Secondary breast cancer: a 5‐year population‐based study with review of the literature

Secondary tumours in the breast are rare. Based on literature, an incidence of 0.4–2% is reported. In this population‐based study, secondary breast tumours from a 5‐year period (2001–2005), not including metastasis from contralateral breast carcinoma, were reviewed (Vestfold County, Norway). A total of 722 patients with breast malignancies were found in this population (89.3% from Vestfold County Hospital). Ten of these, approximately 1.4%, were metastatic tumours, representing four cutaneous melanomas, three pulmonary carcinomas and three malignant lymphomas. The tumours were often solitary, palpable and close to the skin. Radiologically, the lesions mostly resembled primary carcinomas by mammography and ultrasound, which differs from other studies. Comparison with a known primary tumour and use of immunohistochemical profiling is of crucial importance. Melanoma markers (Melan‐A, HMB‐45, S‐100 protein), lung cancer markers (Cytokeratins, TTF1, Chromogranin, Synapthophysin) and lymphoid markers (CD3, CD20) usually help to confirm a secondary breast tumour diagnosis. This approach is especially indicated in diffusely growing tumours with lack of glandular structure and high‐grade cytological features, and staining for ER and GCDFP15 may be helpful. Thus, the diagnosis of a breast metastasis may be suspected by careful mammography and ultrasound imaging, although some cases have atypical radiological features, and histological examination might be necessary to ensure a correct diagnosis and appropriate treatment.     

Mucoepidermoid carcinoma of the thyroid

Clinical and morphological features of three cases of primary mucoepidermoid carcinoma of the thyroid are described. The tumours were composed of two cell types. One of these resembled squamous epithelium and ultrastructurally showed tonofilaments and numerous desmosomes. The other cell type contained Alcian blue and mucicarmine positive mucin and, on electron microscopy, showed mucigen granules. Marked stromal fibrosis and psammoma bodies were seen in all tumours. Immunohistochemical studies showed that the tumour cells were negative for thyroglobulin. A few calcitonin-containing cells were seen in one metastatic tumour. One tumour showed, in addition to the histological features of mucoepidermoid carcinoma, anaplastic areas with obvious transition between the two histological patterns. The same thyroid also had a small thyroglobulin-positive papillary carcinoma in the opposite lobe. All tumours presented lymph node metastases. In two cases the primary tumour was confined within the thyroid capsule but that with anaplastic areas invaded surrounding structures. This patient died 13 months after diagnosis; the other patients are alive and symptomless one and 10 years since diagnosis. Mucoepidermoid carcinoma of the thyroid appears to be a clinicopathological entity that resembles papillary carcinoma in its natural history. The origin of the tumour is unclear. There is, however, some histological and immunohistological data suggesting that the tumour might be related to the ultimobranchial system although some histological features also appear to favour a common origin with papillary carcinoma.     

Primary pulmonary tumours of nerve sheath origin

Primary intrapulmonary tumours of nerve sheath origin are extremely rare. We describe the clinicopathological features of four such peripheral nerve sheath tumours, two benign and two malignant. Of the benign tumours, one was a typical schwannoma and the other an ancient or degenerated schwannoma. The typical schwannoma was endobronchial in origin, diagnosis being established by small bronchoscopic biopsy. The histological diagnosis of malignant peripheral nerve sheath tumour required immunohistochemical and/or ultrastructural evidence of nerve sheath differentiation. One malignant tumour arose in a patient with Von-Recklinghausen's disease. Both malignant tumours behaved aggressively with the development of multiple intrapulmonary metastases, despite the markedly different histological appearance of the two tumours. Flow cytometric analysis of nuclear DNA content was performed on the four tumours, all of which showed a diploid DNA profile.     

Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer

Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B.     

Adenomyoepithelioma of the breast with malignant features

 The clinico-pathological features of 7 cases of adenomyoepithelioma of the breast with features suggestive of malignancy are presented. There was a high incidence of local tumour recurrence, in 2 cases as high-grade infiltrating carcinoma of the breast of no special type (”ductal”, grade III). One patient died as the result of a clinically diagnosed cerebral metastasis. Histological examination of the primary breast tumours reveals two main patterns: (1) tumours consisting in part of typical adenomyoepitheliomas but which merge with areas of obviously invasive malignant cells and (2) neoplasms that have the overall architecture of an adenomyoepithelioma but which, on close examination, are found to contain foci of cellular atypia and increased mitotic activity. The two patterns of tumour exhibit the same clinical behaviour and should be distinguished from adenomyoepitheliomas, which are cytologically bland throughout. Received: 3 April 1997 / Accepted: 27 May 1997     

