Sarcomatoid Carcinoma Manifesting as Recurrent Rectal Cancer and Mimicking Radiation-Induced Extraskeletal Osteosarcoma: A Case Report

Introduction

Sarcomatoid carcinoma of the colon, also called spindle and giant cell or anaplastic carcinoma, is a biphasic carcinoma with a spindle-cell sarcomatoid component in which the tumor cells are at least focally immunoreactive for keratins and its morphologies are similar to those of its counterparts in other organs.^1-3 Sarcomatoid carcinomas occur in various organs, but are most commonly located in the head and neck, lungs, and female genital tract. Within the alimentary tract, the oral cavity, oropharynx, and esophagus are the most common sites ⁴ and only a few cases of sarcomatoid carcinoma have been described within the colon.^1-3,5-10.

Radiation-associated sarcoma (RAS) is a rare, but potential late complication of radiation therapy. The risk of developing RAS is estimated between 0.03% and 0.8%, and RAS accounts for 0.5% to 5.5% of all bone and soft tissue sarcomas. ¹¹ Extraskeletal osteosarcoma (ESOS) is a rare malignancy and a small proportion of ESOSs arise following exposure to radiation. ¹² Colon cancers that develop after radiotherapy for uterine cervical cancer have been reported, and the high incidence of mucin-producing carcinomas is characteristic. ¹³

Here, we describe a case of sarcomatoid carcinoma with prominent intercellular deposition of osteoid-like calcified tissue in a context specific irradiation-associated recurrent rectal cancer in a 76-year-old man. The light microscopic, immunohistochemical, and ultrastructural features are presented herein, and the histogenesis of sarcomatoid carcinoma in recurrent rectal cancer, its differential diagnosis, and its morphologic features mimicking those of ESOS are discussed.

Clinical Summary

A 76-year-old male patient presented with pain located in the anus and left hip, which was especially aggravated during sitting and defecation. Six years ago, he underwent an emergent diverting sigmoid colostomy due to acute peritonitis from sigmoid colon perforation when he was diagnosed with an obstructing primary rectal cancer, clinically cT3N0M0, at the emergency department. Following 3 months of neoadjuvant chemoradiotherapy (5-fluorouracil/leucovorin, total radiation dose of 5400 cGy; 180 cGy/fraction) for rectal cancer, he underwent radical low anterior resection (LAR) with a temporary ileostomy, which was repaired 3 months later.

The surgical specimen revealed complete dissection of the mesorectum (Figure 1A), a well-defined ulceroinfiltrative lesion measuring 2.0 × 1.8 cm (Figure 1B), moderate response after neoadjuvant treatment by the College of American Pathologists (CAP) tumor regression grading criteria (Figure 1C), and a moderately differentiated adenocarcinoma (ypT3 pN1b M0) with multifocal microcalcification (Figure 1D). The proximal, distal, and circumferential radial margins were fairly free of carcinoma. There was no evidence of disease recurrence during the periods of regular follow-up examinations as determined by abdominal computed tomography (CT) scans and blood carcinoembryonic antigen (CEA) levels, except for benign postoperative urinary tract strictures and cholecystitis with gallstones, which were easily managed with a ureteric double-J stent insertion and cholecystectomy. One year ago, he had been declared cured from rectal cancer.

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Figure 1.

The surgical specimen revealed complete dissection of the mesorectum (A), a well-defined ulceroinfiltrative lesion measuring 2.0 × 1.8 cm (B), moderate response after neoadjuvant treatment by the College of American Pathologists tumor regression grading criteria (C), and a moderately differentiated adenocarcinoma (ypT3 pN1b M0) with multifocal microcalcification (D).

However, recent abdominal CT scans showed a newly developed left perirectal mass with gluteus maximus invasion measuring approximately 8 cm in maximum diameter (Figure 2A and B). In the retrospective examination of the previous abdominal CT scans, this lesion could not be found during the previous 5 years (Figure 2C) except for a small focus of calcification a year ago (Figure 2D). A perirectal recurrence of the primary tumor was radiographically suspected and an abdominoperineal resection was performed. A complete resection was considered unfeasible due to anatomical interruption by bony structures of the sciatic foramen. After palliative resection of the bulky pelvic mass, the patient was discharged after refusing further management. Two months later, the patient presented again with necrotizing perineal infections originating from small bowel necrosis and perforations in the pelvic cavity. Despite further repeated aggressive surgery and antibiotic therapies, the patient died of sepsis within 3 months after the recurrence.

