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6.2 In Situ Disease

Updated February 2016

6.2.1 Paget's disease of the Nipple-Areolar Complex

Paget's disease is a lesion involving the epidermis of the nipple-areolar complex characterized by Paget cells. The majority of cases of Paget’s disease is associated with an invasive or in-situ breast cancer. The breast should be imaged with a mammogram and ultrasound, and if these investigations are non-diagnostic, an MRI of the breast should be carried out. Biopsy of any suspicious abnormalities found on imaging should be done. 
Paget’s disease in association with in-situ or invasive carcinoma

Paget’s disease in association with insitu or invasive carcinoma should be resected with clear margins to the insitu disease, invasive disease and to the Paget’s disease. In-continuity resection of the breast carcinoma and Paget’s disease is not required. Recommendations for radiation and systemic therapy are based on the pathology of the underlying breast cancer. 

Isolated Paget’s Disease

If a co-existent breast cancer is not identified pre-operatively, local excision and adjuvant radiation can be offered for treatment of Paget’s disease. A margin of underlying breast tissue should be excised with the nipple-areolar complex to evaluate for an associated in-situ or invasive cancer. Axillary staging is not initially required in the context of breast conserving therapy. Mastectomy represents a surgical option.

A referral to plastic surgery for reconstruction of the nipple-areolar complex should be considered.

6.2.2 Ductal Carcinoma in Situ (DCIS)

Appropriate management of pure DCIS requires detailed mammographic evaluation of the breast to obtain an assessment of the preoperative extent of the lesion. Close cooperation and communication between the radiologist, surgeon, pathologist and oncologist is crucial to ensure adequate local therapy in patients treated with breast conservation. Treatment for patients with concomitant microinvasive and invasive disease should be based on the presence of the invasive disease, as discussed in separate sections.

Axillary staging is not routinely recommended for patients with pure DCIS because the risk of axillary nodal involvement is <1%. Sentinel lymph node biopsy is advised for patients undergoing mastectomy for DCIS due to the possibility of an invasive component in the final surgical specimen.1  

DCIS is a non-obligate precursor of invasive disease.  At present, all patients with pure DCIS are offered treatment. Patients with pure DCIS may be treated with breast conserving therapy or mastectomy. Both management strategies are associated with survival exceeding 98%. Patients undergoing breast conserving surgery (including partial mastectomy, lumpectomy, wide excision, or excisional biopsy) with a positive margin (defined by ink on DCIS) after surgery should undergo wider local excision. A 2-mm margin is associated with a decreased risk of in-breast tumor recurrence compared to narrower margins. Margin widths greater than 2 mm do not confer a significant benefit in local control compared to a 2 mm margin and thus re-excision for margins wider than 2-mm should not be routinely carried out2. Clinical judgment should be utilized for determination of the need for re-excision in patients with a smaller negative margin width (0.1-1.9 mm).2

Radiotherapy reduces the incidence of in situ and invasive breast recurrences after breast conserving surgery by half.3,4,5,6 Currently, adjuvant radiotherapy is recommended after breast conserving surgery for women with DCIS with higher risk features, e.g. younger age, high nuclear grade, larger tumour, comedo carcinoma, or close margins (<5mm) of excision. Women with well differentiated DCIS (cribriform, solid, papillary) that are <1cm in diameter with complete radiographic and pathologic excision (at least 5 mm of normal breast tissue between foci of DCIS and the inked margins) may be considered for management by wide excision alone. All patients should be referred to BC Cancer after breast-conserving surgery for an individualized discussion of the risks and benefits of adjuvant radiotherapy. 

Radiotherapy should optimally start once healing from the partial mastectomy is complete, generally within 10 weeks of partial mastectomy. If post-operative problems occur, including hematoma, large seroma, infection, breast edema with erythema, or wound dehiscence occur, the start of radiotherapy may be delayed to allow resolution. There is no randomised trial evidence showing detriment to delay the start of radiotherapy however, retrospective data from British Columbia shows that there is no detriment to delay up to 20 weeks after BCS for patients with invasive disease7, which likely also applies to DCIS. Radiotherapy planning and prescription is similar to those with invasive disease and are described separately.

Women with very diffuse areas of DCIS (e.g., >5 cm or greater than or equal to ¼ of the breast on mammogram) have a substantial risk of recurrence, even after partial mastectomy and radiotherapy, and mastectomy is recommended.  

There are a number of prognostic models (VNPI, MSKCC)8,9 that can be used to estimate the risk of local recurrence considering factors such as age, margin status, nuclear grade, size of the DCIS lesion, but the performance of these models has been variable.10 In the future, tests using a combination of biomarkers, e.g. tumour gene profiling, may be useful for prognostication. 

The use of adjuvant hormonal therapy is somewhat controversial. Adjuvant tamoxifen has been shown to decrease the occurrence of ipsilateral and contralateral breast cancers in women with in situ disease.4 This benefit is limited to those patients with ER positive tumours. No randomized trial has shown an improvement in survival with tamoxifen.4,5,6 The benefit must be weighed against the increased risk of thromboembolic events and uterine cancer. Adjuvant tamoxifen should not be considered for women with bilateral mastectomies, those with an increased risk of endometrial cancer or thromboembolic events, those with a life expectancy of <10 years or those who have taken tamoxifen for prevention. If used, the recommended tamoxifen dose is 20 mg/day for 5 years. Contraindications to tamoxifen are discussed more thoroughly below.