Metastatic granular cell tumor to the breast diagnosed by fine needle aspiration cytology: A case report with review of the literature

Granular cell tumors (GCT) are mesenchymal neoplasms of Schwann cell/neural origin. Malignant granular cell tumors (MGCTs) represent <1‐2% of all GCT and defined as tumors demonstrating metastases or destructive local growth. Other clinical parameters suggestive of malignancy include rapid growth, size > 4 cm and necrosis. An apparently inconsistent set of histological features have been described in MGCT. Although the histologic parameters of a GCT are not always predictive of biologic behavior, the presence of atypical features may be indicative of an aggressive clinical behavior (recurrence and metastases). A preoperative estimate of features suggestive of malignancy is important for treatment and prognostication. Diagnosis and prognostication from preoperative fine needle aspiration (FNA) cytology is hampered by the fact that only a few case reports on cytologic features of malignant GCT have been published. We report a case of metastatic MGCT to breast and compare cytologic features to that of primary breast GCT and apocrine/histiocytoid variants of breast carcinoma.     

Comparative electron microscopic study of cancer cell differentiation in the primary tumor and the metastases

Comparative ultrastructural analysis of primary carcinomas of the lung, mammary gland, colon, stomach and some other sites and their metastases into the lymph nodes and inner organs is presented. It is established that the main ultrastructural specific features of differentiation typical for the cells of primary tumours are, as a rule, retained in their metastases to various organs and tissues. Carcinoma cells in the metastases repeat most frequently (81% of cases) the types of differentiation of a primary tumour. However, the reduction of a number of differentiated cell types (5%) or appearance of a new ultrastructural cell type (14%) may be found in the secondary tumour deposits. Besides, the retention (74%), decrease (10%) or increase (16%) of the degree of differentiation may be observed in metastases as compared to the primary tumour. The data obtained may be the ground for a proper identification of malignant tumours on the basis of the electron microscopic study of their metastasis.     

Morphological characteristics of metastasis of undifferentiated cancer into the cervical lymph nodes without previous detection of the site of the primary tumor

Morphological examination of the lymph nodes with undifferentiated carcinoma metastasis from 52 patients without an identified primary tumour at the time of biopsy has been performed. Metastases are subdivided morphologically into large-cell, spindle-cell and small-cell. Morphological criteria of differential diagnosis are given. The source of metastases was further determined in 42 patients, this being mainly the tumours of organs of the neck and head, predominantly the nasopharynx. Morphological features of undifferentiated carcinoma metastasis may be sometimes helpful in the determination of the primary tumour. Thus, metastasis of undifferentiated nasopharynx carcinoma has rather specific structure.     

Ultrastructural tissue-specific signs of the cells of cancerous tumors of the human breast

Ultrastructural analysis of mammary carcinoma (45 cases) and its metastasis in the lymph nodes (21 cases) revealed the tissue specific features of the mammary gland: big ducts and intercellular canaliculi, microvilli, various specialized cell-to-cell contacts, basal membrane. Tissue specific features are not associated with a certain organ. In mammary carcinoma, they are more pronounced in carcinomas in situ, invasive tumours of the 1st grade of malignancy (adenocarcinoma) and specific histologic variants. They are less pronounced in solid and scirrhous invasive tumours of the 2nd and especially 3rd grade of malignancy. However it is impossible to conclude about the anaplasia degree on the basis of the number of and the correlation between various tissue specific features. Metastasis retains the capacity of cancer cells to form the tissue specific ultrastructural elements. The tissue specific properties of mammary carcinoma determine the diagnosis in cases when the question on the tissue origin of the tumour is to be solved.     

An approach to the diagnosis of spindle cell lesions of the breast

Although most breast spindle cell lesions (BSCLs) are rare, they constitute a wide spectrum of diseases, ranging from reactive processes to aggressive malignant tumours. Despite their varied histogenesis and behaviour, some lesions show an overlap of morphological features, making accurate diagnosis a challenging task, particularly in needle core biopsies. Clinical history and immunohistochemistry can help in making a correct diagnosis in morphologically challenging cases. To make an accurate diagnosis, it is important to maintain a wide differential diagnosis and be familiar with the diverse morphological appearances of these different entities. BSCLs can generally be classified into bland‐looking and malignant‐looking categories. In the former, the commonest diagnosis is scarring. However, it is important to distinguish low‐grade spindle cell metaplastic breast carcinoma from other benign entities, as the management is clearly different. In the malignant category, it is important to differentiate metaplastic carcinoma from other malignant primary and metastatic malignant spindle cell tumours of the breast, such as malignant phyllodes tumour, angiosarcoma, and melanoma. This review focuses on the classification and histological and molecular diagnosis of various BSCLs, with an emphasis on the diagnostic approach, including in core biopsies.     

