Papillary lesions of the breast: selected diagnostic and management issues

The assessment and categorization of papillary lesions remains one of the most challenging areas in breast pathology. In this review, we will focus on several diagnostic and management issues related to papillary breast lesions that are frequently encountered in daily practice. These include: (i) the distinctions among papillomas with atypia (atypical papillomas), papillomas with ductal carcinoma in situ , and papillary ductal carcinoma in situ ; (ii) recent developments in our understanding of encapsulated ('intracystic') papillary carcinomas and solid papillary carcinomas; and (iii) the impact of core needle biopsy on management decisions and specimen evaluation. The role of immunohistochemistry in the evaluation of these lesions, particularly the role of myoepithelial cell markers, will be emphasized.     

Encapsulated apocrine papillary carcinoma of the breast: Case report with clinicopathologic and immunohistochemical study

We describe a case of encapsulated papillary carcinoma (EPC), apocrine variant in a 50‐year‐old woman. The patient presented a cystic lesion in her right breast, measuring 8 cm in diameter, containing three solid papillary nodules. A fine‐needle aspiration showed isolated apocrine cells containing round nuclei, irregular nuclear membranes, fine chromatin, and prominent macronucleoli. The lesion was excised and showed a pure papillary apocrine carcinoma, which stained diffusely with GCDFP‐15 and androgen receptors. The lesion was totally devoid of myoepithelial cells (smooth muscle actyn, p63, calponin, and collagen IV stains were negative). With MIB1 the proliferative activity was 10%. To the best of our knowledge, this is the first report of EPC apocrine variant with cytologic and immunohistochemical study. This lesion must be included in the list of apocrine lesions of the breast. Diagn. Cytopathol. 2010. © 2010 Wiley‐Liss, Inc.     

Papillary lesions of the breast

Papillary lesions include benign and malignant lesions. As this array of papillary lesions cannot be differentiated by clinical and imaging means, the diagnosis relies on pathologic examination. Intraductal papillomas are benign, and often complicated by superimposed epithelial metaplasia or hyperplasia. When they are involved by atypical duct hyperplasia, the prevailing practice is to upgrade the diagnosis to ductal carcinoma in situ when the extent of involvement is ≥3 mm. Intraductal papillary carcinomas has low grade malignant epithelial changes, retaining an outer myoepithelial layer but lost the myoepithelial cells within the lesion around fibrovascular cores. Encapsulated papillary carcinomas and solid papillary carcinomas have distinctive morphology, but both are characterized by frequent loss of myoepithelial cells surrounding the lesion, although the current classification still consider these to be in situ lesions. Invasion is used for irregular groups, tongues and nests of tumor cells extending into the stroma beyond the rounded boundary. Immunohistochemistry is useful in differentiating papillary lesions, with positivity of myoepithelial markers, high molecular weight cytokeratins and heterogeneous staining of ER denoting benignity and vice versa. Core needle biopsy is frequently used in diagnosing papillary lesions: both under- and over-diagnoses may occur, the former being more frequent. Genetically papillary carcinomas are grouped mostly into luminal cancers, further attesting to the generally low grade nature of all subtypes of papillary carcinomas.     

Loss of myoepithelium is variable in solid papillary carcinoma of the breast

AIMS: Reports on the frequency of myoepithelial loss in solid papillary carcinoma (SPC) of the breast, an unusual variant of papillary carcinoma with a solid pattern of expansile growth, have been strikingly contradictory. The aim was to clarify the frequency of myoepithelial loss in cases of SPC diagnosed at our institution. METHODS AND RESULTS: Eleven cases of SPC with available blocks or unstained slides were retrieved from the M. D. Anderson archives or obtained from outside contributors. Immunohistochemistry for smooth muscle actin (SMA) and p63 was evaluated on the circumscribed nests that appeared to be non-invasive by haematoxylin and eosin morphology. Three of the 11 cases (27%) were positive for both SMA and p63 at the periphery of all such foci, whereas eight cases (73%) lacked staining for both myoepithelial markers in at least one focus. Of these eight cases, one was diagnosed with only microinvasion, yet metastatic tumour resembling the circumscribed primary SPC was identified in two ipsilateral axillary lymph nodes. CONCLUSIONS: SPC of the breast frequently lacks myoepithelial markers at the tumour-stromal interface in spite of a circumscribed non-invasive appearance. Metastases from such tumours are infrequent, but can occur in cases that lack myoepithelial marker expression by immunohistochemistry.     

