Synchronous Primary Papillary Breast Cancer, Medullary Thyroid Carcinoma and Neuroendocrine Tumor in Postmenopausal Woman

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Provided by Archivio della ricerca- Università di Roma La Sapienza Journal of Case Reports in Oncology and Therapy

Synchronous primary papillary breast cancer, medullary thyroid carcinoma and neuroendocrine tumor in postmenopausal woman

Valentina Sini1, Francesca De Iuliis2, Lorena Rossi3, Gianluigi Lunardi4, Antonello Menghi5, Irene Pecorella6, Rosina Lanza5, Susanna Scarpa2 1Sapienza University of Rome, Faculty of Medicine and Psychology, Via di Grottarossa, Rome 2Department of Experimental Medicine, Sapienza University, Viale Regina Elena, Rome 3Department of Oncology, San Giovanni Calibita Hospital, Rome 4Department of Oncology, Sacro Cuore Don Calabria Hospital, Negrar, Verona 5Policlinico Umberto I, Viale del Policlinico, Rome 6Department of Radiologic, Oncologic and Anatomic Pathology, Sapienza University, Viale Regina Elena, Rome

Received May 18, 2015; Revised July 01, 2015; Accepted January 18, 2016; Published Online March 10, 2016

Case Report Abstract

Multiple endocrine neoplasia are syndromes involving two or more endocrine tissues, often correlated to RET proto-oncogene mutations. We herein present the first reported case of a 57-years-old woman with three synchronous primary cancers of breast (papillary), thyroid (medullary) and pancreas (neuroendocrine), the latter with liver metastasis. The patient first underwent surgery for papillary breast cancer with axillary lymph nodes metastases. A staging whole body computerized tomography (CT) showed a right lateral cervical lymph node, pancreatic inhomogeneity, peri-pancreatic nodes and a single liver metastasis. The poor response to an antracycline and taxane-based chemotherapy, the good performance status of patient, and associated symptoms, suggested a different origin for pancreatic and hepatic lesions. A careful re-evaluation of clinical history, an octreotide-labeled scan and an immunohistochemical analysis, on both hepatic and pancreatic tissues and on laterocervical lymph node, determined the diagnosis of synchronous papillary breast cancer, pancreatic neuroendocrine tumor (pNET) with liver metastasis Keywords:and an occult medullary thyroid carcinoma in a patient who had proto-oncogene RET wild type.

IntroductionBreast Cancer; Neuroendocrine Tumors; Medullary Thyroid Carcinoma; MEN Syndromes; RET Oncogene

Multiple endocrine neoplasia (MEN) are autosomal mm of diameter, grade 2, invasive breast papillary dominant syndromes characterized by tumors involving carcinoma with metastatic involvement of 2, among the two or more endocrine tissues. Two, among these 17 examined, axillary lymph nodes. The TNM syndromes, have been clinically and genetically well classification was pT1c pN1 (2/17) pMx; estrogen characterized: the MEN type 1 (MEN1) and type 2 receptor (ER) and progesterone receptor (PR) were (MEN2), which are caused by germline mutations in the negative, Ki 67 index was 20%, Her2 was negative, as MEN1 tumor1 suppressor gene and in the RET well as synaptophysin. (Rearranged during Transfection) proto-oncogene, respectively. However, uncommon situations of Staging radiological examinations were performed and a multiple synchronous cancers, without evident computerized tomography (CT) scan showed metastatic correlation with a particular genetic mutation, can also involvement of a right lateral cervical lymph node, occur, such as atypical MENS. We herein present a inhomogeneity of the pancreatic head with loco-regional clinical entity of three synchronous primary cancers of lymph nodes involvement and the presence of a single the breast (papillary), thyroid (medullary) and pancreas large (8 cm in diameter) hepatic metastasis on the left Case(neuroendocrine), presentation the latter with liver metastasis. hepatic lobe. The patient received a first line chemotherapy for metastatic breast cancer, with an antracycline and taxane-based regimen, and she reached only a stable disease. On February 2001, a well-being 57-year-old woman underwent left mastectomy and axillary lymph nodes She was then suffering persistent heartburn and emesis, dissection. Histology revealed a completely excised, 11 responsive only to anti H2 antagonists, flushing and CiteCorresponding this article Author: as: SiniSusannaV, De-Iuliis ScarpaF, ;RossiDepartmentL, Lunardi of ExperimentalG, Menghi A Medicine,, Pecorella SapienzaI, Lanza University,R, Scarpa VialeS. Synchronous Regina Elena, primary Rome. papillary breast cancer, medullary thyroid carcinoma and neuroendocrine tumor in postmenopausal woman. J Case Rep Onc Ther. 2016; 2(1):211.

