Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Tsubosa, Y
Right arrow Articles by Ushio, K
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsubosa, Y
Right arrow Articles by Ushio, K
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Japanese Journal of Clinical Oncology Pages 42-46

Breast Cancer in Cowden's Disease: a Case Report with Review of the Literature
Introduction
Case Report
Discussion
References

Breast Cancer in Cowden's Disease: a Case Report with Review of the Literature

Breast Cancer in Cowden's Disease: a Case Report with Review of the Literature Yasuhiro Tsubosa1, Takashi Fukutomi1, Hitoshi Tsuda2, Yae Kanai2, Sadako Akashi-Tanaka1, Takeshi Nanasawa1, Gen Linuma3 and Kyousuke Ushio3

1Department of Surgical Oncology, National Cancer Center Hospital, 2Pathology Division, National Cancer Center Research Institute and 3Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan

We report a case of invasive breast cancer in a 62-year-old female patient with Cowden's disease. A left modified radical mastectomy was performed and histopathology of the tumor showed invasive ductal carcinoma, histological grade 3, without lymph node metastasis. The patient had a past history of endometrial cancer at 55 but did not have a family history of malignant disease. Goiter was palpable but aspiration cytology revealed no malignancy. There were several papillomas on the oral mucosa and multiple papillomatous lesions on the right femur. Barium X-ray and endoscopic examination revealed multiple, small, hyperplastic polypoid lesions on the esophagus, stomach and rectum. Histopathology of the biopsy specimens from the esophagus and stomach showed acanthotic squamous epithelium and foveolar hyperplastic polyps. The patient was followed up closely to monitor the thyroid lesions and polyposis of the digestive tract. A total of 12 breast cancer patients who also had Cowden's disease have been reported in Japan and these cases are reviewed in this report.

Key words: Cowden's disease - breast cancer - endometrial cancer - goiter

INTRODUCTION

The most consistent clinical features of Cowden's disease include facial trichilemmomas (flesh-colored papules), oral papillomas and fibromas and acral papillomatous lesions. Internal abnormalities described in Cowden's disease include goiter, hypothyroidism, thyroid adenoma, genitourinary tumors or malformations, gastrointestinal polyps and breast disease. Cowden's disease is a multiple hamartoma syndrome with an autosomal dominant-inheritance pattern, which is associated with an increased susceptibility to malignancies (1-7). There have been few reports, however, of breast cancer in Cowden's disease in Japan (8-15). We report a case of invasive breast carcinoma in a 62-year-old woman with Cowden's disease, who also had a previous history of cancer of the uterus, and review the literature.

CASE REPORT

A 62-year-old woman developed a lump, ~2.5 cm in diameter, in the upper outer quadrant of the left breast and presented at the regional clinic. She had first noticed the tumor 3 months previously although there was no associated nipple discharge. Her menarche had occurred when she was 14 years old and her menopause at 52. She had married at 27 and had had two children. Her medical history included multiple papillomatous lesions of the right femur from the age of 10 years, multiple polypoid lesions of the stomach and esophagus when she was 42 years old and goiter from 52 years of age. When she was 55 years old she had undergone a hysterectomy at another hospital because of Stage II endometrial cancer. Histopathological examination of the uterine tumor had revealed a well-differentiated adenocarcinoma infiltrating into the myometrium but without adnexal invasion. The patient did not smoke or drink alcohol and there was no family history of malignant disease or Cowden's disease. Excisional biopsy of the left breast tumor was performed at the regional clinic. Histopathological examination of this tumor showed invasive ductal carcinoma, histological grade 3, without lymphatic or vascular invasion by tumor cells. The patient was admitted to the National Cancer Center Hospital for radical surgery.


Figure 1. Papillomas on the oral mucosa (gingiva).


Figure 2. Multiple papillomatous lesions on the right femur.


Figure 3. Flesh-colored papules on the right lids.


Figure 4.X-ray of the neck showing coarse calcifications.


Figure 5. Double contrast upper gastrointestinal series showing multiple small polypoid lesions on the esophagus (a), stomach (b) and rectum (c).