Composite encapsulated papillary carcinoma and solid papillary carcinoma

Encapsulated papillary carcinoma (EPC) and solid papillary carcinoma (SPC) are distinctive variants of intraductal papillary carcinomas, each accounting for <1% of breast carcinomas. Here we report a composite carcinoma consisting of EPC and SPC. A 73‐year‐old woman was found to have a high density mass in the left breast on mammogram. A biopsy showed intermediate to high grade ductal carcinoma in situ (DCIS). Gross examination of the lumpectomy specimen revealed a solid, multinodular mass. Microscopic examination demonstrated two morphologically distinct intraductal carcinomas intermingled with each other. One had delicate papillae in multi‐cystic spaces surrounded by thick fibrous capsule, consistent with EPC. The other had solid tumor nests with delicate fibrovascular cores. The cells were monotonous with round nuclei and salt and pepper‐like chromatin, characteristic of SPC. The lack of myoepithelial cells within the papillae and at the periphery of the lesion was confirmed by immunostaining for p63 and CK5/6. Neuroendocrine differentiation of SPC was demonstrated by neuron specific enolase staining. To our knowledge, this is the first reported case of composite EPC and SPC. It raises an interesting question as to a possible common pathway of carcinogenesis of these two rare variants.     

乳腺实性乳头状癌伴浸润性癌临床病理分析

目的探讨乳腺实性乳头状癌(solid papillary carcinoma,SPC)伴浸润性癌的临床病理特点、组织学特征和免疫表型。方法收集乳腺SPC伴浸润性癌8例,总结该组病变的临床资料,采用HE及免疫组化En Vision两步法染色检测组织病理学特征。结果乳腺SPC伴浸润性癌好发于老年女性,平均发病年龄55.5岁,其发生率约占SPC总病例的30%。肿瘤最常见的临床特征为乳腺肿块和乳头溢液,伴浸润癌常见的类型为乳腺非特殊类型癌和黏液癌,亦常伴神经内分泌分化。SPC伴浸润性癌时,浸润癌周边及其癌巢内肌上皮染色均为阴性。SPC与伴随的浸润癌区域ER、PR均阳性且阳性率较高(≥70%),HER-2均阴性,Ki-67增殖指数均≤10%。神经内分泌免疫组化标记Cg A及Syn均双阳性或单个阳性。结论 SPC可能是低级别乳头状导管原位癌的变异型,其具有进展为其他类型乳腺浸润性癌的潜能。SPC可能为伴神经内分泌分化乳腺黏液癌及非特殊类型癌原位癌阶段的病变。     

Aspiration cytology of cystic carcinoma of the breast

Cystic carcinomas of the breast are rarely encountered in fine-needle aspiration (FNA) biopsies. The most common entities comprise intracystic papillary adenocarcinoma, ductal adenocarcinoma with cystic degeneration including comedo forms of ductal adenocarcinoma in situ, medullary carcinoma, squamous carcinoma, and cystic hypersecretory ductal adenocarcinoma. The cytologic diagnosis is often hampered by sparse cellularity, abundant obscuring blood, necrotic debris, and degenerative changes in diagnostic cells. We report on the cytologic features of 10 cases of cystic carcinoma, including 12 FNA biopsies with radiologic and surgical correlation. The original cytologic diagnoses for these cases were: benign (2 cases), atypical (2 cases), suspicious (3 cases), and positive for malignant cells (3 cases). On repeat FNA, one benign case and one atypical case were reclassified, respectively, as atypical and suspicious for carcinoma. The follow-up diagnoses were 5 intracystic papillary adenocarcinomas and 5 cystic ductal adenocarcinomas. Despite 2 false-negative cases, all cases were adequately managed. Correlation with clinical and radiologic findings and direct sampling of any solid component of these cystic neoplasms are crucial in diagnosis and management.     

