Case 3 -

Atypical Pseudolactational Change and Cystic Hypersecretory Hyperplasia Kimberly H. Allison, Univ of WA Med Ctr, Seattle, WA

Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:



under each thumbnail image below. You must have Aperio ImageScope installed on your PC.

If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy:

Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.

If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.

Clinical History 54 year old post-menopausal female now status post breast core needle biopsy for an area of calcifications found on annual mammogram. She is status post bilateral salpingo- oophorectomy at age 38 for benign cysts and has been on hormone replacement therapy for the last 16 years. She is G3P2 with her first pregnancy at age 23. She has no personal or family history of breast cancer but has a half sister with ovarian cancer. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 On low power, this breast needle core biopsy has several areas of potential interest. There is an intra- ductal proliferation present, microcysts, and an expanded lobule in the upper aspect of the image. Case 3 - Figure 2 The targeted calcifications are present in non-atypical ducts and lobules. Case 3 - Figure 3 The intraductal proliferation is characterized by a mixed population of cells with bland, overlapping nuclei. Slit-like spaces are being formed as well as micropapillary structures with small nuclei at their tips. These histologic changes are characteristic of usual ductal hyperplasia without atypia. A small calcification is evident in the epithelium focally as well. Case 3 - Figure 4 The expanded lobule seen on medium power is noted to contain areas with striking cytologic atypia. Some acini also contain a dense eosinophilic secretion reminiscent of thyroid colloid. Case 3 - Figure 5 On higher power the cytologic atypia in the lobule is more evident. The nuclei are very enlarged and contain prominent eosinophilic nucleoli. Many cells are multinucleate. The cytoplasm is also increased in volume and has a bubbly, vacuolated appearance, consistent with pseudolactational change. Case 3 - Figure 6 Blebs of cellular material containing both cytoplasm and nucleus are being shed into the center of the lobular acinus. These are findings associated with lactational and pseudolactational change. Case 3 - Figure 7 Some of the atypical acini contain both cytologic atypia as well as dense eosinophilic secretion where the pseudolactational change merges with cystic hypersecretory change. Several of the cells have spherules of eosinophilic material in their cytoplasm as well. Case 3 - Figure 8 On medium power other acini in the lobule are noted to have pseudolactational changes and cystic hypersecretory change but lack obvious cytologic atypia. Case 3 - Figure 9 More classic pseudolactational change without atypia and with hypersecretory secretion. Case 3 - Figure 10 The bubbly pseudolacataional change is evident in cytoplasm of the cells in these acini without the cytologic atypia present in the previous images. The hypersecretory secretion is present in these acini and is characteristically scalloped at the edges where it meets the surrounding epithelium. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The needle core biopsy in this case has several areas that draw the attention on initial low power scanning, including areas with an intraductal proliferation, scattered microcysts and regions with enlarged lobules. On higher power, the intraductal proliferation is noted to have bland, polyclonal-appearing cells with peripheral slit-like spaces consistent with usual-type ductal hyperplasia. However, one of the enlarged lobular units contains a proliferation of cells with striking cytologic atypia. The cells in this terminal lobular unit have enlarged, very pleomorphic nuclei with particularly prominent nucleoli. The cytoplasm in these cells is also increased in volume and is notable for a bubbly, vacuolated appearance. The atypical cells are frequently multinucleate and there is shedding of nuclear material into the central aspect of the acini along with cytoplasmic blebs. Merging with these areas of severe cytologic atypia are less atypical lobular acini that are dilated by a dense eosinophilic material/secretion that is present in the duct focally as well. A separate lobule is noted to also contain this luminal material but to a more subtle extent without such prominent acinar dilatation. The calcifications that were the targeted imaging finding are present in association with non-atypical ducts and focally with the usual ductal hyperplasia. Differential Diagnoses: Cancerization of lobules by high grade ductal carcinoma in situ Atypical apocrine