Critical Reviews in Oncology/Hematology 94 (2015) 116–121
Neuroendocrine Merkel cell nodal carcinoma of unknown primary site: Management and outcomes of a rare entity E.A. Kotteas, N. Pavlidis ∗ Department of Medical Oncology, School of Medicine, University of Ioannina, 45 500 Niarchos Avenue, Greece Accepted 10 December 2014
Contents 1. 2.
3.
4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients & methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search selection criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Description of content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Patients characteristics and clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Tumour pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Treatment modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NCUP outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
116 117 117 117 117 117 117 119 119 119 120 120 120 120 121
Abstract Merkel cell nodal carcinoma of unknown primary (MCCUP) is a rare neuroendocrine tumour with distinct clinical and biological behaviour. We conducted a review of retrospective data extracted from 90 patients focusing on the management and outcome of this disease. We also compared life expectancy of these patients with the outcome of patients with known Merkel primaries and with neuroendocrine cancers of unidentifiable primary. There is a limited body of data for this type of malignancy, however, patients with Merkel cell nodal carcinoma of unknown primary site, seem to have better survival when treated aggressively than patients with cutaneous Merkel tumours of the same stage and equal survival with patients with low-grade neuroendocrine tumour of unknown origin. The lack of prospective trials, and the inadequate data, hamper the management of these tumours. Establishment of treatment guidelines is urgently needed. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Merkel carcinoma; Unknown primary
1. Introduction In 1875 Friedrich Merkel was the first to describe pale cells in the basal layer of the epidermis as mechanoreceptors ∗
Corresponding author. Tel.: +30 26510 99394; fax: +30 26510 99394. E-mail address: [email protected] (N. Pavlidis).
http://dx.doi.org/10.1016/j.critrevonc.2014.12.005 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
that he believed to be associated with the sense of light touch discrimination of shapes and textures. Malignant transformation of these cells was initially reported by Cyril Toker in 1972 as trabecular carcinoma of the skin. Under his electron micrograph the neoplastic cells shared morphological features similar to neuroendocrine cells from neural crest [1]. Today, the origin of the Merkel cells is debatable, as both
E.A. Kotteas, N. Pavlidis / Critical Reviews in Oncology/Hematology 94 (2015) 116–121
neural crest and epithelial origin have been suggested [2]. Merkel cell carcinoma (MCC) is a rare skin cancer affecting sites of previous sun exposure, usually between the 6th and 8th decade of life. Merkel cell carcinoma has an annual incidence rate of 0.6 per 100,000 [3]. However, there are reported cases of biopsy-proven MCC in which the skin was not the primary affected site. Since 2008 several studies report a viral etiology which integrates Merkel cell polyomavirus (MCV) as an addictive risk factor for carcinogenesis. Immunosupressed population carries a greater risk for MCC [4]. Cancer of unknown primary (CUP) accounts for 3–5% of all human cancers and is the 4th most common cause of cancer death in both sexes. In patients with CUP the primary tumour remains unidentifiable despite all standardised diagnostic work-up [5]. Neuroendocrine CUP (NCUP) accounts for approximately 13% of all neuroendocrine cancers. Three different subtypes of neuroendocrine CUP exist: low-grade neuroendocrine tumours (10%) including carcinoids or islet-cell tumours, small-cell anaplastic carcinoma (15%) and large cell neuroendocrine carcinomas (75%) [6,7]. Neuroendocrine Merkel cell carcinoma of unknown primary (MCCUP) represents a manifestation of MCCUP. In large retrospective studies the incidence of UPMCC among MCC population ranged from 19–25% [8–10]. In this review we present MCCUP as a new entity of good prognosis NCUP and provide significant information concerning the management and the outcomes of this extremely rare form of malignancy.
2. Patients & methods 2.1. Search selection criteria We searched MEDLINE/PUBMED (last search May 2014) using combinations of terms as Merkel carcinoma, unknown primary, unknown origin and occult primary. Data was gathered from case reports and from the few small retrospective studies. We set no geographical restrictions. Non-English literature was excluded. We tracked 227 published cases as MCCUP since 1988. However, we had to exclude 137 cases due to inadequate tumour characterization, mixed survival results in which data from patients with known MCC primaries or different disease stages were included, insufficiently given treatment modalities or demographics. Patients with stage IV disease and cases reporting regressed primaries involving lymph nodes were also excluded. 2.2. Description of content In total, we extracted and analyzed information from 90 patients with clinical nodal stage IIIB MCCUP (According to the AJCC Staging System) for clinical and pathological characteristics, history of previous malignancies, treatment modalities and survival. All the examined patients underwent complete work-up (skin examination, staging with
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Table 1 Summarized patients’ characteristics. Number of patients
90
Males Females Median age History of previous/concurrent malignancy Lymph node involvement Cervical Axillary Inguinal
65 (72.3%) 25 (27.7%) 63.2 (37–85) 11 (12.2%) 38 (42.3%) 16 (17.7%) 36 (40%)
CT, MRI or PET/CT) with no identifiable primary site. Recurrence-free survival (RFS) and overall survival (OS) were calculated from the time of diagnosis until recurrence and death, respectively. Follow-up period was defined from the date of diagnosis until death or last follow-up.