neck swelling. Therefore, an esophagogastroduodenos- 5-fluorouracil for 6 cycles, achieving a clinical partial copy was carried out, which resulted negative. response. Serological evaluation of CEA (carcinoembryonic antigen), neuron specific enolase (NSE), In relation to the histological and immunohistochemical 5-hydroxyindoleacetic acid (5-HIAA) and thyroglobulin features of the pancreatic tumor (mitotic count of 2/10 was negative, but the patient presented high serum HPF, Ki67 index of 5%, synaptophysin +, chromogranin levels of calcitonin (58 pg/ml, normal range < 15 pg/ml) A+/-) and to the high density of somatostatin receptors and weakly positive chromogranin A values (126 ng/ml, on Octreoscan analysis, the patient was also started to a normal range 0-90 ng/ml). treatment with long-acting Octreotide (LAR) 30 mg intramuscularly every 28 days, without toxicities and Somatostatin receptor scintigraphy (Octreoscan), a maintaining clinical partial response. Presently, she is sensitive method for the detection of neuroendocrine still alive, with a good performance status and tumors and metastases bearing the somatostatin preserving a good quality of life. Continuing treatment receptor subtypes 2 (SSTR2) or SSTR 5, demonstrated with long-acting Octreotide did not result in systemic high density of somatostatin receptors in the right toxicities, and allowed for good control of metastatic thyroid-parathyroid area, in the right neck, in neuroendocrine carcinoma, with biochemical and duodeno-pancreatic region and in a focal hepatic site. Discussionsymptomatic responses.

We then performed a fine needle aspiration of the enlarged lateral cervical lymph node, and a liver and We present an intriguing clinical entity of a combined pancreatic biopsy. Lateral cervical lymph node synchronous primary papillary breast carcinoma, cytological examination revealed numerous singly thyroid medullary carcinoma and pancreatic arranged cells of plasmacytoid appearance, well-differentiated neuroendocrine tumor that has not, immunoreactive for calcitonin: these findings were to our knowledge, previously been reported. consistent with a metastatic thyroid medullary carcinoma. Histopathological evaluation of the Our patient was affected by an unusual variety of ductal pancreatic and liver biopsies established a diagnosis of carcinoma, the papillary histotype. Its incidence ranges primary pancreatic well-differentiated neuroendocrine from 0, 5 to 2% of all newly diagnosed breast cancers. It tumor, grade 2 according to WHO (2010), with usually occurs 2in women aged between 50 and 70 years, metastatic involvement of the liver. The tumor showed a and it is characterized by a good prognosis with a long low mitotic count (2/10 high- power field HPF). term survival. Antracyclines and taxanes are some of the most active agents against advanced breast cancer; Immunohistochemical analysis of both tissues showed a the obtainment of a stable disease instead than an Ki67 index of 5%, diffuse synaptophysin and focal objective response to this chemotherapy in the present chromogranin A (Figure 1a) expression in the tumor cell case called into question the diagnosis, so we decided to component (Figure 1b). Yet, RET resulted wild type. The undergo further examinations for a better evaluation of patient underwent radical thyroidectomy and lateral the patient’s disease. cervical lymph node dissection and histology showed a medullary carcinoma, measuring 2.5 cm diameter, with In breast cancer patients a high prevalence of thyroid > 25% calcitonin immunopositive cells in the thyroid. diseases, particularly Hashimoto's thyroiditis,3 has been Additionally, 2 out of the 10 examined loco-regional described, whose relationship and coincidence is still a nodes were involved by metastatic disease (TNM subject of extensive debate and controversy. To a more4 classification pT2 pN1 pMx). careful evaluation of the literature we found two cases of synchronous breast and medullary thyroid cancer. These patients presented high serum CEA levels, and were affected by the usual ductal-type variety of breast carcinoma, differently from the present case. Therefore, the finding of a synchronous thyroid medullary carcinoma was rather unexpected. Figure 1: Medullary thyroid carcinoma is an APUDoma (Amine a) Cromogranin A immunoperoxidase staining of Precursor Uptake and Decarboxylation) arising from the metastatic liver. b) Higher magnification histology of parafollicular C cells. It is sporadic in 75% of cases, and metastatic tumor cells into the liver. familial in 25%, due to RET proto-oncogene germinal mutations. The familial form of medullary thyroid Surgery of the pancreatic neuroendocrine tumor was carcinoma can also be a component of multiple contraindicated, due to the liver metastasis extension endocrine neoplasia (MEN) IIA or IIB. Serum calcitonin and location. Therefore, the patient received a value is an important diagnostic tool for thyroid cancer chemotherapy regimen based on streptozotocin and

