Uncommon morphologic patterns of lobular neoplasia.

Discussions of the morphology of lobular neoplasia (atypical lobular hyperplasia and lobular carcinoma in-situ) usually emphasize the commonplace characteristics. Occasional cases deviate from the expected appearance and thereby cause diagnostic confusion. Unusual cytologic alterations include the formation of signet-ring cells and the presence of nuclear pleomorphism. The growth of lobular neoplasia in breast tissue altered by atrophy, sclerosing adenosis, collagenous spherulosis, and benign tumors gives rise to unexpected patterns that one might mistake for normal tissue, invasive carcinoma, or ductal carcinoma in situ. Solid involvement of ducts by lobular neoplasia and uncommon forms of "pagetoid" growth both resemble the appearance of atypical ductal hyperplasia or ductal carcinoma in situ. The authors illustrate these unusual cytologic and architectural findings and discuss features that permit proper diagnosis and interpretation.     

E-cadherin expression in pleomorphic lobular carcinoma: an aid to differentiation from ductal carcinoma

Pleomorphic lobular carcinoma is a recently described entity separated from classical lobular carcinoma by cytologic pleomorphism. It can have an aggressive clinical course with a higher frequency of recurrence. Histologic differentiation with ductal carcinoma may be difficult, but it is important for this differentiation to be made. E-cadherin is a transmembrane glycoprotein, and complete loss of E-cadherin expression has been observed in invasive lobular carcinoma and lobular carcinoma in situ. Ductal carcinoma retains at least some expression of E-cadherin. We examined the pattern of E-cadherin expression in a series of 14 cases of pleomorphic lobular carcinoma by immunohistochemistry. Twelve of the 14 cases showed no staining (86%); the remaining two cases exhibited 10% to 25% positive cells. In cases with histologic equivocal features, immunohistochemical detection of E-cadherin expression can be a useful diagnostic aid for the differentiation of pleomorphic lobular and ductal carcinoma.     

Invasive pleomorphic lobular carcinoma, negative for ER, PR and Her/2neu--a case report

Pleomorphic variant of lobular carcinoma is a recently described variant of invasive lobular carcinoma. It is reported to be positive for estrogen receptors and progesterone receptors and over express Her2/neu in most cases. We present here a case of invasive variant of pleomorphic lobular carcinoma with coexisting classic and pleomorphic variants of lobular carcinoma in situ along with focal ductal carcinoma in situ. The immunohistochemical results on hormone receptors and high molecular weight cytokeratins in all the above components of the tumor are presented. The invasive tumor was negative for estrogen receptors, progesterone receptors and Her2/neu. Most foci of lobular carcinoma in situ showed morphogenic heterogeneity and a corresponding heterogeneous staining for hormone receptors. The high molecular weight cytokeratins (CK5/6 and CK 903) were non contributory in establishing diagnosis.     

Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation.

Pleomorphic lobular carcinoma of the breast is a recently recognized subtype of invasive lobular carcinoma (ILC). Cytologic features are pleomorphic to a degree that contrasts with the cytologic uniformity of classic ILC. It is this feature that simultaneously gives its name to the tumor and highlights the difficulty of identifying it correctly and distinguishing it from ductal carcinoma. In our series of 10 cases, six tumors also contained lobular carcinoma in situ. Nodal metastases were typically sinusoidal. All tumors showed the dissociated, linear, and single file pattern of classic ILC, together with a targetoid distribution. Intracytoplasmic lumina were present in 50% of the tumors. An eosinophilic, slightly granular cytoplasm suggests the possibility of apocrine differentiation, a suggestion derived also from the frequent presence of foamy cells, a cell type previously identified in histiocytoid lobular carcinoma and shown to have apocrine features. The GCDFP-15 apocrine marker was positive in all 10 tumors, while all control ILCs were negative, confirming the presence of apocrine differentiation in pleomorphic lobular carcinoma. Six of 10 patients died within 42 months of diagnosis. Three other patients developed recurrence or distant metastases at short intervals. Pleomorphic lobular carcinoma is a very aggressive tumor. This behavior is perhaps predictable on the basis of tumor size at presentation and the frequency of nodal metastases. Since grading of lobular carcinoma is difficult, recognition of the pleomorphic subtype is useful in identifying a lethal variant.     

