Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-2974-x
Head and Neck
Management of Merkel cell carcinoma of unknown primary origin: the Vienna Medical School experience Georg Haymerle · Alexandra Fochtmann · Rainer Kunstfeld · Johannes Pammer · Boban M. Erovic
Received: 4 November 2013 / Accepted: 20 February 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Merkel cell carcinoma is a rare, but highly aggressive skin tumor. We describe our single-institution experience with the diagnosis and treatment of Merkel cell carcinoma of unknown primary (MCCUP). We conducted a retrospective medical chart review of patients treated with MCCUP at the Vienna General Hospital between 2002 and 2011. Clinicopathologic variables and outcomes were analyzed. Of the entire cohort of 57 patients, 8 patients (14 %) were diagnosed with MCCUP. Three patients presented with parotid gland involvement, four patients with positive inguinal lymph nodes and one with axillar lymph nodes. CK20 staining was positive in all tumor specimens, whereas MCPyV protein was positive in four out of six patients. The primary surgical modality in five cases was wide local excision. In one patient excisional biopsy was followed by re-resection. In one case only excisional biopsy was performed due to metastatic disease at first diagnosis. Two patients underwent concomitant parotidectomy and neck dissection, and four patients received adjuvant radiation therapy. Median recurrence-free survival was 20 months. Four patients died, three of disease and one of G. Haymerle · A. Fochtmann · B. M. Erovic (*) Department of Otolaryngology Head and Neck Surgery, Medical University of Vienna, Währinger Gürtel 18‑20, 1090 Vienna, Austria e-mail: [email protected] G. Haymerle e-mail: [email protected] R. Kunstfeld Department of Dermatology, Medical University of Vienna, Vienna, Austria J. Pammer Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
other cause. Recurrent disease was observed in two patients and treated with radiotherapy and chemotherapy. The 1and 3-year overall survival rates were 87.5 and 37.5 %, respectively. The 1- and 3-year disease-specific survival rates were 87.5 and 62.5 %, respectively. Our study shows a poor outcome in patients with MCCUP, particularly in patients with node involvement of the trunk. We therefore suggest an aggressive and multimodal treatment approach for patients with MCCUP. Keywords Merkel cell carcinoma of unknown primary · Retrospective
Introduction Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine neoplasm of the skin predominantly in elderly Caucasian patients [1]. The incidence is very low compared to other cutaneous malignancies reported, 1,500 cases annually in the USA [2], and depicts a challenging disease regarding diagnosis and appropriate treatment. MCC is typically presented as a flat or raised, isolated, redpurplish lesion with shiny surface [3]. In 1988 Kaplan and colleagues [4] described for the first time MCC involving lymph nodes without a known primary tumor. Merkel cell carcinoma of unknown primary origin (MCCUP) is defined as clinically positive nodal disease meeting the pathologic criteria of MCC in the absence of a history of an identifiable primary tumor. Immunohistochemical markers include cytokeratin 20, chromogranin A, neural cell adhesion molecule, synaptophysin and TTF1 [5]. In some cases differentiation from other small cell carcinomas such as cutaneous lymphoma, cutaneous metastasis from anaplastic carcinoma and melanomas can be challenging [6].
13
In 2008 a new human polyomavirus was found in Merkel cell carcinoma and was named Merkel cell polyomavirus (MCPyV). Subsequent studies described the incidence of the virus in Merkel cell carcinoma specimens in the range of 70–100 % [7]. Because only a few case reports and small case series have been published since 1992 [8–12], the current staging system by the American Joint Committee on Cancer does not include MCCUP. Treatment guidelines remain controversial in recent literature, as there is still very limited data on outcome. Given the rarity of clinical presentation and limited knowledge concerning diagnostic means, the optimal treatment approach as well as prognostic factors, we present our experience with MCCUP patients at the Vienna Medical School, Vienna, Austria.
Materials and methods Patients Approval for the study was obtained from the institutional research ethics board (1798/2013). A single-institutional retrospective medical chart review was performed of patients newly diagnosed with MCC. Patients without known primary origin who underwent treatment between June 2002 and October 2011 were included in this study. Patients with known primary were excluded, but collected for separate analysis. The most recent patient was included in October 2011 resulting in at least 2 years of follow-up. Patient demographics, diagnostic means at first diagnosis, histopathological factors and treatment type were obtained from hospital records. Recurrence rate, follow-up and outcome were evaluated. Duration of follow-up was calculated from the date of first diagnosis to the date of death or last follow-up. Fine-needle aspiration, ultrasonography, whole-body positron emission tomography (PET), computed tomographic imaging (CT) and/or magnetic resonance imaging (MRI) were performed as diagnostic means at the time of first diagnosis. Immunohistochemistry All patients included in this analysis were histologically confirmed by the Departments of Clinical Pathology or Dermatopathology. Immunohistochemical staining was performed on all tumors including cytokeratin 20 (CK20), neuron-specific enolase (NSE), chromogranin A (CrA), neural cell adhesion molecule (NCAM) and thyroid transcription factor-1 (TTF-1). Staining for MCPyV was performed in a Benchmark Ultra HIC/ISH staining module using the ultra View universal DAB detection Kit (v1.02.0018). Dewaxed
13
Eur Arch Otorhinolaryngol
and rehydrated 4 μ formalin-fixed paraffin-embedded sections were heated in an ultra cell conditioner at 95 °C and subjected to antigen retrieval in a CC1 buffer (pH 6.0) for 170 min. Sections were then titrated and incubated at room temperature with the MCPyV large T-protein antibody CM2B4 (sc136172, 1:200; Santa Cruz, CA, USA) for 1 h. Finally, sections were rinsed with ultraWash and counterstained with Mayer’s hematoxylin.
Results Demographics During the study period (2002–2011), a total of 57 patients underwent biopsy or definite treatment at the Vienna General Hospital for MCC. Eight patients (14 %) were identified as having MCCUP and therefore eligible for inclusion in this study. No patient within the study group was reported with a history or subsequent development of a primary MCC tumor until the last follow-up. The mean and median age at the time of diagnosis was 68 and 67 (range 52–79) years. There was a predominance of 62 % male patients (5/8) compared to 38 % female patients (3/8). Three patients presented with parotid gland involvement, four patients with positive inguinal lymph nodes and one with axillary lymph node involvement. Preoperative imaging included ultrasonography in six patients, thoracic and abdominal CT scan in six patients, PET scan in two patients, octreotide scan in one patient and MRI scan of the head and neck in three patients. Fine-needle aspiration biopsy was performed in two patients at first diagnosis; one was thereby diagnosed with MCC (Table 1). Treatment The primary surgical modality in five cases was wide local excision. In one patient excisional biopsy was followed by re-resection. In one case excisional biopsy was performed due to metastatic disease at first diagnosis. Two patients underwent concomitant parotidectomy and neck dissection and four patients received adjuvant radiation therapy. Recurrent disease was treated with radiotherapy alone or in combination with chemotherapy. Histopathological analysis The histopathological parameters provided in this study are from eight cases diagnosed by the Departments of Clinical Pathology or Dermatology at the Medical University of Vienna. Samples were macroscopically described as blue to yellow-reddish and/or partly necrotic, lymphatic tissue characterized by diffuse infiltration of carcinoma cells.
Eur Arch Otorhinolaryngol Table 1 Demographic and histopathological data of eight patients with MCCUP Location
Age/gender
Stage
Surgery
RT
Recurrence
Metastasis
Vital status (months)
Parotid
75, male
IIIb
Yes
No
No
DNED, 22
Inguinal Axilla Inguinal Inguinal Inguinal Parotid
67, female 79, male 77, male 69, male 52, male 55, female
IIIb IIIb IIIb IV IIIb IIIb
Parotidectomy ND LN excision LN excision LN excision LN biopsy LN excision Parotidectomy ND
No No Yes Yes No Yes
Yes No Yes No No No
Abdominal node Abdominal node Abdominal node, biceps Iliac node No No
DOD, 36 ANED, 17 DOD, 27 DOD, 5 ANED, 67 ANED, 71
Parotid
66, female
IIIb
No
No
No
ANED, 96
Parotidectomy
ANED Alive with no evidence of disease, AWD alive with disease, DNED died with no evidence of disease, DOD died of disease, LN lymph node, ND neck dissection, RT radiation therapy
Immunohistochemical staining was hence performed in all tumors. All samples tested positive for CK20; seven were positive for NCAM and seven for the neuroendocrine marker CrA, but two for synaptophysin. TTF-1 was in four cases negative or not performed. MCPyV staining could only be provided in six out of eight samples, because two specimens were unfortunately not retrievable from the archives. In four probes, 60–100 % of all tumor cells were classified as positive. Two out of six tissue samples were negative for MCPyV (Fig. 1). Outcome The mean and median follow-up times for the study population were 43 and 32 months, respectively, with a range of 5–96 months. At the last follow-up, five patients (62 %) were alive without disease. In the other three patients, recurrent disease was reported in two cases and one patient had metastatic disease at first presentation, respectively. Metastatic disease occurred as abdominal lymph node infiltration. All of them had positive inguinal lymph nodes at first diagnosis. The recurrence-free survival (RFS) time was 20 months (range 12–95). Four patients died, three of disease and one of other cause. The 1- and 3-year overall survival (OS) rates were 87.5 and 37.5 %, respectively. The 1- and 3-year disease-specific survival (DSS) rates were 87.5 and 62.5 %, respectively. Head and neck patients were treated with lateral parotidectomy, neck dissection and radiotherapy. In this cohort, none of the patients either developed recurrent disease or died of disease. In clear contrast, of the patients with nodal involvement of the trunk, one patient had metastatic disease at first diagnosis, two out of five patients showed recurrent disease and three patients died of disease. Both patients who developed recurrent disease were also positive for the MCPyV protein.
Fig. 1 Immunohistochemistry of MCPyV large T cell antigen shows that the antigen is predominantly expressed in the nuclei (arrow) of Merkel cell carcinoma cells. a Demonstrates a negative to weak expression, whereas in b a significant overexpression of MCPyV large T cell antigen can be appreciated. All photomicrographs are taken at ×400 magnification
13
Discussion The choice of adequate therapeutic approach relies upon specific diagnosis before initial treatment in any malignant disease. Concerning malignancies such as MCC, histopathological diagnosis presents a challenging target due to the rarity and diverse clinical presentation of this tumor entity. Immunohistochemistry is necessary for differential diagnosis from other poorly differentiated carcinomas. In our study all tumors were tested positive for cytokeratin 20 and CD 56. Additional staining for thyroid transcription factor-1 was negative, thereby confirming metastatic disease of MCC. Meticulous clinical search could not identify primary lesions of the skin. To date, there is still sparse literature on the guidelines for imaging algorithms of MCC [13, 14]. Therefore, also imaging workup for MCCUP depicts a challenging target. In our current study patients underwent ultrasonography and hence either CT or MRI scan. PET scan was performed in two patients. Ultrasonography should be performed as first-line workup of the lymph node basin as it is cost-effective and accurate. For detection of distant metastases, Peloschek and colleagues [15] showed high specificity and sensitivity in FDG-PET, CT and MRI scanning. Somatostatin receptor scintigraphy is no longer recommended for routine evaluation due to high rates of false-positive and false-negative results [16]. Enzenhofer and co-workers [17] just recently recommended FDG-PET CT as a first-line imaging technique, as it is non-invasive and detection of occult lesions wider than 5 mm in diameter is possible. Follow-up imaging should include chest X-ray, CT and MRI as well as FDG-PET. Recent literature showed that patients with unknown primary MCC had a better overall prognosis compared to patients with MCC of the skin. They demonstrated a significantly better OS, disease-free survival and relapse-free survival time [18]. A retrospective data analysis of 23 new cases and a literature review of 34 cases carried out by Tarantola et al. [19] showed that the OS of stage IIIB UPMCC was significantly improved from 76 to 36 % compared to stage IIIB known primary MCC. These results are consistent with our findings, since our 3-year OS and DSS rates, 37.5 and 62.5 %, respectively, were comparable to the study of Tarantola et al. [19]. Optimal treatment involves a multimodal approach for diagnosis, therapy of the primary tumor as well as recurrent disease and systemic treatment of advanced disease. The optimal regimen still remains controversial, as previous studies could not identify single prognostic factors or statistically significant treatment options. Nevertheless, the impact of clinical variables or treatment type on prognosis was limited due to the study size [19]. In the current literature on MCCUP, the majority of publications include case reports and small case series [8–12]. While this study
13
Eur Arch Otorhinolaryngol
represents a case series of eight patients, it also includes detailed analysis of clinical and histopathological data of MCCUP by a single institution. This study is subject to statistical limitations due to a small study group size. However, we observed three patients with lymph node metastasis of the parotid gland with occult primary, who did not present with recurrent disease after aggressive treatment of the primary tumor. All patients underwent lateral parotidectomy, neck dissection and postoperative radiotherapy. Merkel cell polyomavirus is overexpressed in Merkel cell carcinoma patients, however, a predictive effect or correlation with clinical outcome in MCCUP patients has not yet been described in the current literature. We reported that in four out of six patients a significant overexpression of MCPyV could be detected. Although the number of the investigated patients was low, we still could show that two patients with a recurrent disease had a significant overexpression of MCPyV. In clear contrast to head and neck patients, three patients with inguinal lymph node involvement, after surgical treatment and postoperative radiotherapy, developed recurrent disease and died of disease within 1 year despite radiotherapy or radiochemotherapy. On the basis of these results, we observed a better outcome in patients with lymph node involvement of the head and neck region than of the trunk, despite treatment. This might be explained by the fact that the attention of the patients itself and the physician is drawn later to lymph nodes of the inguinal region compared to the exposed head and neck area. Subsequently tumors of the trunk may present in a significantly enlarged dimension or may have developed metastatic disease by the time of diagnosis compared to those of the head and neck. In summary, experienced pathologists or dermatopathologists should evaluate MCCUP, because of the challenging differential diagnosis determining patient prognosis. MCPyV protein might represent a useful biomarker either as a diagnostic or predictive tool for clinical outcome in patients with Merkel cell carcinoma of unknown primary. The optimal treatment approach remains to be elucidated in multi-centered collaborative studies due to the rarity of this cutaneous malignancy. Nonetheless, we suggest aggressive treatment including wide local excision, lymph node dissection and, depending on individual performance status, postoperative radiotherapy. Conflict of interest No conflict of interest and financial disclosures.
References 1. Toker C (1972) Trabecular carcinoma of the skin. Arch Dermatol 105:107–110 2. Deneve JL, Messina JL, Marzban SS, Gonzalez RJ, Walls BM, Fisher KJ, Chen YA, Cruse CW, Sondak VK, Zager JS (2012)
Eur Arch Otorhinolaryngol Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol 19:2360–2366. doi:10.1245/s10434-011-2213-2 3. Frigerio B, Capella C, Eusebi V, Tenti P, Azzopardi JG (1983) Merkel cell carcinoma of the skin: the structure and origin of normal Merkel cells. Histopathology 7:229–249 4. Kaplan GP, Bookbinder MJ, Hood DR, Bridgers SL (1988) Merkel cell tumor of the skin. Hum Pathol 19:615–616 5. Moll R, Lowe A, Laufer J, Franke WW (1992) Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 140:427–447 6. Ratner D, Nelson BR, Brown MD, Johnson TM (1993) Merkel cell carcinoma. J Am Acad Dermatol 29:143–156 7. Erovic BM, Al Habeeb A, Harris L, Goldstein DP, Ghazarian D, Irish JC (2013) Significant overexpression of the Merkel cell polyomavirus (MCPyV) large T antigen in Merkel cell carcinoma. Head Neck 35:184–189 8. De Cicco L, Vavassori A, Jereczek-Fossa BA, Pruneri G, Catalano G, Ferrari AM, Orecchia R (2008) Lymph node metastases of Merkel cell carcinoma from unknown primary site: report of three cases. Tumori 94:758–761 9. Eusebi V, Capella C, Cossu A, Rosai J (1992) Neuroendocrine carcinoma within lymph nodes in the absence of a primary tumor, with special reference to Merkel cell carcinoma. Am J Surg Pathol 16:658–666 10. Silberstein E, Koretz M, Cagnano E, Katchko L, Rosenberg L (2003) Neuroendocrine (Merkel cell) carcinoma in regional lymph nodes without primary site. Isr Med Assoc J 5:450–451 11. Straka JA, Straka MB (1997) A review of Merkel cell carcinoma with emphasis on lymph node disease in the absence of a primary site. Am J Otolaryngol 18:55–65
12. Wong KK, Oliver GF (2010) Metastatic Merkel cell car cinoma with an unknown primary tumour presenting as lichenoid dermatitis. Australas J Dermatol 51:202–205. doi:10.1111/j.1440-0960.2010.00624.x 13. Eftekhari F, Wallace S, Silva EG, Lenzi R (1996) Merkel cell carcinoma of the skin: imaging and clinical features in 93 cases. Br J Radiol 69:226–233 14. Nguyen BD, McCullough AE (2002) Imaging of Merkel cell carcinoma. Radiographics 22:367–376 15. Peloschek P, Novotny C, Mueller-Mang C, Weber M, Sailer J, Dawid M, Czerny C, Dudczak R, Kletter K, Becherer A (2010) Diagnostic imaging in Merkel cell carcinoma: lessons to learn from 16 cases with correlation of sonography, CT, MRI and PET. Eur J Radiol 73:317–323. doi:10.1016/j.ejrad.2008.10.032 16. Durani BK, Klein A, Henze M, Haberkorn U, Hartschuh W (2003) Somatostatin analogue scintigraphy in Merkel cell tumours. Br J Dermatol 148:1135–1140 17. Enzenhofer E, Ubl P, Czerny C, Erovic BM (2013) Imaging in patients with merkel cell carcinoma. J Skin Cancer 2013:973123. doi:10.1155/2013/973123 18. Foote M, Veness M, Zarate D, Poulsen M (2012) Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease. J Am Acad Dermatol 67:395–399. doi:10.1016/j.jaad.2011.09.009 19. Tarantola TI, Vallow LA, Halyard MY, Weenig RH, War schaw KE, Weaver AL, Roenigk RK, Brewer JD, Otley CC (2013) Unknown primary Merkel cell carcinoma: 23 new cases and a review. J Am Acad Dermatol 68:433–440. doi:10.1016/j.jaad.2012.07.035
13
Head and Neck
Management of Merkel cell carcinoma of unknown primary origin: the Vienna Medical School experience Georg Haymerle · Alexandra Fochtmann · Rainer Kunstfeld · Johannes Pammer · Boban M. Erovic
Received: 4 November 2013 / Accepted: 20 February 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Merkel cell carcinoma is a rare, but highly aggressive skin tumor. We describe our single-institution experience with the diagnosis and treatment of Merkel cell carcinoma of unknown primary (MCCUP). We conducted a retrospective medical chart review of patients treated with MCCUP at the Vienna General Hospital between 2002 and 2011. Clinicopathologic variables and outcomes were analyzed. Of the entire cohort of 57 patients, 8 patients (14 %) were diagnosed with MCCUP. Three patients presented with parotid gland involvement, four patients with positive inguinal lymph nodes and one with axillar lymph nodes. CK20 staining was positive in all tumor specimens, whereas MCPyV protein was positive in four out of six patients. The primary surgical modality in five cases was wide local excision. In one patient excisional biopsy was followed by re-resection. In one case only excisional biopsy was performed due to metastatic disease at first diagnosis. Two patients underwent concomitant parotidectomy and neck dissection, and four patients received adjuvant radiation therapy. Median recurrence-free survival was 20 months. Four patients died, three of disease and one of G. Haymerle · A. Fochtmann · B. M. Erovic (*) Department of Otolaryngology Head and Neck Surgery, Medical University of Vienna, Währinger Gürtel 18‑20, 1090 Vienna, Austria e-mail: [email protected] G. Haymerle e-mail: [email protected] R. Kunstfeld Department of Dermatology, Medical University of Vienna, Vienna, Austria J. Pammer Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
other cause. Recurrent disease was observed in two patients and treated with radiotherapy and chemotherapy. The 1and 3-year overall survival rates were 87.5 and 37.5 %, respectively. The 1- and 3-year disease-specific survival rates were 87.5 and 62.5 %, respectively. Our study shows a poor outcome in patients with MCCUP, particularly in patients with node involvement of the trunk. We therefore suggest an aggressive and multimodal treatment approach for patients with MCCUP. Keywords Merkel cell carcinoma of unknown primary · Retrospective
Introduction Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine neoplasm of the skin predominantly in elderly Caucasian patients [1]. The incidence is very low compared to other cutaneous malignancies reported, 1,500 cases annually in the USA [2], and depicts a challenging disease regarding diagnosis and appropriate treatment. MCC is typically presented as a flat or raised, isolated, redpurplish lesion with shiny surface [3]. In 1988 Kaplan and colleagues [4] described for the first time MCC involving lymph nodes without a known primary tumor. Merkel cell carcinoma of unknown primary origin (MCCUP) is defined as clinically positive nodal disease meeting the pathologic criteria of MCC in the absence of a history of an identifiable primary tumor. Immunohistochemical markers include cytokeratin 20, chromogranin A, neural cell adhesion molecule, synaptophysin and TTF1 [5]. In some cases differentiation from other small cell carcinomas such as cutaneous lymphoma, cutaneous metastasis from anaplastic carcinoma and melanomas can be challenging [6].
13
In 2008 a new human polyomavirus was found in Merkel cell carcinoma and was named Merkel cell polyomavirus (MCPyV). Subsequent studies described the incidence of the virus in Merkel cell carcinoma specimens in the range of 70–100 % [7]. Because only a few case reports and small case series have been published since 1992 [8–12], the current staging system by the American Joint Committee on Cancer does not include MCCUP. Treatment guidelines remain controversial in recent literature, as there is still very limited data on outcome. Given the rarity of clinical presentation and limited knowledge concerning diagnostic means, the optimal treatment approach as well as prognostic factors, we present our experience with MCCUP patients at the Vienna Medical School, Vienna, Austria.
Materials and methods Patients Approval for the study was obtained from the institutional research ethics board (1798/2013). A single-institutional retrospective medical chart review was performed of patients newly diagnosed with MCC. Patients without known primary origin who underwent treatment between June 2002 and October 2011 were included in this study. Patients with known primary were excluded, but collected for separate analysis. The most recent patient was included in October 2011 resulting in at least 2 years of follow-up. Patient demographics, diagnostic means at first diagnosis, histopathological factors and treatment type were obtained from hospital records. Recurrence rate, follow-up and outcome were evaluated. Duration of follow-up was calculated from the date of first diagnosis to the date of death or last follow-up. Fine-needle aspiration, ultrasonography, whole-body positron emission tomography (PET), computed tomographic imaging (CT) and/or magnetic resonance imaging (MRI) were performed as diagnostic means at the time of first diagnosis. Immunohistochemistry All patients included in this analysis were histologically confirmed by the Departments of Clinical Pathology or Dermatopathology. Immunohistochemical staining was performed on all tumors including cytokeratin 20 (CK20), neuron-specific enolase (NSE), chromogranin A (CrA), neural cell adhesion molecule (NCAM) and thyroid transcription factor-1 (TTF-1). Staining for MCPyV was performed in a Benchmark Ultra HIC/ISH staining module using the ultra View universal DAB detection Kit (v1.02.0018). Dewaxed
13
Eur Arch Otorhinolaryngol
and rehydrated 4 μ formalin-fixed paraffin-embedded sections were heated in an ultra cell conditioner at 95 °C and subjected to antigen retrieval in a CC1 buffer (pH 6.0) for 170 min. Sections were then titrated and incubated at room temperature with the MCPyV large T-protein antibody CM2B4 (sc136172, 1:200; Santa Cruz, CA, USA) for 1 h. Finally, sections were rinsed with ultraWash and counterstained with Mayer’s hematoxylin.
Results Demographics During the study period (2002–2011), a total of 57 patients underwent biopsy or definite treatment at the Vienna General Hospital for MCC. Eight patients (14 %) were identified as having MCCUP and therefore eligible for inclusion in this study. No patient within the study group was reported with a history or subsequent development of a primary MCC tumor until the last follow-up. The mean and median age at the time of diagnosis was 68 and 67 (range 52–79) years. There was a predominance of 62 % male patients (5/8) compared to 38 % female patients (3/8). Three patients presented with parotid gland involvement, four patients with positive inguinal lymph nodes and one with axillary lymph node involvement. Preoperative imaging included ultrasonography in six patients, thoracic and abdominal CT scan in six patients, PET scan in two patients, octreotide scan in one patient and MRI scan of the head and neck in three patients. Fine-needle aspiration biopsy was performed in two patients at first diagnosis; one was thereby diagnosed with MCC (Table 1). Treatment The primary surgical modality in five cases was wide local excision. In one patient excisional biopsy was followed by re-resection. In one case excisional biopsy was performed due to metastatic disease at first diagnosis. Two patients underwent concomitant parotidectomy and neck dissection and four patients received adjuvant radiation therapy. Recurrent disease was treated with radiotherapy alone or in combination with chemotherapy. Histopathological analysis The histopathological parameters provided in this study are from eight cases diagnosed by the Departments of Clinical Pathology or Dermatology at the Medical University of Vienna. Samples were macroscopically described as blue to yellow-reddish and/or partly necrotic, lymphatic tissue characterized by diffuse infiltration of carcinoma cells.
Eur Arch Otorhinolaryngol Table 1 Demographic and histopathological data of eight patients with MCCUP Location
Age/gender
Stage
Surgery
RT
Recurrence
Metastasis
Vital status (months)
Parotid
75, male
IIIb
Yes
No
No
DNED, 22
Inguinal Axilla Inguinal Inguinal Inguinal Parotid
67, female 79, male 77, male 69, male 52, male 55, female
IIIb IIIb IIIb IV IIIb IIIb
Parotidectomy ND LN excision LN excision LN excision LN biopsy LN excision Parotidectomy ND
No No Yes Yes No Yes
Yes No Yes No No No
Abdominal node Abdominal node Abdominal node, biceps Iliac node No No
DOD, 36 ANED, 17 DOD, 27 DOD, 5 ANED, 67 ANED, 71
Parotid
66, female
IIIb
No
No
No
ANED, 96
Parotidectomy
ANED Alive with no evidence of disease, AWD alive with disease, DNED died with no evidence of disease, DOD died of disease, LN lymph node, ND neck dissection, RT radiation therapy
Immunohistochemical staining was hence performed in all tumors. All samples tested positive for CK20; seven were positive for NCAM and seven for the neuroendocrine marker CrA, but two for synaptophysin. TTF-1 was in four cases negative or not performed. MCPyV staining could only be provided in six out of eight samples, because two specimens were unfortunately not retrievable from the archives. In four probes, 60–100 % of all tumor cells were classified as positive. Two out of six tissue samples were negative for MCPyV (Fig. 1). Outcome The mean and median follow-up times for the study population were 43 and 32 months, respectively, with a range of 5–96 months. At the last follow-up, five patients (62 %) were alive without disease. In the other three patients, recurrent disease was reported in two cases and one patient had metastatic disease at first presentation, respectively. Metastatic disease occurred as abdominal lymph node infiltration. All of them had positive inguinal lymph nodes at first diagnosis. The recurrence-free survival (RFS) time was 20 months (range 12–95). Four patients died, three of disease and one of other cause. The 1- and 3-year overall survival (OS) rates were 87.5 and 37.5 %, respectively. The 1- and 3-year disease-specific survival (DSS) rates were 87.5 and 62.5 %, respectively. Head and neck patients were treated with lateral parotidectomy, neck dissection and radiotherapy. In this cohort, none of the patients either developed recurrent disease or died of disease. In clear contrast, of the patients with nodal involvement of the trunk, one patient had metastatic disease at first diagnosis, two out of five patients showed recurrent disease and three patients died of disease. Both patients who developed recurrent disease were also positive for the MCPyV protein.
Fig. 1 Immunohistochemistry of MCPyV large T cell antigen shows that the antigen is predominantly expressed in the nuclei (arrow) of Merkel cell carcinoma cells. a Demonstrates a negative to weak expression, whereas in b a significant overexpression of MCPyV large T cell antigen can be appreciated. All photomicrographs are taken at ×400 magnification
13
Discussion The choice of adequate therapeutic approach relies upon specific diagnosis before initial treatment in any malignant disease. Concerning malignancies such as MCC, histopathological diagnosis presents a challenging target due to the rarity and diverse clinical presentation of this tumor entity. Immunohistochemistry is necessary for differential diagnosis from other poorly differentiated carcinomas. In our study all tumors were tested positive for cytokeratin 20 and CD 56. Additional staining for thyroid transcription factor-1 was negative, thereby confirming metastatic disease of MCC. Meticulous clinical search could not identify primary lesions of the skin. To date, there is still sparse literature on the guidelines for imaging algorithms of MCC [13, 14]. Therefore, also imaging workup for MCCUP depicts a challenging target. In our current study patients underwent ultrasonography and hence either CT or MRI scan. PET scan was performed in two patients. Ultrasonography should be performed as first-line workup of the lymph node basin as it is cost-effective and accurate. For detection of distant metastases, Peloschek and colleagues [15] showed high specificity and sensitivity in FDG-PET, CT and MRI scanning. Somatostatin receptor scintigraphy is no longer recommended for routine evaluation due to high rates of false-positive and false-negative results [16]. Enzenhofer and co-workers [17] just recently recommended FDG-PET CT as a first-line imaging technique, as it is non-invasive and detection of occult lesions wider than 5 mm in diameter is possible. Follow-up imaging should include chest X-ray, CT and MRI as well as FDG-PET. Recent literature showed that patients with unknown primary MCC had a better overall prognosis compared to patients with MCC of the skin. They demonstrated a significantly better OS, disease-free survival and relapse-free survival time [18]. A retrospective data analysis of 23 new cases and a literature review of 34 cases carried out by Tarantola et al. [19] showed that the OS of stage IIIB UPMCC was significantly improved from 76 to 36 % compared to stage IIIB known primary MCC. These results are consistent with our findings, since our 3-year OS and DSS rates, 37.5 and 62.5 %, respectively, were comparable to the study of Tarantola et al. [19]. Optimal treatment involves a multimodal approach for diagnosis, therapy of the primary tumor as well as recurrent disease and systemic treatment of advanced disease. The optimal regimen still remains controversial, as previous studies could not identify single prognostic factors or statistically significant treatment options. Nevertheless, the impact of clinical variables or treatment type on prognosis was limited due to the study size [19]. In the current literature on MCCUP, the majority of publications include case reports and small case series [8–12]. While this study
13
Eur Arch Otorhinolaryngol
represents a case series of eight patients, it also includes detailed analysis of clinical and histopathological data of MCCUP by a single institution. This study is subject to statistical limitations due to a small study group size. However, we observed three patients with lymph node metastasis of the parotid gland with occult primary, who did not present with recurrent disease after aggressive treatment of the primary tumor. All patients underwent lateral parotidectomy, neck dissection and postoperative radiotherapy. Merkel cell polyomavirus is overexpressed in Merkel cell carcinoma patients, however, a predictive effect or correlation with clinical outcome in MCCUP patients has not yet been described in the current literature. We reported that in four out of six patients a significant overexpression of MCPyV could be detected. Although the number of the investigated patients was low, we still could show that two patients with a recurrent disease had a significant overexpression of MCPyV. In clear contrast to head and neck patients, three patients with inguinal lymph node involvement, after surgical treatment and postoperative radiotherapy, developed recurrent disease and died of disease within 1 year despite radiotherapy or radiochemotherapy. On the basis of these results, we observed a better outcome in patients with lymph node involvement of the head and neck region than of the trunk, despite treatment. This might be explained by the fact that the attention of the patients itself and the physician is drawn later to lymph nodes of the inguinal region compared to the exposed head and neck area. Subsequently tumors of the trunk may present in a significantly enlarged dimension or may have developed metastatic disease by the time of diagnosis compared to those of the head and neck. In summary, experienced pathologists or dermatopathologists should evaluate MCCUP, because of the challenging differential diagnosis determining patient prognosis. MCPyV protein might represent a useful biomarker either as a diagnostic or predictive tool for clinical outcome in patients with Merkel cell carcinoma of unknown primary. The optimal treatment approach remains to be elucidated in multi-centered collaborative studies due to the rarity of this cutaneous malignancy. Nonetheless, we suggest aggressive treatment including wide local excision, lymph node dissection and, depending on individual performance status, postoperative radiotherapy. Conflict of interest No conflict of interest and financial disclosures.
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