Primary colonic malignant peripheral nerve sheath tumor with biphasic morphology: A case report

Abstract

BACKGROUND

Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive soft tissue sarcoma, in which primary colonic involvement is exceptionally uncommon. Previously reported colonic cases have mostly shown a conventional spindle-cell morphology, while cases with unusual histologic patterns remain poorly characterized.

CASE SUMMARY

In the reported case, a 75-year-old man presented with intermittent right upper abdominal pain and abdominal distension. He underwent contrast-enhanced computed tomography, which revealed a large invasive mass extending from the right subphrenic region to the gallbladder fossa, with indistinct borders from the adjacent liver, duodenum, and pancreatic head. Exploratory laparotomy and right hemicolectomy were performed. Histologically, the tumor displayed a biphasic pattern composed of approximately a 30% spindle-cell component and 70% small round-cell component. The spindle-cell areas consisted of intersecting fascicles of atypical spindle cells with hyperchromatic nuclei and brisk mitotic activity, while the small round-cell areas were composed of densely packed primitive-looking cells with scant cytoplasm and hyperchromatic nuclei. Tumor necrosis was also observed. Immunohistochemically, S-100 showed patchy positivity in approximately 40% of tumor cells, while cytokeratins, smooth muscle markers, melanocytic markers, and Ewing sarcoma-related markers were negative. The Ki-67 Labeling index was very high, at approximately 90%, and a complete loss of H3K27me3 was observed in all the tumor cell nuclei. Based on the morphologic features, immunophenotype, and exclusion of major differential diagnoses, the lesion was diagnosed as a primary sporadic high-grade MPNST of the colon. Despite complete resection of the tumor with negative margins, the patient rapidly developed massive pleural and peritoneal effusions after surgery, which then progressed to respiratory failure, and he ultimately died on postoperative day 13.

CONCLUSION

Primary colonic MPNST may present with an atypical biphasic spindle and small round cell morphology, creating a potential diagnostic overlap with other high-grade mesenchymal malignancies of the colon. In challenging cases, a consideration of the H3K27me3 status may provide important ancillary diagnostic support. Even after complete resection, tumors with high-risk pathologic features may follow an extremely aggressive clinical course, underscoring the need for early recognition, accurate pathologic diagnosis, close postoperative surveillance, and multidisciplinary management.

Key Words: Malignant peripheral nerve sheath tumor; Colon; H3K27me3; Biphasic morphology; Case report

Core Tip: Primary malignant peripheral nerve sheath tumor of the colon is exceptionally rare. We report a sporadic colonic case with unusual biphasic spindle and small round cell morphology, complete loss of H3K27me3, and an extremely aggressive postoperative course despite R0 resection. This case highlights the diagnostic difficulty of high-grade mesenchymal malignancies of the colon and underscores the importance of integrating morphology, immunohistochemistry, and H3K27me3 status for accurate diagnosis, as well as the need for close postoperative surveillance.

INTRODUCTION

Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive soft tissue sarcoma that typically arises along major peripheral nerve trunks in the trunk, extremities, and head and neck region, and is often associated with neurofibromatosis type 1 (NF1) or prior radiation exposure. Primary gastrointestinal involvement is exceptionally uncommon, and primary colonic MPNST is particularly rare, with, to the best of our knowledge, fewer than 10 cases reported to date in the English-language literature.

Most previously reported colonic MPNSTs showed a relatively conventional spindle-cell morphology, whereas those with atypical histologic patterns remain poorly characterized. We report herein the case of a primary sporadic colonic MPNST with an unusual biphasic spindle and small round cell morphology, accompanied by myxoid, vascular-rich stroma, and a complete loss of H3K27me3. These features can create a potential diagnostic overlap with other high-grade spindle-cell or small round-cell neoplasms of the colon, making the correct diagnosis challenging. This unusual case expands the morphologic spectrum of colonic MPNST and highlights the importance of integrating considerations of the tumor morphology, immunohistochemistry results, and H3K27me3 status in the differential diagnosis of challenging cases. The aim of this case report is to enhance the clinical recognition of this rare tumor and to support its more accurate and timely diagnosis in future cases.

CASE PRESENTATION

Chief complaints

A 75-year-old man was admitted to our hospital with intermittent right upper abdominal pain and abdominal distension for 1 week.

History of present illness

The patient had experienced intermittent pain in the right upper abdomen for 1 week before admission. The pain developed without an obvious precipitating factor and was accompanied by abdominal distension. No significant radiation of pain was reported. Because the symptoms gradually persisted, the patient presented to our hospital for further evaluation and treatment.

History of past illness

The patient had undergone hernia repair 1 year earlier, although the specific surgical procedure he had undergone was unknown. He had no known history of other major chronic medical illnesses.

