Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992), pp. 1624-1629
CASE REPORT
Heterotopic Bone Formation in Rectal Carcinoma Case Report and Literature Review KEY WORDS:
M.Q. A N S A R I , I.L. S A C H S , E. M A X , and L.C. A L P E R T adenocarcinoma; ossification; gastrointestinal tract.
An estimated 45,500 new cases of rectal adenocarc i n o m a w e r e e x p e c t e d in the United States in 1991 (1). Despite the high incidence of these tumors, ossification within rectal a d e n o c a r c i n o m a s is an e x t r e m e l y rare condition. D u k e s first reported heterotopic bone formation in four cases of rectal a d e n o c a r c i n o m a in 1939 (2). Since then, heterotopic bone formation has been reported in kidneys (3), liver (4), breast (5), thyroid (6), skin and soft tissues (7, 8), and in additional malignancies of the gastrointestinal tract (9-32). Ossification in gastric (20) and renal (3) carcinomas, as well as in metastatic disease (9, 13, 33), has been reviewed recently. It also has b e e n reported in benign tumors and surgical scars (7, 8, 12, 15, 16). Ossification within rectal a d e n o c a r c i n o m a s , although the m o s t c o m m o n gastrointestinal malign a n c y with ossification, has not b e e n reviewed separately. Therefore, we report this case with literature review, discuss the pathogenetic mechanisms for ossification in this setting, and consider its potential clinical significance. CASE R E P O R T A 54-year-old white woman presented with a fivemonth history of frequent diarrhea, and mucus-filled stools. Her hematocrit was 43.2 and her stools were guaiac positive. At sigmoidoscopy, a 2 • 2-cm polypoid mass was found in the rectum, located about 7 cm from the anal verge. A biopsy of the lesion revealed a welldifferentiated adenocarcinoma with heterotopic ossificaManuscript received January 25, 1991; revised manuscript received December 11, 1991; accepted December 11, 1991. From the Departments of Pathology, Internal Medicine and Surgery, Baylor College of Medicine and The Methodist Hospital, Houston, Texas. Address for reprint requests: Dr. L.C. Alpert, Pathology Rm G-100, Jewish General Hospital, 3755 Cote St-Catherine Road, Montreal, Quebec, Canada H3T 1E2.
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tion (Figure 1). Complete colonoscopy showed an additional villous a d e n o m a , tubular a d e n o m a , and hyperplastic polyp located in the ascending, transverse, and sigmoid colon, respectively. Neither calcification nor ossification was found in these three lesions. No metastatic disease was found on CT scan of the abdomen. Because of the large size of the rectal tumor and its location, the patient received preoperative radiation therapy consisting of 4500 rads. This was delivered to the primary tumor and regional lymph nodes in 25 fractions over 43 days with a four-field technique and custom blocking. Four months after presentation she underwent surgery. During the initial intraoperative evaluation of the abdomen, a single 1-cm nodule was found in and excised from the superficial left hepatic lobe. This nodule was shown by frozen section to be metastatic adenocarcinoma consistent with a colonic primary. A low anterior resection of the rectosigmoid was then performed. The patient did well and was discharged on the 10th postoperative day. Pathology. The initial rectal biopsy showed a welldifferentiated adenocarcinoma with focal necrosis and heterotopic bone formation (Figure 1). The resected 25 cm of rectosigmoid contained a 3.2 x 2.3 • 0.6-cm raised pink granular mass with an eccentrically located round 0.4-cm-diameter ulcer (Figure 2A). Cross sections following fixation showed that the ulcer undermined the mucosa and solid tan tumor extended into subserosal adipose tissue (Figure 3A). Focal calcification was appreciated by localized grittiness. The tumor did not extend to the soft tissue resection margins. The resected specimen was x-rayed intact (Figure 2B) and again following fixation and cross-sectioning because the preceding biopsy was known to contain heterotopic bone (Figure 3B). A distinct and localized snowy pattern of calcification was demonstrated in the tumor at the edge of the ulcer. Microscopically, the tumor consisted of a villous tumor peripherally with progression to invasive, well-differentiated adenocarcinoma. The carcinoma invaded through the muscular wall into subserosal fat and in many areas consisted of pools of mucin with a small number of free-floating malignant cells. Heterotopic bone was located within areas of viable tumor and adjacent to the Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
0163-2116/92/1000-1624506.50/0 9 1992 Plenum Publishing Corporation
OSSIFICATION IN G A S T R O I N T E S T I N A L CANCER
Fig 1. Ossification in biopsyof rectal adenocarcinoma consists of several irregular islands of immature bone (small arrows) that focally abut malignant epithelium (large arrows). The stroma is acutely inflamed with an area of necrosis and nuclear debris shown in the upper right corner. (Bar = 50 p,m.)
