Introduction
Invasive micropapillary carcinoma (IMPC) was first identified as a variant of invasive
breast cancer by Siriaunkgul and Tavassoli [1]. Recently, IMPC has been reported in association with other tissues, including the
urinary bladder, lung, ovary, salivary gland, stomach and colon [2]. IMPC has clinical characteristic carcinoma findings, with a high incidence of lymphatic
involvement, lymph node metastases, and a poor clinical outcome, and has histological
features consisting of round-to-oval micropapillary clusters surrounded by clear spaces
and a lack of fibrovascular cores. IMPC has an inside-outside growth pattern with
reversed polarity, where the stromal-facing surfaces of the tumor cells acquire apical
secretory properties, as demonstrated by MUC1 or EMA immunohistochemical staining
on the surface.
In the case of colorectal IMPC, few descriptions of endoscopic observation via magnifying
colonoscopy and endoscopic mucosal resection exist in the literature. Magnifying endoscopy
was developed for the diagnosis of colorectal tumors. Pit pattern classification of
colorectal lesions determined by magnifying endoscopy has been reported to be related
to the histologic characteristics of the lesions [3]; therefore, this modality is effective for invasion depth diagnosis and treatment
selection. Additionally, given that the irregular microvessels of the lesion are analyzed
with respect to the heterogeneity of their diameter and/or distribution using narrow
band imaging (NBI) magnification, it is possible to discriminate between adenoma versus
carcinoma, and to determine the depth of invasion [4]. Herein we report a case of colon IMPC that underwent colonoscopic observation and
endoscopic mucosal resection.
Case report
A 47-year-old woman visited our hospital as follow-up for a positive fecal occult
blood test. She did not have any symptoms or any remarkable medical or family history.
Blood tests only revealed the existence of mild anemia (hemoglobin, 10.7 g/dL); serum
levels of carcinoembryonic antigen (CEA) and CA19-9 were normal.
Colonoscopy was performed using a magnifying colonoscope (PCF-Q260AZI, Olympus, Tokyo,
Japan). White light colonoscopy revealed a semi-pedunculated reddish polyp < 10 mm
in diameter with a gently irregular surface, but without ulceration or erosion, as
well as mild tension in the sigmoid colon ( [Fig.1]).
Fig. 1 A white light colonoscopic examination of the sigmoid colon revealed a semi-pedunculated
reddish polyp < 10 mm in diameter with a gently irregular surface, but without ulceration
or erosions. The tumor was associated with mild tension, suggestive of submucosal
invasion.
Magnifying NBI colonoscopy showed an irregular surface pattern with heterogeneity
in the vascular diameter and a sparse vascular distribution, suggestive of stromal
invasion of tumor cells ( [Fig. 2]). Magnifying endoscopy using crystal violet staining revealed pits with irregular
margins, unclear contours, and narrowed lumens, and decreased/disappearing stainability
in the stromal area. These findings were considered to indicate a highly irregular
type VI pit pattern [3]. In addition, the stromal area between each duct was dilated ([Fig. 3]). The preoperative diagnosis was early-stage sigmoid colon cancer with submucosal
invasion, and diagnostic endoscopic resection of the sigmoid colon tumor was performed
because the patient strongly hoped for endoscopic resection due to the small size
of the lesion.
Fig. 2 Magnifying NBI colonoscopy findings. A global image is shown in a, and an extended image of the area in the box is shown in b. This polypoid lesion had an irregular surface pattern and heterogeneity in both
vascular diameter and distribution. The vascular distribution was also sparse.
Fig. 3 Magnifying colonoscopic findings using crystal violet staining. A global image is
shown in a, and an extended image of the area in the box is shown in b. The polypoid lesion had irregular margins, unclear contours, and narrow pit lumens,
and the crystal violet stainability in the stromal area was diminished and partially
disappeared.
Macroscopically, the tumor was a 7-mm semi-pedunculated polyp. Microscopically, massive
submucosal invasion to a depth up to 3.6 mm with extensive lymphatic invasions was
observed ([Fig. 4 a]). The lesion was predominantly (~80 %) composed of polygonal cells arranged in clusters
surrounded by lacunar-like clear spaces ([Fig. 4 b]), and the remaining 20 % was moderately differentiated tubular adenocarcinoma. Immunohistochemically,
MUC1 expression was observed at the stromal edges of tumor clusters in the micropapillary
structures, thus appearing as an ‘inside-out’ staining pattern [2] ([Fig. 4 c]). In addition, the tumors cells were positive for cytokeratin 20 ([Fig. 4 d]) and negative for cytokeratin 7 ( [Fig. 4 e]), indicative of primary IMPC of the colon.
Fig. 4 a Histological analysis of the resected specimen showed a massive submucosal invasion
to 3.6 mm, with extensive lymphatic invasion. b This lesion was predominantly composed of polygonal cells arranged in clusters surrounded
by lacunar-like clear spaces. c MUC1 expression of tumor cells was found at the stromal edges of tumor clusters in
the micropapillary structures, a characteristic ‘inside-out’ staining pattern. d Cytokeratin 20 expression was positive in tumor cells. e Cytokeratin 7 expression was negative in tumor cells. These immunohistochemical findings
suggested IMPC of the colon.
Although the vertical margin of the resected specimen was negative and no regional
lymph node swelling or metastasis by chest and abdominal computed tomography (CT)
were apparent, laparoscopy-assisted sigmoidectomy and regional lymph node resection
were performed. No residual cancer cells or lymph node metastases were observed. This
patient remains alive 15 months after surgery, with no recurrence.
