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Premalignant and In Situ Breast Disease: Biology and Clinical Implications

Grazia Arpino, MD; Rodolfo Laucirica, MD; and Richard M. Elledge, MD
[+] Article, Author, and Disclosure Information

From Baylor College of Medicine, The Methodist Hospital, and Ben Taub General Hospital, Houston, Texas.

Grant Support: In part by National Institutes of Health grants P01 CA30195 and P50 CA58183, SPORE Career Development Award, and U-19 CA86809.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Richard M. Elledge, MD, 6550 Fannin Street, Suite 701, Houston, TX 77030; e-mail, relledge@breastcenter.tmc.edu.

Current Author Addresses: Drs. Arpino and Elledge: Breast Care Center, Baylor College of Medicine and The Methodist Hospital, One Baylor Plaza, Houston, TX 77030.

Dr. Laucirica: Department of Pathology, Baylor College of Medicine and Ben Taub General Hospital, 1504 Taub Loop, Houston, TX 77030.

Ann Intern Med. 2005;143(6):446-457. doi:10.7326/0003-4819-143-6-200509200-00009
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Most types of invasive breast cancer are thought to evolve over long periods from specific preexisting benign lesions. Of the many types of benign entities found in the human breast, only a few have clinically significant premalignant potential. Currently, the best-characterized premalignant lesions are atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ. Ductal carcinoma in situ is considered to be a preinvasive malignant lesion. Two additional lesions, unfolded lobules and usual ductal hyperplasia, are sometimes considered to be very early premalignant epithelial abnormalities. Premalignant lesions are currently defined by their histologic features, and not all necessarily progress to invasive cancer. This suggests that although lesions within specific categories look alike, they must possess underlying genetic differences that cause some to remain stable and others to advance. The development of modern molecular genetic techniques has allowed breast cancer researchers to clarify the multistep model of breast carcinogenesis. Recent studies indicate that cancer evolves by highly diverse genetic mechanisms, and research into these altered pathways may identify specific early defects that might be targeted to prevent progression of premalignant lesions to invasive cancer. Current clinical management is heterogeneous and depends on histologic examination and individual patient factors. Options for breast cancer risk reduction and prevention are available.


Grahic Jump Location
Proposed histologic evolution of breast cancer.

Solid arrows represent progression, and the dotted arrow indicates an unclear association.

Grahic Jump Location




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ATM mutations and Carcinoma breast
Posted on September 30, 2005
Prasanta Padhan
Conflict of Interest: None Declared

Dear Editor,

Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation.An increased incidence of breast carcinoma has been reported among relatives of individuals who are affected with this rare autosomal recessive disorder, and those who are heterozygous for mutations in the ataxia- telangiectasia mutated (ATM) gene.The ATM gene located at chromosome 11q22.3 , consists of 66 exons encoding a large protein kinase that orchestrates the recognition and repair of radiation-induced DNA double strand breaks and it regulates several oncoproteins like tumor suppressors p53 and BRCA1.A-T heterozygotes account for about 1% of the general population, and are susceptible to the carcinogenic effect of ionizing radiation because of an increased intrinsic cellular radiosensitivity.This may be important from therapeutic point of view as high dose radiation therapy in A-T heterozygotes with breast carcinoma may increase the risk of cancer in the contralatral breast.

Conflict of Interest:

None declared

Treatment of Low-grade versus High-Grade Ductal Carcinoma in situ
Posted on January 23, 2006
David L. Page
Vanderbilt University Department of Pathology
Conflict of Interest: None Declared

In their review of premalignant and in situ breast disease(1), Arpino, Laucirica, and Elledge note that "Ductal carcinoma in situ represents a heterogeneous group of preinvasive lesions." While recognizing this well-established fact, the authors do not go on to recognize any differences in the treatment of DCIS and its potential for subsequent invasive disease based upon heterogeneity. A major barrier to achieving a greater level of understanding among clinicians and patients attempting to make diagnostic and therapeutic decisions is the erroneous idea that DCIS is one disease. DCIS is a spectrum of disease ranging from extensive high-grade lesions, usually requiring mastectomy, to small low- grade lesions, which can be effectively cured by local excision only. Division of DCIS into high-grade categories with necrosis and a high degree of nuclear atypia (comedo) and a low-grade group with orderly nuclei and no necrosis, each group with wide variations in recurrence according to grade are recognized by Lagios, Silverstein, and Page.(2-4) Several studies have assessed the risk of subsequent invasive carcinoma for patients for whom the diagnosis of DCIS was not made at initial biopsy for small non-comedo lesions.(5) Approximately 1/3 of these patients developed invasive disease in the same breast as their original biopsy within 10-18 years, indicating that not all DCIS lesions will progress to invasion, even after a prolonged interval. Short-term outcomes (median follow-up, 5.4 years) from the EORTC trial indicate that patients with high-grade DCIS have the greatest risk of subsequent life-threatening distant metastases after invasive local recurrence.(6) Optimal clinical management decisions are appropriately guided by pathologic assessment of histologic pattern, grade, size, and margin status, knowledge of natural history, and by the likelihood of therapeutic effectiveness.

1. Arpino G, Laucirica R, Elledge RM. Premalignant and in situ breast disease: biology and clinical implications. Ann Intern Med. 2005;143(6):446-57. 2. Lagios MD, Margolin FR, Westdahl PR, Rose MR. Mammographically detected duct carcinoma in situ. Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer. 1989;63(4):618-24. 3. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer. 1996;77(11):2267-74. 4. Jensen RA, Page, D.L. Ductal carcinoma in situ: Pathology-its role in guiding therapy. In: Singletary SE, Robb, G.L., Hortabgyi G.N., ed. Advanced Therapy of Breast Disease. London: BC Cedker; 2004:281-288. 5. Sanders ME, Schuyler PA, Dupont WD, Page DL. The natural history of low -grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer. 2005;103(12):2481-4. 6. Bijker N, Peterse JL, Duchateau L, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in- situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol. 2001;19(8):2263-71.

Conflict of Interest:

None declared

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