Cytological study of 20 cases of solid-papillary carcinoma of the breast

Solid-papillary carcinoma (SPC) of the breast is a rare variant of low-grade intraductal carcinoma but there are few cytological studies. We examined 20 cases of SPC of the breast, aged 31-80 (mean age 66.0 yr), to define the cytological features. In each of the cytological specimens, we could find both malignant and benign cytological features; the former were characterized by hypercellularity, highly discohesive clusters, numerous isolated cells, and severe overcrowding cells, while the latter were marked by small and bland nuclei, a low nuclear-cytoplasmic ratio, and inconspicuous nucleoli. Neither abnormal naked nuclei of tumor cell origin nor oval naked nuclei of myoepithelial cell origin were seen.We also reviewed the cytological findings of SPC as well as neuroendocrine carcinomas with intraductal components that had been reported and we concluded that the coexistence of malignant and benign features was the most characteristic cytological feature of SPC.     

Papillary carcinoma of the breast in a male patient with a treated prostatic carcinoma diagnosed by fine-needle aspiration biopsy: a case report and review of the literature

Papillary carcinoma of the male breast is very rare. In this case report, we describe the cytologic, histologic, immunohistochemical, and radiological findings of a papillary carcinoma of male breast. A 67-yr-old man, who had a previous history of prostatic adenocarcinoma, presented with a retroareolar painless mass. There was no known history of breast cancer in his family. A fine-needle aspiration biopsy (FNAB) was performed. Cytological examination revealed a cellular aspirate with three-dimensional papillary clusters. A diagnosis of papillary lesion favoring papillary carcinoma was rendered. Immunohistochemical staining of the cell-block of the FNAB revealed the presence of mammaglobin, and the absence of prostatic specific antigen. The patient underwent lumpectomy, which showed a moderately differentiated infiltrating papillary carcinoma with adjacent areas of ductal carcinoma in situ. FNAB is a useful technique in identifying male breast carcinoma. In conjunction with ancillary studies, this procedure can effectively differentiate between a primary versus metastatic lesion.     

Solid Papillary Carcinoma of Breast: An Ultrastructural Study

Solid papillary carcinoma of the breast is a subset of papillary carcinoma, which occurs in older women and usually has a favorable prognosis. It is primarily intraductal but also is often associated with invasive carcinoma, especially mucinous carcinoma. Intracellular and extracellular mucin is also found in the in situ stage, in most tumors. In addition to forming solid papillary masses, the cells palisade around vessels in pseudo-rosettes and show minimal nuclear atypia. Some cells show neuroendocrine differentiation, based on argyrophilia with Grimelius staining. Four examples of this neoplasm were studied electron microscopically. Myoepithelial cells were not found. Neoplastic cells had an ultrastructure that was generally similar to that of other types of mammary carcinoma. There were extracellular microlumens, but intracellular lumens and pseudolumens were few or absent. Secretory activity varied among cells, and those cells appearing active had a variety of granule types, including typical flocculent and “bull's-eye” mucinous granules, small dense-core granules, and large serous-like granules. Some of the dense-core granules were interpreted as neuroendocrine in nature, based on their abluminal or juxtavascular location, whereas others that were apical and subluminal were probably mucinous in type. The large serous-appearing granules were subluminal in some cells and diffuse in others and may also have represented a variant of mucinous granules. The results support earlier opinions that accurate interpretation of specific granular function at the electron microscopic level depends on cytochemical studies using uranaffin as a marker of neuroendocrine activity. Although mucinous granules are identified by their lack of staining with uranaffin, the nature of the serous-appearing granules would still not be answered by this method; that is, a negative reaction would not define whether the granules are truly serous, or simply another form of mucin. Regardless of limitations of this type, correlation and extrapolation of histo-chemical (Grimelius and Alcian blue) and immunohistochemi-cal (chromogranin and synaptophysin) results with subcellular structure are still very useful in establishing cell type.     