3. Results 3.1. Patients characteristics and clinical presentation We observed that MCCUP patients were younger at diagnosis compared with MCC patients since the average age of diagnosis was at 63.2 (37–85) years. In a recent study by Iyer et al. 70% of 8,044 primaries MCC were diagnosed above the age of 70. From our collected data, there was a predominance of 72.3% male patients (65/90) compared with to 27.7% female patients (25/90), which corresponds to a sex ratio of 2.6:1. The respective sex ratio in MCC patients is 2:1. A significant proportion of MCCUP patients (12.2%, 11/90) had a history of a previously or concurrent treated malignancy (eight basal cell carcinomas, one prostate cancer, three patients with chronic lymphocytic leukaemia), two patients were transplant recipients and another three patients were carriers of HIV. In the immunosupressed population an earlier median onset of the disease at 52 years (37–61) was observed [3,11–30]. Almost all evaluable patients presented with clinically palpable non-tender lymph nodes-IIIB disease. For the additional work-up of the examined patients CT and PET/CT were mainly used. The neoplasm showed a rapid, aggressive growth within 1–6 months until diagnosis and a marginal predisposition to arise from the cervical lymph node basin (42.2%, 38/90). Inguinal and axillary lymph node areas were initially involved in 40% (36/90) and 17.7% (16/90) of cases, respectively. Lesions ranged in colour from red, pink to blue of flesh-coloured, sometimes with a shiny surface which may mislead to a basal cell carcinoma diagnosis [11–29]. Characteristics of all patients are summarised in Table 1 and are displayed in details in Table 2. 3.2. Tumour pathology Merkel tumours are, classified into three morphological patterns. The small cell/diffuse pattern characterized
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Table 2 All patients’ characteristics and outcomes. Author/patients
Year
Age/gender
Affected LN
Initial treatment
Relapse
Overall survival/months
Eusebi [11], n=8
1992
Boyle [12], n=5
1995
Ferrara [13], n=2 Straka [14], n = 1 Saramarendra [15], n = 1 Fornelli [16], n = 1 Fotia [17], n = 1
1997
65/F 46/M 37/M 46/F 64/M 68/F 80/F 54/F 79/M 60/M 83/F 57/M 65/M 44/M 66/M 71/F 41/M 65/M 82/F
LE + RT + C/T RLND RLND RLND RLND LE RLND LE LE RT RT LE + RT RLND RLND LE RLND + RT LE RLND RT
No No Yes No Yes (11 months) Yes (3 months) No Yes (5 months) Yes (4 months) No Yes (13months) Yes (82 months) No No Yes (8 months) Yes (10 months) No Yes (18 months) Yes (8 months)
6 (NED) 10 (NED) 25 19 (NED) 25 (NED) 8 26 (NED) 12 (AWD) 7 20 (NED) 15 83 48 (NED) 70 (NED) 19 (AWD) 12 42 (NED) 28 10
RLND Neo-adjuvant C/T RLND + RT RLND + RT RLND RLND + RT LE + C/T Neo-adjuvant C/T RLND + RT LE + RT + C/T
Yes (8 months) Yes (18 months)
9 24
No No No Yes (17 months) Yes (3 months)
12 (NED) 9 (NED) 54 (NED) 28 17
No
16 (NED)
Siberstein [18], n = 2
2003
59/M 69/M
Axillary Inguinal Inguinal Axillary Inguinal Inguinal Cervical Inguinal Inguinal Inguinal Inguinal Inguinal Cervical Inguinal Axillary Cervical Inguinal Cervical Inguinal Iliac Inguinal Inguinal
Kuwabara [19], n = 1 Huber [20], n = 1 Warnick [21], n = 1 De Cicco [22], n=3
2007 2007 2008 2008
53/M 56/M 54/M 69/M 54/M
Axillary Cervical Inguinal Axillary Inguinal
72/F
1997 2000 2001 2002
Ottaviani [23], n = 1 Cozzolino [24], n = 1
2010 2011
41/M 77/M
Inguinal Pelvic Cervical Inguinal
Zhao [25], n = 1 De Zeeuw [26], n = 1
2012 2012
54/M 85/M
Inguinal Cervical
Deneve [27], n = 38
2012
Median age: 67 M:30 F:8
Cervical: 22 Inguinal:8 Axillary: 8
Chen [28], n = 14
2013
Haymerle [29], n = 7
2014
Median age: 67 M:9 F:5 75/M 67/F 79/M 77/M 52/M 66/F 55/F
Cervical: 6 Inguinal: 6 Axillary: 2 Cervical Inguinal Axillary Inguinal Inguinal Cervical Cervical
LE + RT LE + RT
Yes (4 months) Yes (48 months) Local excision RT + C/T Yes (4 months) RLND + RT Yes (5 months) RD RLND + RT + C/T:16 N/R RLND + RT:10 N/R RLND only:3 N/R Yes (14.5 months) RT + C/T:6 RT:3 N/R RLND+ RT:8 N/R N/R LE + RT + C/T:4 N/R LE + C/T:2 RLND + RT Yes LE Yes LE Yes LE + RT Yes LE Yes RLND + RT Yes RLND Yes
14 56 (NED) 21 18 (NED) 104 (median) N/R N/R N/R 20 (Median) N/R N/R N/R 22 36 17 (NED) 27 67 (NED) 96 (NED) 71 (NED)
Abbreviations: LE (Local excision), RLND (Radical lymph node dissection), RT (Radiotherapy), C/T (Chemotherapy), LN (Lymph nodes), NED (No evidence of disease), AWD (Alive with disease), N/R (Not reported).
with hyperchromatic irregular cells arranged in sheets and rarely in ribbons with numerous mitoses and/or necroses. The intermediate presenting with basophilic cells or nests with necrosis and a paranuclear dot-like pattern. The trabecular pattern with basophilic cells in ribbons. In the
available examined specimens the intermediate pattern has been detected in approximately 55% of cases. From the collected data, MCCUP cells expressed a neuroendocrine staining pattern: CD56 was noted mainly along the cell borders, neurofilament protein (NFP) as unphosphorylated
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filaments, Chromogranin-A, CD117, Epithelial Cytokeratin 20 (CK20) expression was found in almost all cases. The staining pattern was membranous, cytoplasmic or mixed. CK7 was found positive in 21–30% of patients. Staining for Thyroid Transcription Factor-1 (TTF-1) and calciumbinding protein S-100 was negative in all examined cases. Taking into account the neuroendocrine origin and the epithelial features of the tumour, differential diagnosis is not an easy task. A lack of diffuse immunoreactivity of TTF-1 is a key element for the exclusion of SCLC or neuroendocine lung carcinoma. It is reported that a combined examination of TTF-1, NFP and CK20 may help to distinguish MCC from neuroendocrine lung tumours with a positive value of 100% (sensitivity 92.3%–specificity 100%) On the other hand, melanomas and lymphomas can be differentiated due to S-100 and CD45/CD20 expression respectively, which was not present in the available examined MCCUP specimens [31]. 3.3. Treatment modalities The majority of patients 56/90 (62.2%), underwent radical lymphadenectomy either as solitary initial treatment or combined with radiation or chemoradiotherapy. From these 56 patients, 14 patients had only radical lymphadenectomy, 24 had radical lymphadenectomy plus adjuvant radiotherapy and 18 patients received adjuvant chemoradiotherapy after surgery. Local excision was performed totally in 21/90 (23.3%) patients. In six cases local excision was followed by adjuvant chemoradiotherapy, in four cases with radiotherapy, three patients received adjuvant chemotherapy and in eight cases local excision was the only therapeutic intervention due to co-morbidities or patient’s unwillingness. For the same reasons six patients had radiotherapy only and seven patients chemoradiotherapy without any prior invasive procedure. In total, 77/90 patients (85.5%) underwent surgical interventions after diagnosis. 52/77 patients (67.5%) received adjuvant radiotherapy. Chemotherapy as the only adjuvant treatment option was not administered either after radical lymphadenectomy or alone. Seven patients had an additional lymph node dissection after local recurrence or as a consequence of a recurrent distant lymph node involvement. Radiotherapy doses of 50–54 Gy where administered as adjuvant treatment. In cases where surgical excision was not possible doses of 60–66 Gy were applied to the nodal basins. Chemotherapy was given when patients entered the metastatic phase of the disease. 23/90 patients (25.5%) of all patients during the follow-up period received chemotherapy after distant relapse. The metastatic pattern of MCCUP is similar to MCC as liver, bone, brain, lung and non-regional lymph nodes were the most common distant targets. Cisplatin or carboplatin combined with etoposide was the primary regimen choice with an overall response rate (ORR) of 59%. Follow-up period ranged from 3–148 months (Table 3). The achieved ORR with platinum salts and etoposide among MCCUP patients, appears to be the same compared with the
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Table 3 Initial treatment modalities. Local excision only Local excision + radiotherapy Local excision + chemoradiotherapy Local excision + chemotherapy Radical lyphadenectomy only Radical lyphadenectomy + radiotherapy Radical lyphadenectomy + chemoradiotherapy Radical lymphadenectomy + chemotherapy Radiotherapy only Chemoradiotherapy only Chemotherapy only
8 (8.8%) 4 (4.4%) 6 (6.6%) 3 (3.3%) 14 (15.5%) 24 (26.6%) 18 (20%) 0 6 (6.6%) 7 (7.7%) 0
ORR (60–66%) given from published series of MCC patients [32,33]. 3.4. Outcomes Regarding RFS and OS a retrospective study by Chen and colleagues evaluated the outcome of 34 patients with known primary compared with 16 patients with MCCUP with a median follow-up period of 17 months. Median RFS was not reached (p = 0.18) due to inadequate follow-up. Patients with unknown origin had a significantly better survival. Median OS for patients with primary MCC was 21 months and also not reached for the remaining patients with MCCUP (p = 0.027), though survival rates were not dependent of follow-up. Multivariate analysis demonstrated that adjuvant radiotherapy was associated with improved RFS (HR: 0.03, 95% CI 0.0–0.22, p = 0.001), but not OS [28]. In another retrospective study by Deneve and colleagues with 38 MCCUP patients, recurrence was documented in 33% of cases reflecting to a median RFS of 35 months. Median follow-up was 25.1 months. At the end of the follow-up period 74% of patients (28/38) were still alive resulting to a 4 year OS of 68%. Median OS for patients treated with surgery and radiotherapy/chemoradiotherapy was 104 months. Patients who received radiotherapy only without surgery showed a shorter median OS of 20 months [27]. Patients with stage IIIB cutaneous MCC demonstrate a 4 year OS of 55% [30]. In both studies the different treatment groups were small thus direct statistical comparisons were not significant. However, taking into account the survival data from the case reports, it is appeared that better outcomes can be reached with radical lymphadenectomy and adjuvant radiotherapy, since the majority of patients received such treatment were alive with no evidence of disease at the end of the follow-up period. The impact of adjuvant chemotherapy in OS in patients treated with surgical excision and radiotherapy could not be estimated due to the relatively small size of the evaluated cohorts.
4. NCUP outcomes Neuroendocrine carcinomas of unknown primary represent a broad spectrum of malignancies with different clinical
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behaviour depending on tumour grade and differentiation. Low-grade carcinomas (typical carcinoids, islet tumours) account for 10% of NCUP and show an indolent course. From SEER registries analysis a median survival of 124 months is estimated for patients with low-grade NCUP while 21% of cases are diagnosed with disseminated disease. Poorly differentiated tumours (atypical carcinoids, large cell carcinomas) are very aggressive and follow a disease course similar to small-cell lung cancer. Patients in 50% of cases present with metastatic disease to the liver and have a median survival of 10 months [7].
5. Discussion Neuroendocrine nodal MCCUP is a rare and poorly understood malignancy. Whether arises de novo from neural cells located in lymph nodes or it has undergone spontaneous regression is unclear. It is quite uncertain if prospective evaluation of patients with known MCC primaries will elucidate this matter. MCCUP however exhibits different behaviour and course than primary MCC despite their common immunophenotype. The first field of controversy between MCCUP and MCC is found in the role of MCV. In MCC MCV is clearly associated with MCC carcinogenesis. In serum of patients with MCC by enzyme-linked immunosorbent assay were found by Touze et al. high antibody titers (>10,000) in 64.7% compared with 7.3% observed in the controls [34]. However, Pan and colleagues found a significantly lower association of MCV in MCCUP than in skin cases (31% vs 76%) [35]. Although, MCV can be detected in healthy individuals, it is profound that not all of them will develop MCC. The mechanisms under which some people infected from MCV finally present with MCC and others don’t, are not a clear picture. In MCCUP cases it is less clear. The next difference between the two malignancies was seen at the outcomes. Patients with nodal MCCUP achieved significantly better median OS than patients with stage IIIB MCC, a fact that cannot be explained by the existing literature. Nevertheless, it must be stated that the power of multivariate analyses which provided the survival data is limited due to the small number of patients and also due to the retrospective nature of the available studies. Also, the majority of cases were published as case reports with inadequate follow-up periods thus making the interpretation of the survival data extremely difficult. We also showed a disease onset at a younger age in the 90 MCCUP patients than in MCC cases. Whether age has a favourable impact on MCCUP outcome is an issue difficult to access because of the rarity of the disease and the paucity of prospective trials. There is no accurate staging system for MCCUP. Initial work-up though of patients with nodal MCCUP should include PET/CT since a rising importance for PET/CT for the evaluation of patients with Merkel carcinoma is reported. PET/CT has a sensitivity and specificity of 90% and 98%, respectively and may upstage up to 16% of patients [36,37].
If PET/CT is not available CT or MRI may be performed. Immunohistochemical staining for CK20, TTF-1 and NFP is mandatory for a documented diagnosis. Concerning treatment modalities, MCCUP must be treated aggressively. Radical lymphadenectomy and postoperative radiotherapy to the tumour bed is the recommended initial approach for patients with nodal MCCUP as it significantly delays recurrence. 22/90 MCCUP patients in our review did not receive postoperative radiotherapy after surgery. The reasons are unknown. There are no official guidelines for MCCUP and it seems that every institution followed a treatment plan based on case reports or personal experience. No survival benefit was found from the adjuvant administration of radiotherapy. The survival benefit from chemotherapy given at the adjuvant setting is debatable. Patients not fit for surgery should be treated with radiotherapy. Once on at the metastatic stage, platinum compounds with etoposide provide the best response rates. Nodal MCCUP is a distinct entity of NCUP with a peculiar biological and clinical behaviour. Although it shows an aggressive phenotype, its clinical course resembles a good prognosis of low-grade NCUP. The molecular mechanisms of MCCUP progression are virtually unknown, making the molecular biology of MCCUP an area which research should focus on. Since the outcome of MCCUP cannot be determined by tumour differentiation, new prognostic factors and through prospective trials must emerge. MCCUP requires multidisciplinary management for the purpose of which treatment guidelines are warranted.
Conflict of interest statement Both authors do not have any conflicts of interest to report.
Reviewers Dr Richard Osborne Dorset Cancer Centre, Poole, Dorset, United Kingdom
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E.A. Kotteas, N. Pavlidis / Critical Reviews in Oncology/Hematology 94 (2015) 116–121 [7] Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after carcinoid: epidemiology of and prognostic factor for neuroendocrine tumors in 35,825 cases in the United Sates. J Clin Oncol 2008;26:3063–72. [8] Fields RC, Busam KJ, Chou JF, Panageas KS, Pulitzer MP, Allen PJ, et al. Five hundred patients with Merkel cell carcinoma evaluated at a single institution. Ann Surg 2011;254:465–564. [9] Veness MJ, Perera L, McCourt J, Shannon J, Hughes TM, Morgan GJ, et al. Merkel cell carcinoma: improved outcome with adjuvant radiotherapy. ANZ Surg 2005;75:275–81. [10] Foote M, Veness M, Zarate D, Poulsen M. Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease. J Am Acad Dermatol 2012;67:395–9. [11] Eusebi V, Capella C, Cossu A, Rosai J. Neuroendocrine carcinoma within lymph nodes in the absence of a primary tumor, with special reference to Merkel cell carcinoma. Am J Surg Pathol 1992;16:658–66. [12] Boyle F, Pendlenbury S, Bell D. Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma. Int J Rad Oncol Biol Phys 1995;31:315–23. [13] Ferrara G, Iannielo GP, Di Vizio D, Napi O. Lymph node Merkel cell carcinoma with no evidence of cutaneous tumor-report of two cases. Tumori 1997;83:868–72. [14] Straka JA, Straka MB. A review of Merkel cell carcinoma with emphasis on lymph node disease in the absence of primary site. Am J Otolaryngol 1997;18:55–65. [15] Saramarendra P, Berkowitz L, Kumari S, Alexis R. Primary nodal neuroendocrine (Merkel cell) tumor in patients with HIV infection. South Med J 2000;93:920–2. [16] Fornelli A, Eusebi V, Pasquinelli G, Quattrone P, Rosai J. Merkel cell carcinoma of the parotic gland associated with Warthin tumour: report of 2 cases. Histopathology 2001;39:342–6. [17] Fotia G, Barni R, Bellan C, Neri A. Lymph node Merkel cell carcinoma:primary or metastatic disease? A clinical case. Tumori 2002;85:424–6. [18] Silberstein E, Koretz M, Cagnano E, Katchko L, Rosenberg L. Neuroendocrine (Merkel cell) carcinoma in regional lymph nodes without primary site. Isr Med Assoc J 2003;5:450–1. [19] Kuwabara H, Mori H, Uda H, Takei K, Ishibashi Y, Takatani N. Nodal neuroendocrine (Merkel cell) carcinoma without an identifiable primary tumor. Acta Cytol 2003;47:515–7. [20] Huber GF, Khail M, Falck V, Matthews TW, Dort JC. Merkel cell carcinoma with solitary parotic gland metastasis: diagnostic dilemma in the absence of a primary site. J Otolaryngol Head Neck Surg 2008;37:E19–21. [21] Warnick M, Singh S, Boisvert ME, Peck GL. Merkel cell carcinoma presenting as lymphadenopathy without primary cutaneous lesion: a report of 2 cases. Arch Dermatol 2008;144:1397–8. [22] De Cicco L, Vavassori A, Jereczek-Fossa B, Pruneri G, Catalano G, Ferrari AM, et al. Lymph node metastases of Merkel cell carcinoma from unknown primary site: report of 3 cases. Tumori 2008;94: 758–61. [23] Ottaviani F, Capaccio P, Villani F, Banderali M, Pruneri G, Klinger M, et al. Bona fide primary Merkel cell carcinoma of intraparotid lymph node in a HIV positive patient. Int J Surg Oncol 2010;18: 406–8. [24] Cozzolino I, Zeppa R, Zeppa P. Lymph nodal Merkel cell carcinoma: primary tumor or metastasis from unknown primary site. J Cutan Pathol 2011;38:836–7. [25] Zhao M, Meng MB. Merkel cell carcinoma with lymph node metastasis in the absence of a primary site: case report and literature review. Oncol Lett 2012;4:1329–34. [26] De Zeeuw S, Schouten van der Velden AP, de Wilt HJ, Wetzels CT, Bokenkamp HJ. A Merkel cell carcinoma presenting as a solitary lymph node metastasis without a primary lesion. Report of a case and review of the literature. Acta Chir Belg 2012;112:317–21.
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[27] Deneve JL, Messina JL, Marzban SS, Gonzalez RJ, Walls BM, Fisher KJ, et al. Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol 2012;19:2360–6. [28] Chen KT, Papavasiliou P, Edwards K, Zhu F, Perlis C, Wu H, et al. A better prognosis for Merkel cell carcinoma of unknown primary origin. Am J Surg 2013;206:752–7. [29] Haymerle G, Fochtmann A, Kunstfeld R, Pammer J, Erovic BM. Management of Merkel cell carcinoma of unknown primary origin: the Vienna Medical School experience. Eur Arch Otorhinolaryngol 2014 [epub ahead of print]. [30] Iyer JG, Storer BE, Paulson KG, Lemos B, Phillips JL, Bichakjian CK, et al. Relationships among primary tumor size, number of involved nodes and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 2014;70:637–43. [31] Bobos M. Immunochistochemical distinction between Merkel cell carcinoma and small cell carcinoma of the lung. Am J Dermatopathol 2006;28:99–104. [32] Tai PT, Yu E, Winguist E, Hammond A, Stitt L, Tonita J, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 2000;18:2493–9. [33] Pectasides D, Pectasides M, Psyrri A, Koumarianou A, Xiros N, Pectasides E, et al. Cisplatin-based chemotherapy for Merkel cell carcinoma of the skin. Cancer Invest 2006;24:780–5. [34] Touze A, Le Bidre E, Laude H, Fleury MJ, Cazal R, Arnold F, et al. High levels of antibodies against Merkel cell polyomavirus identify a subset of patients with Merkel cell carcinoma with better clinical outcome. J Clin Oncol 2011;29:1612–9. [35] Pan Z, Chen YY, Wu X, Trisal V, Wilczynski SP, Weiss LM, et al. Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart. Mod Pathol 2014;27(9):1182–92. [36] Treglia G, Dabbagh-Kakhi VR, Giovanella L, Sadeghi R. Diagnostic performance of fluorine-18-fluorodexyglucose positron emition tomography in patients with Merkel cell carcinoma: a systematic review and meta-analysis. Am J Clin Dermatol 2013;14:437–47. [37] Hawryluk EB, O’ Regan KN, Sheely N, Guo Y, Dorosario A, Sakellis CG, et al. Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients in Dana-Farber/Brigham and Women’s Cancer Center. J Am Acad Dermatol 2013;68:592–9.
Biographies Nicholas Pavlidis is Professor of Medical Oncology and Head of the Department at the University of Ioannina, Greece. Cancer of unknown primary is one of his research fields (more than 55 publications). He was the Chairman of the ESMO Guidelines Committee (2006–2011) and present Chairman of the ASCO/ESMO Core Curriculum of Medical Oncology since 2011. He is member of the Scientific Committee of the European School of Oncology (ESO) and Chairman of various educational activities. He is Editor of Cancer Treatment Reviews and Associate Editor of European Journal of Clinical Investigation. Dr Elias Kotteas is a Medical Oncologist. He was trained at the Medical Oncology Department of the Ioannina University Hospital. He is currently working as a specialist at the Department of Medicine, Sotiria Hospital, University of Athens.
Neuroendocrine Merkel cell nodal carcinoma of unknown primary site: Management and outcomes of a rare entity E.A. Kotteas, N. Pavlidis ∗ Department of Medical Oncology, School of Medicine, University of Ioannina, 45 500 Niarchos Avenue, Greece Accepted 10 December 2014
Contents 1. 2.
3.
4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients & methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search selection criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Description of content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Patients characteristics and clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Tumour pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Treatment modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NCUP outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
116 117 117 117 117 117 117 119 119 119 120 120 120 120 121
Abstract Merkel cell nodal carcinoma of unknown primary (MCCUP) is a rare neuroendocrine tumour with distinct clinical and biological behaviour. We conducted a review of retrospective data extracted from 90 patients focusing on the management and outcome of this disease. We also compared life expectancy of these patients with the outcome of patients with known Merkel primaries and with neuroendocrine cancers of unidentifiable primary. There is a limited body of data for this type of malignancy, however, patients with Merkel cell nodal carcinoma of unknown primary site, seem to have better survival when treated aggressively than patients with cutaneous Merkel tumours of the same stage and equal survival with patients with low-grade neuroendocrine tumour of unknown origin. The lack of prospective trials, and the inadequate data, hamper the management of these tumours. Establishment of treatment guidelines is urgently needed. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Merkel carcinoma; Unknown primary
1. Introduction In 1875 Friedrich Merkel was the first to describe pale cells in the basal layer of the epidermis as mechanoreceptors ∗
Corresponding author. Tel.: +30 26510 99394; fax: +30 26510 99394. E-mail address: [email protected] (N. Pavlidis).
http://dx.doi.org/10.1016/j.critrevonc.2014.12.005 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
that he believed to be associated with the sense of light touch discrimination of shapes and textures. Malignant transformation of these cells was initially reported by Cyril Toker in 1972 as trabecular carcinoma of the skin. Under his electron micrograph the neoplastic cells shared morphological features similar to neuroendocrine cells from neural crest [1]. Today, the origin of the Merkel cells is debatable, as both
E.A. Kotteas, N. Pavlidis / Critical Reviews in Oncology/Hematology 94 (2015) 116–121
neural crest and epithelial origin have been suggested [2]. Merkel cell carcinoma (MCC) is a rare skin cancer affecting sites of previous sun exposure, usually between the 6th and 8th decade of life. Merkel cell carcinoma has an annual incidence rate of 0.6 per 100,000 [3]. However, there are reported cases of biopsy-proven MCC in which the skin was not the primary affected site. Since 2008 several studies report a viral etiology which integrates Merkel cell polyomavirus (MCV) as an addictive risk factor for carcinogenesis. Immunosupressed population carries a greater risk for MCC [4]. Cancer of unknown primary (CUP) accounts for 3–5% of all human cancers and is the 4th most common cause of cancer death in both sexes. In patients with CUP the primary tumour remains unidentifiable despite all standardised diagnostic work-up [5]. Neuroendocrine CUP (NCUP) accounts for approximately 13% of all neuroendocrine cancers. Three different subtypes of neuroendocrine CUP exist: low-grade neuroendocrine tumours (10%) including carcinoids or islet-cell tumours, small-cell anaplastic carcinoma (15%) and large cell neuroendocrine carcinomas (75%) [6,7]. Neuroendocrine Merkel cell carcinoma of unknown primary (MCCUP) represents a manifestation of MCCUP. In large retrospective studies the incidence of UPMCC among MCC population ranged from 19–25% [8–10]. In this review we present MCCUP as a new entity of good prognosis NCUP and provide significant information concerning the management and the outcomes of this extremely rare form of malignancy.
2. Patients & methods 2.1. Search selection criteria We searched MEDLINE/PUBMED (last search May 2014) using combinations of terms as Merkel carcinoma, unknown primary, unknown origin and occult primary. Data was gathered from case reports and from the few small retrospective studies. We set no geographical restrictions. Non-English literature was excluded. We tracked 227 published cases as MCCUP since 1988. However, we had to exclude 137 cases due to inadequate tumour characterization, mixed survival results in which data from patients with known MCC primaries or different disease stages were included, insufficiently given treatment modalities or demographics. Patients with stage IV disease and cases reporting regressed primaries involving lymph nodes were also excluded. 2.2. Description of content In total, we extracted and analyzed information from 90 patients with clinical nodal stage IIIB MCCUP (According to the AJCC Staging System) for clinical and pathological characteristics, history of previous malignancies, treatment modalities and survival. All the examined patients underwent complete work-up (skin examination, staging with
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Table 1 Summarized patients’ characteristics. Number of patients
90
Males Females Median age History of previous/concurrent malignancy Lymph node involvement Cervical Axillary Inguinal
65 (72.3%) 25 (27.7%) 63.2 (37–85) 11 (12.2%) 38 (42.3%) 16 (17.7%) 36 (40%)
CT, MRI or PET/CT) with no identifiable primary site. Recurrence-free survival (RFS) and overall survival (OS) were calculated from the time of diagnosis until recurrence and death, respectively. Follow-up period was defined from the date of diagnosis until death or last follow-up.
3. Results 3.1. Patients characteristics and clinical presentation We observed that MCCUP patients were younger at diagnosis compared with MCC patients since the average age of diagnosis was at 63.2 (37–85) years. In a recent study by Iyer et al. 70% of 8,044 primaries MCC were diagnosed above the age of 70. From our collected data, there was a predominance of 72.3% male patients (65/90) compared with to 27.7% female patients (25/90), which corresponds to a sex ratio of 2.6:1. The respective sex ratio in MCC patients is 2:1. A significant proportion of MCCUP patients (12.2%, 11/90) had a history of a previously or concurrent treated malignancy (eight basal cell carcinomas, one prostate cancer, three patients with chronic lymphocytic leukaemia), two patients were transplant recipients and another three patients were carriers of HIV. In the immunosupressed population an earlier median onset of the disease at 52 years (37–61) was observed [3,11–30]. Almost all evaluable patients presented with clinically palpable non-tender lymph nodes-IIIB disease. For the additional work-up of the examined patients CT and PET/CT were mainly used. The neoplasm showed a rapid, aggressive growth within 1–6 months until diagnosis and a marginal predisposition to arise from the cervical lymph node basin (42.2%, 38/90). Inguinal and axillary lymph node areas were initially involved in 40% (36/90) and 17.7% (16/90) of cases, respectively. Lesions ranged in colour from red, pink to blue of flesh-coloured, sometimes with a shiny surface which may mislead to a basal cell carcinoma diagnosis [11–29]. Characteristics of all patients are summarised in Table 1 and are displayed in details in Table 2. 3.2. Tumour pathology Merkel tumours are, classified into three morphological patterns. The small cell/diffuse pattern characterized
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Table 2 All patients’ characteristics and outcomes. Author/patients
Year
Age/gender
Affected LN
Initial treatment
Relapse
Overall survival/months
Eusebi [11], n=8
1992
Boyle [12], n=5
1995
Ferrara [13], n=2 Straka [14], n = 1 Saramarendra [15], n = 1 Fornelli [16], n = 1 Fotia [17], n = 1
1997
65/F 46/M 37/M 46/F 64/M 68/F 80/F 54/F 79/M 60/M 83/F 57/M 65/M 44/M 66/M 71/F 41/M 65/M 82/F
LE + RT + C/T RLND RLND RLND RLND LE RLND LE LE RT RT LE + RT RLND RLND LE RLND + RT LE RLND RT
No No Yes No Yes (11 months) Yes (3 months) No Yes (5 months) Yes (4 months) No Yes (13months) Yes (82 months) No No Yes (8 months) Yes (10 months) No Yes (18 months) Yes (8 months)
6 (NED) 10 (NED) 25 19 (NED) 25 (NED) 8 26 (NED) 12 (AWD) 7 20 (NED) 15 83 48 (NED) 70 (NED) 19 (AWD) 12 42 (NED) 28 10
RLND Neo-adjuvant C/T RLND + RT RLND + RT RLND RLND + RT LE + C/T Neo-adjuvant C/T RLND + RT LE + RT + C/T
Yes (8 months) Yes (18 months)
9 24
No No No Yes (17 months) Yes (3 months)
12 (NED) 9 (NED) 54 (NED) 28 17
No
16 (NED)
Siberstein [18], n = 2
2003
59/M 69/M
Axillary Inguinal Inguinal Axillary Inguinal Inguinal Cervical Inguinal Inguinal Inguinal Inguinal Inguinal Cervical Inguinal Axillary Cervical Inguinal Cervical Inguinal Iliac Inguinal Inguinal
Kuwabara [19], n = 1 Huber [20], n = 1 Warnick [21], n = 1 De Cicco [22], n=3
2007 2007 2008 2008
53/M 56/M 54/M 69/M 54/M
Axillary Cervical Inguinal Axillary Inguinal
72/F
1997 2000 2001 2002
Ottaviani [23], n = 1 Cozzolino [24], n = 1
2010 2011
41/M 77/M
Inguinal Pelvic Cervical Inguinal
Zhao [25], n = 1 De Zeeuw [26], n = 1
2012 2012
54/M 85/M
Inguinal Cervical
Deneve [27], n = 38
2012
Median age: 67 M:30 F:8
Cervical: 22 Inguinal:8 Axillary: 8
Chen [28], n = 14
2013
Haymerle [29], n = 7
2014
Median age: 67 M:9 F:5 75/M 67/F 79/M 77/M 52/M 66/F 55/F
Cervical: 6 Inguinal: 6 Axillary: 2 Cervical Inguinal Axillary Inguinal Inguinal Cervical Cervical
LE + RT LE + RT
Yes (4 months) Yes (48 months) Local excision RT + C/T Yes (4 months) RLND + RT Yes (5 months) RD RLND + RT + C/T:16 N/R RLND + RT:10 N/R RLND only:3 N/R Yes (14.5 months) RT + C/T:6 RT:3 N/R RLND+ RT:8 N/R N/R LE + RT + C/T:4 N/R LE + C/T:2 RLND + RT Yes LE Yes LE Yes LE + RT Yes LE Yes RLND + RT Yes RLND Yes
14 56 (NED) 21 18 (NED) 104 (median) N/R N/R N/R 20 (Median) N/R N/R N/R 22 36 17 (NED) 27 67 (NED) 96 (NED) 71 (NED)
Abbreviations: LE (Local excision), RLND (Radical lymph node dissection), RT (Radiotherapy), C/T (Chemotherapy), LN (Lymph nodes), NED (No evidence of disease), AWD (Alive with disease), N/R (Not reported).
with hyperchromatic irregular cells arranged in sheets and rarely in ribbons with numerous mitoses and/or necroses. The intermediate presenting with basophilic cells or nests with necrosis and a paranuclear dot-like pattern. The trabecular pattern with basophilic cells in ribbons. In the
available examined specimens the intermediate pattern has been detected in approximately 55% of cases. From the collected data, MCCUP cells expressed a neuroendocrine staining pattern: CD56 was noted mainly along the cell borders, neurofilament protein (NFP) as unphosphorylated
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filaments, Chromogranin-A, CD117, Epithelial Cytokeratin 20 (CK20) expression was found in almost all cases. The staining pattern was membranous, cytoplasmic or mixed. CK7 was found positive in 21–30% of patients. Staining for Thyroid Transcription Factor-1 (TTF-1) and calciumbinding protein S-100 was negative in all examined cases. Taking into account the neuroendocrine origin and the epithelial features of the tumour, differential diagnosis is not an easy task. A lack of diffuse immunoreactivity of TTF-1 is a key element for the exclusion of SCLC or neuroendocine lung carcinoma. It is reported that a combined examination of TTF-1, NFP and CK20 may help to distinguish MCC from neuroendocrine lung tumours with a positive value of 100% (sensitivity 92.3%–specificity 100%) On the other hand, melanomas and lymphomas can be differentiated due to S-100 and CD45/CD20 expression respectively, which was not present in the available examined MCCUP specimens [31]. 3.3. Treatment modalities The majority of patients 56/90 (62.2%), underwent radical lymphadenectomy either as solitary initial treatment or combined with radiation or chemoradiotherapy. From these 56 patients, 14 patients had only radical lymphadenectomy, 24 had radical lymphadenectomy plus adjuvant radiotherapy and 18 patients received adjuvant chemoradiotherapy after surgery. Local excision was performed totally in 21/90 (23.3%) patients. In six cases local excision was followed by adjuvant chemoradiotherapy, in four cases with radiotherapy, three patients received adjuvant chemotherapy and in eight cases local excision was the only therapeutic intervention due to co-morbidities or patient’s unwillingness. For the same reasons six patients had radiotherapy only and seven patients chemoradiotherapy without any prior invasive procedure. In total, 77/90 patients (85.5%) underwent surgical interventions after diagnosis. 52/77 patients (67.5%) received adjuvant radiotherapy. Chemotherapy as the only adjuvant treatment option was not administered either after radical lymphadenectomy or alone. Seven patients had an additional lymph node dissection after local recurrence or as a consequence of a recurrent distant lymph node involvement. Radiotherapy doses of 50–54 Gy where administered as adjuvant treatment. In cases where surgical excision was not possible doses of 60–66 Gy were applied to the nodal basins. Chemotherapy was given when patients entered the metastatic phase of the disease. 23/90 patients (25.5%) of all patients during the follow-up period received chemotherapy after distant relapse. The metastatic pattern of MCCUP is similar to MCC as liver, bone, brain, lung and non-regional lymph nodes were the most common distant targets. Cisplatin or carboplatin combined with etoposide was the primary regimen choice with an overall response rate (ORR) of 59%. Follow-up period ranged from 3–148 months (Table 3). The achieved ORR with platinum salts and etoposide among MCCUP patients, appears to be the same compared with the
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Table 3 Initial treatment modalities. Local excision only Local excision + radiotherapy Local excision + chemoradiotherapy Local excision + chemotherapy Radical lyphadenectomy only Radical lyphadenectomy + radiotherapy Radical lyphadenectomy + chemoradiotherapy Radical lymphadenectomy + chemotherapy Radiotherapy only Chemoradiotherapy only Chemotherapy only
8 (8.8%) 4 (4.4%) 6 (6.6%) 3 (3.3%) 14 (15.5%) 24 (26.6%) 18 (20%) 0 6 (6.6%) 7 (7.7%) 0
ORR (60–66%) given from published series of MCC patients [32,33]. 3.4. Outcomes Regarding RFS and OS a retrospective study by Chen and colleagues evaluated the outcome of 34 patients with known primary compared with 16 patients with MCCUP with a median follow-up period of 17 months. Median RFS was not reached (p = 0.18) due to inadequate follow-up. Patients with unknown origin had a significantly better survival. Median OS for patients with primary MCC was 21 months and also not reached for the remaining patients with MCCUP (p = 0.027), though survival rates were not dependent of follow-up. Multivariate analysis demonstrated that adjuvant radiotherapy was associated with improved RFS (HR: 0.03, 95% CI 0.0–0.22, p = 0.001), but not OS [28]. In another retrospective study by Deneve and colleagues with 38 MCCUP patients, recurrence was documented in 33% of cases reflecting to a median RFS of 35 months. Median follow-up was 25.1 months. At the end of the follow-up period 74% of patients (28/38) were still alive resulting to a 4 year OS of 68%. Median OS for patients treated with surgery and radiotherapy/chemoradiotherapy was 104 months. Patients who received radiotherapy only without surgery showed a shorter median OS of 20 months [27]. Patients with stage IIIB cutaneous MCC demonstrate a 4 year OS of 55% [30]. In both studies the different treatment groups were small thus direct statistical comparisons were not significant. However, taking into account the survival data from the case reports, it is appeared that better outcomes can be reached with radical lymphadenectomy and adjuvant radiotherapy, since the majority of patients received such treatment were alive with no evidence of disease at the end of the follow-up period. The impact of adjuvant chemotherapy in OS in patients treated with surgical excision and radiotherapy could not be estimated due to the relatively small size of the evaluated cohorts.