Personal and family history

The patient had no significant hereditary disease history. He denied both a personal and family history of NF1. No related clinical features, such as café-au-lait macules, axillary or inguinal freckling, or Lisch nodules, were identified.

Physical examination

Upon examination at admission, tenderness and rebound tenderness were found to be present in the right upper abdomen and subxiphoid region. Murphy’s sign was positive.

Laboratory examinations

Laboratory testing showed elevated inflammatory markers and severe anemia, with a hemoglobin (HGB) level of 61 g/L. The white blood cell count (WBC) was 9.86 × 10⁹/L, and the neutrophil percentage (NEUT%) was 82.8%. The carcinoembryonic antigen (CEA) was within the normal range (1.58 ng/mL), while CA125 was found to be elevated (76.20 U/mL) (Table 1).

Table 1 Laboratory test results.

Test Item	Result	Flag	Reference range	Unit
WBC	9.86	↑	3.50-9.50	× 109/L
NEUT%	82.8	↑	40.0-75.0	%
HGB	61	↓	130-175	g/L
CEA	1.58		< 5.00	ng/mL
CA-125	76.20	↑	< 24.00	U/mL

WBC: White blood cell count; NEUT%: Neutrophil percentage; HGB: Hemoglobin; CEA: Carcinoembryonic antigen; CA-125: Carbohydrate antigen 125.

Imaging examinations

Contrast-enhanced abdominal computed tomography revealed a large heterogeneous mass measuring approximately 12.0 cm × 10.9 cm × 15.9 cm in the right subphrenic region, extending to the gallbladder fossa and portacaval space. The lesion had ill-defined margins, and its interface with the adjacent liver, duodenum, and pancreatic head was indistinct, suggesting marked local invasiveness. Magnetic resonance imaging also demonstrated a corresponding heterogeneous solid mass in the right subphrenic/gallbladder fossa region (Figure 1).

Figure 1 Preoperative imaging. A: Abdominal contrast-enhanced computed tomography showing a large, ill-defined heterogeneous mass (approximately 12.0 cm × 10.9 cm × 15.9 cm) extending from the subphrenic region to the gallbladder fossa and portacaval space (orange arrows), with infiltration of nearby liver, duodenum, and pancreatic head; B: Abdominal magnetic resonance imaging revealing a corresponding heterogeneous solid mass (measuring approximately 13.3 cm × 12.4 cm on axial imaging) in the right subphrenic/gallbladder fossa area (orange arrows).

MULTIDISCIPLINARY EXPERT CONSULTATION

Pathological findings

Gross specimen: The resected colon measured 52 cm in length and 4-5 cm in diameter. The lumen contained abundant dark red clot-like material and irregular dark red to gray-white tissue fragments, measuring approximately 17.0 cm × 13.0 cm × 3.0 cm on aggregate. On a cut section, the lesion showed a variegated dark red and gray-white appearance, with focal fish-flesh-like areas (Figure 2).

Figure 2 Gross photograph. A: Gross view of the resected colonic specimen; B: The cut surface of the tumor shows gray-white areas; C: The cut surface exhibits a fish-flesh-like appearance.

Histopathological findings: Histologically, the tumor showed a biphasic pattern composed of an approximately 30% spindle-cell component and 70% small round-cell component, based on a semi-quantitative review of representative hematoxylin and eosin-stained sections. The stroma was vascular-rich and showed extensive myxoid change. The tumor cells had hyperchromatic nuclei, marked atypia, and brisk mitotic activity, averaging approximately 15 mitoses per high-power field (Figure 3).

Figure 3 Histologic findings (A-D, all at × 200 magnification). A: Fascicles of spindle-shaped tumor cells; B: Small round tumor cells; C: Tumor stroma with rich vascularity; D: Tumor stroma showing prominent myxoid change.

Immunohistochemical examinations: Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue sections using an automated staining platform. S-100 showed patchy positivity in approximately 40% of the tumor cells, and the tumor cells were positive for S-100, whereas CD34 highlighted only vascular structures. AE1/AE3, SMA, Desmin, EMA, CD117, DOG1, HMB45, SOX10, GFAP, NKX2.2, and FLI1 were all negative. The Ki-67 Labeling index was approximately 90%. Importantly, H3K27me3 expression was completely lost in all the tumor cell nuclei, whereas the nuclei of the vascular endothelial cells used as an internal control retained positive staining, supporting the interpretation of a complete loss of H3K27me3 (Figures 4, 5 and 6). Details of the antibody clones, manufacturers, dilutions, staining platform, staining results, and positive controls are summarized in Supplementary Table 1.

Figure 4 Immunohistochemical findings (A-F, all at × 100 magnification). A: S-100 protein, focally positive; B: SOX10, negative; C: CD34 highlighting vascular structures only; D: SMA, negative; E: NKX2.2, negative; F: CD117, negative.

Figure 5  Immunohistochemical staining for Ki-67 showing a labeling index of approximately 90%.

