Introduction
============

Appendiceal adenocarcinoma is a rare malignancy, accounting for only 0.5% of all gastrointestinal malignancies ([@B1]). A mucinous type of appendiceal adenocarcinoma (MAA) is frequently accompanied by mucocele ([@B2]). The tumor itself is not aggressive; however, the disease has an unfavorable prognosis due to the absence of specific symptoms and the potential of tumor rupture, resulting in difficulty achieving an early diagnosis ([@B3]-[@B5]). Mucocele rupture leads to pseudomyxoma peritonei (PMP), which is the dissemination of malignant cells in the intraperitoneal cavity ([@B6]). Fistula formation into adjacent organs is an unusual presentation of MAA. Although some authors have reported that fistula formation might improve the patient outcome by preventing the development of PMP ([@B7], [@B8]), the prognosis of such cases remains unclear.

We herein report a case of MAA with fistula formation and review the pertinent literature to discuss the clinical features and prognostic impact of this rare manifestation.

Case Report
===========

A 90-year-old man with no significant medical history was referred to our hospital for a positive fecal occult blood test (FOBT). No remarkable findings were noted in a physical examination. A laboratory analysis revealed a slightly decreased level of hemoglobin (12.7 g/dL; normal range 13.4-17.6 g/dL). Tumor markers (carcinoembryonic antigen and carbohydrate antigen 19-9) were normal. Colonoscopy revealed multiple nodules forming a mass-like lesion 35 mm in diameter and covered with a large amount of mucus at the hepatic flexure of the colon ([Fig. 1](#g001){ref-type="fig"}). Mucinous colon carcinoma was suspected, but biopsies from the lesion showed only mucus products and granulation tissue. Other colonoscopy findings included an elevated lesion with multiple small granular protrusions covered with intact epithelium at the appendiceal orifice ([Fig. 2](#g002){ref-type="fig"}). The biopsy from the appendiceal orifice was negative for cancer cells.

![Colonoscopy revealed multiple nodules forming a mass-like lesion covered with a large amount of mucus, 35 mm in diameter, at the hepatic flexure.](1349-7235-57-2945-g001){#g001}

![Other colonoscopy findings included an elevated lesion with multiple small granular protrusions covered with intact epithelium at the appendiceal orifice.](1349-7235-57-2945-g002){#g002}

A barium enema (BE) showed extrinsic compression at the ileocecum and a filling defect at the hepatic flexure of colon, but the appendix could not be visualized ([Fig. 3](#g003){ref-type="fig"}). Thus, abdominal computed tomography (CT) was performed and revealed a dilated appendix adhering to the hepatic flexure ([Fig. 4](#g004){ref-type="fig"}). A second colonoscopy was then performed. A repeat biopsy from the lesion at the hepatic flexure was positive for mucinous adenocarcinoma. The biopsy from the appendiceal orifice was also positive for adenocarcinoma, which infiltrated the submucosal layer. Based on these findings, a diagnosis of appendiceal carcinoma with fistula to the hepatic flexure was established. He had neither distant metastasis nor peritoneal dissemination.

![A barium enema showed extrinsic compression at the ileocecum and a filling defect at the hepatic flexure of colon (arrow), but the appendix could not be visualized.](1349-7235-57-2945-g003){#g003}

![Abdominal contrast-enhanced computed tomography (coronal image) revealed a dilated appendix adherent to the hepatic flexure (arrow).](1349-7235-57-2945-g004){#g004}

En bloc right hemicolectomy with extended lymph node dissection was performed for curative resection. A pathological examination revealed a well-differentiated mucinous adenocarcinoma originating from the appendiceal tip, which infiltrated the hepatic flexure with histological negative margins ([Fig. 5](#g005){ref-type="fig"}). One of the 27 resected lymph nodes was positive. The final pathological stage was T4bN1M0. No adjuvant chemotherapy was performed because of his advanced age. The postoperative course was good with no signs of recurrence at the time of writing (follow-up period: 12 months).

![A: Macroscopically, the appendiceal tumor had invaded the hepatic flexure with fistula formation (arrows). B: Histological findings showed a well-differentiated mucinous adenocarcinoma (Hematoxylin and Eosin staining; magnification, ×20).](1349-7235-57-2945-g005){#g005}

Discussion
==========

Appendiceal carcinoma is a rare malignancy that comprises less than 0.5% of all gastrointestinal malignancies ([@B1]). This disease is classified into five histological subtypes: colonic-type adenocarcinoma, mucinous type (MAA), signet ring cell type, goblet cell carcinoid, and malignant carcinoid. The 5-year disease-specific survival rate depends on the histologic subtypes, ranging from 93% for carcinoid to 27% for signet ring cell type ([@B3]). Although the tumor itself is well-differentiated and not typically aggressive, the disease-specific survival rate of MAA is only 58%. This unfavorable outcome can be explained by the potential for mucocele rupture as well as a delayed or inaccurate diagnosis as a result of nonspecific symptoms ([@B4], [@B5]).

