Keywords
GI tract - metastasis - non-GI primary - histology-proven - immunohistochemistry
Introduction
Lymph nodes, lung, liver, bone, and brain are the commonest metastatic sites. Metastases
to the hollow organs of gastrointestinal (GI) tract are extremely rare[1]
[2] and are mostly asymptomatic and detected incidentally on autopsy or by imaging studies.[2] They usually present at advanced tumor stages with dismal prognosis.[2] This study aims to describes the spectrum of non-GI malignancies metastatic to hollow
GI tract.
Materials and Methods
This was a retrospective study of 9 years duration from 2015 to 2023 at our institute,
which is a tertiary care center. All cases of histologically proven non-GI metastases
to hollow GI tract were included. Cases with GI primary, hematological malignancies,
exclusive serosal deposits, and direct invasion from an adjacent primary were excluded.
The following data were reviewed and analyzed in each case:
-
Clinical data: age, gender, site of primary tumor, duration of onset of metastasis (time interval
between diagnosis of primary and secondary tumors), tumor markers if any, clinical
findings and indications for endoscopy, type of biopsy (endoscopic biopsy/resection),
and endoscopic/imaging findings. The endoscopic/macroscopic appearance of the tumor
was assessed using the descriptive terms such as polypoidal mass, nodule, intramural
lesion, or ulcerated lesion.
-
Morphological data: histological diagnosis and location of lesion within the wall of GI tract, i.e.,
mucosa, submucosa, muscularis propria, or transmural involvement. Special stains such
as Periodic acid Schiff and Alcian blue and ancillary tests such as immunohistochemistry
(IHC) were done as a part of the routine pathological work-up based on primary site
(if known)/morphology (in cases of carcinoma of unknown primary [CUP]) to confirm
the secondary nature of these lesions.
All the data were analyzed using the Microsoft Excel sheet (Microsoft 365 MSO [Version
2204 Build 16.0.15128.20240] 64-bit).
Ethics
The study was approved by the Nizams Institute of Medical Sciences (NIMS) Institutional
Ethics Committee with approval number EC/NIMS/3446/2024 dated 11.05.2024. The procedures
followed were in accordance with the ethical standards of the responsible committee
on human experimentation (institutional) and with the Helinski Declaration of 1964,
as reviewed in 2013. Consent waiver form was obtained from the Ethics Committee due
to the retrospective nature of the study.
Results
Thirty-six patients were diagnosed with metastases to GI tract from non-GI malignancies
in a span of 9 years). Samples received for histopathology included both endoscopic
biopsies (n = 12) and resections (n = 24).
Age at the time of diagnosis of GI metastasis ranged from 39 to 70 years with an average
of 56 years. Peak incidence was reported in 6th to 7th decade. There was a significant
female (n = 32) preponderance with a male-to-female ratio of 1:8.
In majority (31/36), the diagnosis was made or known prior to presentation/diagnosis
of GI metastasis. In these cases, the time interval between diagnoses of primary and
secondary in GI tract ranged from 3 months to 20 years (240 months) with an average
of 39 months (3.3 years). The remaining five cases presented with GI metastases with
subsequent detection of primary tumor.
The most common endoscopic/gross finding was mass/infiltrative growth (n = 20; 55.5%), followed by ulcerated/nodular mucosa (n = 6, 16.6%), stricture (n = 5; 13.8%), and perforation (n = 3, 8.3%). In two cases, resection was done as a part of debulking surgery post-chemotherapy.
The commonest metastatic sites were small bowel (n = 11), sigmoid colon (n = 9), and rectum (n = 7), followed by stomach (n = 3), appendix (n = 3), gall bladder (n = 2), and ampulla (n = 1). One of these cases had simultaneous involvement of colon and jejunum. The most
common primary in females was ovarian high-grade serous carcinoma followed by squamous
cell carcinoma of cervix. No such preference in the primary site was noted in male
patients with GI metastases. Data on follow-up were not available in most of the cases
to assess the survival rate.
The details of primary malignancies in patients diagnosed with GI metastases are proved
in [Table 1] below.
Table 1
Gender-wise distribution of various GI metastasis and the IHC panel used for confirmation
|
Females (n = 32)
|
IHC results (positive)
|
Primary site
|
No. of cases (%)
|
|
High-grade serous carcinoma
|
CK7, PAX8, CA125, WT1, P53 mutant
|
Ovary
|
21 (%)
|
|
Fallopian tube
|
1 (%)
|
|
Squamous cell carcinoma
|
P40, P16
|
Cervix
|
8 (%)
|
|
Vaginal vault
|
1 (%)
|
|
Low-grade endometrial stromal sarcoma
|
ER, PR, CD10
|
Uterus
|
1 (%)
|
|
Males (
n
= 4)
|
IHC results (positive)
|
Primary site
|
No. of cases (%)
|
|
Adenocarcinoma
|
AMACR, PSA
|
Prostatic
|
1 (%)
|
|
CK7, TTF1, Napsin A
|
Lung
|
1 (%)
|
|
Clear cell RCC
|
CD10, PAX8, CA IX
|
Kidney
|
1 (%)
|
|
Squamous cell carcinoma
|
P 40
|
Buccal mucosa
|
1 (%)
|
Abbreviations: GI, gastrointestinal; IHC, immunohistochemistry; RCC, renal cell carcinoma.
Discussion
GI metastases from non-GI malignancies are extremely rare and represent an advanced
stage of disease.[1]
[2] Incidence of GI metastasis is largely unknown due to the rarity of the disease with
a reported incidence of 3%.[2]
[3]
[4] Reported literature on GI metastases is sparse, mainly in the form of few case studies
and not many large studies. Unlike similar studies in the literature, the present
study was a single-center study which included both endoscopic biopsies and resection
specimens and excluded the cases with direct extension to GI tract and metastatic
lesions with a GI primary. To the best of our knowledge, this is the first Indian
study reporting such a large number of cases over a long span of time.