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Figure 2.

An abdominal computed tomography (CT) scan showed a newly developed left perirectal mass with gluteus maximus invasion measuring approximately 8 cm in maximum diameter (A, B). In the retrospective examination of the previous abdominal CT scan, this lesion could not be found during the previous 5 years (C) except for a small focus of calcification a year ago (D).

Pathological Findings

An irregularly shaped surface area measuring approximately 5.0 × 4.0 cm was identified in the perirectal soft tissue near an anastomosis site of an abdominoperineal resection specimen (Figure 3A). The pathologic examination revealed a highly cellular neoplasm that infiltrated the rectal muscular wall and the mesorectum (Figure 3B). The tumor was composed of solid sheets, or fascicles, of pleomorphic spindle to epithelioid tumor cells. The tumor cells were characterized by vesicular chromatin with irregular and distinct nuclear membranes, a moderate amount of clear or eosinophilic cytoplasm, occasional prominent nucleoli, and scattered bizarre or multinucleation (Figure 3C). Numerous mitotic figures (15-25/10 high-power fields [HPF]) and extensive areas of necrosis were evident. At low power, extensive deposition of osteoid-like calcified fibrous tissue was characteristic in the stroma between the tumor cells (Figure 3D). There was no evidence of gland formation or features of squamous differentiation. No secretory material could be identified on mucicarmine or periodic acid–Schiff with diastase predigestion staining.

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Figure 3.

An irregularly shaped surface area was identified in the perirectal soft tissue near an anastomosis site of an abdominoperineal resection specimen (A). At low power, it revealed a highly cellular neoplasm that infiltrated the rectal muscular wall and the mesorectum (B). The tumor cells were characterized by vesicular nuclei, occasional prominent nucleoli, and scattered bizarre or multinucleation (C). Extensive deposition of osteoid-like calcified fibrous tissue was characteristic in the stroma between the tumor cells (D). The tumor cells of the primary adenocarcinoma were diffusely immunoreactive for pan-cytokeratin (pan-CK) (E) and E-cadherin (F) and negative for vimentin (G) and showed an overexpression of p53 (H). The tumor cells of the recurrent sarcomatoid carcinoma showed patchy pan-CK staining (I), no immunoreactivity of E-cadherin (J), diffuse immunoreactivity of vimentin (K), and no expression of p53 (L).

The tumor cells of the primary adenocarcinoma were diffusely immunoreactive for pan-cytokeratin (pan-CK, 1:200, Novocastra, Newcastle, UK; Figure 3E), CK20 (predilution, Novocastra) and E-cadherin (1:20, Dako, Carpinteria, CA, USA; Figure 3F) and negative for vimentin (1:50, Novocastra; Figure 3G) and showed an overexpression of p53 (1:100, Dako; Figure 3H). The tumor cells of the recurrent sarcomatoid carcinoma showed patchy pan-CK staining (Figure 3I) and was negative for CK20 and E-cadherin (Figure 3J). They were diffusely immunoreactive for vimentin (Figure 3K) and CD99 (1:200, DiNonA, Seoul, Korea), and there was no p53 expression (Figure 3L). The expression level of c-erbB2 (1:40, Dako) and epidermal growth factor receptor (EGFR, 1:50, Dako) was slightly augmented in the recurrent sarcomatoid carcinoma in comparison with the primary adenocarcinoma. Both the primary adenocarcinoma and recurrent sarcomatoid carcinoma were focally immunoreactive for CK19 (1:100, Dako), and epithelial membrane antigen (EMA, 1:200, Novocastra). Both were negative for CK7 (1:50, Dako), CK5/6 (1:50, Dako), and high molecular CK (HM-CK, 1:150, Dako). Immunostaining of mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) was positive in both the primary adenocarcinoma and recurrent sarcomatoid carcinoma. The following antibodies were used to examine only the sarcomatoid carcinoma and were negative in the tumor cells; factor VIII related antigen (factor VIII RA, 1:50, Novocastra), CD31 (1:50, Abcam, Cambridge, UK), D2-40 (predilution, Dako), α-smooth muscle actin (α-SMA, 1:100, Novocastra), CD34 (predilution, Novocastra), c-kit (1:600, Dako), HMB45 (1:40, Dako), Melan A (1:50, Dako), S100 (1:200, Novocastra), calretinin (1:35, Zymed, CA, USA), and CD68 (1:200, Novocastra).