Figure 6 H3K27me3 immunohistochemical staining. A: Retained positive nuclear staining in vascular endothelial cells serving as an internal control; B: Complete loss of H3K27me3 expression in all tumor cell nuclei.

FINAL DIAGNOSIS

Based on a consideration of the anatomic site, distinctive histologic findings, immunophenotype, and the systematic exclusion of other major differential diagnoses, the tumor was diagnosed as a primary sporadic high-grade MPNST of the colon. According to the French Fédération Nationale des Centers de Lutte Contre le Cancer grading system, the tumor was classified as grade 3, with a total score of 6 or higher. Because the eighth edition of the American Joint Committee on Cancer staging system does not provide a site-specific staging scheme for primary colonic MPNST, no standardized American Joint Committee on Cancer pathologic stage could be assigned.

TREATMENT

The patient underwent exploratory laparotomy followed by right hemicolectomy. Because of the fulminant postoperative course, adjuvant chemotherapy or radiotherapy could not be administered.

OUTCOME AND FOLLOW-UP

The immediate postoperative course was initially uneventful. However, on postoperative day 7, the patient developed massive pleural and peritoneal effusions, resulting in respiratory compromise and increased intra-abdominal pressure (Figure 7). Follow-up postoperative imaging did not show definite evidence of tumor dissemination, but the patient’s overall condition deteriorated rapidly. After consideration of his general condition, the family declined further aggressive life-sustaining treatment. The patient died of respiratory failure secondary to massive serous cavity effusions on postoperative day 13.

Figure 7 Postoperative imaging findings. A: Imaging demonstrated moderate-to-large ascites; B: Massive pleural effusion was observed after surgery.

DISCUSSION

MPNST is a rare and highly aggressive soft tissue sarcoma that typically arises from peripheral nerves or through malignant transformation of a benign peripheral nerve sheath tumor. It is characterized by a high rate of local recurrence, a strong propensity for distant metastasis, and an overall poor prognosis[1]. Approximately 50% of MPNSTs are associated with NF1, while about 10% are related to prior radiation exposure, and the remainder occur sporadically[2]. MPNSTs most commonly affect adults between 20 years and 50 years of age, whereas patients with NF1 tend to develop the disease at a younger age, on average approximately 10 years earlier[3]. Anatomically, MPNSTs most often arise along major nerve trunks in the trunk and extremities, whereas primary involvement of the colon is exceptionally uncommon. Owing to its rare location, nonspecific clinical presentation, and histologic heterogeneity, colonic MPNST poses substantial challenges in both clinical and pathologic diagnosis.

A literature search was performed of the PubMed and Web of Science databases up to April 2026, using the terms “malignant peripheral nerve sheath tumor”, “MPNST”, “colon”, “colonic”, “colorectal”, “large intestine”, “biphasic”, “spindle cell”, and “small round cell”. Additional relevant studies were identified by screening the reference lists of the retrieved articles. The most notable features of the present case are its exceedingly rare site of origin and its unusual histologic appearance. Only a limited number of colonic MPNSTs have been reported in the literature, and most of these cases have shown a conventional spindle-cell sarcoma pattern. The typical MPNSTs reported to date have been characterized by malignant spindle cells arranged in fascicles or interlacing bundles, often accompanied by hyperchromatic nuclei, brisk mitotic activity, and tumor necrosis[1]. In contrast, the present tumor contained not only a conventional malignant spindle-cell component but also a conspicuous small round-cell component. Both components coexisted within a vascular-rich stroma with extensive myxoid change, resulting in an unusual biphasic morphology. This unusual pattern not only broadens the current differential diagnostic spectrum but also substantially increases the risk of misdiagnosis. To the best of our knowledge, this is the first reported case of colonic MPNST with a biphasic spindle and small round cell morphology.

Based on our review of the published literature on colonic MPNST, we did not identify any previously reported cases with a histologic pattern fully comparable to that observed in the present case, namely the coexistence of spindle cells and small round cells in a myxoid, vascular-rich background. All previously reported colonic cases appeared to show more conventional histologic patterns, with a spindle-cell morphology predominating in most cases (5/6, 83.3%) (Tables 2 and 3)[4-9]. This comparison further highlights the distinctive nature of the present case and suggests that the morphologic spectrum of colonic MPNST may be broader than previously appreciated.

Table 2 Clinical features, treatment, and follow-up outcomes of reported cases of colonic malignant peripheral nerve sheath tumor.