ulcer (Figure 4). The bone was immature with osteoblasts surrounding irregularly deposited osteoid as shown by the irregular refractile pattern of collagen on polarization. No bone marrow was found. Five pericolic lymph nodes were recovered from the mesentery. No metastatic tumor was found within them. However, two foci of densely sclerotic tissue measuring 2.0 and 1.8 cm were found in the mesentery. Microscopically, these consisted of a small number of tumor cells in a markedly desmoplastic stroma and probably represented nodal metastases with radiation-induced sclerosis, No ossification was found in these lesions. Additional metastatic disease was documented in the portion of liver excised initially for frozen section. No ossification was found in this lesion either. DISCUSSION A d e n o c a r c i n o m a o f the r e c t u m is a n e x t r e m e l y c o m m o n l e s i o n b u t c o i n c i d e n t a l h e t e r o t o p i c ossific a t i o n is d e c i d e d l y rare. I n o u r r e v i e w w e f o u n d Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
Fig 2. (A) Adenocarcinoma in the distal portion of resected rectosigmoid, gross photograph. Raised 3.2 • 2.3-cm tumor with eccentrically located ulcer (asterisk) extends to within 1.5 cm of the distal margin (bottom). (Bar = 2.7 mm.) (B) X-ray of distal portion of resected rectosigmoid. Note localized lacelike calcification that indicates distribution of ossified tissue (arrow). Adjacent irregular radiolucent area (asterisk) corresponds to the ulcer, A and B are taken at approximately the same magnification. (Bar = 2.7 ram.)
o n l y 52 c a s e s o f h e t e r o t o p i c o s s i f i c a t i o n i n v o l v i n g gastrointestinal tract glandular tumors (excluding p a n c r e a s a n d liver) ( T a b l e s 1 a n d 2). M o s t o f t h e s e cases c o n s i s t e d o f p r i m a r y a d e n o c a r c i n o m a s a n d the single m o s t c o m m o n site w a s the l o w e r gastro-
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Fig 3. (A) Cross-sections of the large bowel tumor show the slightly villous configuration of the surface (between the asterisks) and the central ulcer. Adenocarcinoma grossly infiltrates the muscular wall (arrow) (Bar = 3 mm.) (B) X-ray of crosssection of rectal mass shows the delicate pattern of calcification (arrow) located adjacent to the ulcer. (Bar = 3 mm.)
intestinal tract where Dukes suggested an incidence of below 0.4% for ossification in rectal adenocarcinomas (2). We found only 20 other cases of rectal glandular tumors with ossification* either in the primary rectal lesion (15 cases), metastases (six cases), or at both sites (one case), and all but four were associated with adenocarcinoma. These cases are summarized in Table 1. For the malignant cases with ossification in the primary, the male-to-female ratio was 5:7 and the ages ranged from 32 to 72, with a mean of 56 years. Several cases also had heterotopic ossification in local recurrences (2, 10, 13) or in metastasic sites (lungs, pelvic wall, lymph nodes, laparotomy site) (7, 9, 14). Ossification has also been reported in four benign rectal tumors two of which were classified as juvenile polyps (12, 15), one as a tubular adenoma (12), and another as a tubulovillous adenoma (16). *We have limited our review of cases with ossification to those with pathological confirmation. We note for those interested in the radiologic literature that some additional cases referred to as demonstrating ossification are based solely on the pattern of calcification in the x-rays.
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Fig 4. Ossification (arrows) adjacent to the ulcer bed (center right) of the well-differentiated invasive adenocarcinoma. Abundant mucin accumulation is seen (asterisk). The superficial villous component is present along the surface (top left). Muscularis propria is at bottom. Note how the ulcer undermines the mucosa. (Bar = 0.12 mm.)
For comparison of incidence and location, the cases of ossification in glandular tumors in other gastrointestinal sites are also summarized (Table 2). Some authors have commented on the young age of the patients in whom rectal adenocarcinoma with ossification has occurred. From Table 1 it is evident, however, that ossified tumors have been neither consistently nor predominantly associated with youth. Several reports have noted less aggressive behavior of some of these tumors, but this also has not been a consistent observation, and most of the tumors have been well or moderately differentiated, when grade was reported. Metaplasia of the local mesenchymal tissue is probably responsible for bone formation in neoplasms. Although Plenge (in 9) suggested that tumor cells undergo osseous metaplasia, there is little Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
OSSIFICATION IN GASTROINTESTINAL CANCER TABLE 1. OSSIFICATION IN RECTAL GLANDULAR TUMORS AND/OR THEIR METASTASES*
Case
Age
Malignant 1 32 2 63 3 69 4 70t 5 37 6 44 7 55 8 64 9 55 10 72 11 54 12 59 13 51 14 53 15 55 16 17 Benign 1 2 3 4
Sex
Diagnosis
Ossification in primary
Metastases present
Ossification in metastases NA NA NS NS NS NS NS NS NA NS + + + NA + + +
1939 1939 1939 1939 1939 1951 1923 1923 1962 1988 1992 1955 1935 1939 1949
NA NA NA NA
1981 1988 1988 1991
F F M F M F M M F M F F F M M
Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca
+ + + + + + + + + + + + NS -
43 43
F M
Adenoca Adenoca
NS -
NS NS NS + NS NS NS + + + + - at A P resection + at a u t o p s y + +
25 28 58 67
M M M M
Juvenile polyp Juvenile polyp Tubular a d e n o m a Tubulovillous a d e n o m a
+ + + +
NA NA NA NA
Reference D u k e s (2) D u k e s (2) D u k e s (2) Scheideggar (in 9) Scheideggar (in 9) Christie (10) H a s e g a w a (in 9) H a s e g a w a (in 9) U r b a n k e (11) B y a r d (12) Ansari (current case) Plenge (in 9) Clark (7) D u k e s (2) Senturia (13)
1951 Christie (10) 1955 V a n Patter (14) Sperling (15) B y a r d (12) B y a r d (12) G r o i s m a n (16)
*Abbreviations, F, female; M, male; A d e n o c a , A d e n o c a r c i n o m a ; N A , not applicable; NS, not specified; AP, anteriorperineal. t P a t i e n t at a u t o p s y h a d concurrent ossification in m a m m a r y fibroadenoma and gastric leiomyoma.