adenosis Pleomorphic lobular carcinoma in situ Cystic hypersecretory ductal carcinoma in situ Pseudolactational change without atypia Radiation atypia (no history of in this case) Final Diagnosis: Atypical Pseudolactational Change and Cystic Hypersecretory Hyperplasia Case Discussion: The findings in this needle core biopsy are a diagnostic challenge for several reasons: 1) the degree of cytologic atypia present in the enlarged lobular proliferation is so striking that it mimics lobular involvement by a high grade carcinoma in situ, 2) the focal area of histologic interest does not correspond to the targeted imaging finding of calcifications (ie it is an incidental finding), 3) even if recognized, atypical pseudolactational change/cystic hypersecretory hyperplasia is rare and of uncertain significance when found on a needle core biopsy, making it difficult to be certain of treatment recommendations. The degree of cytologic atypia in the enlarged lobule in this case prompts consideration of a diagnosis of lobular involvement by a high grade ductal carcinoma in situ ("cancerization of lobules"). In addition, there is shedding of nuclear material into areas of secretion, which can be a mimic of the central necrosis often associated with high grade DCIS. One might also consider a diagnosis of atypical apocrine adenosis or pleomorphic lobular carcinoma in situ given the lobular location and prominent nuclear atypia with enlarged nucleoli. Another diagnostic consideration with the appropriate clinical history would be radiation-induced atypia, which can be focal and have cytologically bizarre nuclei, particularly in areas of apocrine change (there was no history of radiation in this case). However, the presence of an exclusively lobular process with vacuolated, enlarged cytoplasm with multiple cytoplasmic blebs, many of which contain nuclear material, are key features that will allow the pathologist to recognize cells undergoing pseudolactational change (pregnancy-like change). The frequent multi-nucleation and degree of nuclear pleomorphism in our case is reminiscent of the Arias-Stella reaction described in hypersecretory endometrium and should raise consideration of a hormonally driven "hypersecretory" process. [5] Another clue is the presence of closely associated cystic hypersecretory change, which is characterized by ductal and lobular dilatation by a colloid-like, eosinophilic secretion, a change that has been associated with the presence of pseudolactational change. [11] In this case, even if we recognize this as a pseudolactational/hypersecretory process, we are still left to wonder about the significance of the severe cytologic atypia. Does the unusually high degree of cytologic atypia make this a form of DCIS? Most of the published cases of atypical ductal hyperplasia and ductal carcinoma in situ arising in the setting of a hypersecretory process are described as having a micropapillary architecture, moderate cytologic atypia and key in this diagnosis: involvement of ducts. [5] This is in contrast to our lobulocentric, isolated lesion that lacks distinct architectural patterns of DCIS and has no suggestion of a micropapillary process. Levels to look for any evidence of ductal involvement were performed but the process appeared to be based only in the lobule. Some experts allow for a high degree of cytologic atypia, similar to Arias-Stella like reactions, in pseudolactational change and do not classify such lesions as atypical at all. [5] Given the lack of a duct-based micropapillary component in this case, this case would not be classified as a form of ductal carcinoma in situ on the basis of the findings in the needle core biopsy alone. But because the degree of cytologic atypia is beyond that typically seen in pseudolactational change, classification as atypical pseudolactational change with associated cystic hypersecretory change is recommended in this case. Since the literature on atypical pseudolactational change/hypersecretory change on core needle biopsy is very limited (reviewed below) and because of a reported association with adjacent DCIS and invasive carcinoma, excisional biopsy should be considered. Aside from morphology alone, it is essential to correlate the histologic findings on breast needle core biopsy with the imaging or clinical findings in a particular case to help determine how representative these histologic findings may be of the entire lesion seen on imaging and recommend the most appropriate next steps in treatment. In this case, the targeted imaging finding was a small (4mm) focus of calcifications, which would be unusually small for a case of high grade DCIS, whether hypersecretory or not. In addition, the targeted calcifications were present in the non-atypical areas, arguing that the atypical area may be an incidental finding (although pseudolactational change can have associated calcifications). Correlation of these imaging findings in the setting of unexplained focal cytologic atypia confined to lobules, is another reason to hesitate from making a definitive diagnosis of an in situ carcinoma on needle core sampling. If the pseudolactational qualities are not recognized, the lesion could be preliminarily described as an atypical lobule-based proliferation that warrants excisional biopsy for further characterization. In the final surgical excision of this region, there were no additional areas of pseudolactational change/cystic hypersecretory hyperplasia with or without atypia and there was no ductal carcinoma in situ or invasive carcinoma. The patient stopped her hormone replacement therapy and has continued with surveillance imaging without additional treatment (and without a cancer diagnosis). Review of the Literature/Treatment Options: The pathology literature has documented the presence of lactation-like change in the non-lactating breast for almost 80 years. Moran gets credit for the first description of pseudolactational change/pregnancy-like change in 1935, which he noted in excised fibroadenomas up to 15 months after cessation of lactation. [7] This change was further characterized in a paper in 1951 published by Frantz et al., whose series of 225 autopsy cases had a 3% incidence of "pseudolactational" change in the breast that was oddly not associated with recent pregnancy or lactation (found up to 48 years post pregnancy). Available ultrastructural studies of pseudolactational change describe changes similar to those present during lactation but without as well-organized rough endoplasmic reticulum, mitochondrial swelling or the well-formed membrane bound vacuoles that characterize true lactation. [8] Pseudolactational change is classically considered an incidental finding, and is frequently noted to be multifocal. Although the exact cause of this change is unclear, it is postulated to be the result of hormonal influences either causing persistence of a lactation-like state, or as a focal erratic response to endogenous hormones, exogenous hormones or drugs such as phenothiazine. [6, 4, 13] More recently, Shin and Rosen have described pregnancy-like change associated with calcifications as the primary diagnostic finding in needle core biopsies performed for suspicious calcifications on mammography. [11] The calcifications present in pseudolactational change are often distinctly laminated, rounded basophilic calcifications or "precalcified" secretion with a similarly layered but eosinophilic appearance. Pseudolactational change may be hyperplastic, with production of papillary fronds or solid distention of lobules by the epithelial proliferation. Pseudolactational change is considered atypical (atypical pseudolactational change) when there is also substantial nuclear pleomorphism, as in our case. These architecture of the atypical areas can have a micropapillary growth pattern or solid distention of lobules. While the significance of atypical pseudolactational change is unclear, rarely carcinomas are described arising in association with atypical or non-atypical pseudolactational hyperplasia, usually in combination with the presence of cystic hypersecretory hyperplasia. [10] While there are no studies without significant case selection bias to indicate the significance of this finding on a needle core biopsy, usually an excisional biopsy is recommended to rule out an adjacent carcinoma when atypical pseudolactational change is present but not necessarily when only pseudolactational change without atypia is identified in isolation. In contrast to the more often incidental finding of pseudolactational change, cystic hypersecretory lesions were initially described as mass-forming, clinically palpable lesions. Cystic hypersecretory carcinoma was first described by Rosen and Scott in 1984 as a variant of DCIS and invasive ductal carcinoma characterized by cystic lesions containing a dense eosinophilic secretion with a similar appearance to thyroid colloid. [9] They noted that this unusual histologic variant often arose in a background of cystically dilated ducts containing a similar secretion but with the epithelium lining these areas being bland, flat, cuboidal to columnar cells; a lesion which they termed cystic hypersecretory hyperplasia. Cystic hypersecretory hyperplasia is now noted to occur as a mass without cystic hypersecretory carcinoma as well as incidentally without forming a mass lesion. It is also noted to occur in the lobules, sometimes in isolation, suggesting that the change may begin in the lobules and then spread into the ducts. [8] The significance of isolated/incidental cystic hypersecretory hyperplasia on needle core biopsy is currently unclear, but if the indication for the biopsy was a mass lesion or calcifications associated with the lesion, excision is indicated to rule out associated cystic hypersecretory carcinoma. In the small series available, "hybrid" lesions with both pseudolactational change and cystic hypersecretory change on biopsy, even in the absence of atypia in either component were associated with adjacent in situ carcinoma and therefore these changes in combination have been recommended for excision. [10] However, upgrade rates to carcinoma are not available for these findings on needle core biopsy. There are reports of incompletely excised lesions not recognized as a cystic hypersecretory process that have recurred as cystic hypersecretory carcinoma. [1, 9] Atypical cystic hypersecretory hyperplasia is considered when there is a proliferation of the epithelium with crowding, enlarged nuclei, loss of polarity and early micropapillary tufting. Severe cytologic atypia is usually not a feature, and if present, should raise consideration of a diagnosis of either atypical pseudolactational change (which is often present in close association in the lobules) or cystic hypersecretory carcinoma if there is ductal involvement. Cystic hypersecretory carcinoma in situ is usually characterized by areas with a micropapillary growth pattern and intermediate to high nuclear grade in the setting of the classic ductal secretion described above. [2, 9, 12] Invasive carcinomas occurring in this background are often high grade and negative for estrogen and progesterone receptors, although well-differentiated invasive cancers are also reported in this setting. [3, 10] HER2 protein over-expression has also been reported in both in situ and invasive hypersecretory carcinomas. [12] While the limited numbers of cases reported in the literature report a high frequency of spread to lymph nodes, there is not data to suggest a prognosis different from similar stage and grade invasive ductal carcinomas of no special type. Conclusion(s): The presence of isolated cytologic atypia in breast lobules in a needle core biopsy can be a diagnostic challenge. Recognition of pseudolactational characteristics are critical to distinguishing atypical and non-atypical pseudolactational change from a high grade carcinoma in situ. The association of pseudolactational change with cystic hypersecretory hyperplasia indicates a close relationship between these two lesions. References: Colandrea JM, Shmookler BM, O'Dowd GJ, et al. Cystic hypersecretory duct carcinoma of the breast. Report of a case with fine-needle aspiration. Arch Pathol Lab Med. 1988;112:560-563. Guerry P, Erlandson RA, Rosen PP. Cystic hypersecretory hyperplasia and cystic hypersecretory duct carcinoma of the breast. Pathology, therapy, and follow-up of 39 patients. Cancer. 1988;61:1611-1620. Herrmann ME, McClatchey KD, Siziopikou KP. Invasive cystic hypersecretory ductal carcinoma of breast: a case report and review of the literature. Arch Pathol Lab Med. 1999;123:1108-1110. Huseby RA, Thomas LB. Histological and histochemical alterations in the normal breast tissues of patients with advanced breast cancer being treated with estrogenic hormones. Cancer. 1954;7:54-74. Kasami M, Jensen RA, Simpson JF, et al. Lobulocentricity of breast hypersecretory hyperplasia with cytologic atypia: infrequent association with carcinoma in situ. Am J Clin Pathol. 2004;122:714-720. Kiaer HW, Andersen JA. Focal pregnancy-like changes in the breast. Acta Pathol Microbiol Scand A. 1977;85:931-941. MORAN CS. Fibroadenoma of the breast during pregnancy and lacatation. Arch Surg. 1935;31:688-708. Rosen PP. Rosen's breast pathology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:581-589. Rosen PP, Scott M. Cystic hypersecretory duct carcinoma of the breast. Am J Surg Pathol. 1984;8:31- 41. Shin SJ, Rosen PP. Carcinoma arising from preexisting pregnancy-like and cystic hypersecretory hyperplasia lesions of the breast: a clinicopathologic study of 9 patients. Am J Surg Pathol. 2004;28:789-793. Shin SJ, Rosen PP. Pregnancy-like (pseudolactational) hyperplasia: a primary diagnosis in mammographically detected lesions of the breast and its relationship to cystic hypersecretory hyperplasia. Am J Surg Pathol. 2000;24:1670-1674. Skalova A, Ryska A, Kajo K, et al. Cystic hypersecretory carcinoma: rare and poorly recognized variant of intraductal carcinoma of the breast. Report of five cases. Histopathology. 2005;46:43-49. Tavassoli FA, Yeh IT. Lactational and clear cell changes of the breast in nonlactating, nonpregnant women. Am J Clin Pathol. 1987;87:23-29.