The incidence of this GI metastasis from non-GI primaries was low (1–2 cases/year)
in the earlier years of the study period with an increase in cases (4–5 cases/year)
diagnosed in recent years, which is slightly higher when compared with other studies.[1]
[2] This could be due to increased awareness and increased use of IHC to confirm or
assign a primary.
In the present study, the mean age at diagnosis of the GI metastases was 56 years,
a decade earlier than that reported in other studies. The average time interval between
diagnoses of primary and metastasis was 3.3 years in the present study. This time
interval was longer when compared with other studies,[2] as the cases with direct extension from adjacent primary were excluded. In the present
study, the longest interval was 20 years in a case of high-grade ovarian serous carcinoma
followed by 13 years in a case of renal cell carcinoma and 10 years in case of low-grade
endometrial stromal sarcoma.
The present study showed significant female preponderance with high-grade serous carcinoma
of ovary and squamous cell carcinoma of cervix being the most frequent malignancies.
This could be due to an increase in the incidence of gynecological malignancies as
per recent statistics in India.[5]
Most of the lesions were diagnosed in the lower GI tract like other studies. The reason
for this could be due to vicinity of the abdominal solid viscera to the lower GI tract
with common lymphatic drainage. In this study, the small bowel (ileum) was the most
affected site, followed by sigmoid colon and rectum; whereas stomach and colon were
the most common sites reported in studies done on endoscopic biopsies alone.[1]
[6]
[7] The possible reason could be that stomach and colon were the organs most frequently
examined via endoscopy unlike ileum which is not so easily accessible unless a flexible
endoscopy is available. All the specimens from ileum in our study were resections
and this was the reason for high incidence of metastasis in ileum. This suggests that
many of the ileal metastases can be missed if endoscopy alone is used as a diagnostic
modality. The small bowel is often the most involved GI site for metastasis, likely
due to its greater mass and blood supply.[8]
[9]
[10] Metastasis from primary GI cancers commonly involves the small bowel followed by
stomach[11]; however, these were excluded from our study.
Infiltrative growth (n = 20; 55.5%) followed by ulcerated/nodular mucosa (n = 6, 16.6%) and stricture (n = 5; 13.8%) were the most common endoscopic/gross appearances of the lesions. This
suggests that biopsy of all the visible lesions on endoscopy could increase the incidence
rate of metastasis especially in cases with a prior history of cancer elsewhere in
the body.
Lung cancer is known to frequently metastasize to the GI tract,[2] with the small intestine being the most commonly involved site. The clinical incidence
of lung cancer metastasis to GI tract typically ranges between 0.2 and 1.7%, with
adenocarcinoma and squamous cell carcinoma being the most prevalent histological types.[12] However, in endoscopic biopsies, metastases from lung cancer are observed less frequently,
ranking fifth in terms of occurrence.[13] We reported only one case of metastatic pulmonary adenocarcinoma to jejunum in a
49-year-old male who presented with perforation. A relatively low incidence of metastasis
from lung cancer was observed in recent studies and is likely due to short survival
associated with metastatic lung cancers.[1]
[4]
[14]
We reported a higher incidence of carcinoma ovary (n = 21) followed by cervix (n = 8) in females. Ovarian cancer was the most common cause of metastasis in both upper
and lower GI tract. Among cases with metastasis from ovarian primary, the longest
duration of onset of metastasis was 20 years in a 70-year-old female and the shortest
duration was 3 months. Among the endoscopic biopsies (n = 12), seven cases of metastasis were from ovary and three cases were from cervix.
In 4/5 cases of CUP, ovarian primary was confirmed by ancillary testing. There were
no cases of metastases from carcinoma breast and melanoma in our study, which is a
contradictory finding when compared to other studies.[1]
[6]
[7]
[14]
[15]
[16] Prostate and kidney were the common primaries reported in males similar to other
studies.[1]
[2] In our study, prostatic adenocarcinoma metastasized to rectum and renal cell carcinoma
metastasized to gall bladder.
Of the 36 cases, 11 cases showed mucosal involvement, 10 cases had deposits in submucosa,
6 cases involved muscularis propria, and 9 cases showed full-thickness involvement.
Rarity of this lesion and lack of information about primary malignancies lead to misdiagnosis
in these cases. Autopsy studies usually pick up the mucosal as well as mural metastasis;
however, endoscopic studies miss the mural lesions of GI.[1]
[6]
[7] In our study, mucosal as well as mural metastases were detected and IHC confirmation
was done for all the cases to confirm the metastasis and rule out a second primary.
The limitation of this study is that it only includes histopathology-verified cases,
hence may not reflect true incidence of GI metastasis. Many small, asymptomatic lesions
may remain undetected. This brings forth the need for a careful endoscopic surveillance
and biopsy of all visible lesions detected on endoscopy in a patient with prior history
of non-GI malignancy presenting with GI manifestations. These cases when diagnosed
represent an advanced disease with grave outcome.[14]
[17] The other limitation was follow-up data were not available to assess the survival
rate in these cases.
Conclusion
GI metastases from non-GI malignancies are extremely uncommon. Females are at high
risk of GI metastasis with ovary being the most common primary site followed by cervix.
IHC helps in confirmation of metastases and to rule out second GI primary in patients
with known malignancy. In addition, IHC helps in suggesting primary sources in cases
presenting with unknown primary.