A ruptured mucocele can result in the peritoneal spread of mucus material followed by mucinous ascites, known as PMP. Smeenk et al. reported that 20% of patients with appendiceal mucinous tumor (73% benign, 27% malignant) develop PMP ([@B6]). The most common symptoms included appendicitis-like events, increasing abdominal distention, and new onset hernia ([@B9]). The 3- and 5-year overall survival rates were 51% and 38%, respectively, for patients with PMP from MAA ([@B10]). This suggests that malignant ascites is associated with a worse prognosis than overall MAA. The treatment of patients with PMP depends on the resectability of the tumor. The recommended treatment for invasive MAA is right hemicolectomy with lymph node dissection for complete resection ([@B11]). Taken together, these data indicate that obtaining a diagnosis during the resectable stage of MAA is crucial to ensuring a good prognosis.

In the present case, the positive result of FOBT caused by the fistula formation led to further investigations, such as colonoscopy, BE, and CT. Thus, an early and accurate preoperative diagnosis was made before progression to PMP. Our search of a medical literature database showed that only 29 cases of MAA with fistula formation have been reported in the English literature. The clinical characteristics of these previous patients and our own are summarized in [Table](#t001){ref-type="table"} ([@B7], [@B8], [@B12]-[@B36]). The patients were 19 women and 11 men with a median age of 65.5 years (range, 38 to 90). The organs involved in the fistula were the bladder (n=16), skin (n=9), colon (n=4), vagina (n=2), and ileum (n=1). Chief complaints were associated with blood or mucus discharge from the involved organs in almost all of the patients. Appendiceal tumor was diagnosed in 14 (70%) of the 20 patients, while PMP was observed in only 3 (12.5%) of the 24 patients. Surgery was performed as primary treatment in all cases but two. The median follow-up period was 12 months (range, 3 days to 120 months), and follow-up information was available for all 24 cases. Twenty patients (83.3%) were alive at the end of the follow-up period; of them, only 1 had cancer recurrence. However, 4 patients (16.7%) died, but among them, 2 died of other diseases.

###### 

Summary of Cases of MAA with Fistula Formation.

  --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Reference   Age/\   Fistula location                      Chief complaints                                                         Presumed diagnosis                                                                                                       Therapy                                                                                     PMP   Follow-up          Cause of death
              sex                                                                                                                                                                                                                                                                                                                                                                  
  ----------- ------- ------------------------------------- ------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------- ----- ------------------ -----------------------
  12          82/F    Bladder                               Hematuria, fecaluria                                                     Large bowel tumor invading urinary bladder                                                                               Anterior pelvic exenteration                                                                No    Alive (84Mo)       \-

  13          57/M    Skin                                  Weight loss, skin fistula in the old appendectomy scar                   \-                                                                                                                       RHC, SE                                                                                     \-    Died (3days)       Acute cardiac failure

  14          50/M    Bladder                               Pyuria, dysuria                                                          Appendiceal adenocarcinoma                                                                                               Radical cystoprostatectomy, RHC, RT                                                         \-    Alive (24Mo)       \-

  15          58/M    Bladder                               Pollakiuria, urinary urgency                                             Bladder cancer                                                                                                           RHC, PC, RT                                                                                 \-    \-                 \-

  16          82/F    Bladder                               Urinary tract infections, lethargy, nausea, increasing obtundation       \-                                                                                                                       RHC, PC                                                                                     No    \-                 \-

  17          85/F    Vagina                                Vaginal discharge, rectal bleeding, constipation, urinary incontinence   MAA                                                                                                                      ICR, partial vaginal resection                                                              \-    Alive (9Mo)        \-

  18          60/F    Skin                                  Mucinous discharge from a skin fistula in the old appendectomy scar      MAA                                                                                                                      RT                                                                                          No    Died (6Mo)         Gastric cancer

  19          70/F    Bladder                               Hematuria                                                                \-                                                                                                                       PC, ICR, RT                                                                                 \-    Alive (120Mo)      \-

  19          67/F    Bladder                               Hematuria                                                                \-                                                                                                                       PC, RHC                                                                                     \-    Died (72Mo)        Appendiceal carcinoma

  20          67/M    Bladder                               Dysuria, pollakiuria                                                     Appendiceal neoplasm                                                                                                     RHC, PC, AC                                                                                 No    \-                 \-

  21          80/F    Bladder                               Hematuria                                                                \-                                                                                                                       RHC, PC                                                                                     No    Alive (9Mo)        \-

  22          56/M    Skin                                  Right iliac fossa pain, pyrexia, leukocytosis                            MAA                                                                                                                      RT                                                                                          Yes   Died (39Mo)        Appendiceal carcinoma

  23          46/M    Skin                                  Skin ulcers                                                              Scrofuloderma, tuberculosis, pseudomyxoma, malignant tumor of the ascending colon, cecum, appendix, or retroperitoneum   RHC                                                                                         No    Recurrence (3Mo)   \-