乳腺实性乳头状癌73例临床病理诊断

目的对乳腺实性乳头状癌(solid papillary carcinoma,SPC)的临床病理特征和免疫表型特点、预后和鉴别诊断进行探讨。方法收集伴或不伴有浸润癌的SPC共73例,总结其临床资料、大体和组织病理特征,并行透射电镜观察及免疫组织化学EnVision法染色。选用抗体包括CK、肌上皮标记、神经内分泌标记、增殖标记Ki-67和ER、PR、c-erbB-2等。结果本病好发于老年女性,发病平均年龄64.7岁。肿瘤最常见的临床症状为乳腺肿块和乳头溢液。行腋窝淋巴结清扫术43例中有31例检出癌转移。镜检所有标本均见到实性乳头状病变,25例伴有黏液分泌。周边常可伴有导管内乳头状瘤。肿瘤细胞呈多边形、卵圆形或梭形,呈印戒样。胞质丰富,呈嗜酸性或细颗粒状。细胞核轻度或中度异型,51例核分裂象5个/10HPF。43例伴发浸润癌。肿瘤基底型CK表达呈阴性。平滑肌肌动蛋白SMA、p63在乳头轴心肌上皮的阳性率分别为91.8%、67.1%,在导管周围肌上皮的阳性率分别为91.8%,73.9%。CgA和Syn以及NSE阳性率分别为89.0%,86.3%,95.9%。Ki-67平均阳性指数为10.2%。73例行ER、PR染色的肿瘤大部分呈阳性,Her-2大部分呈阴性。电镜下可见到细胞内的神经内分泌颗粒。结论乳腺SPC是一种低度恶性的乳腺导管内癌,好发于老年女性,有其独特的组织形态、免疫组织化学特征,部分SPC与乳腺黏液癌和神经内分泌癌相关。随访资料显示SPC具有良好的预后。     

Solid-papillary carcinoma of the breast: clinicopathological study of 20 cases

The purpose of the present paper was to evaluate the clinicopathological and biological features of 20 Japanese patients with solid-papillary carcinoma of the breast (SPC) or SPC associated with invasive breast cancer. All the patients were Japanese women, including two sisters. The mean age was 66.0 years. The incidence of SPC among all the breast cancers treated at two institutions was 1.1% and 1.7%, respectively. The mean disease-free interval was 4 years 11 months. Axillary lymph node metastasis or tumor recurrence did not occur in any of the cases. Fifteen cases of SPC contained invasive cancers that ranged from <5% to 60% of the entire tumor area. Histological types of invasive cancers were mucinous carcinoma in five cases and neuroendocrine cell carcinoma in 10 cases. These results indicate that SPC is a potential precursor lesion for neuroendocrine carcinoma as well as mucinous carcinoma. When all the cases were classified and analyzed according to both the 2002 tumor node metastasis (TNM) classification system and the Nottingham histological grade, SPC patients, even those with invasive cancers, seemed to have longer disease-free survival compared to patients with the other invasive breast cancers of matching grade and stage. Clinicopathologically, SPC could be regarded as a separate type of ductal carcinoma in situ.     

乳腺实性乳头状癌11例临床病理分析

目的探讨乳腺实性乳头状癌的临床病理学特点、免疫表型。方法对11例乳腺实性乳头状癌的临床病理学特点、免疫表型及淋巴结转移情况进行分析。结果 11例实性乳头状癌均为女性,8例为原位癌,3例伴浸润癌成分,平均年龄63.2岁。11例实性乳头状癌均表现为乳腺肿块,其中3例为乳头溢血。所有病例大体界限清楚,肿瘤细胞围绕纤细的纤维血管轴心呈实性结节状增生,肿瘤细胞形态单一,核染色质细腻,核分裂象5个/10 HPF,8例可见细胞内外黏液。免疫表型:ER、PR均弥漫强阳性,CK5/6和HER-2均阴性,5例在瘤巢周围可见稀少的p63阳性细胞,4例瘤巢周围可见CK5/6和CD10阳性细胞,3例伴浸润癌成分者,瘤巢周围无p63、CK5/6、CD10阳性细胞;5例表达神经内分泌免疫标记Syn,6例表达Cg A。9例行腋窝淋巴结清扫术,其中1例发生淋巴结转移。结论乳腺实性乳头状癌是一种少见的好发于老年女性的乳腺癌,以肿瘤细胞排列呈实性乳头状结节为特征,常有细胞内外黏液分泌,为腺腔A型乳腺癌的免疫表型,并表达神经内分泌免疫标记,预后良好,较少发生腋窝淋巴结转移。     

