DOI: https://doi.org/10.21203/rs.3.rs-801086/v1
Background: Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare variant of inflammatory myofibroblastic tumors with distinct morphological features and malignant clinical behavior. ALK is positive in all EIMS cases, the RANBP2-ALK fusion gene has been detected in most EIMSs, but several RRBP1-ALK and EML4-ALK fusion genes have also recently been reported.
Case presentation: Here, we report a case of RRBP1-ALK fusion-positive EIMS in the colon. The patient was a 26-year-old man. A pelvic mass was found in a routine physical examination and was completely resected. Microscopically, the tumor cells were rounded and epithelioid in shape. Diffuse collagenous stroma and focal inflammatory infiltration were present. ALK was positive, with a pattern of cytoplasmic staining with perinuclear accentuation, and the RRBP1-ALK fusion gene was detected by targeted next generation sequencing. The patient began to take crizotinib from October 2019 to July 2020, and the patient is presently in good condition. No synchronous or metachronous metastases was found.
Conclusions: EIMSs with different ALK fusion partner genes have unique staining patterns, which may provide clues for diagnosing EIMS. EIMS cases with RRBP1-ALK fusion gene and with diffuse collagenous stroma may have a good prognosis.
Based on evidence to date, IMT is listed in the WHO classification as an intermediate-grade tumor that is prone to local recurrence but of low metastatic risk[1]. However, several studies have shown that some IMTs are morphologically atypical and clinically malignant. Thus, epithelioid inflammatory myofibroblastic sarcoma (EIMS) has recently emerged as a histologically distinctive and clinically aggressive variant, as reported by Marino-Enriquez et al. in 2011. EIMS has a poor prognosis and is associated with the rapid development of local recurrence and metastasis. EIMS exhibits predominantly large round or epithelioid cells with vesicular nuclei and prominent nucleoli, with a minor spindle cell component. The cells are distributed in sheets or clusters within a stroma that is often myxoid[2]. The RANBP2-ALK fusion gene has been detected in most EIMSs, but several RRBP1-ALK and EML4-ALK fusion genes have also recently been reported[3–6].
The patient was a 26-year-old man. A pelvic mass was found in a routine physical examination at a local hospital in January 2019, and he had no obvious symptoms. The patient came to our hospital in February 2019, and CT showed an irregular solid nodule on the left side of the pelvis, with a maximum cross-section of 7 × 3.6 cm (Fig. 1a). Although the internal reinforcement was uneven, the boundaries of the tumor were clear. The tumor was located close to the intestinal wall. The radiologist concluded that it might be a stromal tumor but that a source of mesenchymal tissues could not be excluded. Pelvic mass resection was performed, and the pathological result was epithelioid inflammatory myofibrosarcoma with RRBP1-ALK gene fusion (indicating poor prognosis; close follow-up was recommended). The patient began taking crizotinib after the surgery and is currently in good condition.
The tumor was located on the serosal side of the intestinal wall and invaded muscular layer (Fig. 1b) which was composed of scattered well-circumscribed polygonal and epithelioid tumor cells with distinct nucleoli and an eosinophilic cytoplasm; some of the large cells were fat and fusiform shape (Fig. 3b). The stroma of the tumor was predominantly collagenous and locally myxoid, with inflammatory cell infiltration that mainly consisted of lymphocytes and plasma cells (Fig. 2). These characteristics were different from those of typical myxoid stroma with neutrophil infiltration in most EIMSs described thus far. Mitotic activity did not exceed 1 figure per 10 high-power fields. Necrosis was not identified.
Immunohistochemical analysis revealed the tumor cells to be positive for vimentin, desmin, SMA (focal), and AE 1/AE 3 (focal) and negative for EMA, S-100, CD117, DOG-1, F8, CD31, CD21 and CD35(Fig. 5). In addition, the tumor cells were positive for ALK, exhibiting cytoplasmic stanning with perinuclear accentuation (Fig. 4), and RRBP1-ALK fusion was detected by targeted next generation sequencing (Fig. 6).
