Low-grade Appendiceal Mucinous Neoplasm and Endometriosis: Incidental Coincident Pathologies at Cesarean Section

Summary:

Incidental pathologic findings at the time of Cesarean section are exceedingly uncommon. Similarly, occult low-grade appendiceal mucinous neoplasms and other noninflammatory, non-neoplastic appendiceal pathologies are rare, although appendiceal neoplasia, most commonly well-differentiated neuroendocrine tumors, may be found during evaluation of acute appendicitis. Here we report the first case of incidental coincident low-grade appendiceal mucinous tumor and endometriosis involving the appendix at the time of Cesarean section. We highlight pitfalls in the histopathologic evaluation of these processes, particularly given the setting of decidualization of ectopic endometrial stroma, as well as the prognostic implications of low-grade appendiceal mucinous tumors to emphasize the importance of clinicopathologic correlation and careful intraoperative examination of the appendix and other visible structures during Cesarean section.

CASE REPORT

A 31-yr-old G2P0100 with no significant past medical history presented in active spontaneous labor at 38 wk and 4 d gestation following spontaneous rupture of membranes. Her pregnancy was complicated by prophylactic cerclage placement at 14 wk gestation due to a history of preterm vaginal delivery at 21 wk. On presentation, the patient reported frequent painful contractions. The patient was given epidural anesthesia and terbutaline, along with ampicillin and gentamicin given concerns for chorioamnionitis in the setting of a persistent fever of 100.5°F. The following day, fetal monitoring detected decelerations with bradycardia. The patient failed to progress during the second stage of labor, and a Cesarean section was performed. A healthy infant was delivered without complication.

At this point, several adhesions were noted extending from the right lower abdomen to the left uterine cornua and the appendix, which appeared inflamed. The appendix was dissected from the anterior uterine wall. Emergency General Surgery was consulted intraoperatively due to concern for acute appendicitis. The patient, who was under regional anesthesia and was able to speak with the general surgery team, consented to an emergent appendectomy. The appendix was dissected from the mesoappendix, and the appendix specimen sent to pathology. The patient tolerated the procedure well and met postoperative goals; during admission, she described a history of severe prolonged abdominal pain 8 to 9 yr that resolved and for which no diagnosis was rendered. She was discharged home with her infant on postoperative day 3.

On gross examination by pathology, the appendix showed subtle intramural mucin deposition (Fig. 1A). The appendix was submitted entirely for histologic examination. There was no acute or chronic appendicitis; however, there were 2 subtly distinct abnormal processes. First noted was near circumferential serosal adhesions (Fig. 1B) as well as mural deposits (Fig. 1C) of decidualized tissue with associated glands lined by simple cuboidal epithelium. In other areas, regionally obliterating the appendiceal lumen, were glands with abnormal mucinous intestinal epithelium and abundant associated luminal mucin (Fig. 1D). The mucinous intestinal epithelium showed adenomatous change in many areas, also with surrounding decidualized stroma (Fig. 1E), and there was mural and mesoappendiceal acellular mucin (Fig. 1F), including focal neoplastic epithelium and mucin at the serosal surface (Fig. 1G).

FIG. 1.

Histopathologic evaluation of appendix. (A) Subtle intramural mucin is visualized on a representative cross-section of the appendix upon gross pathologic examination (white arrows: intramural mucin deposits; black arrow: appendiceal lumen). (B) Upon histologic examination, adhesions of decidualized tissue are present on the appendiceal serosal surface (right). The appendiceal lumen in many areas is normal and uninflamed (left) (H&E, 20×). (C) Mural deposits of simple low cuboidal epithelium-lined glands have surrounding decidualized stroma, similar to that composing the serosal adhesions (H&E, 200×). (D) Abnormal mucinous epithelium regionally replaces the normal appendiceal luminal crypt epithelial (lower right) (H&E, 20×). (E) Other regions of the abnormal mucinous epithelium show epithelium pseudostratification, consistent with adenomatous change (H&E, 200×). (F) Intramural acellular mucin is confirmed histologically (H&E, 20×). (G) Neoplastic epithelium overlying decidualized tissue at the serosal surface; note muscularis propria of appendiceal wall (upper left and bottom right) (H&E, 40×). H&E indicates hematoxylin and eosin.