Ref.	Age/sex	NF1 history	Presenting symptoms	Tumor location	Tumor size (cm)	Surgical procedure	Margin status	Adjuvant therapy	Follow-up outcome
Present case	75/M	No	Abdominal pain, abdominal distension	Ascending colon	17 × 13 × 3	Right hemicolectomy	Negative	None	Died on postoperative day 13
Rawal et al[4]	25/M	No	Abdominal distension	Transverse colon	20 × 18 × 10	Transverse colectomy	Negative	None	No recurrence during 6 months of follow-up
Cyriac et al[5]	13/M	No	Abdominal pain	Transverse colon	7 × 3.5	Transverse colectomy	Negative	None	No recurrence during 6 months of follow-up
Lee et al[6]	Neonate, 2 days/F	No	Abdominal distension, vomiting	Ascending colon	5 × 2.5 × 2.5	Partial colectomy	Negative	None	No recurrence during 6 months of follow-up
Marwah et al[7]	30/F	Yes	Abdominal pain	Splenic flexure	10 × 10 × 6	Segmental colectomy	Negative	None	Died 18 months after surgery because of recurrent disease
Al-Shehari et al[8]	46/F	No	Abdominal pain	Sigmoid colon	6 × 5.3 × 5.2	Sigmoid colectomy	Negative	None	No recurrence during 6 months of follow-up
Lakkasani et al[9]	71/M	No	Abdominal pain, anorexia	Right colon and small bowel	Colon: 10; small bowel: 8	Palliative resection	NA	None	Multiple metastases detected 6 months after surgery

NF1: Neurofibromatosis type 1; M: Male; F: Female.

Table 3 Histologic features and immunohistochemical findings of reported colonic malignant peripheral nerve sheath tumor.

Ref.	Histologic features	Immunohistochemical findings
Present case	The tumor showed a biphasic morphology composed of spindle cells arranged in fascicles and small round cells distributed diffusely, set in a vascular-rich stroma with extensive myxoid change	S-100 (+); AE1/AE3 (-); SMA (-); Desmin (-); GFAP (-); NKX2.2 (-); FLI1 (-); SOX10 (-); CD117 (-); CD34 positive only in vascular structures; complete loss of H3K27me3; Ki-67 approximately 90%
Rawal et al[4]	Predominantly composed of spindle cell fascicles	S-100 (+); CD117 (-); DOG1 (-); CD34 (-)
Cyriac et al[5]	Composed of spindle cells and epithelioid cells	S-100 (+); Vimentin (+); HMB45 (-); CD117 (-); DOG1 (-)
Lee et al[6]	Predominantly composed of spindle cell fascicles	S-100 (+); Vimentin (+); AE1/AE3 (-); Desmin (-); Myosin (-); Ki-67 5%-10%
Marwah et al[7]	Predominantly composed of spindle cell fascicles	S-100 (+); CD117 (-); NSE (-); Ki-67 approximately 20%
Al-Shehari et al[8]	Predominantly composed of spindle cell fascicles	S-100 (+); SOX10 (+); CD117 (-); CD34 (-); DOG1 (-); SMA (-); Ki-67 10%
Lakkasani et al[9]	Composed of spindle cell fascicles and pleomorphic cells, with focal rhabdomyoblastic differentiation	S-100 (+); Ki-67 approximately 70%

Of note, MPNSTs themselves exhibit a degree of morphologic plasticity and potential for heterologous differentiation. In the 2013 World Health Organization classification, epithelioid MPNST, malignant Triton tumor, and glandular MPNST were recognized as special histologic subtypes[10], indicating that this group of neoplasms is not confined to a single spindle-cell pattern. Although most reported forms of heterologous differentiation in MPNST involve more clearly defined mesenchymal lineages, such as rhabdomyoblastic, osseous, or cartilaginous differentiation[11,12], a small number of studies have suggested that some MPNSTs may contain primitive small round cell-like areas, raising the possibility of immature neuroectodermal differentiation. For instance, Abe et al[13] reported 5 MPNSTs arising in the trunk that were composed predominantly of small round tumor cells with scant cytoplasm. Utilizing reverse transcription-polymerase chain reaction analysis, they found that all 5 tumors lacked EWS fusion transcripts, and MIC2 expression was negative, suggesting that these lesions were not typical Ewing sarcomas but might represent a small round-cell variant of MPNST showing differentiation toward immature neural cells. Shintaku et al[14] described a posterior mediastinal MPNST containing both a primitive neuroectodermal tumor-like small round-cell component and a pleomorphic spindle-cell sarcomatous component, and speculated that the tumor might have arisen from primitive neuroectodermal cells within a peripheral nerve with a bidirectional differentiation potential. In the present case, the absence of NKX2.2 and FLI1 expression helped exclude an Ewing sarcoma in the appropriate morphological and immunohistochemical context. Taken together, these observations suggest that the small round-cell component observed in the present case does not necessarily indicate the presence of a separate tumor lineage, but may instead represent a primitive or immature neural differentiation phenotype within MPNST.