In 2013, the 4th edition of the World Health Organization (WHO) classification of soft tissue tumors described EIMS as an IMT variant with RANBP2-ALK gene rearrangement and seemed to portend more aggressive clinical behavior, nonetheless, most conventional IMTs have a relatively indolent clinical course with a low rate of recurrence and metastasis[7]. And the latest edition of WHO in 2020 has clearly proposed that EIMS is classified as an aggressive IMT subtype of IMT, and it also mentioned that ALK immunostaining pattern varied depending on the ALK fusion partners.
To date, 40 cases of EIMS arising at any site have been documented in the English literature (Table 1); 30 affected patients were female, and 10 were male, ranging from 7 mo to 76 y in age (mean age of 34.6 y). All tumors arose within the abdomen, with the exceptions of 3 cases in the thorax (2 in the lung and 1 in the pleura) and 2 in the pelvis (1 in the rectum and 1 in the ovary). The EIMSs range in size from 4.3 to 26 cm (mean size of 12.91 cm).
Case |
Fusion type |
Age/Sex |
Site |
Size (cm) |
Treatment |
Recurrence |
Metastasis |
Follow up |
Source |
---|---|---|---|---|---|---|---|---|---|
1 |
RANBP2-ALK |
7y/M |
Abdominal cavity |
NA |
SE, CT |
Yes (5w, 5 m) |
No |
NED (5 m) |
Ma et al. [12] |
2 |
RANBP2-ALK |
7 m/M |
Mesentery and omentum |
11 |
SE |
Yes (5w, 5 m) |
No |
AWD (8 m) |
|
3 |
RANBP2-ALK |
2y/M |
Abdominal cavity |
10 |
SE |
No |
No |
NED (36 m) |
Patel et al. [13] |
4 |
RANBP2-ALK |
34y/M |
Liver |
8 |
SE |
Yes (5 m) |
No |
DOD (5.5 m) |
Chen et al. [14] |
5 |
RANBP2-ALK |
44y/M |
Omentum |
NA |
SE, CT, ALKi |
Yes (5 m) |
Liver (12 m) |
AWD (39 m) |
Butrynski et al. [9] |
6 |
RANBP2-ALK |
41y/M |
Omentum |
26 |
SE, CT, ALKi |
Yes (12 m) |
Liver (12 m) |
NED (40 m) |
Marino-Enriquez et al. [4] |
7 |
RANBP2-ALK |
59y/M |
Mesentery of small bowel |
15 |
SE, CT |
Yes |
No |
DOD (12 m) |
|
8 |
RANBP2-ALK |
6y/M |
Omentum |
10.5 |
SE, CT |
Yes |
No |
AWD (3 m) |
|
9 |
RANBP2-ALK |
28y/M |
Mesentery of small bowel |
NA |
NA |
NA |
NA |
NA |
|
10 |
RANBP2-ALK |
63y/M |
Mesentery of small bowel |
25 |
SE, CT |
Yes |
No |
DOD (3 m) |
|
11 |
RANBP2-ALK |
42y/M |
Intra-abdominal |
NA |
SE, CT |
Yes |
No |
AWD (13 m) |
|
12 |
RANBP2-ALK |
7 m/M |
Peritoneum |
10 |
SE, CT, RT |
Yes |
No |
DOD (36 m) |
|
13 |
RANBP2-ALK |
40y/M |
Peritoneum |
8 |
SE, CT, RT |
Yes |
Lung, liver, lymph node |
NA |
|
14 |
RANBP2-ALK |
31y/M |
Mesentery of small bowel |
17.5 |
SE, CT |
Yes |
No |
DOD (11 m) |
|
15 |
RANBP2-ALK |
6y/M |
Omentum and mesentery |
14 |
SE |
NA |
NA |
NA |
|
16 |
RANBP2-ALK |
39y/M |
Mesentery of small bowel |
15 |
SE |
NA |
NA |
NA |
|
17 |
RANBP2-ALK |
57y/M |
Pleura or chest wall |
NA |
ALKi |
NA |
NA |
NA |
Kozu et al.[15] |
18 |
RANBP2-ALK |
19y/F |
Mesentery of small bowel |
19 |
SE |
Yes(9w) |
No |
DOD (12w) |
Li et al. [16] |
19 |
RANBP2-ALK |
39y/M |
Mesentery of colon |
15 |
SE, CT |
Yes (4 m) |
No |
AWD (12 m) |
|
20 |
RANBP2-ALK |
22y/M |
Mesentery of small bowel |
6 |
SE, CT, ALKi |
Yes (3 m, 4 m) |
No |
AWD (14 m) |
Kimbara et al. [17] |
21 |
RANBP2-ALK |
37/F |
Rectum |
5 |
SE |
No (8 m) |
No |
NED (8 m) |
Lin Yu et al.[4] |
22 |
RANBP2-ALK |
55/M |
Mesentery of ileum |
11 |
SE, CT |
Yes (2 m) |
No |
NED (10 m) |
|
23 |
RANBP2-ALK |
22/M |
Mesentery of colon |
20 |
SE, ALKi |
Yes (2 m) |
No |
AWD (14 m) |
|
24 |
RANBP2-ALK |
58/F |
Omentum |
5.5 |
SE, CT |
Yes (2 m) |
No |
DOD (8 m) |
|
25 |
RANBP2-ALK |
15/F |
Transverse colon |
12 |
SE |
No (7 m) |
No |
NED (7 m) |
|
26 |
RANBP2-ALK |
42/M |
Abdominal cavity |
NA |
ALKi |
Yes (8 m) |
NA |
AWD (40 m) |
Jen-Chieh Lee et al.[18] |
27 |
RANBP2-ALK |
34/M |
Liver |
NA |
NA |
Yes |
NA |
DOD (5 m) |
|
28 |
RANBP2-ALK |
76/F |
Abdominal cavity |
NA |
NA |
Yes |
NA |
DOD (4 m) |
|
29 |
RANBP2-ALK |
62/M |
Omentum |
25 |
SE, CT |
NA |
NA |
DOD (2 m) |
Jen-Chieh Lee et al.[19] |
30 |
RANBP2-ALK |
30/M |
Abdominal cavity |
10 |
SE |
Yes (4 m) |
NA |
DOD (8 m) |
|
31 |
RANBP2-ALK |
16/F |
Lung |
8 |
SE, CT, ALKi |
Yes (1 m) |
NA |
AWD (33 m) |
|
32 |
RANBP2-ALK |
22/M |
Mesentery of colon |
10.42 |
SE, ALKi |
NO |
NO |
AWD (16 m) |
Liu, Q.et al. [20] |
33 |
RANBP2-ALK |
47/F |
Mesentery of colon |
7.5 |
SE, CT |
Yes (2 m) |
liver, lungs |
DOD (6 m) |
Wu, H.et al.[21] |
34 |
RANBP2-ALK |
15/F |
Ovary |
NA |
SE, CT, ALKi |
Yes |
rectosigmoid colon, uterine serosa, |
DOD(2y) |
Fang, H.et al.[22] |
35 |
RANBP2-ALK |
35/F |
Stomach |
NA |
SE |
No |
No |
NED (11m) |
Xu, P.et al. [23] |
36 |
RRBP1-ALK |
62/M |
Abdominal cavity |
NA |
NA |
NA |
NA |
DOD (2m) |
ZLee, J. C. et al[3] |
37 |
RRBP1-ALK |
26/M |
Abdominal cavity |
NA |
NA |
Yes(7m,16m) |
intra-abdominal dissemination |
AWD (16m) |
|
38 |
RRBP1-ALK |
39/F |
Abdominal cavity |
NA |
NA |
Yes(36m) |
intra-abdominal and pleural dissemination |
DOD(36m) |
|
39 |
EML4-ALK |
45/M |
Abdominal cavity |
20 |
NA |
Yes(1m) |
Liver,spleen, small intestine, right pleural cavity |
DOD(6w) |
.Jiang, Q., et al[5] |
40 |
EML4-ALK |
67/M |
Lung |
4.3 |
NA |
NA |
Brain, liver |
DOD (57m) |
Sokai, A., et al. [6] |
ALKi ALK inhibitor, AWD alive with disease, CT chemotherapy, DOD dead of disease, NA not available, NED no evidence of disease, RT radiation therapy, SE surgical excision |
As cases of EIMS are rare, the diagnosis should only be made based on strict histological and clinical manifestations. EIMS has distinctive morphological features: the tumor is typically characterized by loosely arrayed, round or epithelioid neoplastic cells with vesicular nuclei, prominent large nucleoli and an amphophilic to eosinophilic cytoplasm distributed in a widespread myxoid stroma. The striking feature of EIMS is the presence of obvious inflammatory infiltrates frequently composed of neutrophils[4]; however, this was not found in our case, with the infiltrate being mostly composed of lymphocytes and plasma cells. Furthermore, the stroma in our case was predominantly collagenous and locally myxoid, and some of the epithelial tumor cells with a spindle-like morphology may be squeezed by the dense collagen fibers in the stroma, which is different from the typically round epithelioid tumor cells in loosely myxoid stroma. Marino-Enriquez et al. has reported 2 cases with predominantly collagenous stroma and 2 cases with mixed collagenous and myxoid stroma[2], however, there is a lack of detailed description of morphology and prognosis.