Histiocytoid breast carcinoma: an enigmatic lobular entity

Histiocytoid breast carcinoma is an uncommon entity that is mostly regarded as a variant of lobular carcinoma. Its occurrence with apocrine lobular carcinoma in situ and consistent expression of gross cystic disease fluid protein 15 suggest apocrine differentiation. Its recognition is often challenging, particularly when histiocytoid tumour cells occur in a metastatic site before the primary diagnosis of breast carcinoma, or in limited core biopsy or cytology material. In the breast, its bland histological appearances can lead to a benign diagnosis. Clues to the correct conclusion include finding tumour cells with more cytological atypia, the presence of cytoplasmic vacuoles and secretions, coexistence with more traditional invasive lobular carcinoma patterns and/or lobular neoplasia, and the use of immuohistochemistry to confirm their epithelial nature. Close clinicoradiological correlation and awareness of histological mimics are needed to achieve an accurate diagnosis of this enigmatic condition that should be appropriately subsumed within the invasive lobular histological subtype.     

Invasive ductal carcinoma of the breast with a microglandular adenosis pattern

Invasive breast carcinomas of special type are composed of up to 35% of all cases, such as tubular carcinoma, mucinous carcinoma, invasive cribriform carcinoma, lobular carcinoma, metaplastic carcinoma, medullary carcinoma, and other rare variants. They are recognized by their specific growth and morphologic patterns, glandular differentiation, and cytologic and nuclear features. These features are also present as a focal or minor component in many carcinomas of no special type. In addition, there are a number of lesions that are mimickers of invasive carcinoma, which can sometimes create diagnostic difficulties. It is important for pathologists to recognize these histologic variants and mimickers of breast carcinoma, particularly in evaluating needle or core biopsies. We report a case of a 64-year-old woman with breast carcinoma of no special type with areas having features with resemblance to microglandular adenosis. Differential diagnosis and their histologic features are discussed.     

Fine-needle aspiration biopsy of invasive micropapillary carcinoma of the breast: a report of five cases

Invasive micropapillary carcinoma of the breast is an uncommon variant of infiltrating ductal carcinoma. Observing its distinctive cytologic appearance and aggressive behavior is important for early diagnosis by fine-needle aspiration cytology (FNAC). There are only a few reported cases in the literature. Five women presented with breast masses. FNAC showed malignant epithelial tumors, and mastectomy materials showed invasive micropapillary carcinoma for all of them. Three patients had axillary lymph node metastases. Invasive micropapillary carcinoma, with its angulated papillary clusters lacking a fibrovascular core, and irregular crowded nuclei, has a distinctive cytologic appearance which correlates with its histological features. A differential diagnosis from other primary or metastatic papillary lesions of the breast may be possible using immunohistochemistry and some cytologic features. The limited experience with invasive micropapillary carcinoma should not discourage others from undertaking further studies.     

Lobular carcinoma in situ diagnosed by core needle biopsy: when should it be excised?

Core needle biopsy is the preferred technique for evaluating breast masses and abnormal mammographic findings. The frequency of detection of noninvasive lobular lesions by core needle biopsy is increasing. Historically, the diagnosis of lobular carcinoma in situ has been considered a risk factor for the development of invasive carcinoma, and treatment has consisted of careful clinical follow-up with or without chemopreventive therapeutic agents such as tamoxifen citrate. We retrospectively reviewed core needle biopsy material with the primary diagnoses of lobular carcinoma in situ, atypical lobular hyperplasia, and lobular neoplasia in conjunction with clinical and radiographic findings to make recommendations as to when excision may be merited. We searched our database for core needle biopsy cases with lobular carcinoma in situ, atypical lobular hyperplasia, and lobular neoplasia as the primary diagnosis. Microcalcifications had been sampled with a stereotactically guided, 11 G Mammotome biopsy device, and masses had been sampled with an ultrasound guided, 18 G core needle. Glass slides were reviewed and histological parameters assessed. Mammographic findings were reviewed, and clinical information was obtained from the medical record. When available, excisional biopsy material was reviewed. The 2337 breast core needle biopsies performed from January 1995 to December 2001 included 35 (1.5%) with classic lobular carcinoma in situ (14), lobular neoplasia (4), and atypical lobular hyperplasia (17) as the primary diagnosis. Twelve of these 35 cases (34%) had histological evidence of microcalcifications directly associated with the lobular carcinoma in situ, lobular neoplasia, atypical lobular hyperplasia. Radiologic review revealed 21 calcifications, 6 ultrasonographic masses, and 8 mammographic masses and/or architectural distortions. Excisional biopsy had been performed in 17 cases (49%). In six cases diagnosed as in situ on core needle biopsy, excisional biopsy revealed invasive carcinoma. All of these patients had radiographically detectable masses. Eleven cases had excisional biopsies that showed histology similar to that of the core needle biopsies. The most important predictor of invasive carcinoma on excision was a synchronous mass lesion. Lobular carcinoma in situ involving adenosis and lobular carcinoma in situ with pagetoid spread on core needle biopsies did not show a histologically more aggressive lesion on excision and, therefore, may not require additional surgery. Histologically identified calcifications were associated with lobular lesions 34% of the time; however, their presence inside an in situ lobular lesion did not portend worse pathology on re-excision and should not be a criterion for excision. Based on these findings, we recommend excisional biopsy of lobular carcinoma in situ, atypical lobular hyperplasia or lobular neoplasia only when it is associated with a synchronous mass lesion.     

