Peutz-Jeghers syndrome

A 90-year-old woman underwent evaluation for rectal bleeding. A rectal mass was detected 10 cm from the anal verge. A rectal endoscopie biopsy showed a well-differentiated adenocarcinoma. Within some of the biopsy fragments, well-formed trabecular bone was seen. The bone was microscopically normal, without atypia or architectural derangement, suggestive of sarcoma (Figure, A).

Preoperative abdominal computed tomography (Figure, B) showed a large rectal mass with diffuse rectal wall thickening, infiltration through the bowel wall, and stippling suggestive of microcalcifications. There was an enlarged perirectal lymph node. No liver lesions were seen. The patient received a course of radiotherapy to the pelvis.

A lower anterior resection procedure was performed. The resection specimen contained an 8.0 × 6.5 × 3.0-cm, yellow-tan, lobulated lesion involving the full thickness of the rectal wall and extending into the subserosal fat. One regional lymph node contained metastatic tumor.

Microscopic examination showed a well-differentiated colonie adenocarcinoma with intense stromal desmoplasia. Well-formed trabecular bone was present (Figure, C and D).

What is your diagnosis?

Pathologic Diagnosis: Colonic Adenocarcinoma With Osseous Metaplasia

Abstract

Osseous metaplasia is an uncommon finding in benign and malignant gastrointestinal tumors. It also has been described in neoplasms outside the gastrointestinal tract. The tumors are usually mucinous adenocarcinomas. Pathogenesis is thought to involve bone morphogénie proteins. Osseous metaplasia has no prognostic significance, but an awareness of the phenomenon is necessary to prevent the overdiagnosis of bone invasion by carcinoma or misdiagnosis of metaplastic carcinoma.

Heterotopic bone formation, also known as osseous metaplasia, in colonie carcinomas is a rare phenomenon, despite the high incidence of colonie adenocarcinoma. Osseous metaplasia has been described in other adenocarcinomas, including those of the lung, breast, thyroid, parotid, and pancreas.1 In 1923, Hasegawa2 first described 2 cases of rectal adenocarcinoma with bone formation. In 1939, Dukes3 was the first investigator to describe ossification in rectal carcinoma in the English literature.

Ossification can occur throughout the gastrointestinal tract and has been described in benign colonie polyps, gastric carcinoid, adenocarcinoma, and mucocele of the appendix.4^6 Ossification is more likely to be found in gastrointestinal tumors of the lower gastrointestinal tract, and most affected tumors have been diagnosed as well-differentiated or moderately differentiated lesions.7 This phenomenon is rare. The overall incidence is approximately 0.4%, as suggested by Dukes.3 The course and prognosis of adenocarcinoma with osseous metaplasia does not differ from that of colonie adenocarcinoma without osseous metaplasia, although it appears to be more common in slow-growing neoplasms in younger individuals.8

Ossification refers to the formation of mature (benign) bone elements in the stroma of the neoplasms and is a complex process requiring the presence of osteoblasts.7'8 Grossly, the tumors can ulcerate, fungate, or infiltrate, and usually have a mucinous cut surface with areas of calcification and metaplastic bone formation.5 By microscopy, they are usually mucinous adenocarcinomas, with the heterotopic bone consisting of osteoblasts surrounding irregularly deposited osteoid.

The widely accepted hypothesis for the cell of origin for osseous metaplasia in colonie adenocarcinoma was proposed by Rhone and Horowitz.9 They postulated that ossification might result from metaplasia of pluripotent mesenchymal cells into osteoblasts. The bone morphogenetic proteins (BMPs) are a family of bioactive proteins, of which 20 different types have been cloned.7 Imai et al7 studied the immunohistochemical expression of BMPs in colonie adenocarcinoma and found that BMP-5 and BMP6 were prominent in the cytoplasm of tumor cells, but were weakly expressed in the osteoblast-like cells adjacent to the nearby bone. BMP-2 and BMP-4 were strongly expressed in the surrounding mesenchymal cells and weakly expressed in the tumor cells and osteoblast-like cells. This pattern suggests that the tumor cells mainly produce BMP-5 and BMP-6, which may induce proliferation of surrounding mesenchymal cells into preosteoblasts and osteoblasts expressing BMP-2 and BMP-4.7 BMP-2 and BMP4 are potent inducers of osteoblastic differentiation when compared to other BMPs.10