Immunohistochemically, ALK is positive in all EIMSs. Desmin expression is diffuse and strong in almost all cases. In addition, the tumor displays variable expression of CD30, SMA and CK[4]. RANBP2-ALK is the most common fusion gene involved, but two other fusion gene types have recently been, including RRBP1-ALK and EML4-ALK. When ALK fuses with different partner genes, unique stanning patterns arise. For example, tumors with RANBP2-ALK show a distinctive nuclear membranous localization, owing to the roles of RANBP2 in the nuclear pore complex. All 3 cases of RRBP1-ALK fusion specifically displayed cytoplasmic staining with perinuclear accentuation by ALK immunohistochemistry, as RRBP1 is a coiled-coil protein that functions in interactions between ribosomes and the endoplasmic reticulum and in microtubule binding[3]. Cases with EML4-ALK show cytoplasmic staining under the membrane, consistent with the distribution of EML4 in the cell[5]; Richards MW reported that the EML4-ALK fusion protein localizes in the cytoplasm and is possibly associated with microtubules[8]. The unique stanning patterns of different fusion partner genes can be clues for diagnosing EIMS.
Three patients (21, 25 and 35 in Table 1) with the RANBP2-ALK fusion gene experienced no metastasis or recurrence and lived with no evidence of disease as of the follow-up date, which was inconsistent with the malignant clinical features of EIMS in previous articles. Therefore, it is possible that the RANBP2-ALK fusion gene was be involved in conventional IMT, as EML4 was considered a typical partner gene in conventional IMT until it was first confirmed in EIMS in 2017.
EIMS appears to have a poor prognosis with a short survival time after surgical treatment and following chemotherapy and/or radiotherapy; it is also prone to relapse and metastasis. The effectiveness of alternative treatment modalities, such as radiotherapy, chemotherapy, and steroids, is uncertain. Butrynski reported a case of IMT in a patient carrying the RANBP2-ALK fusion gene who was treated with the ALK inhibitor crizotinib after surgical tumor resection, with no evidence of recurrence after 19 months[9]. Kurihara-Hosokawa and Fujiya also recently presented a patient with recurrent EIMS who continued to be alive with disease at 14 months after surgical treatment and administration of crizotinib[10, 11]. Therefore, some researchers have suggested that surgery and the ALK inhibitor crizotinib may become the standard treatment for EIMS positive for the RANBP2-ALK fusion gene [21]. The current case was also treated with the ALK inhibitor crizotinib after tumor resection, and he at present shows no evidence of recurrence and metastasis.
In conclusion, we encountered an unusual case of RRBP1-ALK fusion gene-positive colon EIMS with a collagenous stroma. To the best of our knowledge, this may be the fourth case of EIMS involving such a fusion type. EIMS with different ALK partner fusion genes exhibit unique staining patterns, which may be clues for diagnosing EIMS. ALK inhibitors are a promising treatment for this aggressive tumor.
EIMS: Epithelioid inflammatory myofibroblastic sarcoma; IMT: inflammatory myofibroblastic tumors; ALK: Anaplastic lymphoma kinase; WHO: World Health Organization
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent for the publication of this article and any accompanying images was obtained from the family members of the patient.
Availability of data and materials
As a case report, all data generated or analyzed are included in this article.
Competing interests
The authors declare that they have no competing interests.
Funding
This project was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2016-I2M-3-001).
Authors' contributions
NC searched the literatures and wrote the majority of the paper. LYX provided the interesting case that we reported, as well as guidance and editing throughout the writing process. All authors have read and approved the final manuscript.
Acknowledgements
None.