“Carcinoid” tumor of the breast: A variant of conventional breast cancer?

A breast tumor with the morphologic features of a carcinoid tumor and containing large amounts of estrogen receptor protein was associated with areas of typical in situ and infiltrating lobular carcinoma. The carcinoid areas were argyrophilic and ultrastructurally contained electron dense granules on which silver grains were localized. Of 21 other examples of ordinary breast cancer, five showed histologic similarities to carcinoid tumors. Focal argyrophilia was observed in 11 invasive tumors. The presence of argyrophilic granules could not be correlated with the presence of “neurosecretory” granules, although groups of such granules were found in one case of in situ lobular carcinoma. Argyrophilic and “neurosecretory” granules imply the presence of hormonal substances, although in breast tumors these granules have not yet been chemically or immunochemically characterized. Until such evidence becomes available it would appear that most cases reported as primary carcinoid tumors of the breast have much more in common with conventional breast cancer than with the usual carcinoid tumor. Within this context it can be acknowledged that some breast cancers may focally exhibit a carcinoid-like differentiation.     

Invasive lobular carcinoma: to grade or not to grade.

Grading of invasive ductal carcinoma of no special type using the Nottingham combined histologic grading system provides independent prognostic information. The prognostic utility of grading invasive lobular carcinomas, however, has not been fully elucidated. In addition, the relationship between grade in invasive lobular carcinomas and expression of predictive biomarkers is less certain. The purpose of this study was to correlate histologic grade in invasive lobular carcinoma with known prognostic and predictive markers. All primary resections for invasive mammary carcinomas diagnosed in Mount Sinai Hospital, Toronto, between the years 1996 and 2002 were reviewed (n=1053). Of these cases, 50 were pure invasive lobular carcinoma (incidence 4.7%). The median age at diagnosis was 64 years. These tumors were graded using the Nottingham combined histologic grading system and analyzed for estrogen receptor, progesterone receptor, HER2/neu and E-cadherin expression. Tumor grade was correlated with tumor size (P=0.03), and the American Joint Committee on Cancer nodal status (P=0.05). Assessment of the individual components of grade showed that the mitotic score was highly correlated with tumor size (P=0.02), lymph node positivity (P=0.02) and overall American Joint Committee on Cancer stage (P=0.01). Estrogen receptor and progesterone receptor were highly expressed irrespective of the grade of tumor. HER2/neu protein overexpression and E-cadherin protein expression was absent in all invasive lobular carcinomas studied. We conclude that pure invasive lobular carcinoma is uncommon and occurs predominantly in postmenopausal women. Increasing tumor grade is correlated with median tumor size and the American Joint Committee on Cancer nodal stage, but not correlated with the expression of estrogen receptor, progesterone receptor, E-cadherin or HER2/neu protein overexpression.     

Tubulolobular carcinoma of the breast with grooved and cerebriform nuclei: failure to identify this specific subtype in a case during routine fine needle aspiration cytology and histopathological diagnosis

Tubulolobular carcinoma (TLC) is a rare tumor of the breast in which histologic features of both tubular and lobular carcinoma are combined. We report a case of TLC, in which the specific subtype was missed at routine cytologic and histopathological examination. A 69-year-old woman presented with a right breast lump. Imaging studies indicated a malignant lesion in right upper quadrant. Routine fine needle aspiration (FNA) cytology diagnosis was a duct cell carcinoma (small cell type). In a setting of cystic thyroid lesions, presence of excessive nuclear grooves, and rare intranuclear cytoplasmic inclusion, metastatic papillary thyroid carcinoma was also considered. However, both these possibilities were not supported by immunocytochemical findings (estrogen receptor+, thyroglobulin-, and chromogranin-). The histopathology diagnosis was invasive duct cell carcinoma. Review of FNA smears and paraffin sections led to the diagnosis of TLC, which was supported by positive immunohistochemical stainings for markers like e-cadherin and β-catein.     