Oncocytic carcinoma of the breast: frequency, morphology and follow-up

Oncocytic breast carcinomas are tumors composed of no fewer than 70% of oncocytic cells (World Health Organization). The purpose of this study was to determine the frequency, morphologic, immunohistochemical, and clinical features of invasive oncocytic carcinoma in a large series. Twenty-eight cases of putative oncocytic breast carcinoma (selected cases group) and 76 consecutive cases of invasive breast carcinoma (consecutive cases group) were analyzed. Immunohistochemistry for mitochondria, gross cystic disease fluid protein 15, chromogranin, estrogen receptor, progesterone receptor, androgen receptor, HER2/Neu, cytokeratin 7, cytokeratin 14, epithelial membrane antigen, and differentiation cluster 68 was performed. Score for mitochondria was based on intensity and percentage of immunopositive cells. Classes were as follows: (1) oncocytic carcinoma: at least 70%, 3+; (2) mitochondrion-rich carcinoma: 50% to 70%, 3+, or more than 50%, 2+; and (3) all the other cases were referred to as invasive breast carcinoma. Ultrastructural examination was available for 6 cases of oncocytic carcinoma. Morphologic and immunohistochemical features of the 3 groups were compared using Fisher exact test (P < .05). For overall survival analysis, Kaplan-Maier curves were compared using log-rank and Wilcoxon tests (P < .05). Our results suggest that oncocytic breast carcinoma is a morphologic entity with distinctive histologic and ultrastructural features. Mitochondrion-rich carcinomas are histologically similar to oncocytic carcinomas and constitute 19.7% of all invasive carcinomas, indicating that cytoplasmic eosinophilia in breast cancer cells is often due to accumulation of mitochondria. Oncocytic carcinomas and mitochondrion-rich carcinomas are more often grade III tumors and show human epidermal growth factor receptor 2 overexpression. Clinical features and overall survival of oncocytic carcinomas are not distinctive because they are similar to those of the other cases when matched for grade and stage.     

Stromal changes in invasive breast carcinoma: an ultrastructural study

The stroma in infiltrating breast carcinomas, with particular reference to stromal spindle cells, has been studied by electron microscopy. A mixture of cells including resting fibroblasts, active fibroblasts, early myofibroblasts, and mature myofibroblasts has been identified. In loose stroma, myofibroblasts possessed prominent organelles and showed secretory products along the cell surface, whereas in dense stroma, there was relative prominence of cytoplasmic filaments as well as other features consistent with a contractile state of myofibroblasts. The degree of myofibroblastic proliferation was related to the growth pattern of the tumour. It is suggested that the infiltrating process of cancer cells is analogous to wound production and healing with continuous granulation tissue and scar formation resulting in the characteristic desmoplastic reaction seen in certain breast carcinomas.     

Fine‐needle aspiration cytology of solid papillary carcinoma of the breast

We report a case of solid papillary carcinoma (SPC) of the breast, of which the cytologic findings of the nipple discharge and the fine needle aspiration (FNA), and the pathology of the resected tumour are described in detail. Imaging studies demonstrated an intra‐ductal tumour of the breast, which seemed responsible for the bloody nipple discharge. The cytologic features of the nipple discharge and the FNA targeted to the intra‐ductal tumour suggested low‐grade carcinoma. Additional findings of mucin production and rosette‐formation (possibly neuroendocrine differentiation) indicated SPC as a major differential diagnosis. Histologically, the lesion consisted of mainly ductal proliferation of low‐grade carcinoma associated with prominent rosette formation within the tumour and mucin production. Permeation of mucin with cancer cell clusters into the adjacent adipose tissue was also noted. Immunohistochemically, the tumour cells, especially those forming rosettes, were partially positive for CD56. Histological diagnosis was SPC with invasion. SPC is a rare tumour, and its cytologic and pathologic features have only been sporadically reported. Our case was unique in that there was a good correlation between cytologic and histologic findings. The cytologic findings that are important to predict the histologic diagnosis are emphasized. A brief review of the relevant literature is also included.