To resolve the origins of these 2 distinct lesions (Fig. 2A), tissue immunohistochemical stains were performed. The decidualized tissue expressed CD10, consistent with endometrial stroma (Fig. 2B). The partially adenomatous mucinous epithelium expressed cytokeratin 20 (CK20), CDX2, and SATB2 and was negative for cytokeratin 7 (CK7) and PAX8 (Fig. 2C–G), consistent with gastrointestinal origin and an appendiceal mucinous neoplasm; the simple low cuboidal epithelial process showed the opposite pattern: expression of CK7 and PAX8 and lack of expression of CK20, CDX2, and SATB2 (Fig. 2C–G), consistent with Müllerian origin. Therefore, the final pathologic diagnoses were low-grade appendiceal mucinous neoplasm (LAMN) with mucinous epithelium involving the serosa and concurrent endometriosis with decidualized endometrial stroma.

FIG. 2.

Immunohistochemical evaluation of 2 distinct appendiceal pathologies. Adjacent abnormal glandular structures in the appendiceal wall show one with simple low cuboidal epithelium (left) and one with partially pseudostratified mucinous epithelium (right). (A) H&E. (B) CD10. (C) CK20. (D) CDX2. (E) SATB2. (F) CK7. (G) PAX8. All images: 40× magnification. CD10 indicates cluster of differentiation 10; CDX2, caudal type homeobox transcription factor 2; CK7: cytokeratin 7; CK20, cytokeratin 20; H&E, hematoxylin and eosin; PAX8, paired box gene 8; SATB2, special AT-rich sequence-binding protein 2.

A surgical oncology team met with the patient postoperatively and discussed the implications of LAMN. A computed tomography (CT) scan of the abdomen and pelvis was scheduled, with a plan to reimage every 12 mo; the patient did not appear for the first CT appointment.

DISCUSSION

We report the first co-occurrence of LAMN and appendiceal endometriosis found incidentally during Cesarean section. This case highlights the similarities and potential subtleties of both processes intraoperatively and histopathologically, particularly in the setting of gestational changes where decidualization of ectopic endometrial stroma may obscure recognition of the mucinous neoplasm component. To our knowledge, there is only one previous report of LAMN diagnosed with concurrent appendiceal endometriosis (1); that patient had already been diagnosed with endometriosis, unlike the patient described here. Identification of LAMN is crucial given the potential complications of the disease, most notably pseudomyxoma peritonei (PMP). Prognostic implications and future management are contingent upon histologic assessment and tumor staging.

Mucinous neoplasms of the appendix occur in about 0.2% to 0.7% of appendectomies, and approximately one third (31%–34%) are LAMNs (2,3). The majority of appendiceal mucinous neoplasms are diagnosed incidentally (4). These tumors are often found operatively and diagnosed histologically. Approximately 50% of patients are asymptomatic; however, patients late in the disease course may present with abdominal pain, nausea and vomiting, and/or weight loss (4). Initial clinical differential diagnoses may include acute appendicitis, ovarian mass (in women), colon cancer, retroperitoneal cyst, peritoneal sarcomatosis, or even disseminated peritoneal fungal infection (2).

Interestingly, 2 studies at separate institutions demonstrated that patients above the age of 40 undergoing interval appendectomy (surgical indication being complicated appendicitis) were diagnosed with appendiceal tumors in 27.7% to 29.4% of cases (3,5). Most appendiceal mucinous neoplasms occur in females in the fourth to sixth decade of life (3). In fact, the female to male ratio of reported cases is 4:1 (4). These findings may inform care for older female patients presenting with appendicitis-like symptoms or right lower quadrant abdominal pain. In addition, the rare but real possibility of appendiceal mucinous neoplasia and/or endometriosis presenting during pregnancy could be considered where appropriate in patients with bloating or pain out of proportion to the gestation.

LAMN is defined as a well-differentiated noninvasive adenomatous lesion that arise in the appendix. Despite the fact that LAMN is characterized by the absence of infiltrative invasion, it can proliferate outside of the appendix in a malignant manner. The lack of destructive invasion yet capacity to metastasize has caused a great deal of controversy with regard to the classification and nomenclature of this tumor (6). In addition, the location and curious biologic behavior of LAMN makes it difficult to diagnose.

Histologically, LAMN demonstrates replacement of normal appendiceal mucosa with a flat or villiform proliferation of mucinous intestinal-type epithelial cells. Cytologically the cells contain abundant apical mucin, elongated nuclei, and low-grade nuclear atypia. Architecturally, there may be invasion through and loss of the muscularis mucosae and mucosal crypts, fibrosis of the submucosa, atrophy of lymphoid tissue, mural dissection of acellular mucin, and circumferential involvement of the mucosa (7). The lesional epithelial cells express gastrointestinal epithelial markers CK20, CDX2, and SATB2. Many of these tumors express KRAS and/or GNAS mutations (8).

Several staging systems for LAMN have been developed. The most widely used is the 2017 American Joint Committee on Cancer (AJCC) staging system in the eighth edition of the AJCC Staging Manual (9). The AJCC Staging Manual recommends a staging system for LAMN similar to that used for other appendiceal cancers. Tumors confined to the muscularis propria are categorized as in situ tumors or Tis (previously T1 and T2). This designation implies that the entire appendix has been submitted and the margins are negative. These tumors are associated with no recurrence and have an excellent prognosis. LAMN that extends beyond the muscularis propria into the subserosal tissues or mesoappendix are designated T3. Those penetrating the visceral peritoneum, including cellular mucin such as our case, or involving the serosa of the appendix are categorized as T4a. Tumors directly involving adjacent organs or structures are categorized as T4b.

There is no convincing evidence of an increased risk of recurrence of stage T4a tumors with acellular mucin when the entire appendix is examined histologically; nonetheless, there are 2 cases in the literature in which the entire appendix was not submitted and tumors were found to recur. It is possible that neoplastic cells were not sampled in these cases but given the lack of conclusive data and the small number of reported cases, these tumors are considered low risk. For this reason, patients typically undergo regular clinical and radiologic follow-up (6). The recurrence rate increases significantly with the presence of neoplastic epithelium beyond the muscularis propria. Tumor cells confined to the right lower quadrant pose a risk of 33%, and cases beyond that region recur 69% of the time (10).

Tumors that present with intraperitoneal acellular mucin only and no identifiable epithelial component are categorized as M1a and have a lower risk of recurrence than M1b tumors, which present with peritoneal mucin deposits containing tumor cells. Any LAMN that presents with metastasis outside of the peritoneum is labeled M1c and portends a high risk for recurrence requiring aggressive therapy and ongoing follow-up (6).

Although uncommon, the diagnosis of LAMN and other appendiceal neoplasms has important implications for the patient due to serious complications that can result from delayed or improper management. The most noteworthy complication is PMP, a life-threatening condition associated with significant morbidity and mortality. PMP is the result of tumor rupture leading to dissemination of mucinous ascites and malignant cells into the peritoneum. A retrospective study of 547 patients diagnosed with LAMN demonstrated a PMP incidence of 20%, the majority of which occurred within 2 yr of surgical appendectomy (11). Treatment for PMP can be arduous given the high rate of recurrence and mortality. Other complications of LAMN include local tumor recurrence and other local complications including intussusception, volvulus, small bowel obstruction, and ureteral obstruction.

The prognosis for LAMN varies depending on the level of tumor involvement. Tumors confined to the appendix are virtually cured with complete resection of the appendix and therefore do not require strict follow-up. LAMNs with low-volume peritoneal involvement of acellular mucin have a very low recurrence risk (4%), but clinical-radiologic surveillance is a reasonable approach. These cases sometimes require more extensive resection, including right hemicolectomy. If the presence of extra-appendiceal neoplastic epithelium is identified, cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy is warranted (12). The risk for recurrence and dissemination is higher in these patients and requires frequent follow-up and surveillance by crosssectional imaging (10).

Endometriosis of the appendix is reported relatively infrequently, arising in 2.8% of patients with known endometriosis, and is found incidentally in 0.3% of appendectomy specimens (1). Endometriosis has been described in association with appendiceal neoplasms on 13 occasions in the literature, one of those being a LAMN and all other cases being simple mucoceles (1). It is hypothesized that endometriosis can lead to scarring, which obstructs appendiceal mucinous outflow and can result in a mass, most commonly a mucocele (13).

A relationship between endometriosis and appendiceal mucinous neoplasms was proposed in 1977 by Hapoke and Bigelow (14) who hypothesized that smooth muscle hypertrophy of the muscularis propria caused by endometriosis leads to entrapment of mucin, formation of mucinous cysts, inflammation of the mucosa and in some cases malignant changes leading to tumor formation. Given the rarity of concurrent identification of these 2 pathologies, it is not likely that patients with endometriosis are at increased risk for appendiceal tumors. However, this possibility highlights the importance of careful histopathologic examination of endometriosis, given that its histopathologic distinction from adjacent LAMN may be subtle. The potential for malignant transformation when compared with other obstructive and inflammatory causes of appendiceal neoplasms is an important topic beyond the scope of this report, but future investigations may change the way clinicians approach endometriosis patients who present with abdominal pain.

In summary, LAMN and endometriosis are uncommon pathologies encountered at the time of Cesarean section. We report the first incidental co-occurrence of these diseases in an appendix adherent to the gravid uterine serosa noted during Cesarean section in order to highlight these rare disorders and clinicopathologic pitfalls in their diagnosis.