Signet Ring Cells in Breast Carcinoma

Two cases of breast carcinoma composed predominantly of neoplastic cells with a signet ring appearance, one a case of invasive lobular carcinoma (ILC) and the other a case of invasive ductal carcinoma (IDC), were examined electron microscopically and immunohistochemically. In signet ring cells in the ILC, mucin was demonstrated ultrastructur-ally in the intracytoplasmic lumina and also to a small degree in the cytoplasmic mucous granules, whereas in signet ring cells in the IDC, mucin was found only in the cytoplasmic mucous granules. Immunohistochemically, signet ring cells in the ILC were intensely positive for gross cystic disease fluid protein (GCDFP-15), but those in the IDC showed no immunoreaction for GCDFP-15. Thus ultrastructural features and GCDFP 15 immunoreactivity appear to be useful for distinguishing between the two different types of signet ring cells.     

Alveolar Variant of Invasive Lobular Carcinoma of the Breast: An Electron Microscopic Study

Four cases of alveolar variant of invasive lobular carcinoma of the breast were examined by electron microscopy, and their appearance compared with those of in situ and classical invasive lobular carcinoma. The individual tumor cells in the alveolar variant were basically similar to those described in the other two lobular tumors. The neoplastic alveoli consisted mostly of light cells, although a few dark cells were sometimes seen at the periphery. The nuclei were large, rounded and rich in euchromatin. The cytoplasm contained a variable amount of mitochondria and endoplasmic reticulum, and a few cells had intracytoplasmic filaments. Numerous tumor cells with membrane-bound electron-dense granules were occasionally seen. A few cells also had intracytoplasmic lumina. Tumor cells were usually seen in close contact with each other. Interdigitating processes and desmosomes were present. In general the tumor cells were not surrounded by basal lamina, but most alveoli were surrounded by elongated fibroblasts or myofibroblasts. These findings confirm both the lobular and the invasive nature of this distinct variant of breast carcinoma.     

Signet ring cells in breast carcinoma. An immunohistochemical and ultrastructural study.

Two cases of breast carcinoma composed predominantly of neoplastic cells with a signet ring appearance, one a case of invasive lobular carcinoma (ILC) and the other a case of invasive ductal carcinoma (IDC), were examined electron microscopically and immunohistochemically. In signet ring cells in the ILC, mucin was demonstrated ultrastructurally in the intracytoplasmic lumina and also to a small degree in the cytoplasmic mucous granules, whereas in signet ring cells in the IDC, mucin was found only in the cytoplasmic mucous granules. Immunohistochemically, signet ring cells in the ILC were intensely positive for gross cystic disease fluid protein (GCDFP-15), but those in the IDC showed no immunoreaction for GCDFP-15. Thus ultrastructural features and GCDFP-15 immunoreactivity appear to be useful for distinguishing between the two different types of signet ring cells.     

Cytologic diagnosis of invasive lobular carcinoma: factors associated with negative and equivocal diagnoses

Fine-needle aspiration biopsy (FNAB) of invasive lobular carcinoma (ILC) is associated with notoriously high rates of false negative and equivocal diagnoses. To identify causative factors, we reviewed the cytologic features of presurgical FNAB smears of ILC and correlated the cytologic findings with the number of passes, tumor size, mammographic findings, and the histologic characteristics of the tumor. Smear cellularity, presence of single intact epithelial cells, nuclear size, nuclear atypia, palpability of the tumor, and histologic type of ILC (classic versus nonclassic) were statistically significant in establishing an unequivocally positive diagnosis. We also found that the cytologic cellularity of the lesion does not reflect the actual cellularity of the tumor but instead is an indicator of the architectural arrangement of the neoplastic cells; tumors that form epithelial cell groups, such as in nonclassic ILC, tend to yield more cellular aspirates that are diagnostic for carcinoma. In contrast, classic ILC, in which single neoplastic cells are embedded in fibrous stroma, is more likely to yield a paucicellular smear with subtle atypia and rare single intact epithelial cells. As such, an inconclusive diagnosis in a certain percentage of classic ILC cases may be unavoidable.     

Histiocytoid breast carcinoma: an apocrine variant of lobular carcinoma

Two cases of in situ and invasive histiocytoid breast carcinoma are described. The invasive components of both tumours showed architectural and cytological similarities to lobular carcinoma. The in situ components showed areas of classical lobular carcinoma in situ, areas of lobular carcinoma with apocrine features and areas with transitional features. It is concluded that histiocytoid carcinoma represents an apocrine variant of lobular carcinoma. Differentiation of this tumour from chronic sclerosing inflammation may be difficult in both primary and secondary lesions.     