Primary invasive micropapillary carcinoma of the colon

AIMS: Invasive micropapillary carcinoma (IMPC) is associated with frequent lymph node metastasis and adverse clinical outcome. IMPC has been reported in breast, urinary bladder, ureter, lung and parotid gland but not in colon. We present the clinicopathological features of three cases of primary IMPC of the colon with a review of the literature. METHODS AND RESULTS: The patients (one man and two women) were 53, 67 and 68 years old, respectively. The size of the tumour ranged from 20 to 100 mm in diameter. Histologically, all cases were composed predominantly of papillary tumour cell clusters with spaces in a background of fine fibrocollagenous stroma. One of the tumours (case 1) was nearly completely composed of IMPC, but the other two were associated with foci of adenocarcinoma and concurrent mucinous carcinoma, respectively. MUC1 was positive in all cases, suggestive of reverse cell orientation which is responsible for its unique histological features. CONCLUSIONS: We report three cases of primary IMPC of the colon. Its clinical significance remains undetermined but the presence of this component may represent a poor prognostic factor.     

Monitoring serum CEA in women with primary breast tumours positive for oestrogen receptor and with spread to lymph nodes.

Serum carcinoembryonic antigen concentrations (serum CEA) in 80 patients with primary breast cancer were measured preoperatively, one month after operation, and thereafter serially every third month. These data were related to histological and morphometric features of the primary breast carcinoma and the lymph node metastases and to clinical follow up data. Analysis of the serum CEA values showed significant correlations with size of tumour, the presence of lymph node metastases, oestrogen receptor, and occurrence of distant metastases. Furthermore, the results indicated that serial determination of serum CEA in the first two years after operation may be useful in monitoring for the occurrence of distant metastases in patients with metastatic spread to lymph nodes and with large (greater than or equal to 2 cm) primary breast tumours positive for oestrogen receptor. In agreement with other studies, however, it was found that the predictive value of serum CEA concentrations in general is weak and costs may prohibit the implementation of the routine assessment of CEA concentrations.     

Phyllodes tumours of the breast: a consensus review

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.     

Correlation of carcinoembryonic antigen in tissue sections with spread of mammary carcinoma

An immunoperoxidase technique for the histological demonstration of Carcinoembryonic Antigen (CEA) was applied to paraffin sections from 74 breast carcinomas and 43 benign breast lesions. Sixty-six per cent of the carcinomas and the only case of granular cell myoblastoma examined were CEA positive. Two examples of mammary dysplasia (7%) showed foci of CEA positive acini. All tumour tissue found in lymphatics and in metastases in lymph nodes was CEA positive, including two cases where the primary tumour was CEA negative, and all the metastases examined from CEA positive tumours. A significant relationship was found between CEA positivity of the primary tumour and the presence of lymph node metastases.     

Immuno-histochemical staining expression of Ki67 protein in canine mammary gland carcinoma

Canine mammary gland carcinoma is ranked second after skin tumours in dogs in terms of frequency. Due to certain microscopic and biological features, canine tumours are very similar to human carcinomas, which may make the dog a good animal model. The objective of this study was to describe Ki67 protein expression properties using immuno-histochemical (IHC) staining using human antibody. In this study, 30 mammary gland tumour samples were studied. The histological diagnosis was made on the basis of the current World Health Organization classification for canine mammary tumours. Tumours were then graded histologically in accordance with the Elston and Ellis method for human breast tumours. IHC staining using MIB-1 antibody for detecting expression of Ki67 proteins (pKi67), was performed on canine mammary gland carcinoma tissue. Results from the semi-quantitative IHC assessment of pKi67 showed that 20% were negative, 20% were one plus, 36.5% were two plus, 23.3% were three plus. There was a significant difference between histological grade and pKi67 expression. This method would help the pathologist and clinician in determining a more accurate prognosis and treatment in canine mammary carcinoma and facilitate comparative studies of canine and human research.     

Granular cell tumour of the mammary gland simulating malignancy

Summary Primary granular cell tumours of the breast in 35 2and 55 year old women were studied by light microscopy, transmission electron microscopy and immunohistochemistry. Light and electron microscopy revealed a neural origin of the tumours and this was further substantiated by immunohistochemical studies, with positive S-100 protein reaction and negative reactions for surface heavy and light chains, CEA, alfa-1-antitrypsin, muramidase and GFA-protein. Granular cell tumour of the mammary gland is a very rare tumour. Clinically it sometimes simulates carcinoma because of its fibrous consistency, fixation to pectoral fascia and skin retraction. The diagnosis of granular cell tumour should be included in the differential diagnosis of carcinoma of the breast.The granular cell tumour is derived from neuro-ectodermal tissue. Whether it represents a neurogenic cell-confined metabolic disturbance with lysosomal activation, or a true neoplasm remains to be elucidated.     