Furthermore, in the present case, the presence of a small round-cell component raised a broad differential diagnostic consideration. Because the tumor contained both spindle-cell and small round-cell areas within a myxoid, vascular-rich background, its morphology seemingly overlapped with that of an Ewing sarcoma/primitive neuroectodermal tumor, gastrointestinal stromal tumor, leiomyosarcoma, clear cell sarcoma, melanoma, and synovial sarcoma. We thus considered each of these in order, as described below.

Ewing sarcomas are typically composed of relatively uniform small round blue cells and often show the expression of NKX2.2 and FLI1, together with EWSR1 rearrangement. In the present case, both NKX2.2 and FLI1 were negative, and a conspicuous malignant spindle-cell component was present, findings that are not in keeping with a classic Ewing sarcoma and therefore do not support that diagnosis.

Gastrointestinal stromal tumors, although one of the more common mesenchymal neoplasms of the gastrointestinal tract, typically express CD117 and DOG1. However, in this case, both CD117 and DOG1 were completely negative, and the morphologic features were also not typical of such a tumor.

Leiomyosarcomas usually show a malignant spindle cell proliferation with abundant eosinophilic cytoplasm, cigar-shaped nuclei, and fascicular growth, together with the expression of smooth muscle markers, such as SMA, Desmin, and h-caldesmon. However, all the corresponding markers were negative in the present case, arguing against smooth muscle differentiation and thus a leiomyosarcoma.

Clear cell sarcomas and melanomas may express S-100 and may occasionally involve the gastrointestinal tract, but they typically also express melanocytic markers, such as HMB45, Melan-A, and SOX10. In the present case, both HMB45 and SOX10 were negative, and the patient had no history of melanoma.

Synovial sarcomas are uncommon within the abdominal cavity and often show a relatively monotonous spindle cell proliferation, sometimes accompanied by a vascular-rich stroma, with the expression of EMA, cytokeratins, and TLE1. In this case, both AE1/AE3 and EMA were negative, arguing against a synovial sarcoma.

Taken together, the morphologic features, immunohistochemical findings, complete loss of H3K27me3, and systematic exclusion of the major histologic mimics (Table 4) ultimately supported the diagnosis of a primary high-grade MPNST of the colon. This case illustrates how the final diagnosis did not rely on any single finding, but rather on an integrated assessment based on the distinctive morphology of the tumor, the broad exclusion of alternative diagnoses, and the support from key ancillary markers.

Table 4 Major differential diagnoses considered in the present case and the corresponding pathologic basis.

Tumor type	Key morphologic features	Common immunophenotype	Findings in the present case	Diagnostic interpretation
MPNST	Predominantly composed of spindle cells, often with marked atypia, high mitotic activity, and focal necrosis; some cases may show heterologous differentiation or marked morphologic heterogeneity	S-100 often focal or patchy positive; SOX10 may be positive or negative; complete loss of H3K27me3 is common in high-grade tumors	Coexistence of spindle cells and small round cells; S-100 positive, SOX10 negative; complete loss of H3K27me3; Ki-67 approximately 90%	Supported
Gastrointestinal stromal tumor	Spindle cell or epithelioid morphology, often arranged in fascicular, whorled, or palisading patterns	CD117 positive, DOG1 positive, often with CD34 positivity	CD117 negative; DOG1 negative	Excluded
Leiomyosarcoma	Fascicular spindle cell proliferation with eosinophilic cytoplasm and cigar-shaped nuclei	SMA positive, Desmin positive, h-caldesmon positive	SMA negative; dsmin negative	Excluded
Ewing sarcoma/primitive neuroectodermal tumor	Relatively uniform small round blue cells with scant cytoplasm, sometimes with necrosis	FLI1 positive, NKX2.2 positive, EWSR1 rearrangement	NKX2.2 negative; FLI1 negative; and a definite spindle cell component was present	Excluded
Clear cell sarcoma	Clear or eosinophilic tumor cells arranged in nests or fascicles	S-100 positive, HMB45 positive, Melan-A positive	HMB45 negative	Excluded
Melanoma	May show spindle cell or epithelioid morphology with marked atypia, sometimes with melanin pigment	S-100 positive, SOX10 positive, HMB45 positive, Melan-A positive	HMB45 negative; SOX10 negative; no history of melanoma	Excluded
Synovial sarcoma	Monophasic tumors are often composed of relatively uniform spindle cells and may show a vascular-rich background	AE1/AE3 positive, EMA positive, TLE1 positive	AE1/AE3 negative; EMA negative	Excluded

MPNST: Malignant peripheral nerve sheath tumor.

