Abstract
Abstract
Introduction
T
Methods
A Medline® search was conducted, using the term
Results
In addition to lesions that usually affect the uterine fundus or cervix, some lesions are unique to the LUS. Adenocarcinomas arising in the LUS can be associated with Lynch syndrome. Endometrial adenocarcinoma spreading to the LUS may indicate an increased risk of lymph-nodal involvement. Endometrial carcinomas arising in the LUS, as well as those spreading to the LUS, may have unique prognostic implications.
Discussion
Anatomy and histology
The LUS, also originally known as the isthmus uteri of Aschoff, 1 was the subject of much early debate. The lowermost aspect of the LUS has an easy-to-identify gross structure, the anatomic internal os. The histologic internal os, the transition from LUS to endocervical mucosa, lies 6–10 mm below that. 1 The uppermost portion, where the LUS meets the lowermost portion of the uterine fundus, is not so well-delineated. In studies utilizing the lowermost aspect of low lying placentas to identify the upper limit of the LUS, Morrison 2 estimated that, at 20 weeks, the LUS measured 0.5 cm in length, with an increasing length during gestation. Much of what has been written about the exact location of the LUS is in relationship to pregnancy and labor.
In the nonpregnant patient, the significance of the LUS is different. A normal LUS may be sampled during endometrial sampling, and it does not cycle or respond to hormones to the same degree. Thus, it does not decidualize or shed with menses to the same degree as the stratum functionalis. 3 As such, it may be interpreted as inactive endometrium if it is not recognized, and the clinician may not be alerted to the fact that the area of interest, the functional endometrium, has not been sampled. LUS mucosa is characterized variously by a mix of endocervical and endometrial glands, hybrid glands with mixed features, or inactive endometrial glands. Ciliated epithelium in these glands is a normal finding. 4 The stroma is more eosinophilic and less cellular that that of the stratum functionalis, reflecting greater amounts of collagen. The muscle bundles of the LUS wall are arranged somewhat differently, and are fewer than that of the corpus proper, 1 in a manner to accommodate labor.
Recognition of cytologic features of the LUS have been emphasized for cytopathologists, to avoid overinterpretation of LUS sampling after radical trachelectomy as being atypical. 5
Benign lesions
Cesarean-section scar and associated complications
In a series of hysterectomy specimens, Morris 6 looked for pathologic changes in the region of old Cesarean-section scars that might be associated with clinical symptomatology. Findings that might correlate with abnormal uterine bleeding included overhang of congested endometrium above the scar and the formation of polyps. Pain symptoms—such as abdominal pain, dyspareunia, and dysmenorrhea—were thought to be potentially correlated with inflammation, fibrosis, and tissue distortion. Other findings of note included residual suture material, dilated capillaries, hemorrhage, endometrial distortion and breakdown, and iatrogenic adenomyosis. 6
Much has been written about the use of ultrasound in evaluating patients for a trial of labor after prior Cesarean section. In one meta-analysis, 7 the measurement of LUS thickness by ultrasound was found to be useful for predicting risk of dehiscence and rupture during labor. Cesarean scars can rupture spontaneously in both the pregnant and nonpregnant uterus, as well as during labor. In one case, neglected ruptured membranes led to sepsis and spontaneous uterine dehiscence of a repeat lower uterine scar at 20 weeks. 8 Of note, uterine rupture of the pregnant uterus in the absence of a prior scar is most often in the LUS as well, which is most likely related to thinning of the region. 9
Cesarean-scar pregnancy, the implantation of pregnancy in a prior lower segment scar, with thinning of the LUS wall, has a high complication rate, and can result in catastrophic rupture and hemorrhage in the first trimester, 10 but has rarely resulted in a live pregnancy. In one study of cases identified by first-trimester ultrasound, patients opting for minimally invasive interventions to terminate this kind of pregnancy markedly reduced the need for hysterectomy. Women with viable pregnancies who continued had a 62.5% liveborn rate, but 37.5% of these women had hysterectomy for accreta. 11 Minimally invasive methodology for treatment has included hysteroscopic resection after chemoembolization 12 and robotic-assisted laparoscopic resection. 13 Pharmacologic therapy with methotrexate as well as surgical resection have also been utilized, as in a case of recurrent scar pregnancy in a patient treated by surgery the first time and methotrexate the second time. 10
In addition to obstetric complications associated with Cesarean-scar defects, gynecologic complications have been described, including abnormal uterine bleeding, dysmenorrhea, pelvic pain, infertility, and complications during gynecologic procedures. Rare abscesses and fistulas have also occurred. Symptomatic scar defects may be amenable to repair with minimally invasive surgery. 14
Vascular and hemorrhagic lesions
LUS varicosities can be present, particularly with placenta previa 15 and may pose a dilemma at Cesarean section. It has been suggested that they can be responsible for both antenatal and postpartum bleeding as well. 16 Prior classical Cesarean section has also been suggested as a potential underlying etiology. 17 Suggested methods of delivery have included clamping the vessels before the lower segment uterine incision, 15 and fundal transverse hysterotomy. 17
A case of a patient with Klippel–Trénaunay–Weber syndrome, a syndrome associated with vascular malformations, was documented by Bouchard-Fortier et al. 18 The patient, who had a prior history of severe postpartum hemorrhage, was found to have multiple abnormal vessels in her LUS on ultrasound; these vessels were seen at the time of her classical Cesarean section.
Cavernous hemangioma of the LUS may lead to abnormal vaginal bleeding, as well as suspicion of the presence of a neoplasm. Imaging modalities, such as ultrasound and magnetic resonance imaging, can help clarify the presence of a hemangioma. 19
It has been postulated that LUS atony in the absence of fundal atony can result in severe postpartum bleeding, with ballooning of the LUS. 20
Vesicouterine fistulas
While considerably less frequent than vesicovaginal fistulas, vesicouterine fistulas are highly associated with lower-segment Caesarean delivery and may relate to devitalization of bladder tissue at that time. They may present immediately or delay presentation until after Cesarean birth. 21 Presenting symptoms can include cyclic menouria, vaginal urinary leakage, amenorrhea, infertility, and first-trimester pregnancy loss. 22 Youssef's syndrome is cyclic hematuria, amenorrhea, menouria, and urinary continence. 23 Cystograms and hysterograms have been used for diagnosis. 21 Although conservative management is sometimes attempted, many of these cases require surgery. 22
Benign masses
Leiomyomata arising in the LUS may obstruct labor or cause urinary retention, 24 and have been associated with greater frequency of Caesarean sections and retained placentas. 25 In 1 case, a large LUS leiomyoma was the cause of uterine sacculation—a rare pregnancy complication wherein an aneurysmal dilatation of the uterine wall occurs—and can be associated with a variety of complications. 26
Rarely, condyloma accuminatum can involve the endocervix and the LUS. In one such case, the large lesion filled the endocervical canal and may well have been the cause of the patient's persistent uterine pain, which resolved after hysterectomy. 27
An unusual case of a pyogenic cervical cyst, arising at the site of incision of a prior LUS myomectomy was described. 28 In this case, the cyst contained evidence of endometriosis as well as Escherichia coli, and it was postulated that the endometriosis may have been an iatrogenic effect of the myomectomy, where the site may have become infected, although 13 years had elapsed since the myomectomy. If arising in the LUS, an intramyometrial abscess may also obstruct labor. 29
Miscellaneous lesions
It has been suggested that, although fewer adenomyotic nests are present in the LUS than the fundus, in patients undergoing hysterectomy for symptomatic adenomyosis, if a supracervical hysterectomy is performed, care be taken to remove the entire LUS to minimize the likelihood of persistent lesional tissue. 30 Mass-forming adenomyomas have also occurred in the LUS. 31
Amniotic fluid embolus is thought to arise from entry of amniotic fluid through LUS vessels exposed via tears during labor or trauma. 32
A case of psammoma body formation in LUS endometrium, but not the stratum functionalis, was reported. 33 The patient was nulliparous and had been treated with clomiphene. The authors attributed the formation of the psammoma bodies to the patient's altered hormonal milieu and demonstrated that this finding is not always associated with malignancy.
Endosalpingiosis, a lesion usually seen on peritoneal surfaces and lymph nodes, and rarely presenting as a mass, has occasionally produced mass-like lesions, and a few cases have involved the LUS and cervix. In those cases, distinction from an adenoma malignum was emphasized. 34
Pathologic uterine rings (Bandl's rings) are obstructive rings at the junction between the LUS and upper uterus. These rings are most commonly found in obstructed labor and are much less often seen with the institution of liberal Cesarean section. Bandl's rings have been reported to cause traumatic brain injury and cerebral palsy rarely by compressive injury to the fetal head. 35
An inflammatory myofibroblastic tumor is a rare mesenchymal lesion that usually occurs in the lungs, mesentery, omentum, or retroperitoneum, but has also been reported to occur in the uterus. 36 In the largest reported series of 6 cases, 3 arose from the LUS. The tumor behaves in a benign fashion or is locally recurrent but needs to be distinguished from more-aggressive, more-common uterine mesenchymal lesions. The presence of ALK positivity, negative or weak muscle markers, a lymphoplasmacytic infiltrate in the spindle cells, and a myxoid background are helpful features. 36
A case of an intermediate trophoblastic lesion histologically similar to the benign placental site plaque/nodule, but coating the LUS, upper endocervix, and bilateral fistulous tracts to the parametria, was attributed to prior Cesarean sections. 37
Neoplasms of uncertain malignant potential
Atypical polypoid adenomyoma
An atypical polypoid adenomyoma is a lesion most often arising from the LUS. This neoplasm is composed of atypical endometrial glands—that are sometimes worrisome histologically—embedded in a benign neoplastic smooth-muscle stroma. The lesions tend to be well-circumscribed and polypoid. LUS lesions may protrude through the cervical os. 38 Squamous metaplasia is common. The lesion tends to occur in reproductive-age to premenopausal women, with a mean age of 39.7 in Young et al.'s series, 39 raising issues of preservation of fertility. While most cases have been treated with hysterectomy, curettage has occasionally been successful, although the lesion may persist. There are cases, wherein this neoplasm had undergone malignant degeneration, although most of these neoplasms behave in a benign fashion.39,40
Epithelioid trophoblastic tumor (ETT)
This neoplasm is a more recently described tumor that falls under the category of lesions of intermediate trophoblast, along with the better-known placental-site trophoblastic tumor. An ETT is similar in behavior as well and has an uncertain malignant potential. An ETT most commonly arises in the LUS and endocervix, which can make distinction from cervical squamous-cell carcinoma a challenge, particularly as both neoplasms are positive for p63 and cytokeratins, however ETT stains for inhibin as well as for some trophoblastic markers. 41
Malignant neoplasms
Adenocarcinoma of the LUS
While it is possible at times to determine if adenocarcinomas arising in the LUS are of endometrial or endocervical origin, this is not always possible. Tumors that arise from the LUS represent ∼ 3%–6% of endometrial cancers, 42 have been shown to be deeper and more aggressive than corpus tumors,43,44 and have increased risk of being associated with Lynch syndrome. 44 Lynch syndrome is known to be associated with endometrial but not endocervical tumors. 45 Testing for mismatched repair protein mutations has been suggested, particularly if the origin of a LUS cancer cannot be determined 45 as well as when the tumor is of endometrial origin. Distinction is aided by molecular testing and immunohistochemistry, with estrogen-receptor and vimentin favoring endometrial origin, and p16 and human papilloma virus DNA positivity favoring cervical origin. 42
Endometrial carcinoma involving the LUS in addition to the fundus does not upstage the tumor without cervical involvement; however, in some studies, LUS involvement has been shown to worsen prognosis. In one series, LUS spread of lower-stage cancers decreased both survival and disease-free survival. 46 Stage I high-grade endometrial adenocarcinoma, defined as grade-3 endometrioid, serous, clear-cell, carcinosarcoma, or mixed histology, spreading to the LUS was shown to be associated with pelvic and paraaortic nodal disease in one study, 47 and this held true in another study for endometrioid histology as a predictor of nodal histology as well, although nodal group was not specified. 48 However, the same group of researchers 49 found that, in cases of surgically staged endometrial cancer, if the nodes were negative, LUS involvement did not worsen prognosis.
Rare malignancies
A patient treated for diffuse large B-cell lymphoma of the LUS and cervix subsequently had delivery of a full-term pregnancy. 50 A rare alveolar soft-part sarcoma of the LUS was also reported. 51 Finally, a primitive neuroectodermal tumor (PNET) arising in the LUS was discovered at the time of Caesarean section. 52
Conclusions
As noted in the Results section: (1) carcinomas arising in the LUS can be associated with Lynch syndrome; (2) endometrial carcinoma spreading to the LUS may indicate an increased risk of lymph-nodal involvement; and (3) identifying such lesions may have unique prognostic implications.
Understanding the scope of LUS lesions, as presented in this review, will assist in developing a differential diagnosis if a patient with such a lesion is encountered.
Footnotes
Disclosure Statement
No competing financial conflicts exist.