopausal women with breast cancer and receiving TAM. But, Cohen et al.¹⁶ found that the frequency of endometrial pathology was significantly higher in symptomatic patients receiving TAM, which contradicted our findings. In reality, the need for screening and surveillance in asymptomatic TAM patients is a subject of debate among researches, as it has been demonstrated that symptomatic patients are more likely to have a disease that can be easily detected when they visit care facility. If asymptomatic TAM patients were not recommended to keep track of for endometrial assessment, they may be lost.

Upon correlating the ultrasound and hysteroscopic findings and their efficiency in detection of endometrial changes with histopatalogy results, we only checked the correlation and diagnosis from the hand, identification of the presence or absence of endometrial changes, but not the condition of lesion, i,e, benign, orpremalignant (atypical EH.) or malignant. Our study reveled that regarding TVUS,14 (82.3%) were true positives, 7 patients (70%) were false positive i.e, inspite of increased the ET in those patients more than the cut off values, but, they revealed normal proliferative endometrium on histopathological report,3 patients (17.7%) were false negatives this resulting from missed diagnosis of 2 cases of polyp and one case with normal ET revealed simple EH on histopathology, 3 patients (30%) were true negative (Table 4, Figure 1, 2, 3).

Regarding the hysteroscopic findings when they correlated with histopathology, 16(94.1%) were true positives, 4(40%) were false positive (i, e, revealed normal with histopatalogy), 1(5.9) was false negative and 6(60%) were true negatives (Table 4, Figure 4).

 The diagnostic performance of ultrasonography and hysteroscopy in detection of endometrial changes regarding the histopathological reference, we found that hysteroscopy was more sensitive than ultrasound in the diagnosis of endometrial lesions, table 4,and this was consistent with the result of Le Donne et al.¹⁷ who showed a significant association between hysteroscopy and histological findings regarding the diagnosis of endometrial atrophy, polyps, hyperplasia and cancer (P<0.001). Similarly, Mukhopadhayay et al.²³ found a high sensitivity (71.4%) and specificity (100.0%) for hysteroscopy for diagnosing polyps.

Amer et al. ¹ found that TVUS was not accurate in identifying hyperplasia and polyps. Moreover, Dijkhuize et al. ²⁴ reported that, due to the echogenic, irregular, cystic effect induced by TAM on endometrial stroma and gland and on the myometrium, without essentially inducing epithelial changes, therefore endometrial thickness cannot be used in those patients to define abnormalities ²⁵. Similarly Jeon et al. ⁵ reported that TAM causes subendometrial glandular hypertrophy, so ET can increase even in absence of pathologies^15.. So some researchers suggested that TVUS endometrial testing has limited predictive value in asymptomatic patients with false positive result. Additionally, TVUS has been confirmed to provide false-negative diagnoses of small polyps, localised atypical hyperplasia and endometrial cancer ⁷.

On Contrary, Hetta et al.¹²and Cohen et al.¹⁶ disagree with our result, they revealed that TVUS was more diagnostic than hysteroscopy.

In the paractice, inspite the value of hysteroscopy in detecting the endometrial pathology, however it doesn’t distinguish between typical and atypical hyperplasia, unless the latter is associated with focal lesion, additionally, in this situation hysteroscopy is only suspecting but not confirming the pathology. Similarly Barati et al.²⁶ reported that, EH can develop visible space-occupying lesions that are simple to diagnose by hysteroscopy, but it may not noticeable, particularly in the early stages of the disease, so, histopathology tests are essential for the definitive diagnosis of exact pathology.

We couldn't find a correlation between the duration of TAM therapy and the occurrence of endometrial changes, similarly Donnez et al.²⁷  didn't observed any relation between duration of TAM use and endometrial changes, nevertheless the previous authors found that increased the incidence of endometrial cancer in patients used TAM for more than four years. In the present study we also found, inspite there no relation was found between the incidence of endometrial changes and duration of TAM therapy ,but, there was association between the latter and the severity of endometrial  changes i, e, our study revealed all patients who had atypical hyperplasia were used TAM > 2years duration. This means that incidence of premalignant lesion is increased with lengthing the duration of treatment.

CONCLUSION

TVUS is a suitable for endometrial screening for intrauterine pathology. However,  because of certain discrepancies  between TVUS and histopathological results in TAM treated women, TVUS is not the ideal tool for evaluating the endometrium in those patients. The utility of the hysteroscopic image processing helps in the triage of women who require endometrial surveillance, so it will reduce the pathologist's needless workload and the patient's apprehension while waiting histopathology result. Nevertheless hysteroscope cannot establish a conclusive diagnosis of premalignant or malignant lesion, but it provides a direct view of the endometriaum for detection of focal lesion and chance of conducting targeted biopsies to create a definitive diagnosis.