evidence to support this theory. Byard and Thomas (12) discounted Plenge's hypothesis because they did not see any intermediate stage between the neoplastic cells and the osteoblasts in the two tumors that they examined ultrastructurally. Furthermore, in experimental models in rats, Werner et al (34) have shown the different stages of heterotopic bone formation quite clearly from fibroblast through osteoblast in tumors of the gastric stump. The stimulus for transformation of the fibroblast to an osteoblast is, however, incompletely understood (35, 36). When the bone is intimately associated with the cancer cells, it might be inferred that some factor from the malignant cells alters the environment and induces the metaplasia. However, no chemical factor able to induce osseous metaplasia has yet been isolated from tumor cells. Randall et al (32), having shown the presence of alkaline phosphatase (bone-liver-kidney isoenzyme) in osteoblasts and surrounding mesenchymal cells in a case of rectal adenocarcinoma, consider that alkaline phosphatase may play a role in neoplastic ossification similar to that in the normal skeleton (35, 36). Ischemia may be a predisposing factor to tumorassociated ossification. The site of ossification in stomach cancers is cited in support of this, since Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
ossification usually occurs in the least perfused part of the stomach wall. Fukuoka et al (3), reviewing ossification in kidney tumors, found that five of their six examples (83%) were hypovascular, whereas most renal cell carcinomas (75-85%) are hypervascular. Therefore, they hypothesized " a causal relationship between ischemic degeneration and heterotopic bone formation." A causal relationship with necrosis has been suggested by Dukes (2) and others but is apparently not a prerequisite factor, since Byard et al (12) found that ossification could occur in the absence of necrosis, inflammation, extracellular mucin production, preexisting calcification, and preexisting stromal hypervascularity. Nevertheless, these may be contributory factors, and both mucin production and necrosis were present in our case. In summary, we report a 54-year-old woman with heterotopic ossification present together with adenocarcinoma in a biopsy of a rectal tumor. The mechanism for ossification in this site is not well understood. The rectum is the most frequent gastrointestinal site where tumor associated ossification occurs, although overall, ossification in rectal adenocarcinomas is rare with this being only the twelfth case reported with pathologic documentation in the literature reviewed. We conclude that,
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ANSARI ET AL TABLE 2. HETEROTOPIC BONE FORMATION IN GASTROINTESTINAL GLANDULAR TUMORS AND/OR THEIR METASTASES*
Age
Sex
Site
Diagnosis
Ossification in primary
Metastases present
Ossification in metastases
59 66 56 72 45 65 63 56 63 66 54 55 66 58 45 58 51 70 32 63 40 44 59 51 48 46 59 51 74 81 69
M M M F F M F M F M M F M M F M F F F M F M F F M M M M M F M
Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Gallbladder Small bowel Appendix Appendix Sigmoid Ascending Cecum Ascending Sigmoid Cecum Sigmoid Rectosigmoid Rectosigmoid Intestine Descending Sigmoid Descending Colon Sigmoid Transverse
Adenoca Adenoca Carcinoid Adenoca Muc adenoca Adenoca Adenoca Muc adenoca Adenoca Adenoca Muc adenoca Adenoca Adenoca Adenoca Mucocele Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Muc adenoca Adenoca Adenoca Adenoca Adenoca Muc adenoca Adenoca Mus adenoca Adenoca Adenoca
+ + + + + + + + + + + + + + + + + NS -
NS NS + + + + + + + + + + NA + NS + + + + + + + + + +
NA NS NS + + + + + + + + + NA NA NA NA NS NA NA + + + + + + + + + +
Reference 1913 1923 1972 1991 1973 1932 1963 1971 1971 1976 1984 1933 1924 1928 1948 1955 1961 1962 1962 1962 1972 1962 1955 1935 1951 1955 1962 1968 1971 1979 1989
G r u b e r (17) H a s e g a w a (in 9) S a m p s e l (18) Alpertt Y a s u m a (19) L a u b m a n n (20) R u t t n e r (in 9) D o m i n o k (in 9) R u t t n e r (in 9) R h o n e (21) R o s e n b a u m (22) Micseh (23) O e h l e c h e r (24) Nishii (in 9) J u v a r a (25) V a n Patter (14) D e l a n e y (26) Hall (27) S h e v a c h (28) Engel (29) Oertel (30) Engel (29) Plenge (in 9) Clark (7) Christie (10) V a n Patter (14) Engel (29) Govoni (31) D o m i n o k (in 9) Calouri (in 9) Randall (32)
*Excluding r e c t u m (see Table 1), Liver, Pancreas. Abbreviations: F, female; M, male; M u c , m u c i n o u s ; A d e n o c a , a d e n o c a r c i n o m a ; N A , not applicable; NS, not stated. t P e r s o n a l observation.
when ossification is detected by either radiographic methods or tissue biopsy, full evaluation of the lesion is indicated. A polypectomy may suffice in the rare cases of ossification in relatively small and benign tumors for which complete colonoscopic excision is possible. However, if biopsy of a large tumor with ossification shows only tubular and/or villous components, the possibility of an underlying malignancy should be seriously considered and further evaluated, since 12 of the 16 reported cases of ossification in rectal glandular mucosal masses occurred in malignant tumors.
represents the twelfth case in the literature of heterotopic bone formation in a primary rectal adenocarcinoma and the first such finding in a colonic biopsy from one of these malignancies. The average age of these patients was 56 years (range 32-72) and the male-to-female ratio was 5:7. The rectum is the most common site of ossification in the gastrointestinal tract. The exact mechanism of heterotopic ossification is unknown, but it is probably the result of metaplasia of fibroblasts. Adenocarcinoma has been associated with 12 of the 16 reported cases of rectal glandular tumors with heterotopic bone.
SUMMARY A case of heterotopic bone formation in a primary rectal adenocarcinoma was recently observed in a 54-year-old woman. This unusual finding was present both in the diagnostic biopsy and in the subsequently resected bowel. Pertinent gross and microscopic f e a t u r e s are p r e s e n t e d . This report 1628
REFERENCES 1. Boring CC, Squires TS, T o n g T: C a n c e r statistics 1991. C A 41:19-36, 1991 2. D u k e s CE: Ossification in rectal cancer. Proc R Soc M e d 32:1489-1494, 1939 3. F u k u o k a T, H o n d a M, Namiki M, T a d a Y, M a t s u d a M,
Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
OSSIFICATION
4.
5.
6.
7. 8.
9.
10. 11. 12. 13.
14. 15. 16. 17. 18. 19.
IN GASTROINTESTINAL
CANCER
Sonada T: Renal cell carcinoma with heterotopic bone formation. Urol Int 42:458-460, 1987 Maeda M, Kanayama M, Uchida T, Hasumura Y, Takeuchi J: A case of hepatocellular carcinoma associated with ossification. Cancer 57:134-137, 1986 An T, Grathwohl M, Frable WJ: Breast carcinoma with osseous metaplasia: An electron microscopic study. Am J Clin Pathol 80:127-132, 1983 Wasiljew BK, Apostol JV, Sambasiva M: Heterotopic ossification in a lymph node with metastatic follicular carcinoma of thyroid. J Surg Oncol 17:45-48, 1981 Clark A: Heterotopic bone formation associated with adenocarcinoma in an abdominal scar. Br J Surg 22:889-890, 1935 Apostolidis NS, Legakis NC, Gregoriadis GC, Androulakakis PA, Romanos AN: Heterotopic bone formation in abdominal operation scars. Am J Surg 142:555-559, 1981 Caluori D, Gallo P: Case report of heterotopic bone formation in metastatic carcinoma of the colon. Tumori 65:345351, 1979 Christie AC: Ossification in intestinal neoplasms: A report of three cases. J Pathol Bacteriol 63:338-340, 1951 Urbanke A: Heterotopic ossification in rectal carcinoma. Gastroenterologia 98:48-53, 1962 Byard RW, Thomas MJ: Osseous metaplasia within tumors. A review of 11 cases. Ann Pathol 8:64-66, 1988 Senturia HR, Schechter SE, Hulbert B: Heterotopic ossification in an area of metastasis from rectal carcinoma. Am J Roentgenol 60:507-510, 1948 Van Patter HT, Whittick JW: Heterotopic ossification in intestinal neoplasms. Am J Pathol 31:73-91, 1955 Sperling MH, Friedman CJ: Osseous metaplasia in a benign colon polyp. Gastrointest Endosc 27:198-199, 1981 Groisman G: Osseous metaplasia occurring in a benign colonic polyp. Am J Gastroenterol 86:930-931, 1991 Gruber GB: Knochenbildung in einem magenkarzinom. Beitr Pathol Anat 55:368-370, 1913 Sampsel JW, Callaway F: Gastric carcinoid with ossification. Am J Surg 124:108-111, 1972 Yasuma T, Hashimoto K, Miyazawa R, Hiyama Y: Bone formation and calcification in gastric cancer. Acta Path Jpn 23:155-172, 1973
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20. Laubmann W: Beitrag zur osteoplastischen carcinose. Virchows Arch (Pathol Anat) 285:168-181, 1932 21. Rhone DP, Horowitz RN: Heterotopic ossification in the pulmonary metastases of gastric adenocarcinoma. Cancer 38:1773-1780, 1976 22. Rosenbaum LH, Nicholas JJ, Slasky BS, Obley DL, Ellis LD: Malignant myositis ossificans: Occult gastric carcinoma presenting as an acute rheumatic disorder. Ann Rheum Dis 43:95-97, 1942 23. Micseh G: Knochenbildung im gallenblasenkrebs und in seinen metastasen. Frankfurt Z Pathol 44:430-438, 1933 24. Oehlecher: Dundarmkazinom mit echter knochenbildung. Dtsch Med Wochenschr 50:98, 1924 25. Juvara I, Borcescu U: Heterotopic ossification of an appendicular mucocele. Brit Med J 1:931-933, 1948 26. Delaney WE, Graham TF: Carcinoma of the colon with ossification. Gastroenterology 41:277-280, 1961 27. Hall CW: Calcification and osseous metaplasia in carcinoma of colon. J Can Assoc Radiol 13:135-139, 1962 28. Schevach MR: Calcification and ossification in a mucinous adenocarcinoma of the colon: Report of case. Am J Dig Dis 7:356-359, 1962 29. Engel S, Dockerty MB: Calcification and ossification in rectal malignant processes. JAMA 179:347-350, 1962 30. Oertel WH: Ektopische knochenbildung in einem karzinom des coecums. Zentralbl Allg Pathol 115:253-258, 1972 31. Govoni AF, Alcantara AN: Ossifying metastatic carcinoma of the colon. Am J Roentgenol 104:561-565, 1968 32. Randall JC, Morris DC, Tomita T, Anderson HC: Heterotopic ossification: A case report and immunohistochemical observations. Hum Pathol 20:86-88, 1989 33. Bettendorf U, Remmele W, Laaff H: Bone formation by cancer metastases. Virchows Arch A Pathol Anat Histol 369:359-365, 1976 34. Werner B, Dahm K, Breucker H: Ossification in cancer of the stomach. Z Krebsforsch 86:147-154, 1976 35. Anderson HC: Osteogenetic epithelial-mesenchymal cell interactions. Clin Orthop 119:211-224, 1976 36. Anderson HC: Biology of disease: Mechanism of mineral formation in bone. Lab Invest 60:320-330, 1989
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CASE REPORT
Heterotopic Bone Formation in Rectal Carcinoma Case Report and Literature Review KEY WORDS:
M.Q. A N S A R I , I.L. S A C H S , E. M A X , and L.C. A L P E R T adenocarcinoma; ossification; gastrointestinal tract.
An estimated 45,500 new cases of rectal adenocarc i n o m a w e r e e x p e c t e d in the United States in 1991 (1). Despite the high incidence of these tumors, ossification within rectal a d e n o c a r c i n o m a s is an e x t r e m e l y rare condition. D u k e s first reported heterotopic bone formation in four cases of rectal a d e n o c a r c i n o m a in 1939 (2). Since then, heterotopic bone formation has been reported in kidneys (3), liver (4), breast (5), thyroid (6), skin and soft tissues (7, 8), and in additional malignancies of the gastrointestinal tract (9-32). Ossification in gastric (20) and renal (3) carcinomas, as well as in metastatic disease (9, 13, 33), has been reviewed recently. It also has b e e n reported in benign tumors and surgical scars (7, 8, 12, 15, 16). Ossification within rectal a d e n o c a r c i n o m a s , although the m o s t c o m m o n gastrointestinal malign a n c y with ossification, has not b e e n reviewed separately. Therefore, we report this case with literature review, discuss the pathogenetic mechanisms for ossification in this setting, and consider its potential clinical significance. CASE R E P O R T A 54-year-old white woman presented with a fivemonth history of frequent diarrhea, and mucus-filled stools. Her hematocrit was 43.2 and her stools were guaiac positive. At sigmoidoscopy, a 2 • 2-cm polypoid mass was found in the rectum, located about 7 cm from the anal verge. A biopsy of the lesion revealed a welldifferentiated adenocarcinoma with heterotopic ossificaManuscript received January 25, 1991; revised manuscript received December 11, 1991; accepted December 11, 1991. From the Departments of Pathology, Internal Medicine and Surgery, Baylor College of Medicine and The Methodist Hospital, Houston, Texas. Address for reprint requests: Dr. L.C. Alpert, Pathology Rm G-100, Jewish General Hospital, 3755 Cote St-Catherine Road, Montreal, Quebec, Canada H3T 1E2.
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tion (Figure 1). Complete colonoscopy showed an additional villous a d e n o m a , tubular a d e n o m a , and hyperplastic polyp located in the ascending, transverse, and sigmoid colon, respectively. Neither calcification nor ossification was found in these three lesions. No metastatic disease was found on CT scan of the abdomen. Because of the large size of the rectal tumor and its location, the patient received preoperative radiation therapy consisting of 4500 rads. This was delivered to the primary tumor and regional lymph nodes in 25 fractions over 43 days with a four-field technique and custom blocking. Four months after presentation she underwent surgery. During the initial intraoperative evaluation of the abdomen, a single 1-cm nodule was found in and excised from the superficial left hepatic lobe. This nodule was shown by frozen section to be metastatic adenocarcinoma consistent with a colonic primary. A low anterior resection of the rectosigmoid was then performed. The patient did well and was discharged on the 10th postoperative day. Pathology. The initial rectal biopsy showed a welldifferentiated adenocarcinoma with focal necrosis and heterotopic bone formation (Figure 1). The resected 25 cm of rectosigmoid contained a 3.2 x 2.3 • 0.6-cm raised pink granular mass with an eccentrically located round 0.4-cm-diameter ulcer (Figure 2A). Cross sections following fixation showed that the ulcer undermined the mucosa and solid tan tumor extended into subserosal adipose tissue (Figure 3A). Focal calcification was appreciated by localized grittiness. The tumor did not extend to the soft tissue resection margins. The resected specimen was x-rayed intact (Figure 2B) and again following fixation and cross-sectioning because the preceding biopsy was known to contain heterotopic bone (Figure 3B). A distinct and localized snowy pattern of calcification was demonstrated in the tumor at the edge of the ulcer. Microscopically, the tumor consisted of a villous tumor peripherally with progression to invasive, well-differentiated adenocarcinoma. The carcinoma invaded through the muscular wall into subserosal fat and in many areas consisted of pools of mucin with a small number of free-floating malignant cells. Heterotopic bone was located within areas of viable tumor and adjacent to the Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
0163-2116/92/1000-1624506.50/0 9 1992 Plenum Publishing Corporation
OSSIFICATION IN G A S T R O I N T E S T I N A L CANCER
Fig 1. Ossification in biopsyof rectal adenocarcinoma consists of several irregular islands of immature bone (small arrows) that focally abut malignant epithelium (large arrows). The stroma is acutely inflamed with an area of necrosis and nuclear debris shown in the upper right corner. (Bar = 50 p,m.)
ulcer (Figure 4). The bone was immature with osteoblasts surrounding irregularly deposited osteoid as shown by the irregular refractile pattern of collagen on polarization. No bone marrow was found. Five pericolic lymph nodes were recovered from the mesentery. No metastatic tumor was found within them. However, two foci of densely sclerotic tissue measuring 2.0 and 1.8 cm were found in the mesentery. Microscopically, these consisted of a small number of tumor cells in a markedly desmoplastic stroma and probably represented nodal metastases with radiation-induced sclerosis, No ossification was found in these lesions. Additional metastatic disease was documented in the portion of liver excised initially for frozen section. No ossification was found in this lesion either. DISCUSSION A d e n o c a r c i n o m a o f the r e c t u m is a n e x t r e m e l y c o m m o n l e s i o n b u t c o i n c i d e n t a l h e t e r o t o p i c ossific a t i o n is d e c i d e d l y rare. I n o u r r e v i e w w e f o u n d Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
Fig 2. (A) Adenocarcinoma in the distal portion of resected rectosigmoid, gross photograph. Raised 3.2 • 2.3-cm tumor with eccentrically located ulcer (asterisk) extends to within 1.5 cm of the distal margin (bottom). (Bar = 2.7 mm.) (B) X-ray of distal portion of resected rectosigmoid. Note localized lacelike calcification that indicates distribution of ossified tissue (arrow). Adjacent irregular radiolucent area (asterisk) corresponds to the ulcer, A and B are taken at approximately the same magnification. (Bar = 2.7 ram.)
o n l y 52 c a s e s o f h e t e r o t o p i c o s s i f i c a t i o n i n v o l v i n g gastrointestinal tract glandular tumors (excluding p a n c r e a s a n d liver) ( T a b l e s 1 a n d 2). M o s t o f t h e s e cases c o n s i s t e d o f p r i m a r y a d e n o c a r c i n o m a s a n d the single m o s t c o m m o n site w a s the l o w e r gastro-
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ANSARI ET AL
Fig 3. (A) Cross-sections of the large bowel tumor show the slightly villous configuration of the surface (between the asterisks) and the central ulcer. Adenocarcinoma grossly infiltrates the muscular wall (arrow) (Bar = 3 mm.) (B) X-ray of crosssection of rectal mass shows the delicate pattern of calcification (arrow) located adjacent to the ulcer. (Bar = 3 mm.)
intestinal tract where Dukes suggested an incidence of below 0.4% for ossification in rectal adenocarcinomas (2). We found only 20 other cases of rectal glandular tumors with ossification* either in the primary rectal lesion (15 cases), metastases (six cases), or at both sites (one case), and all but four were associated with adenocarcinoma. These cases are summarized in Table 1. For the malignant cases with ossification in the primary, the male-to-female ratio was 5:7 and the ages ranged from 32 to 72, with a mean of 56 years. Several cases also had heterotopic ossification in local recurrences (2, 10, 13) or in metastasic sites (lungs, pelvic wall, lymph nodes, laparotomy site) (7, 9, 14). Ossification has also been reported in four benign rectal tumors two of which were classified as juvenile polyps (12, 15), one as a tubular adenoma (12), and another as a tubulovillous adenoma (16). *We have limited our review of cases with ossification to those with pathological confirmation. We note for those interested in the radiologic literature that some additional cases referred to as demonstrating ossification are based solely on the pattern of calcification in the x-rays.
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Fig 4. Ossification (arrows) adjacent to the ulcer bed (center right) of the well-differentiated invasive adenocarcinoma. Abundant mucin accumulation is seen (asterisk). The superficial villous component is present along the surface (top left). Muscularis propria is at bottom. Note how the ulcer undermines the mucosa. (Bar = 0.12 mm.)
For comparison of incidence and location, the cases of ossification in glandular tumors in other gastrointestinal sites are also summarized (Table 2). Some authors have commented on the young age of the patients in whom rectal adenocarcinoma with ossification has occurred. From Table 1 it is evident, however, that ossified tumors have been neither consistently nor predominantly associated with youth. Several reports have noted less aggressive behavior of some of these tumors, but this also has not been a consistent observation, and most of the tumors have been well or moderately differentiated, when grade was reported. Metaplasia of the local mesenchymal tissue is probably responsible for bone formation in neoplasms. Although Plenge (in 9) suggested that tumor cells undergo osseous metaplasia, there is little Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
OSSIFICATION IN GASTROINTESTINAL CANCER TABLE 1. OSSIFICATION IN RECTAL GLANDULAR TUMORS AND/OR THEIR METASTASES*
Case
Age
Malignant 1 32 2 63 3 69 4 70t 5 37 6 44 7 55 8 64 9 55 10 72 11 54 12 59 13 51 14 53 15 55 16 17 Benign 1 2 3 4
Sex
Diagnosis
Ossification in primary
Metastases present
Ossification in metastases NA NA NS NS NS NS NS NS NA NS + + + NA + + +
1939 1939 1939 1939 1939 1951 1923 1923 1962 1988 1992 1955 1935 1939 1949
NA NA NA NA
1981 1988 1988 1991
F F M F M F M M F M F F F M M
Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca
+ + + + + + + + + + + + NS -
43 43
F M
Adenoca Adenoca
NS -
NS NS NS + NS NS NS + + + + - at A P resection + at a u t o p s y + +
25 28 58 67
M M M M
Juvenile polyp Juvenile polyp Tubular a d e n o m a Tubulovillous a d e n o m a
+ + + +
NA NA NA NA
Reference D u k e s (2) D u k e s (2) D u k e s (2) Scheideggar (in 9) Scheideggar (in 9) Christie (10) H a s e g a w a (in 9) H a s e g a w a (in 9) U r b a n k e (11) B y a r d (12) Ansari (current case) Plenge (in 9) Clark (7) D u k e s (2) Senturia (13)
1951 Christie (10) 1955 V a n Patter (14) Sperling (15) B y a r d (12) B y a r d (12) G r o i s m a n (16)
*Abbreviations, F, female; M, male; A d e n o c a , A d e n o c a r c i n o m a ; N A , not applicable; NS, not specified; AP, anteriorperineal. t P a t i e n t at a u t o p s y h a d concurrent ossification in m a m m a r y fibroadenoma and gastric leiomyoma.
evidence to support this theory. Byard and Thomas (12) discounted Plenge's hypothesis because they did not see any intermediate stage between the neoplastic cells and the osteoblasts in the two tumors that they examined ultrastructurally. Furthermore, in experimental models in rats, Werner et al (34) have shown the different stages of heterotopic bone formation quite clearly from fibroblast through osteoblast in tumors of the gastric stump. The stimulus for transformation of the fibroblast to an osteoblast is, however, incompletely understood (35, 36). When the bone is intimately associated with the cancer cells, it might be inferred that some factor from the malignant cells alters the environment and induces the metaplasia. However, no chemical factor able to induce osseous metaplasia has yet been isolated from tumor cells. Randall et al (32), having shown the presence of alkaline phosphatase (bone-liver-kidney isoenzyme) in osteoblasts and surrounding mesenchymal cells in a case of rectal adenocarcinoma, consider that alkaline phosphatase may play a role in neoplastic ossification similar to that in the normal skeleton (35, 36). Ischemia may be a predisposing factor to tumorassociated ossification. The site of ossification in stomach cancers is cited in support of this, since Digestive Diseases and Sciences, Vol. 37, No. 10 (October 1992)
ossification usually occurs in the least perfused part of the stomach wall. Fukuoka et al (3), reviewing ossification in kidney tumors, found that five of their six examples (83%) were hypovascular, whereas most renal cell carcinomas (75-85%) are hypervascular. Therefore, they hypothesized " a causal relationship between ischemic degeneration and heterotopic bone formation." A causal relationship with necrosis has been suggested by Dukes (2) and others but is apparently not a prerequisite factor, since Byard et al (12) found that ossification could occur in the absence of necrosis, inflammation, extracellular mucin production, preexisting calcification, and preexisting stromal hypervascularity. Nevertheless, these may be contributory factors, and both mucin production and necrosis were present in our case. In summary, we report a 54-year-old woman with heterotopic ossification present together with adenocarcinoma in a biopsy of a rectal tumor. The mechanism for ossification in this site is not well understood. The rectum is the most frequent gastrointestinal site where tumor associated ossification occurs, although overall, ossification in rectal adenocarcinomas is rare with this being only the twelfth case reported with pathologic documentation in the literature reviewed. We conclude that,
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ANSARI ET AL TABLE 2. HETEROTOPIC BONE FORMATION IN GASTROINTESTINAL GLANDULAR TUMORS AND/OR THEIR METASTASES*
Age
Sex
Site
Diagnosis
Ossification in primary
Metastases present
Ossification in metastases
59 66 56 72 45 65 63 56 63 66 54 55 66 58 45 58 51 70 32 63 40 44 59 51 48 46 59 51 74 81 69
M M M F F M F M F M M F M M F M F F F M F M F F M M M M M F M
Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Gallbladder Small bowel Appendix Appendix Sigmoid Ascending Cecum Ascending Sigmoid Cecum Sigmoid Rectosigmoid Rectosigmoid Intestine Descending Sigmoid Descending Colon Sigmoid Transverse
Adenoca Adenoca Carcinoid Adenoca Muc adenoca Adenoca Adenoca Muc adenoca Adenoca Adenoca Muc adenoca Adenoca Adenoca Adenoca Mucocele Adenoca Adenoca Adenoca Adenoca Adenoca Adenoca Muc adenoca Adenoca Adenoca Adenoca Adenoca Muc adenoca Adenoca Mus adenoca Adenoca Adenoca
+ + + + + + + + + + + + + + + + + NS -
NS NS + + + + + + + + + + NA + NS + + + + + + + + + +
NA NS NS + + + + + + + + + NA NA NA NA NS NA NA + + + + + + + + + +
Reference 1913 1923 1972 1991 1973 1932 1963 1971 1971 1976 1984 1933 1924 1928 1948 1955 1961 1962 1962 1962 1972 1962 1955 1935 1951 1955 1962 1968 1971 1979 1989
G r u b e r (17) H a s e g a w a (in 9) S a m p s e l (18) Alpertt Y a s u m a (19) L a u b m a n n (20) R u t t n e r (in 9) D o m i n o k (in 9) R u t t n e r (in 9) R h o n e (21) R o s e n b a u m (22) Micseh (23) O e h l e c h e r (24) Nishii (in 9) J u v a r a (25) V a n Patter (14) D e l a n e y (26) Hall (27) S h e v a c h (28) Engel (29) Oertel (30) Engel (29) Plenge (in 9) Clark (7) Christie (10) V a n Patter (14) Engel (29) Govoni (31) D o m i n o k (in 9) Calouri (in 9) Randall (32)
*Excluding r e c t u m (see Table 1), Liver, Pancreas. Abbreviations: F, female; M, male; M u c , m u c i n o u s ; A d e n o c a , a d e n o c a r c i n o m a ; N A , not applicable; NS, not stated. t P e r s o n a l observation.
when ossification is detected by either radiographic methods or tissue biopsy, full evaluation of the lesion is indicated. A polypectomy may suffice in the rare cases of ossification in relatively small and benign tumors for which complete colonoscopic excision is possible. However, if biopsy of a large tumor with ossification shows only tubular and/or villous components, the possibility of an underlying malignancy should be seriously considered and further evaluated, since 12 of the 16 reported cases of ossification in rectal glandular mucosal masses occurred in malignant tumors.
represents the twelfth case in the literature of heterotopic bone formation in a primary rectal adenocarcinoma and the first such finding in a colonic biopsy from one of these malignancies. The average age of these patients was 56 years (range 32-72) and the male-to-female ratio was 5:7. The rectum is the most common site of ossification in the gastrointestinal tract. The exact mechanism of heterotopic ossification is unknown, but it is probably the result of metaplasia of fibroblasts. Adenocarcinoma has been associated with 12 of the 16 reported cases of rectal glandular tumors with heterotopic bone.
SUMMARY A case of heterotopic bone formation in a primary rectal adenocarcinoma was recently observed in a 54-year-old woman. This unusual finding was present both in the diagnostic biopsy and in the subsequently resected bowel. Pertinent gross and microscopic f e a t u r e s are p r e s e n t e d . This report 1628
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OSSIFICATION
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20. Laubmann W: Beitrag zur osteoplastischen carcinose. Virchows Arch (Pathol Anat) 285:168-181, 1932 21. Rhone DP, Horowitz RN: Heterotopic ossification in the pulmonary metastases of gastric adenocarcinoma. Cancer 38:1773-1780, 1976 22. Rosenbaum LH, Nicholas JJ, Slasky BS, Obley DL, Ellis LD: Malignant myositis ossificans: Occult gastric carcinoma presenting as an acute rheumatic disorder. Ann Rheum Dis 43:95-97, 1942 23. Micseh G: Knochenbildung im gallenblasenkrebs und in seinen metastasen. Frankfurt Z Pathol 44:430-438, 1933 24. Oehlecher: Dundarmkazinom mit echter knochenbildung. Dtsch Med Wochenschr 50:98, 1924 25. Juvara I, Borcescu U: Heterotopic ossification of an appendicular mucocele. Brit Med J 1:931-933, 1948 26. Delaney WE, Graham TF: Carcinoma of the colon with ossification. Gastroenterology 41:277-280, 1961 27. Hall CW: Calcification and osseous metaplasia in carcinoma of colon. J Can Assoc Radiol 13:135-139, 1962 28. Schevach MR: Calcification and ossification in a mucinous adenocarcinoma of the colon: Report of case. Am J Dig Dis 7:356-359, 1962 29. Engel S, Dockerty MB: Calcification and ossification in rectal malignant processes. JAMA 179:347-350, 1962 30. Oertel WH: Ektopische knochenbildung in einem karzinom des coecums. Zentralbl Allg Pathol 115:253-258, 1972 31. Govoni AF, Alcantara AN: Ossifying metastatic carcinoma of the colon. Am J Roentgenol 104:561-565, 1968 32. Randall JC, Morris DC, Tomita T, Anderson HC: Heterotopic ossification: A case report and immunohistochemical observations. Hum Pathol 20:86-88, 1989 33. Bettendorf U, Remmele W, Laaff H: Bone formation by cancer metastases. Virchows Arch A Pathol Anat Histol 369:359-365, 1976 34. Werner B, Dahm K, Breucker H: Ossification in cancer of the stomach. Z Krebsforsch 86:147-154, 1976 35. Anderson HC: Osteogenetic epithelial-mesenchymal cell interactions. Clin Orthop 119:211-224, 1976 36. Anderson HC: Biology of disease: Mechanism of mineral formation in bone. Lab Invest 60:320-330, 1989
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