Ultrastructural examination by transmission electron microscopy was performed on formalin-fixed, paraffin-embedded tissue, using standard procedures. The sections were examined using a Hitachi HT-7700 electron microscope (Japan) and demonstrated surface microvilli in the intercellular space (Figure 4). We performed mutational analysis of rat sarcoma viral oncogenes (KRAS and NRAS) and the B-type raf proto-oncogene (BRAF), but these mutations were not detected in either the primary adenocarcinoma or recurrent sarcomatoid carcinoma.

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Figure 4.

At ultrastructural examination, the neoplastic cells disclosed surface microvilli in the intercellular space (arrows, ×3000).

Discussion

Sarcomatoid carcinoma is a rare tumor that displays both malignant epithelial and mesenchymal components. Sarcomatoid carcinoma of the colon is a rare clinical and pathological entity and, to the best of our knowledge, only a few cases have been reported in the literature.^1-3,5-10 First described by Virchow in 1864, diverse terms have been applied to describe sarcomatoid carcinoma. These reflect the ambiguity of histogenesis and classification of the sarcomatoid carcinomas and their related entities. The predominant feature of all sarcomatoid carcinomas is the immunohistochemical property of positivity of epithelial antibodies, such as CK, or ultrastructural evidence of epithelial differentiation for both the sarcomatous and carcinomatous elements. However, if sarcomatous elements do not express epithelial immunophenotypes or substructural epithelial differentiation, the preferred term is carcinosarcoma.^14,15 In this case, the sarcomatous component of the recurrent tumor was focally immunoreactive for CK and EMA, and showed the ultrastructural features of epithelial differentiation, such as surface microvilli.

The histogenesis of sarcomatoid carcinoma remains unclear and has been controversial despite the advent of advanced detection methodologies, such as immunohistochemistry and electron microscopy. A proposed hypothesis is one of multiclonality, that is, collision theory, suggesting that each of the components are derived from separate cell clones. ¹⁶ The other is a monoclonal theory, as common immunophenotypes have been seen among the different populations of neoplastic cells. It could even possibly be a malignant transformation of pluripotent stem cells capable of carcinomatous and sarcomatous differentiation, or that the sarcomatous component arises from an epithelial-mesenchymal transition (EMT) of the carcinomatous component. Several genetic studies have exhibited a common origin of both components of sarcomatoid carcinoma. ¹⁷ Delahunt et al ¹⁸ suggested that the conversion of the carcinomatous phenotype to a sarcomatous one was associated with progressive accumulation of p53 proteins. Lee et al ¹⁰ demonstrated a clear histological adenoma-adenocarcinoma-sarcomatoid phenotype sequence of progression in one image of the surgically resected specimen and showed increasing accumulation of p53 levels from tubulovillous adenoma to adenocarcinoma and finally to the sarcomatous area. However, in our case, the p53 protein was not detected immunohistochemically in the component of sarcomatoid carcinoma of the recurrent cancer even though it was overexpressed in the primary adenocarcinoma. Recently, Widel et al ¹⁹ showed that human colorectal carcinoma HCT116 cells differing in the status of the p53 gene responded in different ways not only to radiation, but also to bystander signals generated by irradiated cells. P53 knockout cells having p53 gene deletion or loss of function due to mutations respond to radiation via p53-independent apoptosis, but cells with the wild type p53 gene demonstrate nuclear factor–κB (NF-κB) pathway activation, and thereby stimulate transcription of proinflammatory cytokines, which when secreted to the extracellular environment mediate a bystander effect in the unexposed cells. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species, resulting in cancer cell death. However, radiation paradoxically promotes invasion and metastasis of cancer cells by inducing EMT. ²⁰ In this case, 5 years ago, the patient had received adjuvant chemoradiation therapy and subsequent LAR and the primary tumor was composed of conventional colonic, moderately differentiated adenocarcinoma. However, the recurrent tumor was exclusively composed of a sarcomatous component without gland formation and extensive deposition of osteoid-like calcified fibrous tissue. Our case may become the plausible example illustrating that different cells with different genetic profiles, including p53 gene profile, and varying levels of radiosensitivity exist in a neoplasm, and can therefore postulate that the late onset of this rectal sarcomatoid carcinoma could have manifested itself through overgrowth and EMT of the cell population having a radio-resistant genotype in the clinical context of radiation therapy. KRAS and NRAS mutations predict resistance to EGFR inhibitors and have been detected in 30% to 40% of colorectal cancers. BRAF mutation is a rare event, frequently associated with the CpG island hypermethylation phenotype and microsatellite instability high in right-sided sporadic colon cancers. According to recent systematic review and meta-analysis, it appears to be associated with distinct, unfavorable clinicopathologic parameters in colorectal cancers. ²¹ However, in our case, the immunostaining of MLH1 and MSH2 was positive and mutations of KRAS, NRAS, and BRAF genes were not detected in both the primary adenocarcinoma and recurrent sarcomatoid carcinoma.