The presence of osseous tissue in colonie biopsy material might be confused with colonie adenocarcinoma invading into bone or with a carcinosarcoma (metaplastic carcinoma). In the present case, the resection specimen definitely showed islands of metaplastic bone superficial to the muscularis propria, thus excluding sacral invasion.

In summary, osseous metaplasia may occur in both benign lesions and adenocarcinomas of the gastrointestinal tract. Although the pathogenesis of this rare phenomenon remains incompletely understood, current studies suggest a relationship with overexpression of BMPs by tumor cells, inducing the differentiation of surrounding pluripotent mesenchymal cells into osteoblasts. Osseous metaplasia is of no prognostic significance, but an awareness of the phenomenon is important in order to prevent the overdiagnosis of bone invasion by carcinoma or misdiagnosis of metaplastic carcinoma.

References

1. Byard RW, Thomas Mj. Osseous metaplasia within tumours: a review of 11 cases. Ann Pathol. 1988:8:64-66.

2. Hasegawa T. Zur Kenntnis Stromaverknocherung in Karzinomen des Digestionstrakes. Wien KlinWochenschr. 1923;36:653-656.

3. Dukes CE. Ossification in rectal cancer. Proc R Soc Mod. 1939:32:1489-1494.

4. Ansari MQ, Sachs IL, Max E, Alpert LC. Heterotopic bone formation in rectal carcinoma: case report and literature review. Dig Dis Sd. 1992;37:1 624-1629.

5. Haque S, Eisen RN, West AB. Heterotopic bone formation in the gastrointestinal tract. Arch Pathol Lab Med. 1996:120:666-670.

6. Narita T, Ohnuma H, Yokoyama S. Peutz-Jeghers syndrome with osseous metaplasia of the intestinal polyps. Pathol Int. 1995:45:388-392.

7. lmai N, Iwai A, Hatakeyama S, et al. Expression of bone morphogenetic proteins in colon carcinoma with heterotopic ossification. Pathol Int. 2001 ;51: 643-648.

8. Kypson AP, Morphew E, Jones R, Gottfried MR, Seigler HF. Heterotopic ossification in rectal cancer: rare finding with a novel proposed mechanism. J Surg Oncol. 2003;82:132-136.

9. Rhone DP, Horowitz RN. Heterotopic ossification in the pulmonary métastases of gastric adenocarcinoma: report of a case and review of the literature. Cancer. 1976;38:1 773-1 780.

10. Yamaguchi A, Ishizuya T, Kintou N, et al. Effects of BMP-2, BMP-4, and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochem Biophys Res Commun. 1996:220:366-371.

Hatim Al-Maghrabi, MD; Bruce M. Jamison, MDCM, FRCPC; John P. Veinot, MD, FRCPC

Accepted for publication June 16, 2005.

From the Department of Pathology and Laboratory Medicine, University of Ottawa (Drs AI-Maghrabi, Jamison, and Veinot); Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Ottawa Hospital (Drs Jamison and Veinot), Ottawa, Ontario.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: John P. Veinot, MD, FRCPC, Division of Anatomical Pathology, Department of Laboratory Medicine, Ottawa Hospital, Civic Campus, 1053 Carling Ave, Ottawa, Ontario, Canada K1 Y 4E9 (e-mail: jpveinot@ottawahospital.on.ca).

Reprints not available from the authors.

Copyright College of American Pathologists Oct 2005
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