Conclusion 5 and high levels are usually found in the medullary thyroid cancer. Our case report highlights an unusual association of Neuroendocrine tumors (NETs) are rare neoplasms, multiple synchronous tumors, all characterized by low with an incidence6 of about 1 case per 100,000 in the incidence. This case suggests that sometimes atypical population per year, with variations due to their forms of MEN with wild type RET can remain histotype. Recently, an increase in the incidence of undiagnosed and that a neuroendocrine tumor should these tumors has been observed, from 1.09 to7 5.25 cases be kept in mind when facing with a patient with an per 100,000 in the USA population per year. In 70% of Conflictextensive disease, of interest not responsive to key-drugs. the cases, NETs are highly differentiated6 tumors, and are characterized by long patient’s survival. They can be sporadic or familial diseases. The authors declare that they have no conflicts of interest. The authors alone are responsible for the The peculiar association of such unusual tumors, content and writing of the paper. suggested a careful genetic evaluation, despite her References negative family history, that revealed no first-degree relatives with history of cancer. RET proto-oncogene analysis surprisingly indicated that the patient 1. Lodish MB, Stratakis CA. RET oncogene in MEN2, expressed wild type RET, ruling out a MEN syndrome, MEN2B, MTC and other formset al of thyroid cancer. not excluding a case of atypical MEN. However, as Expert Rev Anticancer Ther. 2008; 8:625-32. medullary thyroid cancer has a common origin with 2. Pal SK, Lau SK, Kruper L, . Papillary carcinoma neuroendocrine tumors, this patient could harbor of the breast: an overview. Breast Canceret al Res Treat. genetic alterations other than RET germinal mutations. 2010; 122:637-45. Recent literature reported, for example, the expression6 3. Tanaka H, Tsukuma H, Koyama H, . Second of Kit protein and CD34 and the mutation of Kit receptor primary cancers following breast cancer in the tyrosine kinase gene in multiple endocrine neoplasia. Japanese female population. Jpn J Canceret al Res. 2001; 92:1-8. Gastro-entero-pancreatic neuroendocrine tumors can be 4. Andry G, Wildschutz T, Chantrain G, . Elevated associated to other synchronous or metachronous CEA in breast cancer patients with overlooked primary epithelial malignancies, accounting for about7 medullary thyroid carcinoma. Eur J Surget al Oncol. 10% of cases, and, even less frequently (1.3% cases), 1993; 19:305-8. they can be associated to non-epithelial neoplasms. 5. Costante G, Meringolo D, Durante C, . Predictive value of serum calcitonin levels for preoperative Nuclear imaging by Octreoscan plays a key role in the diagnosis of medullary thyroid carcinoma in a diagnosis of NETSs. Therapy with somatostatin analogs, cohort of 5817 consecutive patients with thyroid such as long-acting repeatable octreotide (LAR), can nodules. J Clin Endocrinol Metab. 2007; 92: 450-5. improve symptoms and stabilize tumor growth in many 6. Cirillo F. Neuroendocrine tumors and their patients. Results from the PROMID study showed that association with rare tumors: observation of 4 LAR octreotide is an effective molecule8 for patients with cases. Eur Rev Med Pharmacol Sci. 2010; 14: newly diagnosed, functionally active or inactive, well- 577-88. differentiated metastatic midgut NETs. CLARINET study 7. Yao JC, Hassan M, Phan A. One hundred years after conducted on 200 patients with metastatic “carcinoid”: epidemiology of and prognostic factors enteropancreatic neuroendocrine9 tumors treated with for neuroendocrine tumors in 35,825 caseset al in the lanreotide demonstrated a significantly prolonged United States. J Clin Oncol. 2008; 26: 3063-72. progression-free survival. 8. Rinke A, Müller HH, Schade-Brittinger C, . Placebo-controlled, double-blind, prospective, The use of LAR octreotide instead of standard octreotide10 randomized study on the effect of octreotide LAR in demonstrated an improvement in tumor mass decrease the control of tumor growth in patients with and survival prolongation with long acting molecules. metastatic neuroendocrine midgut tumors: a report This new formulation requires only one monthly from the PROMID Study Group.etJ Clinal Oncol. 2009; intramuscular injection, and shows better acceptability 27:4656-63. and patient compliance to therapy, so it seems 9. Caplin ME, Pavel M, Ćwikła JB, . Lanreotide in preferable in clinical practice. Indeed, minimal adverse metastatic enteropancreatic neuroendocrineet al effects of somatostatin analogs permitted to our patient tumors. N Engl J Med. 2014; 371: 224-33. a prolonged treatment period without alteration of her 10. Dogliotti L, Tampellini M, Stivanello M, . The quality of life. clinical management of neuroendocrine tumors with long-acting repeatable (LAR) octreotide: comparison with standard subcutaneous octreotide therapy. Ann Oncol. 2001; 12Suppl 2:S105-9.