Unusual presentation of granulocytic sarcoma in the breast: a case report and review of the literature

This is a case of granulocytic sarcoma presenting as bilateral breast masses in a 40-yr-old woman with concurrent unsuspected chronic myeloid leukemia diagnosed by fine-needle aspiration. The granulocytic differentiation was recognized on Diff-Quik-stained cytology smears and confirmed rapidly on flow cytometry on the same day. The breast has been reported to be an uncommon site for granulocytic sarcoma. We found that 38.8% of granulocytic sarcomas diagnosed by fine-needle aspiration in the English-language literature occurred in the breast. In the absence of clinical history or hematological abnormality, granulocytic sarcoma may be misdiagnosed, depending on the degree of myeloid differentiation present within the tumor. The differential diagnosis includes large-cell non-Hodgkin's lymphoma, lobular carcinoma of the breast, undifferentiated carcinoma, malignant melanoma, extramedullary hemopoiesis and inflammation. The key morphological features and useful ancillary tests are discussed.     

对乳腺浸润性导管癌和浸润性小叶癌鉴别诊断的探讨

目的 探讨组织形态上易混淆的浸润性导管癌(IDC)与浸润性小叶癌(ILC)的鉴别诊断方法 .方法 收集北京大学第一医院1998年1月至2001年12月4年间普通外科诊治并有完整随访资料的IDC Ⅰ级24例、ILC 12例和具有混合性导管-小叶特征的浸润性癌(简称混合癌)14例共50例原发性乳腺癌患者资料和标本.采用EnVision法免疫组织化学染色检测E-钙黏蛋白(E-cad)、p120连环蛋白(p120ctn)、上皮膜蛋白(EMP)1和DVL1.结果 E-cad在IDC Ⅰ级和ILC中的阳性率分别为83.3%(20/24)和0,其差异有统计学意义(P<0.01);p120ctn在IDC Ⅰ级中阳性率为100.0%,且均为胞膜着色,在ILC中亦为12例均阳性,但均为细胞质着色;EMP1和DVL1在IDC Ⅰ级和ILC中的阳性分别为95.8%(23/24)和12例,54.2%(13/24)和5例,其差异无统计学意义(P>0.05).E-cad和p120ctn联合使用将14例混合痛确诊为IDC 12例和ILC 2例.结论 E-cad和p120ctn联合使用可以鉴别易混淆的IDC和ILC,使组织分型更准确.EMP1、DVL1不能作为鉴别IDC和ILC的指标.     

In situ and invasive lobular neoplasia of the breast

Lobular neoplasia of the breast represents a group of related malignancies with clinical implications ranging from risk lesions [atypical lobular hyperplasia and lobular carcinoma in situ (LCIS)] through to aggressive invasive lesions, notably invasive pleomorphic lobular carcinoma. The diversity in lobular carcinoma is evident at the morphological level, at the molecular marker level and in cytogenetic profiles. Research in these areas is already changing the face of the disease group, for example suggesting that some lobular and ductal carcinomas are closely related and even that one of the lobular group, the tubulo-lobular carcinomas, should, in fact, be regarded as a ductal cancer. More research is required to understand the long-term pathogenic implications of a diagnosis of in situ lobular neoplasia, particularly pleomorphic LCIS , and to understand the genetics behind the well-recognized high risk of bilateral disease. For invasive carcinoma, molecular studies will allow refinement of therapy and the possibility of novel targeted therapies, for example directed against fibroblast growth factor receptor 1.     

The significance of lobular neoplasia on needle core biopsy of the breast

The management of a core biopsy diagnosis of lobular neoplasia is controversial. Detailed radiological–pathological review of 47 patients with cores showing classical lobular neoplasia was performed (patients with pleomorphic lobular carcinoma in situ (LCIS) or associated risk lesions were considered separately). Immediate surgical excision in 25 patients showed invasive carcinoma in 7, ductal carcinoma in situ (DCIS) in 1 and pleomorphic LCIS in 1; radiological–pathological review showed that the core biopsy missed a mass in 5, missed calcification in 2 and that calcification appeared adequately sampled in 2. Nineteen patients had follow-up of at least 2 years. Four patients developed malignancy at the site of the core biopsy (invasive carcinoma in three, DCIS in one); one carcinoma was mammographically occult, one patient had dense original mammograms and two had calcifications apparently adequately sampled by the core. In conclusion, most carcinomas identified at the site of core biopsy showing lobular neoplasia were the result of the core missing the radiological lesion, emphasising the importance of multidisciplinary review and investigation of any discordance. Some carcinomas were found after apparently adequate core biopsy, raising the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia.