Background: Metastases to the breast from extramammary malignancies are very rare, and ruling out the

diagnosis of primary breast tumor is important in order to decide on clinical management and predict prognosis.

Case presentation: Clinical examination revealed in a 49-year-old hairdresser a 3-cm hard lump adherent to

the underlying layers in the right breast. Trucut biopsy was performed. Histology showed a solid proliferation of

medium-sized neoplastic polygonal cells. Immunohistochemical analysis showed tumor cells diffusely positive for

cytokeratin 8/18 and calretinin and focally positive for cytokeratin 5/6 and Wilms’ tumor 1, e-cadherin, and human

bone marrow endothelial-1. Estrogen receptors and progesterone receptors were negative. The final diagnosis was

metastatic epithelioid malignant pleural mesothelioma.

Conclusions: Immunohistochemistry is an important tool for a conclusive diagnosis of malignant pleural

mesothelioma. Owing to the degree of histological and immunohistochemical overlap, a high level of clinical

suspicion is essential in order to avoid unnecessary mutilating surgery

Derme, Martina

FRAMARINO DEI MALATESTA, Marialuisa

Iannini, Isabella

Masselli, Gabriele

Pecorella, Irene

Sammartino, Paolo

World Journal of Surgical Oncology

English

PubMed

Background: Metastases to the breast from extramammary malignancies are very rare, and ruling out the
diagnosis of primary breast tumor is important in order to decide on clinical management and predict prognosis.
Case presentation: Clinical examination revealed in a 49-year-old hairdresser a 3-cm hard lump adherent to
the underlying layers in the right breast. Trucut biopsy was performed. Histology showed a solid proliferation of
medium-sized neoplastic polygonal cells. Immunohistochemical analysis showed tumor cells diffusely positive for
cytokeratin 8/18 and calretinin and focally positive for cytokeratin 5/6 and Wilms’ tumor 1, e-cadherin, and human
bone marrow endothelial-1. Estrogen receptors and progesterone receptors were negative. The final diagnosis was
metastatic epithelioid malignant pleural mesothelioma.
Conclusions: Immunohistochemistry is an important tool for a conclusive diagnosis of malignant pleural
mesothelioma. Owing to the degree of histological and immunohistochemical overlap, a high level of clinical
suspicion is essential in order to avoid unnecessary mutilating surgery

SAMMARTINO, Paolo

DERME, MARTINA

IANNINI, ISABELLA

PECORELLA, Irene

Archivio della ricerca- Università di Roma La Sapienza

WORLD JOURNAL OF SURGICAL ONCOLOGY Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 DOI 10.1186/s12957-015-0491-zCASE REPORT Open AccessBreast cancer or metastasis? An unusual case ofmetastatic malignant pleural mesothelioma to thebreastMarialuisa Framarino-dei-Malatesta1*, Paolo Sammartino2, Martina Derme1, Isabella Iannini1, Gabriele Masselli3and Irene Pecorella4AbstractBackground: Metastases to the breast from extramammary malignancies are very rare, and ruling out thediagnosis of primary breast tumor is important in order to decide on clinical management and predict prognosis.Case presentation: Clinical examination revealed in a 49-year-old hairdresser a 3-cm hard lump adherent tothe underlying layers in the right breast. Trucut biopsy was performed. Histology showed a solid proliferation ofmedium-sized neoplastic polygonal cells. Immunohistochemical analysis showed tumor cells diffusely positive forcytokeratin 8/18 and calretinin and focally positive for cytokeratin 5/6 and Wilms’ tumor 1, e-cadherin, and humanbone marrow endothelial-1. Estrogen receptors and progesterone receptors were negative. The final diagnosis wasmetastatic epithelioid malignant pleural mesothelioma.Conclusions: Immunohistochemistry is an important tool for a conclusive diagnosis of malignant pleuralmesothelioma. Owing to the degree of histological and immunohistochemical overlap, a high level of clinicalsuspicion is essential in order to avoid unnecessary mutilating surgery.Keywords: Malignant pleural mesothelioma, Breast metastasis, Breast cancerBackgroundBreast cancer is the most common malignancy in women,whereas metastases to the breast from extramammarymalignancies are very rare, accounting for only 0.43% ofall malignant breast tumors [1]. The most common pri-mary tumors metastasizing to the breast are melanoma(29.8%), lung carcinoma (16.4%), gynecological carcinoma(12.7%), intestinal carcinoma (9.9%), leukemia and lym-phoma (8.4%), rhabdomyosarcoma (7.3%), and renal cellcarcinoma (1.5%) [1]. The time interval between diagnosisof primary cancer and the appearance of breast metastasesranges from 1 to 5 years [2]. Differential diagnosis be-tween primary breast tumor and metastases to the breastfrom extramammary malignancies is important in orderto decide on clinical management and predict expectedresults and prognosis.* Correspondence: marialuisa.framarino@gmail.com1Department of Gynaecological, Obstetrical and Urological Sciences, Umberto IHospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome,ItalyFull list of author information is available at the end of the article© 2015 Framarino-dei-Malatesta et al.; licenseethe Creative Commons Attribution License (htdistribution, and reproduction in any mediumDomain Dedication waiver (http://creativecomarticle, unless otherwise stated.Malignant pleural mesothelioma (MPM) is a rare andaggressive tumor with a median survival of 4 to 12months, officially recognized as an occupational diseaseand a signal disease for asbestos exposure [3]. More than80% of patients with MPM are men [4]. Because theclinical manifestations of MPM are usually nonspecific,diagnosis is often delayed, commonly for as much as 6months [5]. Pemetrexed- and cisplatin-based chemother-apy is the reference treatment [6].We report an unusual case of a woman presentingwith a breast mass in which trucut biopsy underultrasound guidance enabled assessment of metastaticMPM.Case presentationA 49-year-old hairdresser was referred to our BreastUnit for suspected right breast cancer. A family historyof breast cancer in a first-degree relative was reported.The patient had no symptoms, such as fever, nightBioMed Central. This is an Open Access article distributed under the terms oftp://creativecommons.org/licenses/by/4.0), which permits unrestricted use,, provided the original work is properly credited. The Creative Commons Publicmons.org/publicdomain/zero/1.0/) applies to the data made available in thisFramarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 2 of 5sweats, cough, and chest pain. Clinical examination re-vealed a 3-cm hard lump adherent to the underlyinglayers in the right breast and extending into the axillarytail. Breast sonography showed a solid polylobated mass(3 × 2.5 cm) with heterogeneous echogenicity and noacoustic shadowing behind the tumor. Mammogramswere difficult to interpret due to high breast density.Trucut biopsy was performed.Histology showed a solid proliferation of medium-sizedneoplastic polygonal cells bearing large round vesicularnuclei with central nucleoli and moderate amounts ofpale, pinkish cytoplasm. There was little intervening fibril-lary stroma and no breast parenchyma (Figure 1). Immu-nohistochemical analysis showed tumor cells diffuselypositive for cytokeratin (CK) 8/18 and calretinin andfocally positive for CK 5/6 and Wilms’ tumor 1 (WT1),e-cadherin, and human bone marrow endothelial- 1(HBME-1) (Figure 2). Estrogen receptors (ER), proges-terone receptors (PgR), epidermal growth factor re-ceptor 2 (c-erbB 2), anti-human epithelial antigen(Ber-EP4), thrombomodulin, and carcinoembryonic anti-gen (CEA) were negative. Proliferation index using Ki-67was 60%. The final diagnosis was metastatic epithelioidMPM. Upon further questioning, the patient reported ahistory of daily professional use of asbestos-containinghandheld hair dryers.In order to confirm the diagnosis and assess thoracic ex-tension, computed tomography (CT) of the chest was per-formed revealing a parenchymatous neoformation (6 cm)in the right parietal pleura and a lump near the right axilla(3 cm) (Figure 3).The patient refused conventional cancer treatmentpreferring alternative therapies. After 9 months, she isstill alive.Figure 1 Hematoxylin and eosin stain (H&E; 96 × 96 dpi).Infiltrative growth of neoplastic polygonal cells bearing hyperchromaticand pleomorphic nuclei with large eosinophilic nucleolus and a smallamount of pale, pinkish cytoplasm.ConclusionsOnly five cases of metastatic MPM presenting with abreast mass as the initial sign of the disease are reportedin the literature, two of them affecting male patients.Ribeiro-Silva et al. and Vergier et al. described the clini-copathological features of extramammarian malignanciesmetastasizing to the breast. In both studies, the primarysites of the malignancies included one case of mesothe-lioma, but breast lesion was not the initial sign [7,8].Sneige et al. reviewed 64 fine-needle aspirates (FNA)performed on the male breast from 1985 to 1992. Onecase of metastatic MPM was found [9]. Sheen-Chen et al.reported a case of a 51-year-old woman with a largepleural mesothelioma and an irregular left breast le-sion (4 × 3.5 cm), which proved to be a metastaticdeposit. Further immunohistochemical study was per-formed, and the tumor cells were positive for low andhigh molecular weight cytokeratin and thrombomodu-lin and focally positive for CEA [10]. More recently,Aujayeb et al. presented a case of a 60-year-old malepatient with a right breast mass (13 cm) found to bea metastatic MPM. Immunohistochemistry showed astrong positive expression of calretinin, epithelial mem-brane antigen, WT1, pan-cytokeratin, thrombomodulin,anti-D240 antibody (D2-40), e-cadherin, and CK 5, 6,and 7 [11].Breast metastasis was the first manifestation of MPMin our patient. The histopathological appearance of MPMvaries and may therefore be a diagnostic challenge, par-ticularly in the presence of a biopsy specimen of an unre-lated site. The 2004 World Health Organization (WHO)classification includes three histological subtypes: epithe-lioid, sarcomatoid, and biphasic mesothelioma. Rare vari-ants are desmoplastic type, undifferentiated type, anddeciduoid type. The entirely solid microscopic architec-ture of the present lesion and the absence of mammaryparenchyma in the biopsy specimen raised suspicion ofprimary non-breast malignancy and prompted further in-vestigation, which led to the correct diagnosis.Immunohistochemistry is an important tool for a con-clusive diagnosis of MPM. The main positive MPMmarkers include calretinin, WT1, CK 5/6, and HBME-1,whereas gross cystic disease fluid protein 15 (GCDFP-15)and mammaglobin are used to confirm breast cancer,although these markers may be only focally positivedepending on the antibody clone used as well as thehormone receptor status of the tumor [12].As reported in Case presentation section the tumorcells were diffusely positive for calretinin and CK 8/18and focally positive for CK 5/6, WT1, e-cadherin, andHBME-1.Calretinin shows strong nuclear and/or cytoplasmicpositivity in mesothelial cells and is expressed in epithe-lioid MPM, but not in the sarcomatoid variant of MPM.Figure 2 Immunohistochemical stainings (96 × 96 dpi). (a) For calretinin, (b) for cytokeratin 8, (c) for cytokeratin 5/6, and (d) for HBME-1(avidin-streptavidin-peroxidase-DAB).Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 3 of 5However, calretinin expression is not exclusive to MPM[13] as it is expressed in approximately 15% of breastprimary tumors, particularly high-grade, ER-negative,and basal-like carcinoma. Consequently, calretinin ex-pression alone could not rule out breast carcinoma inthis case.CK 8/18 is a low molecular weight cytokeratin foundin simple epithelium and secretory epithelium. CK 8/18is markedly upregulated in epithelioid MPM, whereasonly ductal in situ carcinoma is diffusely positive for thisluminal cell marker [14]. Accordingly, the positive resultobtained in the present case was useful for ruling outhigh-grade invasive breast carcinoma.CK5/6 is a basal cell marker, which is expressed inonly 10 to 15% of breast tumors, predominantly inbasal-like carcinoma, metaplastic carcinoma, and ade-noid cystic carcinoma. In contrast, 75 to 100% of MPMsare CK 5/6-positive [15].Approximately 75 to 80% of breast tumors are posi-tive for ER and/or PR, but MPMs are not. However,this percentage is reduced to only 2% in breast cancernuclear grade 3. The present lesion was negative forER and PgR [16].Approximately 15% of breast primary cancers of thepapillary mucinous subtype are positive for WT1, anindependent marker for mesothelioma [17]. However,the present case did not show papillary mucinousdifferentiation, and WT1 positivity was therefore consist-ent with a serosal membrane origin of this malignancy.E-cadherin is normally expressed in the cell membraneof breast ductal cancer cells but not in mesothelial cells.Nevertheless, the present tumor presented focal positiveimmunostaining, like the case reported by Aujayeb et al.[11], thereby hampering its specificity for ruling out MPM.HBME-1 normally reacts with an antigen present inthe membrane of benign and malignant mesothelialcells, and it was focally expressed in our case. How-ever, sensitivity of HBME-1 is high while specificityis low in mesothelial differentiation, as this markerstains various types of adenocarcinoma. HBME-1 isalso nonreactive with sarcomatous mesothelioma andwith the sarcomatous components of the biphasicvariants [18].Ber-EP4, thrombomodulin, and CEA were negative inthis case. Ber-EP4 and CEA are expected to be negativein MPM, but the negativity for thrombomodulin wassurprising, considering that the reported sensitivity andspecificity of thrombomodulin in epithelioid mesotheli-oma range from 61% to over 80% [19].According to the limited data reported in the litera-ture, mesothelioma is immunonegative for both mam-maglobin and GCDFP-15. Confirmation of breast originmay therefore be obtained using immunostaining withmammaglobin, GCDFP-15, and androgen receptor inFigure 3 CT of the chest (96 × 96 dpi). Sagittal reformatted CT image demonstrates the presence of a parenchymatous neoformation (6 cm) inthe right parietal pleura (white arrow) and of another mass in the right axillary extension (3 cm) (black arrow).Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 4 of 5difficult cases, which seem to fit into the triple-negativecategory of breast carcinoma [20].In conclusion, as symptomatic metastases of MPM areunusual and metastases to the breast are very rare, clin-ical and histological misdiagnosis is possible. Owing tothe degree of histological and immunohistochemicaloverlap, a high level of clinical suspicion is essential inorder to avoid unnecessary mutilating surgery. A largepanel of immunoreactions is necessary to establish a cor-rect diagnosis. We found that CK 8/18, CK 5/6, andWT1 formed a useful panel in this respect, particularly ifassociated with negative results for ER and PR.Despite the metastatic disease and the refusal of treat-ment, this patient is still alive after 9 months, possiblydue to the favorable epithelioid histology of the tumor,which is associated with the longest survival (a medianoverall survival of 16 months).ConsentWritten informed consent was obtained from the patientfor publication of this case report and any accompanyingimages. A copy of the written consent is available forreview by the Editor-in-Chief of this journal.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsMFdM carried out the clinical management and drafted the manuscript; PSparticipated in the study design; IP is the pathologist responsible for themicroscopical diagnosis; GM carried out the imaging; and MD and II draftedthe clinical case. All authors read and approved the final manuscript.Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 5 of 5Author details1Department of Gynaecological, Obstetrical and Urological Sciences, Umberto IHospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome,Italy. 2Department of Surgery “Pietro Valdoni,” Umberto I Hospital, SapienzaUniversity of Rome, Viale del Policlinico 155, 00161 Rome, Italy. 3Radiology DeaDepartment, Umberto I Hospital, Sapienza University of Rome, Viale delPoliclinico 155, 00161 Rome, Italy. 4Department of Radiological, Oncological andAnatomical Pathology Sciences, Umberto I Hospital, Sapienza University ofRome, Viale Regina Elena 324, 00161 Rome, Italy.Received: 25 September 2014 Accepted: 1 February 2015References1. Koch A, Richter-Marot A, Wissler MP, Baratte A, Mathelin C. Mammarymetastasis of extramammary cancers: current knowledge and diagnosticdifficulties. Gynecol Obstet Fertil. 2013;41:653–9.2. Lee AH. The histological diagnosis of metastases to the breast fromextramammary malignancies. J Clin Pathol. 2007;60:1333–41.3. Goswami E, Craven V, Dahlstrom DL, Alexander D, Mowat F. Domesticasbestos exposure: a review of epidemiologic and exposure data.Int J Environ Res Public Healt. 2013;10:5629–70.4. Delgermaa V, Takahashi K, Park E, Le G, Hara T, Sorahan T. Globalmesothelioma deaths reported to the World Health Organization between1994 and 2008. Bull World Health Organ. 2011;89:716–24.5. Champbell N, Kindler H. Update on malignant pleural mesothelioma.Semin Respir Crit Care Med. 2011;32:102–10.6. Campbell K, Brosseau S, Reviron-Rabec L, Bergot E, Lechapt E, Levallet G,et al. Malignant pleural mesothelioma: 2013 state of the art. Bull Cancer.2013;100:1283–93.7. Ribeiro-Silva A, Mendes CF, Costa IS, de Moura HB, Tiezzi DG, Andrade JM.Metastases to the breast from extramammary malignancies: aclinicopathologic study of 12 cases. Pol J Pathol. 2006;57:161–5.8. Vergier B, Trojani M, De Mascarel I, Coindre JM, Le Treut A. Metastases to thebreast: differential diagnosis from primary breast carcinoma. J Surg Oncol.1991;48:112–6.9. Sneige N, Holder PD, Katz RL, Dekmezian RH, Shabb NS, Singletary SE.Fine-needle aspiration cytology of the male breast in a cancer center.Diagn Cytopathol. 1993;9:691–7.10. Sheen-Chen SM, Liu YW, Eng HL, Huang CC, Ko SF. Metastatic malignantpleural mesothelioma to the breast. South Med J. 2006;99:1395–7.11. Aujayeb A, Clague H, Pollock S, Stamenkovic S, Hughes A. Malignantmesothelioma presenting as a breast mass. J R Coll Physicians Edinib.2012;42:27–31.12. Ordóñez NG, Sahin AA. Diagnostic utility of immunohistochemistry indistinguishing between epithelioid pleural mesotheliomas and breastcarcinomas: a comparative study. Hum Pathol. 2014;45:1529–40.13. Powell G, Roche H, Roche WR. Expression of calretinin by breast carcinoma andthe potential for misdiagnosis of mesothelioma. Histopathology. 2011;59:950–6.14. Boecker W, Moll R, Dervan P, Buerger H, Poremba C, Diallo RI, et al. Usualductal hyperplasia of the breast is a committed stem (progenitor) cell lesiondistinct from atypical ductal hyperplasia and ductal carcinoma in situ.J Patholn. 2002;98:458–67.15. Pleura [http://www.pathologyoutlines.com/topic/pleuramesothelioma.html]16. Immunostain update: diagnosis of metastatic breast carcinoma,emphasizing the distinction from gynecologic cancers [http://pathology.ucsf.edu/uploads/289/123_ihc_for_metastatic_breast_cancer_2010.pdf]17. Domfeh AB, Carley AL, Striebel JM, Karabakhtsian RG, Florea AV, McManus K,et al. WT1 immunoreactivity in breast carcinoma: selective expression inpure and mixed mucinous subtypes. Mod Pathol. 2008;21:1217–23.18. Mocanu L, Cîmpean AM, Raica M. Value of antimesothelioma HBME-1 inthe diagnosis of inflammatory and malignant pleural effusions. Romanian JMorphol Embryol. 2006;47:351–5.19. King JE, Thatcher N, Pickering CA. Sensitivity and specificity ofimmunohistochemical markers used in the diagnosis of epithelioidmesothelioma: a detailed systematic analysis using published data.Histopathology. 2006;48:223–32.20. Takeda Y, Tsuta K, Shibuki Y, Hoshino T, Tochigi N, Maeshima AM, et al.Analysis of expression patterns of breast cancer-specific markers (mamma-globin and gross cystic disease fluid protein 15) in lung and pleural tumors.Arch Pathol Lab Med. 2008;132:239–43.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Breast cancer or metastasis? An unusual case of metastatic malignant pleural mesothelioma to the breast