The histopathologic differential diagnosis included radiation-induced ESOS and epithelioid angiosarcoma, epithelioid leiomyosarcoma, extragastrointestinal stromal tumor, malignant melanoma, malignant mesothelioma, and other deep-seated epithelioid neoplasms. In our case, the tumor cells showed no immunoreactivity for factor VIII RA, CD31, D2-40, α-SMA, CD34, c-kit, HMB45, Melan A, S100 protein, and calretinin. Therefore, we were able to exclude the aforementioned differential diagnoses besides ESOS. In our case, we found extensive deposition of osteoid-like calcified fibrous tissue was prominent in the stroma between tumor cells. This finding can simulate the features of osteosarcoma but several epithelial markers were immunohistochemically expressed in excess of focal immunoreactivity that would be seen in osteosarcoma. In addition, epithelial differentiation, such as surface microvilli, was evident in our case. With the previous history of radiation therapy present and the fact that definite epithelial differentiation was not seen, the possibility of radiation-induced sarcoma may be taken into consideration than anything else, especially in a case with the deposition of prominent extracellular osteoid-like material. To make target therapy possible and to proceed cautiously, it is very important to differentiate between the recurrence manifested as undifferentiated or sarcomatoid carcinoma and radiation-induced sarcoma. In this situation, it is exceptionally clear that the immunostaining for cytokeratins and ultrastructural examination are indispensable for differential diagnosis. If this situation is encountered in the small biopsies, we suggest that it is better to recommend the surgical excision rather than to make a conclusive diagnosis to avoid the potential diagnostic pitfalls.

Complete resection could not be accomplished in our patient owing to the bulky size of the tumor, its deep location, and the fibrotic adhesion to the surrounding tissue. On retrospective review of the abdominal CT imaging, a small calcified nodular lesion was identified in the tumor a year ago. Perhaps if we had regarded it as a precedent sign of tumor development and recurrence, we believe that a small calcified lesion would not be overlooked and early proper management, including complete resection could be possible.

In this study, we present a case of sarcomatoid carcinoma mimicking radiation-induced ESOS that recurred after surgery and neoadjuvant chemoradiotherapy in a patient with previous primary rectal adenocarcinoma. The different immunoreactivities of the primary and recurrent tumors for p53 were interesting. We hypothesize that the recurrent sarcomatoid carcinoma developed through the overgrowth and EMT of the tumor cells possessing a radio-resistant genotype. Careful histopathologic examination, including immunohistochemistry and electron microscopy is needed for correct diagnosis. We conclude that awareness of this unusual scenario of tumor development exemplifies why the careful consideration of a calcified lesion as a precedent sign of radiation-induced tumors is very important in follow-up management of post-operative patients with colon cancer.