  24          78/F    Bladder                               Pollakiuria, micturition pain                                            Cecal or appendiceal tumor                                                                                               RHC, PC                                                                                     No    Alive (12Mo)       \-

  7           75/F    Skin                                  Skin ulcer with mucus discharge                                          Appendiceal carcinoma, colonic adenocarcinoma, ovarian adenocarcinoma                                                    RHC, SE                                                                                     No    Alive (84Mo)       \-

  25          60/F    Skin                                  Skin swelling                                                            Myxoid variant of liposarcoma or desmoid tumor                                                                           RHC, SE                                                                                     No    Alive (2Mo)        \-

  26          48/F    Vagina                                Lower abdominal pain, vomiting, anorexia, pyrexia                        Diverticulitis                                                                                                           Ap, rectosigmoid resection, oophorectomy                                                    No    \-                 \-

  27          67/F    Bladder                               Urinary tract infections, hematuria, pollakiuria, urinary urgency        Colonic cancer                                                                                                           RHC, PC                                                                                     No    Alive (3Mo)        \-

  28          59/F    Ascending colon                       Right lower quadrant abdominal pain                                      MAA                                                                                                                      RHC                                                                                         No    Alive (6Mo)        \-

  29          44/F    Bladder                               Right lower quadrant abdominal pain, hematuria                           MAA                                                                                                                      RHC, PC, right salpingo-oophorectomy, AC                                                    Yes   \-                 \-

  30          51/F    Skin                                  Skin ulcer with mucus discharge                                          \-                                                                                                                       Ap including a portion of the iliac bone, AC                                                No    Alive (36Mo)       \-

  31          38/M    Small bowel, sigmoid colon, bladder   Abdominal pain, rectal bleeding, hematuria                               Crohn's disease, sigmoid malignancy small bowel malignancy or lymphoma                                                   RHC, Sx, PC, AC                                                                             No    Alive (10Mo)       \-

  32          68/F    Skin                                  Skin swelling                                                            Acute appendicitis, appendiceal carcinoma                                                                                RHC, SE, AC                                                                                 No    \-                 \-

  33          64/F    Bladder                               Abdominal discomfort, pollakiuria                                        \-                                                                                                                       RHC, PC, AC                                                                                 No    Alive (2Mo)        \-

  34          68/M    Skin                                  Mucinous discharge from a skin fistula in the old appendectomy scar      \-                                                                                                                       RHC, SE, HIPEC                                                                              No    Alive (12Mo)       \-

  35          63/M    Bladder                               Dysuria, mucusuria                                                       Appendiceal pseudomyxoma                                                                                                 ICR, PC, electrovaporization of gelatinous nodules, HIPEC                                   Yes   Alive (15Mo)       \-

  36          45/F    Bladder                               Pyuria, mucusuria                                                        \-                                                                                                                       RHC, PC                                                                                     No    Alive (60Mo)       \-

  36          78/F    Bladder                               Mucusuria                                                                Appendiceal carcinoma                                                                                                    RHC, PC                                                                                     No    Alive (36Mo)       \-

  8           68/M    Sigmoid colon                         Right lower quadrant abdominal pain, tenderness, constipation            \-                                                                                                                       Ap, Sx, ICR, resection of right vas deferens, testicular vessels, anterior abdominal wall   No    Alive (12Mo)       \-

  Our case    90/M    Hepatic flexure                       Positive fecal occult blood test                                         Appendiceal carcinoma                                                                                                    RHC                                                                                         No    Alive (12Mo)       \-
  --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

AC: adjuvant chemotherapy, Ap: appendectomy, F: female, HIPEC: hyperthermic intraperitoneal chemotherapy, ICR: ileocecal resection, M: male, MAA: mucinous appendiceal adenocarcinoma, Mo: months, PC: partial cystectomy, PMP: pseudomyxoma peritonei, RHC: right hemicolectomy, RT: radiotherapy, SE: skin excision, Sx: sigmoidectomy

Our literature review suggests that, as in our case, the symptoms caused by the fistula led to a further investigation and an early accurate diagnosis, which resulted in the potential for curative resectability. PMP is less frequently observed than typical appendiceal mucinous tumors in patients with MAA with a fistula. Nakao et al. and Hakim et al. reported that fistula formation might improve the prognosis by preventing PMP ([@B7], [@B8]). Fistula formation secondary to MAA may confine the disease to a resectable state by causing drainage of the malignant ascites into the involved organs. The operability itself may explain the good outcome of MAA with fistula formation; indeed, surgery was performed in almost all of the reported cases. However, a publication bias cannot be excluded, so further studies are required to determine the influence of fistula formation on the prognosis of patients with MAA.

We herein report the case of a 90-year-old man with MAA with fistula to the hepatic flexure. Our case shows that fistula formation secondary to MAA may allow for the early diagnosis and resectability, which results in a better prognosis.

**The authors state that they have no Conflict of Interest (COI).**

[^1]: Correspondence to Dr.　Masataka Yokode, <ykdmstk0428@gmail.com>