Discussion
IMPC was first reported as a variant type of invasive breast cancer by Siriaunkgul
and Tavassoli in 1993 [1]. IMPCs of the colon are being increasingly recognized since Sakamoto et al. reported
3 colon IMPC cases in 2005 [2]. However, the endoscopic features of and optimal therapeutic management strategies
for colon IMPC have not yet been elucidated. We recently encountered a case of early-stage
colon IMPC, and performed a minute magnifying colonoscopic observation, including
NBI endoscopy and crystal violet chromoendoscopy. In the current report, we have discussed
the endoscopic diagnosis and the therapeutic strategy for this case of colon IPMC.
Most colon IMPC cases are identified at an advanced stage; therefore, surgery and
chemotherapy are the primary clinical management strategies. Only 5 cases of colon
IMPC (including the current case) have been categorized as T1 (TNM classification)
tumors ([Table 1]) [5]
[6]
[7]
[8]. In 4 cases including the current one, endoscopic resection was performed [5]
[6]
[8]. However, in all of these cases, submucosal invasion and lymphatic vessel invasion
were observed. Additional surgeries were performed in 3 cases, and conservative treatment
was selected in the fourth case due to severely complicated disease. In the latter
case, unfortunately, colonoscopy and CT scans revealed local recurrence and multiple
distant metastases in the lung, liver, lymph node, and spleen 6 months after endoscopic
resection [6]. Thus, sufficient attention should be paid to colon IMPC even if the disease is
diagnosed at an early clinical stage, because these patients have been reported to
experience a worse prognosis than those with non-IMPC early-stage colon cancer [9]
[10].
Table 1
Five cases of colon IMPC categorized as T1 (TNM classification) tumors.
Case
|
Author
|
Age
|
Sex
|
Location
|
Tumor size (mm)
|
Macroscopic findings
|
Histology
|
ly
|
v
|
Therapy
|
Lymph
node metastasis
|
Prognosis
|
1
|
Kondo
|
70
|
M
|
S
|
11
|
ND
|
IMPC (< 5 %) with mostly tubulovillous adenoma
|
+
|
ND
|
ER
+ surgery
|
None
|
Alive
|
2
|
Sonoo
|
64
|
M
|
S
|
30 × 25 × 20
|
Pedunculated polyp
|
IMPC (80 %) with moderately adenocarcinoma
|
+
|
+
|
Surgery
+ chemotherapy
|
Existent
|
Alive (25 months)
|
3
|
Hisamori
|
71
|
F
|
S
|
20 × 15
|
Pedunculated, cauliflower-like polyp with a depressed surface
|
IMPC (100 %)
|
+
|
–
|
ER
|
None by CT
|
Dead 12 months after ER due to a local recurrence and multiple distant metastases
|
4
|
Mukai
|
82
|
M
|
S
|
20
|
Pedunculated polyp
|
IMPC (70 %) with poorly adenocarcinoma
|
+
|
ND
|
ER
+ surgery
+ chemotherapy
|
Existent
|
Alive (12 months)
|
5
|
Present case
|
47
|
F
|
S
|
7
|
Semi-pedunculated polyp
|
IMPC (80 %) with moderately differentiated tubular adenocarcinoma
|
+
|
–
|
ER
+ surgery
|
None
|
Alive (15 months)
|
ly, lymphatic invasion; v, venous invasion; S, sigmoid colon; ND, not described; ER,
endoscopic resection; CT, computed tomography
In the current case, white light and magnifying colonoscopy using NBI and crystal
violet staining were performed. First, white light colonoscopy revealed a semi-pedunculated
reddish polyp with a gently irregular surface and producing mild tension despite its
small size, suggestive of submucosal invasion. Magnifying NBI colonoscopy showed an
irregular surface pattern with heterogeneity in vascular diameter and distribution,
and magnifying endoscopy using crystal violet staining revealed a highly irregular
type VI pit pattern [3]. In addition, the vascular contribution was sparse, and the stromal area between
each duct was dilated. Based on these endoscopic findings, the current case was not
considered to be a typical mucosal adenoma or carcinoma, and distinction from an unusual
type of carcinoma, such as mucinous or undifferentiated carcinoma with submucosal
deep invasion, was required. An endoscopically resected specimen revealed massive
submucosal invasion and was composed of micropapillary cells. IMPC consists of neoplastic
cells without fibrovascular cores that proliferate into the stroma, and the tumor
clusters are surrounded by clear spaces. The present case was 7 mm, which is the smallest
colonic IMPC thus far reported. We suggest that IMPC should be considered in the differential
diagnosis if colonoscopy suggests a submucosal deep invasion, an irregular pit pattern
with a wide stromal area, and an invisible vascular pattern despite a small size.
These may be characteristic features of early-stage colon IMPC identifiable with magnifying
colonoscopy. However, a future study with a larger number of cases is required to
confirm these findings.
The clinical characteristic findings of colon IMPC include a high incidence of lymphatic
involvement and lymph node metastases, as well as a poor clinical outcome. Extensive
lymphatic involvement was observed in the current case, despite the very small size
of the lesion. Kim et al. showed that metastases to local lymph nodes were observed
in 2 out of 3 patients with IMPC tumors that infiltrated into the submucosal membrane
(pT1) [9]. Xu et al. reported that stage I and II IMPC patients experience shorter survival
compared to non-IMPC patients [10]. In conclusion, we suggest that cases of colon IMPC should be diagnosed at the earliest
stage possible and should be appropriately treated. We have found that submucosal
deep invasion, an irregular pit pattern with a wide stromal area, and invisible vascular
patterns despite a small tumor size are key endoscopic features of colon IMPC.