The role of adjuvant aromatase inhibitors is not clearly established. A randomized study of adjuvant tamoxifen versus anastrozole in women with DCIS treated with lumpectomy showed that anastrozole offers a similar degree of benefit and similar number of side effects as tamoxifen, although the side effect profile differed.12

References

  1. Lyman GH1, Giuliano AE, Somerfield MR, Benson AB 3rd, Bodurka DC, Burstein HJ, Cochran AJ, Cody HS 3rd, Edge SB, Galper S, Hayman JA, Kim TY, Perkins CL, Podoloff DA, Sivasubramaniam VH, Turner RR, Wahl R, Weaver DL, Wolff AC, Winer EP; American Society of Clinical Oncology. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol. 2005 Oct 20;23(30):7703-20. Epub 2005 Sep 12.
  2. Morrow M, Van Zee KJ, Solin LJ, Houssami N, Chavez-MacGregor M, Harris JR, Horton J, Hwang S, Johnson PL, Marinovich ML, Schnitt SJ, Wapnir I, Moran MS. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Ductal Carcinoma In Situ.  Ann Surg Oncol. 2016 Nov;23(12):3801-3810.
  3. F Wärnberg, H Garmo, S Emdin , etal: Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: Twenty-year follow-up in the randomized SweDCIS trial J Clin Oncol 32: 3613– 3618,2014
  4. IL Wapnir, JJ Dignam, B Fisher , etal: Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS J Natl Cancer Inst 103: 478– 488,2011
  5. M Donker, S Litière, G Werutsky , etal: Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial J Clin Oncol 31: 4054– 4059,2013
  6. J Cuzick, I Sestak, SE Pinder , etal: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Long-term results from the UK/ANZ DCIS trial Lancet Oncol 12: 21– 29,2011
  7. Olivotto IA, Lesperance ML, Truong PT, Nichol A, Berrang T, Tyldesley S, et al. Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy. J Clin Oncol. 2009 Jan 1;27(1):16-23 
  8. Di Saverio S1, Catena F, Santini D, Ansaloni L, Fogacci T, Mignani S, Leone A, Gazzotti F, Gagliardi S, De Cataldis A, Taffurelli M. 259 Patients with DCIS of the breast applying USC/Van Nuys prognostic index: a retrospective review with long term follow up.Breast Cancer Res Treat. 2008 Jun;109(3):405-16. Epub 2007 Aug 9.
  9. Rudloff U, Jacks LM, Goldberg JI, et al. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. J Clin Oncol. 2010;28:3762–3769.
  10. Yi M, Meric-Bernstam F, Kuerer HM, Mittendorf EA, Bedrosian I, Lucci A, Hwang RF, Crow JR, Luo S, Hunt KK. Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision. J Clin Oncol. 2012 Feb 20;30(6):600-7. doi: 10.1200/JCO.2011.36.4976. Erratum in: J Clin Oncol. 2012 Jul 1;30(19):2424.
  11. A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone.  Rakovitch E, Nofech-Mozes S, Hanna W, Baehner FL, Saskin R, Butler SM, Tuck A, Sengupta S, Elavathil L, Jani PA, Bonin M, Chang MC, Robertson SJ, Slodkowska E, Fong C, Anderson JM, Jamshidian F, Miller DP, Cherbavaz DB, Shak S, Paszat L.  Breast Cancer Res Treat. 2015 Jul;152(2):389-98. doi: 10.1007/s10549-015-3464-6.
  12. Forbes JF, Sestak I, Howell A, Bonanni B, Bundred N, Levy C, von Minckwitz G, Eiermann W, Neven P, Stierer M, Holcombe C, Coleman RE, Jones L, Ellis I, Cuzick J; IBIS-II investigators.   Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet. 2016 Feb 27;387(10021):866-73. doi: 10.1016/S0140-6736(15)01129-0.

6.2.3 Lobular Carcinoma In Situ (LCIS)

Use of this term is controversial. Most modern authors regard this as indicating a high risk for the development of infiltrating carcinoma in either or both breasts. The risk for subsequent carcinoma is not confined to the segment of the breast involved by the in situ change. The risk to each breast is approximately equal and approaches fifteen percent within ten to fifteen years. When LCIS is identified on a core needle biopsy, a surgical excisional biopsy should be considered to rule out an associated malignancy as typically LCIS alone does not explain an imaging finding. When LCIS is identified on an excision specimen, re-excision is not required, although should be considered in pleomorphic LCIS if the margin is not adequate. Patients can be given the option of either careful follow-up or occasionally, bilateral mastectomy with or without immediate or delayed reconstruction. Tamoxifen was shown to decrease the risk of invasive cancer in women with LCIS in the NSABP prevention trial using tamoxifen 20 mg daily for 5 years, although there was no improvement in survival. Tamoxifen can be considered if breast cancer prevention is the primary goal. 

6.2.4 Pleomorphic LCIS

Classic LCIS behaves as an indicator lesion for higher risk of breast malignancy in any region of the breast. Pleomorphic LCIS (PLCIS) has pathologic features similar to DCIS and is frequently associated with DCIS or invasive breast cancer.  When detected in isolation, PLCIS has a pattern of recurrence more similar to a precursor lesion such as DCIS with a higher risk of malignancy within that region of the breast.  There are no randomized trials that describe what margin should be achieved with surgery or the efficacy of adjuvant breast radiotherapy in the setting breast conserving surgery for PLCIS. It is recommended that patients with PLCIS on biopsy have excision to rule out additional pathology and achieve clear margins for PLCIS and should also have a discussion regarding the possible benefits of adjuvant breast radiotherapy or more definitive breast surgery.

SOURCE: 6.2 In Situ Disease ( )
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