Marialuisa Framarino-dei-Malatesta

Paolo Sammartino

Martina Derme

Isabella Iannini

Gabriele Masselli

Irene Pecorella

Crossref

WORLD JOURNAL OF SURGICAL ONCOLOGY Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 DOI 10.1186/s12957-015-0491-zCASE REPORT Open AccessBreast cancer or metastasis? An unusual case ofmetastatic malignant pleural mesothelioma to thebreastMarialuisa Framarino-dei-Malatesta1*, Paolo Sammartino2, Martina Derme1, Isabella Iannini1, Gabriele Masselli3and Irene Pecorella4AbstractBackground: Metastases to the breast from extramammary malignancies are very rare, and ruling out thediagnosis of primary breast tumor is important in order to decide on clinical management and predict prognosis.Case presentation: Clinical examination revealed in a 49-year-old hairdresser a 3-cm hard lump adherent tothe underlying layers in the right breast. Trucut biopsy was performed. Histology showed a solid proliferation ofmedium-sized neoplastic polygonal cells. Immunohistochemical analysis showed tumor cells diffusely positive forcytokeratin 8/18 and calretinin and focally positive for cytokeratin 5/6 and Wilms’ tumor 1, e-cadherin, and humanbone marrow endothelial-1. Estrogen receptors and progesterone receptors were negative. The final diagnosis wasmetastatic epithelioid malignant pleural mesothelioma.Conclusions: Immunohistochemistry is an important tool for a conclusive diagnosis of malignant pleuralmesothelioma. Owing to the degree of histological and immunohistochemical overlap, a high level of clinicalsuspicion is essential in order to avoid unnecessary mutilating surgery.Keywords: Malignant pleural mesothelioma, Breast metastasis, Breast cancerBackgroundBreast cancer is the most common malignancy in women,whereas metastases to the breast from extramammarymalignancies are very rare, accounting for only 0.43% ofall malignant breast tumors [1]. The most common pri-mary tumors metastasizing to the breast are melanoma(29.8%), lung carcinoma (16.4%), gynecological carcinoma(12.7%), intestinal carcinoma (9.9%), leukemia and lym-phoma (8.4%), rhabdomyosarcoma (7.3%), and renal cellcarcinoma (1.5%) [1]. The time interval between diagnosisof primary cancer and the appearance of breast metastasesranges from 1 to 5 years [2]. Differential diagnosis be-tween primary breast tumor and metastases to the breastfrom extramammary malignancies is important in orderto decide on clinical management and predict expectedresults and prognosis.* Correspondence: marialuisa.framarino@gmail.com1Department of Gynaecological, Obstetrical and Urological Sciences, Umberto IHospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome,ItalyFull list of author information is available at the end of the article© 2015 Framarino-dei-Malatesta et al.; licenseethe Creative Commons Attribution License (htdistribution, and reproduction in any mediumDomain Dedication waiver (http://creativecomarticle, unless otherwise stated.Malignant pleural mesothelioma (MPM) is a rare andaggressive tumor with a median survival of 4 to 12months, officially recognized as an occupational diseaseand a signal disease for asbestos exposure [3]. More than80% of patients with MPM are men [4]. Because theclinical manifestations of MPM are usually nonspecific,diagnosis is often delayed, commonly for as much as 6months [5]. Pemetrexed- and cisplatin-based chemother-apy is the reference treatment [6].We report an unusual case of a woman presentingwith a breast mass in which trucut biopsy underultrasound guidance enabled assessment of metastaticMPM.Case presentationA 49-year-old hairdresser was referred to our BreastUnit for suspected right breast cancer. A family historyof breast cancer in a first-degree relative was reported.The patient had no symptoms, such as fever, nightBioMed Central. This is an Open Access article distributed under the terms oftp://creativecommons.org/licenses/by/4.0), which permits unrestricted use,, provided the original work is properly credited. The Creative Commons Publicmons.org/publicdomain/zero/1.0/) applies to the data made available in thisFramarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 2 of 5sweats, cough, and chest pain. Clinical examination re-vealed a 3-cm hard lump adherent to the underlyinglayers in the right breast and extending into the axillarytail. Breast sonography showed a solid polylobated mass(3 × 2.5 cm) with heterogeneous echogenicity and noacoustic shadowing behind the tumor. Mammogramswere difficult to interpret due to high breast density.Trucut biopsy was performed.Histology showed a solid proliferation of medium-sizedneoplastic polygonal cells bearing large round vesicularnuclei with central nucleoli and moderate amounts ofpale, pinkish cytoplasm. There was little intervening fibril-lary stroma and no breast parenchyma (Figure 1). Immu-nohistochemical analysis showed tumor cells diffuselypositive for cytokeratin (CK) 8/18 and calretinin andfocally positive for CK 5/6 and Wilms’ tumor 1 (WT1),e-cadherin, and human bone marrow endothelial- 1(HBME-1) (Figure 2). Estrogen receptors (ER), proges-terone receptors (PgR), epidermal growth factor re-ceptor 2 (c-erbB 2), anti-human epithelial antigen(Ber-EP4), thrombomodulin, and carcinoembryonic anti-gen (CEA) were negative. Proliferation index using Ki-67was 60%. The final diagnosis was metastatic epithelioidMPM. Upon further questioning, the patient reported ahistory of daily professional use of asbestos-containinghandheld hair dryers.In order to confirm the diagnosis and assess thoracic ex-tension, computed tomography (CT) of the chest was per-formed revealing a parenchymatous neoformation (6 cm)in the right parietal pleura and a lump near the right axilla(3 cm) (Figure 3).The patient refused conventional cancer treatmentpreferring alternative therapies. After 9 months, she isstill alive.Figure 1 Hematoxylin and eosin stain (H&E; 96 × 96 dpi).Infiltrative growth of neoplastic polygonal cells bearing hyperchromaticand pleomorphic nuclei with large eosinophilic nucleolus and a smallamount of pale, pinkish cytoplasm.ConclusionsOnly five cases of metastatic MPM presenting with abreast mass as the initial sign of the disease are reportedin the literature, two of them affecting male patients.Ribeiro-Silva et al. and Vergier et al. described the clini-copathological features of extramammarian malignanciesmetastasizing to the breast. In both studies, the primarysites of the malignancies included one case of mesothe-lioma, but breast lesion was not the initial sign [7,8].Sneige et al. reviewed 64 fine-needle aspirates (FNA)performed on the male breast from 1985 to 1992. Onecase of metastatic MPM was found [9]. Sheen-Chen et al.reported a case of a 51-year-old woman with a largepleural mesothelioma and an irregular left breast le-sion (4 × 3.5 cm), which proved to be a metastaticdeposit. Further immunohistochemical study was per-formed, and the tumor cells were positive for low andhigh molecular weight cytokeratin and thrombomodu-lin and focally positive for CEA [10]. More recently,Aujayeb et al. presented a case of a 60-year-old malepatient with a right breast mass (13 cm) found to bea metastatic MPM. Immunohistochemistry showed astrong positive expression of calretinin, epithelial mem-brane antigen, WT1, pan-cytokeratin, thrombomodulin,anti-D240 antibody (D2-40), e-cadherin, and CK 5, 6,and 7 [11].Breast metastasis was the first manifestation of MPMin our patient. The histopathological appearance of MPMvaries and may therefore be a diagnostic challenge, par-ticularly in the presence of a biopsy specimen of an unre-lated site. The 2004 World Health Organization (WHO)classification includes three histological subtypes: epithe-lioid, sarcomatoid, and biphasic mesothelioma. Rare vari-ants are desmoplastic type, undifferentiated type, anddeciduoid type. The entirely solid microscopic architec-ture of the present lesion and the absence of mammaryparenchyma in the biopsy specimen raised suspicion ofprimary non-breast malignancy and prompted further in-vestigation, which led to the correct diagnosis.Immunohistochemistry is an important tool for a con-clusive diagnosis of MPM. The main positive MPMmarkers include calretinin, WT1, CK 5/6, and HBME-1,whereas gross cystic disease fluid protein 15 (GCDFP-15)and mammaglobin are used to confirm breast cancer,although these markers may be only focally positivedepending on the antibody clone used as well as thehormone receptor status of the tumor [12].As reported in Case presentation section the tumorcells were diffusely positive for calretinin and CK 8/18and focally positive for CK 5/6, WT1, e-cadherin, andHBME-1.Calretinin shows strong nuclear and/or cytoplasmicpositivity in mesothelial cells and is expressed in epithe-lioid MPM, but not in the sarcomatoid variant of MPM.Figure 2 Immunohistochemical stainings (96 × 96 dpi). (a) For calretinin, (b) for cytokeratin 8, (c) for cytokeratin 5/6, and (d) for HBME-1(avidin-streptavidin-peroxidase-DAB).Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 3 of 5However, calretinin expression is not exclusive to MPM[13] as it is expressed in approximately 15% of breastprimary tumors, particularly high-grade, ER-negative,and basal-like carcinoma. Consequently, calretinin ex-pression alone could not rule out breast carcinoma inthis case.CK 8/18 is a low molecular weight cytokeratin foundin simple epithelium and secretory epithelium. CK 8/18is markedly upregulated in epithelioid MPM, whereasonly ductal in situ carcinoma is diffusely positive for thisluminal cell marker [14]. Accordingly, the positive resultobtained in the present case was useful for ruling outhigh-grade invasive breast carcinoma.CK5/6 is a basal cell marker, which is expressed inonly 10 to 15% of breast tumors, predominantly inbasal-like carcinoma, metaplastic carcinoma, and ade-noid cystic carcinoma. In contrast, 75 to 100% of MPMsare CK 5/6-positive [15].Approximately 75 to 80% of breast tumors are posi-tive for ER and/or PR, but MPMs are not. However,this percentage is reduced to only 2% in breast cancernuclear grade 3. The present lesion was negative forER and PgR [16].Approximately 15% of breast primary cancers of thepapillary mucinous subtype are positive for WT1, anindependent marker for mesothelioma [17]. However,the present case did not show papillary mucinousdifferentiation, and WT1 positivity was therefore consist-ent with a serosal membrane origin of this malignancy.E-cadherin is normally expressed in the cell membraneof breast ductal cancer cells but not in mesothelial cells.Nevertheless, the present tumor presented focal positiveimmunostaining, like the case reported by Aujayeb et al.[11], thereby hampering its specificity for ruling out MPM.HBME-1 normally reacts with an antigen present inthe membrane of benign and malignant mesothelialcells, and it was focally expressed in our case. How-ever, sensitivity of HBME-1 is high while specificityis low in mesothelial differentiation, as this markerstains various types of adenocarcinoma. HBME-1 isalso nonreactive with sarcomatous mesothelioma andwith the sarcomatous components of the biphasicvariants [18].Ber-EP4, thrombomodulin, and CEA were negative inthis case. Ber-EP4 and CEA are expected to be negativein MPM, but the negativity for thrombomodulin wassurprising, considering that the reported sensitivity andspecificity of thrombomodulin in epithelioid mesotheli-oma range from 61% to over 80% [19].According to the limited data reported in the litera-ture, mesothelioma is immunonegative for both mam-maglobin and GCDFP-15. Confirmation of breast originmay therefore be obtained using immunostaining withmammaglobin, GCDFP-15, and androgen receptor inFigure 3 CT of the chest (96 × 96 dpi). Sagittal reformatted CT image demonstrates the presence of a parenchymatous neoformation (6 cm) inthe right parietal pleura (white arrow) and of another mass in the right axillary extension (3 cm) (black arrow).Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 4 of 5difficult cases, which seem to fit into the triple-negativecategory of breast carcinoma [20].In conclusion, as symptomatic metastases of MPM areunusual and metastases to the breast are very rare, clin-ical and histological misdiagnosis is possible. Owing tothe degree of histological and immunohistochemicaloverlap, a high level of clinical suspicion is essential inorder to avoid unnecessary mutilating surgery. A largepanel of immunoreactions is necessary to establish a cor-rect diagnosis. We found that CK 8/18, CK 5/6, andWT1 formed a useful panel in this respect, particularly ifassociated with negative results for ER and PR.Despite the metastatic disease and the refusal of treat-ment, this patient is still alive after 9 months, possiblydue to the favorable epithelioid histology of the tumor,which is associated with the longest survival (a medianoverall survival of 16 months).ConsentWritten informed consent was obtained from the patientfor publication of this case report and any accompanyingimages. A copy of the written consent is available forreview by the Editor-in-Chief of this journal.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsMFdM carried out the clinical management and drafted the manuscript; PSparticipated in the study design; IP is the pathologist responsible for themicroscopical diagnosis; GM carried out the imaging; and MD and II draftedthe clinical case. All authors read and approved the final manuscript.Framarino-dei-Malatesta et al. World Journal of Surgical Oncology  (2015) 13:79 Page 5 of 5Author details1Department of Gynaecological, Obstetrical and Urological Sciences, Umberto IHospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome,Italy. 2Department of Surgery “Pietro Valdoni,” Umberto I Hospital, SapienzaUniversity of Rome, Viale del Policlinico 155, 00161 Rome, Italy. 3Radiology DeaDepartment, Umberto I Hospital, Sapienza University of Rome, Viale delPoliclinico 155, 00161 Rome, Italy. 4Department of Radiological, Oncological andAnatomical Pathology Sciences, Umberto I Hospital, Sapienza University ofRome, Viale Regina Elena 324, 00161 Rome, Italy.Received: 25 September 2014 Accepted: 1 February 2015References1. Koch A, Richter-Marot A, Wissler MP, Baratte A, Mathelin C. Mammarymetastasis of extramammary cancers: current knowledge and diagnosticdifficulties. Gynecol Obstet Fertil. 2013;41:653–9.2. Lee AH. The histological diagnosis of metastases to the breast fromextramammary malignancies. J Clin Pathol. 2007;60:1333–41.3. Goswami E, Craven V, Dahlstrom DL, Alexander D, Mowat F. Domesticasbestos exposure: a review of epidemiologic and exposure data.Int J Environ Res Public Healt. 2013;10:5629–70.4. Delgermaa V, Takahashi K, Park E, Le G, Hara T, Sorahan T. Globalmesothelioma deaths reported to the World Health Organization between1994 and 2008. Bull World Health Organ. 2011;89:716–24.5. Champbell N, Kindler H. Update on malignant pleural mesothelioma.Semin Respir Crit Care Med. 2011;32:102–10.6. Campbell K, Brosseau S, Reviron-Rabec L, Bergot E, Lechapt E, Levallet G,et al. Malignant pleural mesothelioma: 2013 state of the art. Bull Cancer.2013;100:1283–93.7. Ribeiro-Silva A, Mendes CF, Costa IS, de Moura HB, Tiezzi DG, Andrade JM.Metastases to the breast from extramammary malignancies: aclinicopathologic study of 12 cases. Pol J Pathol. 2006;57:161–5.8. Vergier B, Trojani M, De Mascarel I, Coindre JM, Le Treut A. Metastases to thebreast: differential diagnosis from primary breast carcinoma. J Surg Oncol.1991;48:112–6.9. Sneige N, Holder PD, Katz RL, Dekmezian RH, Shabb NS, Singletary SE.Fine-needle aspiration cytology of the male breast in a cancer center.Diagn Cytopathol. 1993;9:691–7.10. Sheen-Chen SM, Liu YW, Eng HL, Huang CC, Ko SF. Metastatic malignantpleural mesothelioma to the breast. South Med J. 2006;99:1395–7.11. Aujayeb A, Clague H, Pollock S, Stamenkovic S, Hughes A. Malignantmesothelioma presenting as a breast mass. J R Coll Physicians Edinib.2012;42:27–31.12. Ordóñez NG, Sahin AA. Diagnostic utility of immunohistochemistry indistinguishing between epithelioid pleural mesotheliomas and breastcarcinomas: a comparative study. Hum Pathol. 2014;45:1529–40.13. Powell G, Roche H, Roche WR. Expression of calretinin by breast carcinoma andthe potential for misdiagnosis of mesothelioma. Histopathology. 2011;59:950–6.14. Boecker W, Moll R, Dervan P, Buerger H, Poremba C, Diallo RI, et al. Usualductal hyperplasia of the breast is a committed stem (progenitor) cell lesiondistinct from atypical ductal hyperplasia and ductal carcinoma in situ.J Patholn. 2002;98:458–67.15. Pleura [http://www.pathologyoutlines.com/topic/pleuramesothelioma.html]16. Immunostain update: diagnosis of metastatic breast carcinoma,emphasizing the distinction from gynecologic cancers [http://pathology.ucsf.edu/uploads/289/123_ihc_for_metastatic_breast_cancer_2010.pdf]17. Domfeh AB, Carley AL, Striebel JM, Karabakhtsian RG, Florea AV, McManus K,et al. WT1 immunoreactivity in breast carcinoma: selective expression inpure and mixed mucinous subtypes. Mod Pathol. 2008;21:1217–23.18. Mocanu L, Cîmpean AM, Raica M. Value of antimesothelioma HBME-1 inthe diagnosis of inflammatory and malignant pleural effusions. Romanian JMorphol Embryol. 2006;47:351–5.19. King JE, Thatcher N, Pickering CA. Sensitivity and specificity ofimmunohistochemical markers used in the diagnosis of epithelioidmesothelioma: a detailed systematic analysis using published data.Histopathology. 2006;48:223–32.20. Takeda Y, Tsuta K, Shibuki Y, Hoshino T, Tochigi N, Maeshima AM, et al.Analysis of expression patterns of breast cancer-specific markers (mamma-globin and gross cystic disease fluid protein 15) in lung and pleural tumors.Arch Pathol Lab Med. 2008;132:239–43.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

https://wjso.biomedcentral.com/track/pdf/10.1186/s12957-015-0491-z?site=wjso.biomedcentral.com

Breast cancer or metastasis? An unusual case of metastatic malignant pleural mesothelioma to the breast

Abstract

Similar works

Full text

Available Versions

Archivio della ricerca- Università di Roma La Sapienza

Crossref