|Year : 2011 | Volume
| Issue : 4 | Page : 671-682
|Core biopsies of the breast: Diagnostic pitfalls
Megha Joshi1, Sriharshan J Reddy2, Manjiri Nanavidekar3, John P Russo4, Armand V Russo5, Ram Pathak6
1 Chief Pathologist and Director of Laboratories, Lawrence General Hospital, Lawrence, MA, USA
2 Medical Education, Hackensack University Medical Center, Hackensack, NJ, USA
3 Krishna Institute of Medical Sciences, Karad, Maharashtra, India
4 St. George's University School of Medicine Grenada, West Indies
5 Dartmouth Medical School, Hanover, NH, USA
6 Medical Education, Drexel University School of Medicine, Philadelphia, PA, USA
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|Date of Web Publication||6-Jan-2012|
| Abstract|| |
The incidence of breast cancer is increasing worldwide. In this review article, the authors compare and contrast the incidence of breast cancer, and the inherent differences in the United States (US) and India in screening techniques used for diagnosing breast cancer. In spite of these differences, core biopsies of the breast are common for diagnosis of breast cancer in both countries. The authors describe "Best Practices" in the reporting and processing of core biopsies and in the analysis of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor Receptor 2 (Her2/neu). The pitfalls in the diagnosis of fibroepithelial lesions of the breast on core biopsy are discussed, as also the significance of pseudoangiomatous stromal hyperplasia of the breast (PASH) is discussed in core biopsy. In this review, the management and diagnosis of flat epithelial atypia and radiation atypia are elaborated and the use of immunohistochemistry (IHC) in papillary lesions, phyllodes tumor, and complex sclerosing lesions (radial scars) is illustrated. Rarer lesions such as mucinous and histiocytoid carcinoma are also discussed.
Keywords: Breast, biopsy, breast cancer, carcinoma, ductal carcinoma in situ, ER, fibroepithelial lesions, Her2-neu, PR, phyllodes tumor
|How to cite this article:|
Joshi M, Reddy SJ, Nanavidekar M, Russo JP, Russo AV, Pathak R. Core biopsies of the breast: Diagnostic pitfalls. Indian J Pathol Microbiol 2011;54:671-82
|How to cite this URL:|
Joshi M, Reddy SJ, Nanavidekar M, Russo JP, Russo AV, Pathak R. Core biopsies of the breast: Diagnostic pitfalls. Indian J Pathol Microbiol [serial online] 2011 [cited 2022 Jan 18];54:671-82. Available from: https://www.ijpmonline.org/text.asp?2011/54/4/671/91490
| Introduction|| |
The incidence of breast cancer in India is rising.  A recent article, providing information from The Indian Council for Medical Research (ICMR) stated that though cervical cancer incidence fell by roughly 50% in 24 years, breast cancer was showing an upsurge, and breast cancer cases had almost doubled, between 1982 and 2005 [Figure 1]. The analysis covered four major cities, Mumbai, Delhi, Bangalore, and Chennai. Fortunately, the breast cancer rates in India are much lower than the West (30/100,000 vs. >100 case/100,000). In four major cities, breast cancer incidence rates have surpassed cervical cancer. A western lifestyle, increased consumption of fat products, obesity, late marriages, delayed child bearing, fewer children being conceived, has led to reduced breast feeding and possibly an increased incidence of breast cancer.
Though breast cancer is increasing in India, mammographic screening is not as prevalent, and breast cancer is diagnosed at a much higher stage. Most breast cancers in the west are detected through screening and mammography and are nonpalpable. Stereotactic and ultrasound-guided core biopsies are the preferred method of diagnosis in the US. Breast cancers in India are usually detected as large palpable masses, and fine needle aspiration cytology (FNAC) is performed as the initial diagnostic procedure. If FNAC is unsuccessful, excisional biopsies are performed. In large cities however, core biopsies of the large palpable masses are usually performed for diagnosis and prognosis. Core biopsies correctly identify benign and malignant disease in more than 90% of cases.  However, the gun required for core biopsy is not easily available everywhere in India, and hence, FNAC is preferred over core biopsies for the diagnosis of breast masses.
Reporting and Processing of Core Biopsies
The principle aim of the core biopsy is to provide a diagnosis of a breast abnormality prior to, and in many cases avoiding the need for, open surgical biopsy. It is of utmost importance that the pathologist correlates the histopathology findings with the radiologic abnormality. Radiologic pathologic correlation conferences are encouraged. Core biopsies are processed in a routine manner to paraffin embedding. The time of preservation of core biopsies in formalin is also recorded. The optimal time in formalin fixation for accurate receptor analysis is 6-72 h. The protocol for sectioning will vary, but a minimum of three sections at 50 micron intervals are recommended. This will allow for further levels and immunohistochemistry if so desired. Core biopsies are preferred over excisional specimens for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor Receptor 2 (Her2-neu) assessment. Please refer to [Figure 2]a-d example of reporting invasive carcinoma.
|Figure 2: (a) Invasive carcinoma, H and E, ×20; (b) Invasive carcinoma, immunostaining for ER showing strong nuclear positivity, 99%, ×20; (c) Invasive carcinoma, immunostaining for PR showing nuclear positivity, 85%, ×20; (d) Invasive carcinoma, immunostaining for Her2 neu showing absent membrane positivity; positive control in inset ×20|
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For routine breast cancer patients, who will have excisional surgery following a core biopsy, a minimalist approach is preferred. The type of carcinoma and LVI, if definitely present, are recorded. Receptor analysis (ER, PR, and Her2-neu) is also performed. There is generally good correlation between prognostic factors derived from core biopsies and the subsequently excised specimen, although histologic grade may be underestimated, because of a lower mitotic rate seen in a smaller sample. ,, For those patients in whom neo-adjuvant therapy is planned (and this may apply to a larger number of patients in India, who typically present with larger tumors and at a higher stage), the full range of prognostic and predictive information must be provided. This information will include type of malignancy, histologic grade, LVI, ER, PR, and Her 2-neu.
Reporting of Ductal Carcinoma in situ
In the US, pure ductal carcinoma in situ (DCIS) (noninvasive carcinoma) constitutes 50% of breast cancer diagnoses and is a common form of malignancy detected by mammography and diagnosed by core biopsy. Most patients with occult DCIS present with abnormal microcalcifications (72%), whereas a minority present with a mass lesion (10%). Approximately 12% have a mass lesion associated with microcalcifications  on mammography.
In the US, DCIS is routinely analyzed for ER and PR receptors, but not for Her2-neu [Figure 3]a and b. A pathology report of a core biopsy on DCIS should include the type of DCIS (solid, cribriform, micropapillary, papillary, and comedo), nuclear grade, and the presence of necrosis. Presence of microcalcifications should be correlated with the radiologic findings. These factors are important in predicting risk of invasion and risk of recurrence.  More details on the reporting of DCIS and invasive breast cancer are available in the revised cancer protocols,  published by the College of American Pathology at their website www.cap.org.
|Figure 3: (a) Secretory DCIS, H and E, ×20; (b) secretory DCIS, negative for ER receptor immunohistochemical staining, ×20|
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ER, PR, and Her2-neu in Breast Carcinoma
Recent microarray-based analysis of breast cancers has led to a new molecular classification scheme:
Luminal A (ER+, PR+, Her2/neu-)
Luminal B (ER+, PR+, Her2/neu+)
Basal-like (ER-, PR-, Her2/neu-, CK17+, CK14+, EGFR+, CK5/6+)
Her2-neu (ER-, PR-, Her2/neu+)
Normal breast-like (ER-, PR-, Her2/neu-) 
The basal-like and normal breast-like phenotypes have also been referred to as triple negative breast cancers. 
In the US, ER positivity is seen in 75-85% of breast cancers,  whereas Her2-neu is amplified in 18-20% of breast cancers. These percentages may vary in the Indian population. ER assays tend to suffer from false negatives and Her2-neu assays from false positives. It is crucial for each laboratory and surgical pathology center to evaluate their own ER and Her2-neu positive rates and compare them to known national rates. This will ensure good quality assurance, and test the robustness of the entire assay, from formalin fixation to paraffin embedding to immunohistochemistry.
Shown below are the ER, PR, and Her2-neu data at a community hospital in the US [Table 1]. In 2008, breast cancer cases diagnosed between 1st Jan 2008 and 31st Dec 2008 were reviewed and ER, PR, and Her2-neu, and the results were tabulated. ER positivity was 75%; Her2-neu positivity was 14%. Results were reassuring and confirmed that there was no problem of false negatives with ER or false positives with Her2-neu determination.
Indian DataFrom 2002 to 2009, at Krishna Institute of Medical Sciences, Karad, India, ER, PR, and Her2-neu were determined in all breast cancers. The analysis is not performed in house, but sent out to a reputable laboratory in Mumbai. Results show that 50% of carcinomas were ER, PR positive, and 13% were Her2-neu positive. The number of carcinomas that were triple negative was 36%. As compared to the US, the ER and PR positivity rates are low. For immunohistochemistry tests that provide independent predictive or prognostic information, the College of American Pathologist requires that patient report include information on specimen processing, the antibody clone, and the scoring method used [Table 2]. ,,
|Table 2: Krishna Institute of Medical Sciences breast cancer data. (Data obtained from the Late Dr Nanivadekar, KIMS, Karad, India)|
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ER and PR Testing by Immunohistochemistry
Appropriate positive and negative controls should be used. Ideally, the positive control tissue would be the same specimen type as the patient test specimen (e.g., small biopsy, large tissue section, and cell block) and would be processed and fixed in the same manner (e.g., formalin-fixed, alcohol-fixed, and decalcified) as the patient specimen. Normal breast tissue should be used as a positive internal control.  If the normal tissue is negative for ER, repeated studies on the same specimen or different specimen should be considered. External positive controls are also necessary and including the positive control section on the same slide as the patient tissue is optimal practice; however, one separate positive control per staining run for each antibody in the run (batch control) may be sufficient provided that the control slide is closely scrutinized by a qualified reviewer. Ideally, positive control tissues should possess low levels of antigen expression. Exclusive use of normal tissues that have high levels of antigen expression may result in antibody titers of insufficient sensitivity, leading to false-negative results. The findings must be correlated with the type and grade of the cancer. The study should be repeated for discordant results (ER negative tubular carcinoma or invasive lobular carcinoma, low grade). 
A negative tissue control must be processed for each antibody in a given run. Negative reagent control and negative tissue control are recommended by the College of American Pathologists. The lowest limit of ER or PR positivity that should be considered "positive" has not been defined. In most instances carcinomas with <1% positive cells are considered negative. , The H score  and The Allred score for ER and PR use quantification systems that use both intensity of staining and the number of positive cells.  Other systems use only the proportion of positive cells. Computer-assisted analysis is considered better than mere eyeballing or visually estimating the percentage of positive cells. 
Her 2/neu Testing by Immunohistochemistry
Approximately 15-20% of breast carcinomas express Her2-neu positivity. Common reasons for false-positive immunohistochemistry (IHC) results are overstaining, and the assay should be adjusted till normal ducts and lobules show no immunoreactivity. Edge artifact may cause well-differentiated invasive lobular carcinomas (rarely positive <5%) on core biopsies to show false-positive staining. FISH studies can help in these and other equivocal cases. DCIS can show strong immunoreactivity and care should be taken to evaluate only the invasive component.
CAP/ASCO Guidelines for Her-2 Assessment
Formalin fixation no less than 6 h, and no more than 48 h
IHC and FISH correlation standards should show:
90% of tumors with IHC scores 0, with no amplification by FISH
95% of tumors with IHC scores 1+, with no amplification by FISH
90% of tumors with IHC scores 3+, with amplification by FISH 
In India, often time of surgery and when specimen was fixed is not mentioned; hence, following CAP/ASCO guidelines is at times impossible.
When to Recommend Excision after Core Biopsy
Certain types of lesions in core biopsies can be associated with pitfalls in diagnosis and may require complete excision and immunohistochemical work up for an accurate assessment. Such lesions could be the following:
Pseudoangiomatous stromal hyperplasia (PASH)
Atypia including flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), and lobular neoplasia, and radiation atypia
complex sclerosing lesion
Microcalcifications not associated with a specific pathology
Malignant processes that mimic benign lesions
A mammary fibroepithelial lesion is a neoplastic proliferation of the specialized stroma of the breast.  The overgrowth of stroma distorts the epithelial elements and incorporates them in the lesion. The resulting tumor has benign epithelial elements, but neoplastic stromal elements. Fibroepithelial lesions in the breast can range from fibroadenomas to malignant phyllodes tumor (PT). Most fibroepithelial lesions such as fibroadenomas can be diagnosed with confidence and certainty on core biopsy specimens. Often they present as nodules or mass lesions on mammograms and ultrasound examination. Occasionally, fibroadenomas can present as abnormal calcifications [Figure 4]a or a mass lesion with associated microcalcifications [Figure 4]b. Though fibroadenomas can be distinguished from PTs with relative ease in excision specimens, core biopsies can be problematic. The point to remember is that PTs often have heterogeneity within them and cellular areas may alternate with fibroadenoma-like areas. In core biopsies, where only sampling of the lesion is possible, a PT may be missed and underdiagnosed as a fibroadenoma or a cellular fibroadenoma [Figure 4]c. Hence, all fibroadenomas with cellular stroma on core biopsies should be excised. , The question of "fibroadenoma" or "PT" is a recurrent one in breast pathology. The diagnosis will greatly influence clinical management as fibroadenomas can be watched, while PTs need excision with clear margins [Figure 5].
|Figure 4: (a) 53-year-old female presents with for abnormal microcalcifications in her breast. The stereotctic core biopsy shows a benign calcified fibroadenoma, H and E, ×10; (b)46-year-old female, presenting with a mass at 8'oclock in her breast shows on core biopsy a benign myxoid fibroadenoma, H and E, ×20; (c) 32-year-old female with a ultrasound guided core biopsy for a mass, shows a cellular fibroadenoma on H and E, ×20; stromal mitoses in inset, ×40|
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|Figure 5: (a) Benign phyllodes tumor, H and E, ×20; inset ×40; (b) malignant phyllodes tumor, H and E, ×20; inset shows tumor heterogeneity at ×40|
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The pathologist's first encounter with a fibroepithelial lesion in the US is often a core biopsy. In India, it could be an FNA or a core biopsy. Jacklin et al. have shown that FNA has a high false-negative rate of 25%, with under diagnosis of PT.  PTs can be misdiagnosed as fibroadenomas on core biopsy too, and in a study by Dillon et al. 9 out of 23 cases diagnosed as phyllodes had a prior core that was diagnosed as fibroadenoma or benign, with a false-negative rate of 39%. Jacobs et al. assessed findings on excision specimens of 29 cases of fibroepithelial lesions with cellular stroma (FELCS) on core biopsy. They found that 16 cases were fibroadenomas, and 12 cases were PTs. Marked cellularity, stromal mitoses and higher immunoreactivity for Ki-67 favored the diagnosis of a PT [Table 3]. Lee et al. suggest the following features as being helpful in distinguishing fibroadenomas from PT: fragments of stroma lined by epithelium on one or two opposing edges, stromal overgrowth, and stromal expansion. The literature consistently cites that distinction of fibroadenomas from PTs cannot be done accurately by FNA or core biopsy. Foxcroft et al. were able to diagnose phyllodes accurately only on 23% of FNAs and 65% of core specimens. Infiltrative edges, if seen, can be helpful to suspect PT on core biopsies, as also the presence of entrapped fat.  Extensive sampling of a large tumor is more likely to yield a correct diagnosis according to a study performed by Yoohe and Yeh.  Large size (>3cm) and rapid tumor growth also suggest a serious lesion, even when the morphologic features on a core biopsy are those of a fibroadenoma.  It is prudent to excise such lesions.
|Table 3: Morphological features of phyllodes tumor (PT) [Figures 5]a and b|
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Immunohistochemistry of PT
The differential diagnosis of a PT may involve a spindle cell carcinoma. If the tumor cells are positive for basal cytokeratins CK5/6, CK14, and myoepithelial marker p63, the tumor may indeed represent a spindle cell carcinoma with myoepithelial differentiation. 
Recently, Sawyer et al. found strong c-kit expression in four out of eight cases of malignant PTs, but lacked expression in 20 benign PTs. Also Tse et al. evaluated CD 10 in fibroepithelial lesions and found CD10 expression was rare in fibroadenomas (1/33) and benign PT (6/102), but more frequent in borderline PT (16/51) and malignant PT (14/28). Though the findings of Sawyer  and Tse  are interesting, routine clinical application of these markers is not warranted at this time.
The proliferation marker Ki-67 can be useful to differentiate between fibroadenomas from PTs; however, benign PTs and borderline PTs may sometimes show low expression of Ki-67. 
Pseudoangiomatous Stromal Hyperplasia of Breast (PASH)
Pseudoangiomatous stromal hyperplasia of breast (PASH) [Figure 6] is an unusual benign breast lesion first described in 1986.  The pathogenesis of this lesion is attributed to hyperplasia of stromal fibroblasts in response to hormonal stimuli. ,, PASH is extremely common in gynecomastia.  PASH is an incidental finding in about 23% of breast biopsy specimens, occurs most commonly in premenopausal women and is also seen in postmenopausal women taking hormone replacement therapy. In rare cases, PASH can cause peau d'orange and skin ulceration. ,, PASH can produce diffuse enlargement of the breast during pregnancy. 
PASH often forms a circumscribed, nonencapsulated mass with a lobulated tan-pink to yellow cut surface, and ranges in size from 1 to 15 cm in greatest dimension.  This lesion is detected mammographically as an uncalcified mass, which appears solid and hypoechoic by ultrasonographic examination.  The histologic diagnosis of PASH is based on specific stromal changes that are believed to originate as a response to progesterone in estrogen-primed tissue.  Microscopically, PASH consists of slit-like, anastomosing spaces bordered by flat, elongated myofibroblasts separated by bands of eosinophilic hyalinized tissue. The myofibroblasts possess scant cytoplasm and small bland nuclei. These changes predominantly involve the interlobular stroma, but uncommon cases do show involvement of intralobular stroma. The morphology of PASH is reminiscent of low-grade angiosarcoma; hence, the name of the lesion.  Multiple lines of evidence indicate that the pseudovascular spaces of PASH do not represent artifacts.  These spaces are present in frozen tissue and display Alcian-blue reactivity that is sensitive to hyaluronidase pretreatment.  The pseudovascular spaces of PASH seen in patients with type 1 nuerofibromatosis contain multinucleated giant cells and infiltration of the spaces by carcinoma and non-Hodgkins lymphoma has been described. ,,[ 40] The spindle cells of PASH can be conspicuous and form compact sheets with only rare pseudovascular spaces and scant collagen. The architecture of lobules and ducts associated with cellular PASH is preserved. Although focal infiltration of adipose tissue is possible, cellular PASH does not show nuclear atypia or mitoses. Occasionally, keloid-like areas may be seen. PTs can show PASH-like areas. PASH may be mistaken for a PT on core biopsies. Epithelial hyperplasia without atypia is often present near PASH and can be florid. The spindle cells in PASH are positive for Vimentin and CD34; focal clusters of myoid cells, seen in about two thirds of cases, are immunoreactive for alpha smooth muscle actin (SMA). Nuclear immunoreactivity for progesterone receptor is common, supporting the hypothesis that PASH is influenced by ovarian hormones. ER reactivity is rare. Experience with the histological and clinical features of PASH enables to make the diagnosis without the aid of these special studies in most situations. Ultrastructurally, the pseudovascular spaces are intermittently lined by fibroblasts and myofibroblasts. 
|Figure 6: Psuedoangiomatous stromal hyperplasia of breast (PASH), H and E, ×20|
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If a diagnosis of PASH is rendered on core biopsy, excision is not mandatory. However, a fibroepithelial neoplasm with PASH-like areas cannot be entirely excluded. Clinical correlation is recommended. No treatment is required if PASH is an incidental finding on a biopsy, and unless it forms a mass. Recurrence of PASH in the same or contralateral breast has been reported. 
Flat Epithelial Atypia
In some lesions of columnar cell change or columnar cell hyperplasia, the epithelial cells show cytologic atypia.  This atypia may be extremely subtle and can be missed at low power. The epithelial cells show relatively round or ovoid nuclei with an increase in the nuclear/cytoplasmic ratio, and nuclear stratification. The nuclear chromatin may be evenly dispersed or slightly marginated and nucleoli are variably prominent. Mitotic figures may be seen but are uncommon. In other cases, the columnar cells may resemble the cells comprising the tubules of tubular carcinoma. Columnar cell lesions of this type have been described under a variety of names including columnar cell change with atypia or columnar cell hyperplasia with atypia and "clinging carcinoma of the monomorphic type." ,, Recently the World Health Organization Working Group on the Pathology and Genetics of Tumors of the Breast proposed that the term "FEA" be used for these lesions.  Architectural changes associated with DCIS are not a feature of FEA.
Flat Epithelial Atypia and Neoplasia
Recent data suggest that when a columnar cell lesion with FEA is encountered in a core biopsy specimen, subsequent excision shows a more advanced lesion in about one-quarter to one-third of cases. ,,
Columnar cell lesions and FEA are sometimes associated with lobular neoplasia (lobular carcinoma in situ and atypical lobular hyperplasia) and tubular carcinoma. , When FEA is seen on a core biopsy, levels must be obtained and a diligent search for a more significant lesion, such as ADH, DCIS, or invasive carcinoma must be undertaken.
Core biopsy is often performed to assess microcalcifications seen in the irradiated breast, following breast conservation and radiation therapy for invasive carcinoma or DCIS. The calcifications may be seen in the area of fat necrosis near a scar. The differential diagnosis includes DCIS with microcalcifications. Often a history of past radiation does not accompany the core biopsy. In the absence of such a history, the atypia seen may be misinterpreted as in situ or invasive carcinoma. The importance of history in a patient with prior radiation to the breast cannot be overemphasized. The most characteristic finding is epithelial cell atypia in the terminal duct lobular unit. There may be associated varying degrees of lobular sclerosis and atrophy.  Similar changes are also described with chemotherapy prior to excision.  Occasionally, the lobular sclerosis is so marked, such that the atypical cells infiltrating the stroma as single cells may be mistaken for invasive carcinoma. Less frequently, the atypia may involve large ducts, fibroblasts in the stroma, and radiation-related vascular changes might be seen. Prominent myofibroblasts and thickened basement membranes may also be seen.  Interestingly, stromal fibrosis is so variable among irradiated and nonirradiated breasts, such that it is not a reliable marker for radiation-induced injury in the breast [Figure 7]a-b.
|Figure 7: (a) Radiation-induced changes, basement membrane thickening, and inter and intralobular stromal sclerosis, H and E, ×20; (b) radiation-induced changes, epithelial atypia, H and E, ×40|
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The presence of mitoses and the histologic similarity to the prior carcinoma may help in the diagnosis of recurrent/residual DCIS. It is important to review the slides of the previous carcinoma and compare the histology to the current biopsy.
Intracystic papillary carcinoma, papillomas with and without atypia/DCIS, and frank invasive papillary carcinomas are some of the papillary lesions that are encountered in a core biopsy specimen. In most instances, when papillary lesions are encountered in a core biopsy, excision follows. An exception to this rule may occur when the lesion is a small benign papilloma (millimeters in size), and the postbiopsy images show complete excision of the lesion following a mammotome/vacuum assisted core biopsy [Figure 8]a-d.
|Figure 8: (a) Intraductal papilloma, H and E, ×20; (b) intraductal papilloma, immunostaining for colponin showing the presence of myoepithelial cell, ×20; (c) intraductal papilloma, immunostaining for p63 showing nuclear positivity in the myoepithelial cell, ×20; (d) intraductal papilloma, triple stain, showing the presence of red, CD8/18, positive, luminal cells and brown p63, nuclear positivity in the myoepithelial cells, ×40|
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To distinguish intraductal papillary carcinoma from a papilloma with hyperplasia and atypia, immunohistochemical stains demonstrating the presence or absence of myoepithelial cells are recommended. Generally, a nuclear and cytoplasmic stain combination is preferred. p63 is a nuclear stain, whereas smooth muscle myosin heavy chain (SMMHC) and SMA are cytoplasmic stains. p63 and SMMHC are considered the most specific and consistent. Benign papillomas will show myoepithelial cells, whereas myoepithelial cells will be absent in carcinomas. Because papillomas can be heterogenous lesions and large benign intraductal papillomas can show malignant areas after complete excision following core biopsies, at the current time, excision of papillary lesions diagnosed on core biopsies is recommended.  Jacobs et al. reported carcinoma in 0-25% of cases following a diagnosis of a benign papilloma without atypia on a core biopsy.
Usually, the diagnosis of a mucinous carcinoma on a core biopsy is straightforward. In the US, most mucinous carcinomas present as a mass lesion on screening mammography. Sometimes the mass lesion has associated microcalcifications. The calcifications are histologically seen within the mucin pools. The mucinous lesion that presents with difficulty in diagnosis and management on a core biopsy is "the mucocele-like lesion." In this lesion, the source of mucin is often a distended duct, and mucin extravasation in the stroma is often seen. Calcifications may also be seen associated with the extruded mucin. The lining of the duct may be normal/cuboidal or atypical/DCIS. Because a mucinous carcinoma cannot be entirely ruled out in such a lesion, it is prudent to follow such a core with excision.
One can view mucocele-like lesions as presenting a spectrum from benign entities to mucinous carcinoma.  Mucocele-like lesions present a significant risk of underdiagnosis from the limited material present in a core biopsy. Excision of mucocele-like lesions is recommended.
Radial Scar/Complex Sclerosing Lesion
A core biopsy of a part of a radial scar may pose difficulty in diagnosis and differentiation from an invasive carcinoma [Figure 9]a-d. Myoepithelial cell markers can be extremely useful in such instances, and p63, SMMHC, and CD10 are recommended. Radial scars [Figure 10]a-c may be incompletely excised on cores and may contain foci of ADH/DCIS. Large, incompletely excised radial scars on core biopsies are usually followed by excisions. It is the small, incidental radial scars that are completely excised on vacuum assisted cores that can be left alone and pursued by close follow-up/imaging. There is evidence to suggest that greater the volume sampled by vacuum-assisted biopsy and absence of atypia, greater the likelihood that a benign diagnosis will follow excision or follow-up. 
|Figure 9: 56-year-old female with a prior benign breast biopsy 12 years ago. Now presents with calcifications at the site of prior biopsy. H and E at ×10 shows invasive carcinoma Keratin immunostains show positive staining of the invasive carcinoma. The absence of myoepithelial cells as demonstrated by lack of smooth muscle actin (SMA), p63, and smooth muscle myosin heavy chain (SMMHC) immunostaining confirms the malignant nature of the proliferation|
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|Figure 10: (a) Radial scar, H and E, ×20; (b) the presence of myoepithelial cells, as demonstrated by SMMHC; (c) the presence of myoepithelial cells, as demonstrated by nuclear p63 immuno-staining, confirms the benign nature of the proliferation|
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Postcore biopsy, radial scars may show epithelial entrapment simulating invasive carcinoma, and one must be wary of overdiagnosing invasion in such instances.
Microcalcifications not Associated with a Specific Pathology
Occasionally, a core biopsy performed for microcalcifications may reveal the calcifications on the core biopsy section, but the calcifications may not be associated with a specific lesion. In such instances, it is incumbent on the pathologist to get deeper sections through the block, till the causal or associated lesion is identified. The deeper sections may even reveal a lurking comedo carcinoma. A diagnosis of stromal calcifications is insufficient. What is the cause of the microcalcifications? What are the calcifications associated with? It is important for the pathologist to answer these questions. Microcalcifications may be associated with mucin, a fibroadenoma, in situ or invasive carcinoma, sclerosing adenosis, calcium oxalate crystals, macrocysts, and papillomas amongst other things.
Malignant Processes that Mimic Benign Lesions
Histiocytoid carcinoma ,,,,, and granular cell tumor [Figure 11]a-c.
|Figure 11: (a) 62-year-old female, Roght breast mass, US-guided core biopsy, showing a granular cell tumor, H and E, ×20; inset ×40; (b) positive immunostaining for CD68, a histiocytic marker, confirms the diagnosis of Granular cell tumor; ×40; (c) positive immunostaining for S100, confirms the diagnosis of granular cell tumor; ×20|
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The term histiocytoid carcinoma was first used by Hood et al. in 1973. Some consider histiocytoid carcinoma to be an apocrine [Figure 12] variant of invasive lobular carcinoma. It often is positive for GCDFP-15, an apocrine marker and is negative for E cadherin. It often is associated with LCIS. The important fact is that it can be missed and diagnosed as a benign lesion consisting of histiocytes, or as a granular cell tumor, xanthoma, or inflammation. It can simulate fat necrosis to the unwary. The following table shows the help immunohistochemistry can provide in differentiating these lesions. Histiocytoid breast carcinoma (HBC) can be distinguished from histiocytic lesions by the lack of histiocytic markers (CD68, HAM-56, lysozyme, CD1a, and S100 protein) and the consistent expression of markers of epithelial and apocrine differentiation, namely, cytokeratins, epithelial membrane antigen, and GCDFP-15 [Table 4]. Granular cell tumor may show a remarkable histologic similarity to HBC; however, the former expresses S100 protein, calretinin, and α-inhibin and is negative for epithelial markers and hormone receptors.
|Figure 12: 79-year-old with a palpable mass; apocrine carcinoma, H and E, ×40|
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|Table 4: Markers are used to differentiate between histiocytoid, granular, and histiocytes|
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To summarize, breast core biopsies can be used for diagnostic and prognostic purposes. In cancer patients, core biopsies are preferred over FNA samples for the assessment of ER, PR, and Her 2 analysis. Pitfalls to be avoided in the diagnosis of core biopsies are radiation atypia, missing a PT, and missing a more significant lesion with calcifications. IHC can aid in the accurate diagnosis of invasion in a core biopsy, in differentiating ADH from DCIS, and discerning papillary carcinoma in a papilloma. Rarer lesions such as histiocytoid carcinoma should be differentiated from granular cell tumor.
| References|| |
|1.||Sinha K. Breast and Cervical Cancer Incidence in India: The ICMR data. Times of India August 2009. |
|2.||Ver Koojien HM. Diagnostic accuracy of stereotactic large core needle biopsy for non-palpable breast disease: Results of a multicenter prospective study with 95% surgical confirmation. Int J Cancer 2002;99:853-59. |
|3.||Harris GC, Denley HE, Pinder SE, Lee AH, Ellis IO, Elston CW, et al. Correlation of histologic prognostic factors in core biopsies and therapeutic excisions of invasive breast carcinoma. Am J Surg Pathol 2003;27:11-5. |
|4.||Hoda SA, Harigopal M, Harris GC, Pinder SE, Lee AH, Ellis IO. Expert opinion: Reporting needle core biopsies of breast carcinomas. Histopathology 2003;43:84-90. |
|5.||McIlhenny C, Doughty JC, George WD, Mallon EA. Optimum number of core biopsies for accurate assessment of histological grade in breast cancer. Br J Surg 2002;89:84-5. |
|6.||Stomper PC, Connolly JL, Meyer JE, Harris JR. Clinically occult ductal carcinoma in situ detected with mammography: Analysis of 100 cases with radiologic-pathologic correlation. Radiology 1989;172:235-41. |
|7.||Harris GC, Denley HE, Pinder SE, Lee AH, Ellis IO, Elston CW. Correlation of histologic prognostic factorsin core biopsies and therapeutic excisions of invasive breast carcinoma. Am J Surg Pathol 2003;27:11-5. |
|8.||Lester SC, Bose S, Chen YY, Connolly JL, de Baca ME, Fitzgibbons PL, et al. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Arch Pathol Lab Med 2009;133:1515-38. |
|9.||Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, et al. Basal-like and triple-negative breast cancers: A critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 2011;24:157-67. |
|10.||OíLeary TJ. Standardization in immunohistochemistry. Appl Immunohistochem Mol Morphol 2001;9:3-8. |
|11.||NCCLS. Quality Assurance for Immunocytochemistry; Approved Guideline. NCCLS document MM4-AC (ISBN 1-56238-396-5). NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 1999. |
|12.||Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784-95. |
|13.||McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses: Correlation of biochemical and immuno-histochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985;109:716-21. |
|14.||Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand binding assay for predicting response to adjuvant therapy in breast cancer. J Clin Oncol 1999;17:1474-81. |
|15.||Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007;131:18-43. |
|16.||Giri D. Recurrent Challenges in the Evaluation of Fibroepithelial Lesions. Arch Pathol lab Med 2009;133:713-21. |
|17.||Jacobs TW, Chen YY, Guinee DG, Holden JA, Cha I, Bauermeister DE, et al. Fibroepithelial lesions with cellular stroma on breast core needle biopsy: Are there predictors of outcome on surgical excision? Am J Clin Pathol 2005;124:342-54. |
|18.||Jacklin RK, Ridgway PF, Ziprin P, Healy V, Hadjiminas D, Darzi A. Optimising preoperative diagnosis in phyllodes tumor of the breast. J Clin Pathol 2006;59:454-9. |
|19.||Dillon MF, Quinn CM, McDermott EW, O'Douherty A, O'Higgins N, Hill AD. Needle core biopsy in the diagnosis of phyllodes neoplasm. Surgery 2006;140:779-84. |
|20.||Lee AHS, Hodi Z, Ellis IO, Elston CW. Histologic features useful in the distinction of phyllodes tumor and fibroadenomas on needle core biopsy of the breast. Histopathology 2007;51:336-44. |
|21.||Foxcroft LM, Evans EB, Porter AJ. Difficulties in the pre operative diagnosis of phyllodes tumor of the breast: A study of 84 cases. Breast 2007;16:27-37. |
|22.||Yohe YS, Yeh IT. "Missed" diagnoses of phyllodes tumor on breast biopsy: Pathologic clues to its recognition. Int J Surg Pathol 2008;16:137-42. |
|23.||Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatoses, and phyllodes tumor of the breast. Histopathology 2008;52:45-57. |
|24.||Sawyer EJ, Poulsom R, Hunt FT, Jeffery R, Elia G, Ellis IO, et al. Malignant phyllodes tumors show stromal overexpression of c-myc and c-kit. J Pathol 2003;200:59-64. |
|25.||Tse GM, Tsang AK, Putti TC, Scolyer RA, Lui PC, Law BK, et al. Stromal CD 10 expression in mammary fibroadenomas and phyllodes tumors. J Clin Pathol 2005;58:185-9. |
|26.||Salvador R, Lirola JL, Dominguez R, Lopez M, Risueno N. Pseudoangiomatous stromal hyperplasia presenting as a breast mass: Imaging findings in three patients. Breast 2004;13:431-5. |
|27.||Gow KW, Mayfield KJ, Lloyd D, Shehata B. Pseudoangiomatous stromal hyperplasia of the breast in two adolescent females. Am Surg 2004;70:605-8. |
|28.||Brogi E. Benign and Malignant Spindle cell lesions of the breast. Semin Diagn Pathol 2004;21:57-64. |
|29.||Iancu D, Nochomovitz LE. Pseudoangiomatous stromal hyperplasia: Presentation as a mass in the female nipple. Breast J 2001;7:263-5. |
|30.||Badve S, Sloane JP. Pseudoangiomatous hyperplasia of the male breast. Histopathology 1995;26:463-6. |
|31.||Vuitch MF, Rosen PP, Erlandson RA. Pseudoangiomatous hyperplasia of mammary stroma. Hum Pathol 1986;17:185-91. |
|32.||Ibrahim RE, Sciotto CO, Weidner N. Pseudoangiomatous hyperplasia of mammary stroma, Some observations regarding its clinico pathologic spectrum. Cancer 1989;63:1154-60. |
|33.||Rosen PP. Breast Pathology. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2001. |
|34.||Anderson C, Ricci A Jr, Pedersen CA, Cartun RW. Immunocytochemical analysis of estrogen and progesterone receptors in benign stromal lesions of the breast. Evidence for hormonal etiology in pseudoangiomatous hyperplasia of mammary stroma. Am J Surg Pathol 1991;15:145-9. |
|35.||Powell CM, Cranor ML, Rosen PP. Pseudoangiomatous stromal hyperplasia (PASH). A mammary stromal tumor of myofibroblastic differentiation. Am J Surg Pathol 1995;19:270-7. |
|36.||Cohen MA, Morris EA, Rosen PP, Dershaw DD, Liberman L, Abramson AF. Pseudoangiomatous stromal hyperplasia: Mammographic, sonographic, and clinical patterns. Radiology 1996;198:117-20. |
|37.||Asioli S, Eusebi V, Gaetano L, Losi L, Bussolati G. The pre-lymphatic pathway, the rooths of the lymphatic system in breast tissue: A 3D study. Virchows Arch 2008;453:401-6. |
|38.||Damiani S, Eusebi V. Gynecomastia in type-1 neurofibromatosis with features of pseudoangiomatous stromal hyperplasia with giant cells. Report of two cases. Virchows Arch 2001;438:513-6. |
|39.||Zamecnik M, Michal M, Gogora M, Mukensnabl P, Dobias V, Vano M. Gynecomastia with pseudoangiomatous stromal hyperplasia and multinucleated giant cells. Association with neurofibromatosis type-1 Hum Pathol 1995;17:185-91. |
|40.||Damiani S, Eusebi V, Peterse JL. Malignant neoplasms infiltrating pseudoangiomatous stromal hyperplasia of the breast: An unrecognized pathway of tumor spread. Histopathology 2002;41:208-15. |
|41.||Schnitt SJ, Vincent-Saloman A. Columnar cell lesions of the breast. Adv Anat Pathol 2003;10:113-24. |
|42.||Azzopardi JG. Problems in Breast Pathology. Philadelphia: WB Saunders; 1979. |
|43.||Eusebi V, Feudale E, Foschini MP, Micheli A, Conti A, Riva C, et al. Long-term follow-up of in situ carcinoma of the breast. Semin Diagn Pathol 1994;11:223-35. |
|44.||Tavassoli FA, Hoefler H, Rosai J, Holland R, Ellis IO, Schnitt SJ, et al. Intraductal Proliferative Lesions. In: Tavassoli FA, Devilee P, editor. Pathology and Genetics: Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003. p. 63-73. |
|45.||Brogi E, Tan LK. Findings at excisional biopsy (EBX) performed after identification of columnar cell change (CCC) of ductal epithelium in breast core biopsy (CBX) [abstr]. Mod Pathol 2002;15:29A-30A. |
|46.||Harigopal M, Yao DX, Hoda SA, DeLellis RA, Vazquez MF. Columnar cell alteration diagnosed on mammotome core biopsy for indeterminate microcalcifications: Results of subsequent mammograms and surgical excision. Mod Pathol 2002;15:36A. |
|47.||Nasser S, Fan MJ. Does atypical columnar cell hyperplasia on breast core biopsy warrant follow-up excision? Mod Pathol 2003;16:42A. |
|48.||Rosen PP. Columnar cell hyperplasia is associated with lobular carcinoma in situ and tubular carcinoma. Am J Surg Pathol 1999;23:1561. |
|49.||Brogi E, Oyama T, Koerner FC. Atypical cystic lobules in patients with lobular neoplasia. Int J Surg Pathol 2001;9:201-637. |
|50.||Schnitt SJ, Connolly JL, Harris JR, Cohen RB. Radiation induced changes in the breast. Hum Pathol 1984;15:545-50. |
|51.||Kennedy SM, Merino MJ. Histologic evaluation of the effects of chemotherapy and hormonal therapy in residual and tumoral breast tissues: Their significance in diagnoses. Lab Invest 1988;58:47A. |
|52.||Moore GH, Schiller JE, Moore GK. Radiation-induced histopathlogic changes of the breast. The effects of time. Am J Surg Pathol 2004;28:47- 53. |
|53.||Liberman L, Tornos C, Huzjan R, Bartella L, Morris EA, Dershaw DD. Is surgical excision warranted after benign, concordant diagnosis of papilloma at percutaneous breast biopsy? Am J Roentgenol 2006;186:1328-34. |
|54.||Jacobs TW, Connolly JL, Schnitt SJ. Nonmalignant lesions in breast core needle biopsies: To excise or not to excise? Am J Surg Pathol 2002;26:1095-110. |
|55.||Weaver MG, Abdul-Karim FW, al-Kaisi N. Mucinous lesions of the breast: A pathological continuum. Pathol Res Pract 1993;189:873-6. |
|56.||Brenner RJ, Jackman RJ, Parker SH, Evans WP 3rd, Philpotts L, Deutch BM, et al. Percutaneous core needle biopsy of radial scars of the breast: When is excision necessary? Am J Roentgenol 2002;179:1179-84. |
|57.||Hood CI, Font RL, Zimmerman LE. Metastatic mammary carcinoma in the eyelid with histiocytoid appearance. Cancer 1973;31:793-800. |
|58.||Eusebi V, Foschini MP, Bussolati G, Rosen PP. Myoblastomatoid (histiocytoid) carcinoma of the breast: A type of apocrine carcinoma. Am J Surg Pathol 1995;19:553-62. |
|59.||Walford N, ten Velden J. Histiocytoid breast carcinoma: An apocrine variant of lobular carcinoma. Histopathology 1989;14:515-22. |
|60.||Shimizu S, Kitamura H, Ito T, Nakamura T, Fujisawa J, Matsukawa H. Histiocytoid breast carcinoma: Histological, immunohistochemical, ultrastructural, cytological and clinicopathological studies. Pathol Int 1998;48:549-56. |
|61.||Gupta D, Croitoru CM, Ayala AG, Sahin AA, Middleton LP. E-cadherin immunohistochemical analysis of histiocytoid carcinoma of the breast. Ann Diagn Pathol 2002;6:141-7. |
|62.||Fine SW, Li M. Expression of calretinin and the alpha-subunit of inhibin in granular cell tumors. Am J Clin Pathol 2003;119:259-64. |
|63.||Bellocq JP, Magro G. Fibroepithelial tumors In: Tavassoli FA, Devilee P, editors. World Health Organization Classification of TumorsTumors of the Breast and Female Genital Organs. Lyon, France: IARC Press; 2003. p. 99-103. |
Chief Pathologist and Director of Laboratories, Lawrence General Hospital, Lawrence, MA 01842
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
[Table 1], [Table 2], [Table 3], [Table 4]
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