In the pathologic diagnosis of the present case, the observance of a complete loss of H3K27me3 was of critical significance. H3K27me3 is a histone modification mediated by polycomb repressive complex 2 (PRC2), whose core components include SUZ12 and EED. Recent studies have shown that PRC2 inactivation is one of the key molecular events in high-grade MPNST and may lead to the loss of nuclear H3K27me3 expression, thereby promoting tumor progression through enhancer reprogramming and epigenetic dysregulation[15]. In PRC2-deficient MPNST, the complete loss of H3K27me3 is accompanied by the aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their downstream developmental pathways[16]. This molecular alteration is highly enriched in MPNST but is rarely encountered in its benign precursor lesion, neurofibroma[17], making it a potentially useful marker for distinguishing malignant from benign peripheral nerve sheath tumors. The immunohistochemical assessment of H3K27me3 has gradually emerged as an important ancillary tool in the diagnosis of challenging cases of MPNST. Previous studies have reported a loss of H3K27me3 expression in 34.5% to 72% of MPNSTs[18], and this finding appears to be more common in high-grade, sporadic, and radiation-associated tumors[19,20]. In the present case, nuclear H3K27me3 expression was completely absent in the tumor cells, whereas non-neoplastic vascular endothelial cells retained positive nuclear staining, consistent with the standard interpretation pattern of a “complete loss”. This finding provided strong support for the diagnosis of MPNST.

It should be emphasized that the diagnostic utility of H3K27me3 depends on a standardized interpretation and appropriate contextual evaluation. In general, only a complete loss is considered to have a relatively robust supportive value in the diagnosis of MPNST[17,21], as a partial loss may also occur in certain non-MPNST neoplasms, including synovial sarcoma and leiomyosarcoma, and therefore cannot be used in isolation to support a diagnosis of MPNST[21]. Accordingly, H3K27me3 should not be interpreted independently of a consideration of the tumor morphology and other immunohistochemical findings in routine practice.

The value of the present case lies in the fact that, whereas the conventional neural markers were not entirely characteristic, the complete loss of H3K27me3 provided strong molecular-pathologic support for the diagnosis of MPNST. Although S-100 is a classic marker of Schwannian differentiation, both its sensitivity and specificity in MPNST are limited, and its staining is often only focal or patchy. SOX10 has been suggested in some studies to be more indicative of neural crest differentiation than S-100, but a proportion of MPNSTs still lack SOX10 expression[22]. Therefore, the combination of S-100 positivity and SOX10 negativity in the present case was not necessarily contradictory. In the present case, S-100 showed patchy positivity in the tumor cells, while SOX10 and GFAP were negative, which made the diagnosis more challenging. However, this immunophenotypic pattern is within the known spectrum of marker variability in MPNST and so did not preclude the final diagnosis of MPNST.

Whether the small round-cell component is related to PRC2-associated dedifferentiation, however, remains uncertain. Previous studies have suggested that PRC2 inactivation may confer an earlier, less differentiated neural crest-like phenotype on tumor cells, thereby resulting in dedifferentiated features[16]. Enhancer reprogramming and the dedifferentiated state induced by the loss of PRC2 may create a permissive chromatin environment that facilitates the emergence of distinct cellular populations, including the small round-cell component. The high Ki-67 Labeling index of 90% observed in this case may reflect, at least in part, the proliferative advantage associated with such a dedifferentiated state. In this context, the coexistence of small round cells and conventional spindle cells may represent one manifestation of the morphologic heterogeneity driven by epigenetic disequilibrium. Primitive neural differentiation, histologic heterogeneity, and PRC2 inactivation-associated dedifferentiation are therefore not necessarily mutually exclusive phenomena in this case, but may instead have jointly contributed to its unusual morphologic appearance. While the relative contribution of each mechanism cannot be determined from a single case, their coexistence highlights the complex molecular landscape of this tumor. Although no molecular testing was available to confirm alterations in NF1, SUZ12, EED, or other related genes, the phenotype of a complete H3K27me3 Loss may suggest the involvement of PRC2-related molecular pathways in the development and progression of this tumor. Further molecular studies, such as next-generation sequencing, may help clarify the mechanisms underlying this rare morphologic presentation.

Importantly, the present case exhibited an extremely aggressive clinical course. Although the patient underwent right hemicolectomy with R0 resection, he died rapidly in the early postoperative period from respiratory failure secondary to massive pleural and peritoneal effusions. His postoperative complete blood count showed a normal WBC count of 4.75 × 10⁹/L, increased NEUT% of 87.6%, decreased lymphocyte percentage of 10.5%, severe anemia with HGB of 73 g/L, and platelet count (PLT) with a PLT of 62 × 10⁹/L. Furthermore, peritoneal fluid biochemical analysis showed a low total protein of 3.3 g/L, markedly elevated lactate dehydrogenase (LDH) of 1021.75 U/L, glucose of 4.6 mmol/L, and adenosine deaminase of 7.0 U/L. The markedly elevated LDH level suggested substantial cellular injury, inflammation, or tumor-related necrosis (Tables 5 and 6). Furthermore, while imaging did not show definite evidence of tumor dissemination, pulmonary embolism, cardiac events, infection, hypoalbuminemia-related fluid shifts, and paraneoplastic mechanisms could not be completely excluded. Therefore, the relationship between the aggressive tumor biology and the fatal postoperative effusions remains possible but unproven.