Physical examination on admission showed no residual breast mass or lymph node swelling in the axillae, neck or supraclavicular regions. A soft, movable nodule, 4.0 cm in diameter, was palpable in the anterior part of the neck and was suggestive of goiter. There were several papillomas on the oral mucosa (Fig. 1), multiple papillomatous lesions on the right femur (Fig. 2) and flesh-colored papules on the right lids (Fig.3 ). The RBC count was 437 × 104/mm3 and the Hb level 13.4 g/dl. The WBC count was 9500/mm3. The level of total protein was 6.4 g/dl, the total bilirubin level was 0.5 mg/dl, the GOT level was 11 IU/l (normal range <28 IU/l) and the GPT level was 10 IU/l (normal range <26 IU/l). The serum levels of CEA, CA15-3 and ST-439 were within normal limits at 5.0 ng/ml, 28 U/ml and 4.5 U/ml, respectively. Although the serum levels of TSH, T3, T4 and free-T4 were all within normal ranges (0.3-2.6 µIU/ml, 115-204 ng/dl, 5.3-10.4 µg/dl and 0.7-1.7 ng/dl, respectively), the serum thyroglobulin level (167 ng/ml) was well above the normal range (<45 ng/ml). Mammography and ultrasonography of the breast showed no abnormalities. An X-ray and ultrasonogram of the neck disclosed diffuse swelling of the thyroid gland with coarse calcifications (Fig. 4), which was suspicious of cancer of the thyroid. Aspiration cytology of the thyroid lesion, however, showed no malignancy. Barium X-ray examination revealed multiple small polypoid lesions on the esophagus, stomach and rectum (Fig. 5). Endoscopic examination revealed multiple hyperplastic keratosis of the esophagus and numerous small polypoid lesions on the stomach (Fig. 6). The histopathology of the biopsy specimens from the esophagus and stomach showed acanthotic squamous epithelium and foveolar hyperplastic polyps. Based on these clinical findings, the patient was diagnosed with breast cancer in association with Cowden's disease.


Figure 6. Endoscopic view showing hyperplastic keratosis of the esophagus (a) and polyposis of the gastric antrum (b).

Modified radical mastectomy (Auchincloss' mode) was performed. Axillary lymph nodes were free of disease on pathological examination. The estrogen and progesterone receptor status of the tumor was unknown because there was no residual tumor in the mastectomy specimen for testing. It was decided to follow up the patient closely to monitor the thyroid lesions and polyposis of the digestive tract. The patient is currently well 4 months after surgery, without adjuvant therapy.

Table 1. Cases of breast cancer in association with Cowden's disease in Japan
Case Age at surgery Skin and oral mucosal lesions Digestive tract polyposis Goiter Family history
Malignant disease Cowden's disease
1 Rt Breast ~37 + - + + +
2 Lt Breast ~47 Gastric ~48 + + + + -
3 Rt Breast ~48 Gastric ~60 + + + - -
4 Bil. Breast ~53 Thyroid ~53 + + + Unknown Unknown
5 Lt Breast ~36Rt Breast ~38 + Unknown + Unknown Unknown
6 Thyroid ~31Bil. Breast ~41 + + + Unknown Unknown
7 Rt Breast ~46 + + Unknown + -
8 Lt Breast ~40 + + + + Unknown
9 Lt Breast ~43Rt breast ~51 Cervical ~54 + + Unknown Unknown Unknown
10* Lt Breast ~53 + + + + -
11* Rt Breast ~36 + + + + -
12*[dagger] Endometrial ~55Lt Breast ~62 + + + - -
*Treated at the National Cancer Center Hospital; [dagger]this case.

DISCUSSION

Cowden's disease is a rare condition characterized by the presence of multiple hamartoma (6,7,16-18) and has been reported to be associated with an increased incidence of breast cancer (1-3). There have been 11 breast cancer diagnoses in nine patients with Cowden's disease reported previously in Japan (8-15) and we have seen a further three cases in this hospital (Table 1). The average age of these patients at surgery was 43.2 years, indicating early onset of breast cancer in patients with Cowden's disease. Bilateral breast cancers were observed in four (33%) of the 12 cases which have been reported. Early onset and a bilateral occurrence are important characteristics of hereditary breast cancers, which may indicate that breast cancer in patients with Cowden's disease is also hereditary.

Multiple primary cancers were observed in six (50%) cases, including two cases of thyroid cancer, two cases of gastric cancer and two cases of cancer of the uterus. Goiter is also common in patients with Cowden's disease. Ten (83%) patients had thyroid disease, including eight follicular adenomas and two carcinomas. Abnormalities of the gastrointestinal tract, including the presence of polyps, were reported in 41% of patients with Cowden's disease. However, there have been few reports of associated carcinomas of the stomach or colon. In the Japanese cases, digestive tract polyposis was confirmed in 10 (83%) patients; there is a possibility that the two gastric cancers were coincidental. Genitourinary cancers were noted in 55% of female patients with Cowden's disease. Our patient had suffered from cancer of the uterus 7 years previously but histopathologically her breast carcinoma appeared to be a primary cancer. It is important that this patient should have periodic check-ups for other malignant tumors. Regular breast and gynecological examinations are important for patients with Cowden's disease.

One-third of patients with Cowden's disease have been reported to have a family history of the disease (19). This patient had no family history of malignant disease or Cowden's disease. Recently, Nelen et al. (1) reported that the putative gene for Cowden's disease could be localized to chromosome 10q22-23, using linkage analysis of 12 affected families. They also documented that the major breast cancer susceptibility genes, BRCA1 and BRCA2, might not play important roles in Cowden's disease (1). The differential loss of heterozygosity in the Cowden locus was observed in sporadic thyroid follicular adenomas (5). Although this Cowden locus seems to be a breast cancer susceptibility gene, the pathogenetic role of the locus is still unclear (3).

In summary, we suggest that recognition of Cowden's disease may facilitate the early diagnosis of cancer. Further work to investigate the mechanisms of cancer development in this condition is important.

References

1. Nelen MR, Padberg GW, Peeters EAJ, Lin AY, van den Helm B, Frants RR,et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nature Genet 1996;13:114-6. MEDLINE Abstract

2. Brownstein MH, Wolf M, Bikowski JB. Cowden's disease: A cutaneous marker of breast cancer. Cancer 1978;41:2393-8. MEDLINE Abstract

3. Greene MH. Genetics of breast cancer. Mayo Clin Proc 1997;72:54-65. MEDLINE Abstract

4. Lloyd KM, Dennis M. Cowden's disease: A possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58:136-42.

5. Marsh DJ, Zheng Z, Zedenius J, Kremer H, Padberg GW, Larsson C,et al.Differential loss of heterozygosity in the region of the Cowden locus within 10q22-23 in follicular thyroid adenomas and carcinomas. Cancer Res 1997;57:500-3. MEDLINE Abstract

6. Bardenstein DS, McLean IW, Nerney J, Boatwright RS. Cowden's disease. Ophthalmology 1988;95:1038-41. MEDLINE Abstract

7. Camisa C, Bikowski JB, McDonald SG. Association with squamous cell carcinoma of the tongue and perianal basal cell carcinoma. Arch Dermatol 1984;120:677-8. MEDLINE Abstract

8. Kawamura T, Matsumoto S, Kouno S, Kawaguchi S. Cowden's disease. Hihubyou Shinryou 1984;6:703-6 (in Japanese).

9. Tsuyuki A, Fujishiro Y, Amano H, Ohashi S, Harada R, Hosoda Y. Cowden's disease (multiple hamartoma syndrome) with gastric carcinoma: a case report. Saishiu Igaku 1986;41:1666-72 (in Japanese).

10. Kosaka M, Ishiguro N, Higaki Y, Kawashima M, Hidano A, Oochi T. A case of Cowden's disease. Rinshou Hihuka 1990;44:197-201 (in Japanese).

11. Suzuki A, Ogawa S, Takeda Y, Takeda R. Cowden's disease. Nippon Rynshou 1991;49:2932-7 (in Japanese).

12. Sakurai O, Kikuchi H, Nakazaki T, Sasaki E, Nakayoshi A, Fujita R,et al.Synchronous bilateral breast cancer in Cowden's disease. J Jpn Soc Clin Surg 1991;52:314 (in Japanese).

13. Yokota M, Matsuba S, Tsuji T. A case of Cowden's disease. Rinshou Hihuka 1992;46:471-3 (in Japanese).

14. Sumioka M, Watanabe C, Yamada H, Fujii Y, Koike N, Hata J,et al. Nippon Shoukakibyou Gakkai Zasshi 1994;91:2219-24 (in Japanese).

15. Kunitomo K. Cowden disease and breast cancer. In: Abe R, Nomizu T, Tsuchiya A, editors. Familial Breast Cancer. Tokyo: Shinohara, 1996;141-8.

16. Carlson GJ, Nivatvongs S, Snover DC. Colorectal polyps in Cowden's disease (multiple hamartoma syndrome). Am J Surg Pathol 1984;8:763-70. MEDLINE Abstract

17. Gold BM, Bagla S, Zarrabi MH. Radiologic manifestations of Cowden disease. Am J Roentgenol 1980;135:385-7.

18. Hauser H, Ody B, Plojoux O, Wettstein P. Radiological findings in multiple hamartoma syndrome (Cowden disease). Radiology 1980;137:317-23. MEDLINE Abstract

19. Weary PE, Gorlin RJ, Gentry WC, Comer JE, Greer KE. Multiple hamartoma syndrome (Cowden's disease). Arch Dermatol 1972;106:682-90. MEDLINE Abstract

Received June 16, 1997; accepted August 28, 1997
For reprints and all correspondence: Takashi Fukutomi, Department of Surgical Oncology, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan
Abbreviations: RBC, red blood cells; WBC, white blood cells; GOT, glutamic oxaloacetic transaminase; CEA, carcinoembryonic antigen; CA15-3, carbohydrate antigen 15-3

This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1998.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Tsubosa, Y
Right arrow Articles by Ushio, K
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsubosa, Y
Right arrow Articles by Ushio, K
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?