Comparative studies of the metastatic potential of three transplantable rat mammary carcinomas of spontaneous origin

The metastatic potential of 3 spontaneously arising mammary carcinomas (Sp4, Sp15 and Sp22) has been examined when transplanted in the form of a viable cell suspension into the tissue of origin. Primary tumours were excised at different times after implantation and it was found that the metastatic potential of the immunogenic tumour Sp4 was directly correlated with the size of the primary tumour when excised. By contrast, the incidence of metastases from the non-immunogenic tumours Sp15 and Sp22 was similar irrespective of the size of the primary tumour on excision. The pattern of metastasis also differed between the tumours, although here there was no relation to immunogenicity. Thus, resection en bloc of large primary Sp4 or Sp15 tumours plus regional lymph nodes could be completely curative, signifying initial spread of tumours via the lymphatics and only subsequently via the blood stream. On the other hand, resection en bloc of primary Sp22 tumours plus regional lymph nodes at a similar stage of primary tumour development was never curative, signifying early spread via the blood stream. Other studies showed that the metastatic potential of mammary carcinoma Sp4 was an innate characteristic of the tumour and not related to the tissue of implantation since in addition to metastasizing from the mammary pad it metastasized when implanted either s.c. or intradermally in a region devoid of mammary tissue. Furthermore, a rat sarcoma Mc7 showed a negligible tendency to metastasize when implanted either in the mammary pad or in the s.c. tissue, where it had been induced with methylcholanthrene.     

Comparative studies of the metastatic potential of three transplantable rat mammary carcinomas of spontaneous origin.

The metastatic potential of 3 spontaneously arising mammary carcinomas (Sp4, Sp15 and Sp22) has been examined when transplanted in the form of a viable cell suspension into the tissue of origin. Primary tumours were excised at different times after implantation and it was found that the metastatic potential of the immunogenic tumour Sp4 was directly correlated with the size of the primary tumour when excised. By contrast, the incidence of metastases from the non-immunogenic tumours Sp15 and Sp22 was similar irrespective of the size of the primary tumour on excision. The pattern of metastasis also differed between the tumours, although here there was no relation to immunogenicity. Thus, resection en bloc of large primary Sp4 or Sp15 tumours plus regional lymph nodes could be completely curative, signifying initial spread of tumours via the lymphatics and only subsequently via the blood stream. On the other hand, resection en bloc of primary Sp22 tumours plus regional lymph nodes at a similar stage of primary tumour development was never curative, signifying early spread via the blood stream. Other studies showed that the metastatic potential of mammary carcinoma Sp4 was an innate characteristic of the tumour and not related to the tissue of implantation since in addition to metastasizing from the mammary pad it metastasized when implanted either s.c. or intradermally in a region devoid of mammary tissue. Furthermore, a rat sarcoma Mc7 showed a negligible tendency to metastasize when implanted either in the mammary pad or in the s.c. tissue, where it had been induced with methylcholanthrene.     

Pathology of primary and metastatic mucinous ovarian neoplasms

Recent years have seen a dramatic change in the pathological approach to ovarian mucinous neoplasms. A substantial proportion of tumours previously considered to be ovarian primaries actually represent secondary ovarian involvement by tumours elsewhere in the body. Two major categories of tumour have completely disappeared from the diagnostic spectrum: ovarian 'borderline' mucinous tumour associated with pseudomyxoma peritonei, and widely disseminated mucinous carcinomas. The emergent picture of true ovarian primary carcinoma of pure mucinous morphology is that this is a rare malignancy that is low grade and low stage at presentation in the vast majority of cases, with a very low likelihood of aggressive clinical behaviour. A large volume of literature has appeared concerning the pathological distinction of primary from metastatic ovarian mucinous neoplasms in view of the dramatically different prognosis and treacherously similar morphology. Clinicopathological parameters useful in the distinction of primary from metastatic mucinous ovarian carcinomas are reviewed. Major features favouring metastases are bilaterality, size <10 cm, surface involvement, extensive intra-abdominal spread and an extensive infiltrative pattern with desmoplasia. Two morphological patterns essentially exclude ovarian origin: colloid and signet ring carcinomas. Features favouring primary ovarian origin are unilaterality, large size >12 cm, smooth external surface and association with other ovarian pathology. An admixture of benign, borderline and malignant patterns in the same tumour favour primary origin, but can be misleading as a 'maturation' pattern in metastases can result in the same appearance.