Table 5 Postoperative complete blood count findings.

Test item	Result	Flag	Reference range	Unit
WBC	4.75		3.50-9.50	× 109/L
NEUT%	87.6	↑	40.0-75.0	%
LYMPH%	10.5	↓	20.0-50.0	%
HGB	73	↓	130-175	g/L
PLT	62	↓	125-350	× 109/L

WBC: White blood cell count; NEUT%: Neutrophil percentage; LYMPH%: Lymphocyte percentage; HGB: Hemoglobin; PLT: Platelet count.

Table 6 Biochemical analysis of peritoneal fluid.

Test item	Result	Flag	Reference range	Unit
TP	3.3		< 25.0	g/L
LDH	1021.75	↑	< 200	U/L
GLU	4.6		3.6-5.5	mmol/L
ADA	7.0		< 40.0	U/L

TP: Total protein; LDH: Lactate dehydrogenase; GLU: Glucose; ADA: Adenosine deaminase.

Among the aforementioned parameters, the most striking was the extremely high Ki-67 Labeling index of 90%, which is substantially higher than the levels reported in most previously published cases of MPNST. Previous studies have shown that an elevated Ki-67 Labeling index is closely associated with an adverse prognosis in MPNST[23]. Specifically, a high proliferative index generally suggests more rapid tumor growth, greater invasive potential, and poorer survival outcomes. In a survival analysis of 43 cases of MPNST, Watanabe et al[24] demonstrated that a high Ki-67 Labeling index was associated with significantly reduced survival. Likewise, the systematic review by Martin et al[25] identified a high Ki-67 Labeling index as an important prognostic marker in MPNST. In the present case, the Ki-67 Labeling index of 90% not only reflected exceptionally active tumor cell proliferation but was also highly concordant with the rapidly progressive clinical course, which culminated in the patient’s death within 2 weeks after surgery.

In addition to the high Ki-67 Labeling index, the complete loss of H3K27me3 may itself be associated with a more aggressive biologic behavior. Previous studies have suggested that PRC2-deficient MPNSTs, in addition to showing more pronounced dedifferentiation, may also harbor greater chromosomal instability, more extensive genomic remodeling, and lower levels of immune cell infiltration, thereby conferring them with an enhanced proliferative and immune-evasive capacity[26]. In the present case, the complete loss of H3K27me3 co-occurred with high-grade histologic features, an extremely high Ki-67 Labeling index, and a fulminant clinical course. This concordance suggests that H3K27me3 could serve not only as a diagnostic marker but also, to some extent, as a surrogate indicator of the molecular basis underlying the tumor aggressiveness.

In addition, the distinctive anatomic location of the colon may itself have an adverse impact on prognosis. Compared with MPNSTs arising in the extremities or deep soft tissues of the trunk, primary colonic MPNSTs are located within the abdominal cavity, where early clinical manifestations are usually nonspecific and may be mistaken for more common inflammatory or neoplastic abdominal diseases, thereby delaying diagnosis. In the present case, the patient initially presented only with nonspecific gastrointestinal symptoms, including abdominal pain and distension, and had no features suggestive of NF1, such as café-au-lait macules, axillary or inguinal freckling, or Lisch nodules. Although preoperative imaging demonstrated the presence of a large invasive mass, definitive characterization remained difficult. Rapid expansion of a colonic MPNST may cause intra-abdominal hypertension and impair diaphragmatic excursion, which may in turn contribute to respiratory compromise, as observed in this patient. From an anatomic perspective, the colonic wall is relatively thin, and once the tumor breaches the bowel wall or serosal surface, it may rapidly lead to intra-abdominal contamination, local dissemination, or severe complications. Intraoperatively, extensive fish-flesh-like necrotic tissue and purulent material were found to be already present in this case, indicating severe local tissue destruction and suggesting that a complex intra-abdominal pathologic environment may have developed before surgery. The presence of extensive necrosis and purulent material suggests that a profound inflammatory milieu existed preoperatively, which may have predisposed the patient to postoperative capillary leakage and serosal effusions. This may have been one of the factors contributing to the patient’s rapid postoperative deterioration.

Based on a pooled analysis of 8 reported cases of colonic MPNST, including the present case, we found that although most patients underwent complete surgical resection, with an R0 resection rate of 85.7% (6/7), the recurrence rate was still close to 28%. In addition, some patients developed metastasis or died within 6 months after surgery, indicating a considerable degree of aggressiveness. Most previously reported cases were predominantly spindle-cell tumors, and there is currently insufficient evidence regarding the relationship between unusual histologic patterns and prognosis given their rarer occurrence. However, the present case combined multiple high-risk features, including a rare biphasic morphology, complete loss of H3K27me3, an extremely high Ki-67 Labeling index, and death within a very short postoperative interval, suggesting that the biologic behavior of colonic MPNST may be more complex and aggressive than previously appreciated. Although a single case is insufficient to establish a direct causal relationship between the presence of a small round-cell component and a worse outcome in MPNST, this morphologic feature may warrant particular attention in future case accumulation and analysis.

With regard to treatment, the conventional view is that complete surgical excision with negative margins remains the cornerstone of management for MPNST and the basis for the treatment of localized diseases[15]. However, in a case of high-grade MPNST arising in the setting of SMARCB1-related schwannomatosis, Khalilullah et al[27] observed that recurrence and distant metastasis may still occur even after en bloc resection with negative margins, reflecting the intrinsically aggressive biology of this tumor. Similarly, Al-Shehari et al[8] emphasized that, given the aggressive nature and high recurrence potential of MPNSTs, long-term follow-up should be maintained in patients with colonic MPNST. In the present case, the patient died on postoperative day 13 from respiratory failure secondary to massive serous cavity effusions despite R0 resection, and the imaging studies did not show definite evidence of tumor dissemination. In retrospect, an earlier identification of the high-risk pathologic features, such as the Ki-67 Labeling index of 90% and complete loss of H3K27me3, might have prompted a consideration of neoadjuvant or immediate adjuvant therapy, although the patient’s rapid decline precluded such an intervention. This observation suggests that, in colonic MPNSTs with highly malignant pathologic features, surgery alone may be insufficient to control the rapid progression of this highly aggressive disease. Accordingly, R0 resection should perhaps not be regarded as the endpoint of treatment, but rather as the beginning of systematic postoperative management. Close postoperative surveillance remains necessary to enable the timely recognition and management of intra-abdominal complications, effusions, respiratory deterioration, and potential occult dissemination.

Although these novel therapeutic approaches were not applicable to our patient because of his rapid decline, they may represent future treatment options for unresectable or metastatic MPNST. For patients with very large tumors, recurrent disease, or metastatic disease, the treatment options remain limited, and adjuvant radiotherapy or chemotherapy may be considered[2,28]. Nevertheless, chemotherapy should be individualized according to the patient’s medical condition and the risk of recurrence; however, the available evidence for gastrointestinal MPNST remains limited, and therefore, its benefit is still uncertain. Immune checkpoint inhibition, including anti-PD-1/PD-L1 therapy, has also raised the potential for new therapeutic strategies for MPNSTs[29]. However, the optimal treatment strategy for a primary colonic MPNST remains unclear because of its rarity.

However, compared with targeted and immunotherapeutic approaches that remain largely investigational, the more practical and immediately relevant issue in current clinical practice is still the appropriate use of H3K27me3, S-100, and relevant exclusionary markers to improve diagnostic accuracy.

This study has several limitations to note. First, although the major differential diagnoses were excluded using a relatively comprehensive immunohistochemical panel, due to the limited tissue availability, no molecular testing was performed to evaluate SUZ12, EED, or other related genetic alterations; therefore, the mechanism underlying the unusual biphasic morphology could not be directly confirmed at the molecular level. Second, because the patient deteriorated rapidly after surgery, long-term follow-up data were unavailable, precluding further assessments of recurrence and the metastatic patterns. Nevertheless, given the rare anatomic site, distinctive morphology, broad immunohistochemical exclusion of major mimics, and complete loss of H3K27me3, the diagnosis in this case remains well supported. In summary, this case expands the morphologic spectrum of colonic MPNST and underscores the diagnostic value of H3K27me3, while also highlighting its potentially aggressive behavior even after R0 resection.

CONCLUSION

Primary sporadic MPNST of the colon is exceptionally rare and may follow a highly aggressive clinical course. In addition to arising at an unusual site, the present case exhibited a biphasic morphology composed of spindle cells and small round cells, a pattern that has rarely been described in colonic MPNST. It was further characterized by myxoid, vascular-rich stroma, a complete loss of H3K27me3, and an extremely high Ki-67 Labeling index, all of which contributed to the substantial diagnostic difficulty. This case suggests that MPNST should be included in the differential diagnosis of high-grade mesenchymal malignancies arising in the colon, particularly when the morphology is atypical and when conventional immunohistochemical markers are of limited diagnostic value. In such challenging cases, assessment of the H3K27me3 status may provide important ancillary diagnostic support. In the present case, despite R0 resection, the patient deteriorated rapidly and died shortly after surgery following a fulminant postoperative course, indicating that colonic MPNSTs with high-risk pathologic features may still have a very poor prognosis even after complete resection. Early recognition, accurate pathologic diagnosis, close postoperative surveillance, and multidisciplinary management remain essential for optimizing the outcomes in such patients.

ACKNOWLEDGEMENTS

We wish to thank Department of Pathology, The Affiliated Hospital of Qinghai University for generous help.