4. NCUP outcomes Neuroendocrine carcinomas of unknown primary represent a broad spectrum of malignancies with different clinical
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behaviour depending on tumour grade and differentiation. Low-grade carcinomas (typical carcinoids, islet tumours) account for 10% of NCUP and show an indolent course. From SEER registries analysis a median survival of 124 months is estimated for patients with low-grade NCUP while 21% of cases are diagnosed with disseminated disease. Poorly differentiated tumours (atypical carcinoids, large cell carcinomas) are very aggressive and follow a disease course similar to small-cell lung cancer. Patients in 50% of cases present with metastatic disease to the liver and have a median survival of 10 months [7].
5. Discussion Neuroendocrine nodal MCCUP is a rare and poorly understood malignancy. Whether arises de novo from neural cells located in lymph nodes or it has undergone spontaneous regression is unclear. It is quite uncertain if prospective evaluation of patients with known MCC primaries will elucidate this matter. MCCUP however exhibits different behaviour and course than primary MCC despite their common immunophenotype. The first field of controversy between MCCUP and MCC is found in the role of MCV. In MCC MCV is clearly associated with MCC carcinogenesis. In serum of patients with MCC by enzyme-linked immunosorbent assay were found by Touze et al. high antibody titers (>10,000) in 64.7% compared with 7.3% observed in the controls [34]. However, Pan and colleagues found a significantly lower association of MCV in MCCUP than in skin cases (31% vs 76%) [35]. Although, MCV can be detected in healthy individuals, it is profound that not all of them will develop MCC. The mechanisms under which some people infected from MCV finally present with MCC and others don’t, are not a clear picture. In MCCUP cases it is less clear. The next difference between the two malignancies was seen at the outcomes. Patients with nodal MCCUP achieved significantly better median OS than patients with stage IIIB MCC, a fact that cannot be explained by the existing literature. Nevertheless, it must be stated that the power of multivariate analyses which provided the survival data is limited due to the small number of patients and also due to the retrospective nature of the available studies. Also, the majority of cases were published as case reports with inadequate follow-up periods thus making the interpretation of the survival data extremely difficult. We also showed a disease onset at a younger age in the 90 MCCUP patients than in MCC cases. Whether age has a favourable impact on MCCUP outcome is an issue difficult to access because of the rarity of the disease and the paucity of prospective trials. There is no accurate staging system for MCCUP. Initial work-up though of patients with nodal MCCUP should include PET/CT since a rising importance for PET/CT for the evaluation of patients with Merkel carcinoma is reported. PET/CT has a sensitivity and specificity of 90% and 98%, respectively and may upstage up to 16% of patients [36,37].
If PET/CT is not available CT or MRI may be performed. Immunohistochemical staining for CK20, TTF-1 and NFP is mandatory for a documented diagnosis. Concerning treatment modalities, MCCUP must be treated aggressively. Radical lymphadenectomy and postoperative radiotherapy to the tumour bed is the recommended initial approach for patients with nodal MCCUP as it significantly delays recurrence. 22/90 MCCUP patients in our review did not receive postoperative radiotherapy after surgery. The reasons are unknown. There are no official guidelines for MCCUP and it seems that every institution followed a treatment plan based on case reports or personal experience. No survival benefit was found from the adjuvant administration of radiotherapy. The survival benefit from chemotherapy given at the adjuvant setting is debatable. Patients not fit for surgery should be treated with radiotherapy. Once on at the metastatic stage, platinum compounds with etoposide provide the best response rates. Nodal MCCUP is a distinct entity of NCUP with a peculiar biological and clinical behaviour. Although it shows an aggressive phenotype, its clinical course resembles a good prognosis of low-grade NCUP. The molecular mechanisms of MCCUP progression are virtually unknown, making the molecular biology of MCCUP an area which research should focus on. Since the outcome of MCCUP cannot be determined by tumour differentiation, new prognostic factors and through prospective trials must emerge. MCCUP requires multidisciplinary management for the purpose of which treatment guidelines are warranted.
Conflict of interest statement Both authors do not have any conflicts of interest to report.
Reviewers Dr Richard Osborne Dorset Cancer Centre, Poole, Dorset, United Kingdom
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Biographies Nicholas Pavlidis is Professor of Medical Oncology and Head of the Department at the University of Ioannina, Greece. Cancer of unknown primary is one of his research fields (more than 55 publications). He was the Chairman of the ESMO Guidelines Committee (2006–2011) and present Chairman of the ASCO/ESMO Core Curriculum of Medical Oncology since 2011. He is member of the Scientific Committee of the European School of Oncology (ESO) and Chairman of various educational activities. He is Editor of Cancer Treatment Reviews and Associate Editor of European Journal of Clinical Investigation. Dr Elias Kotteas is a Medical Oncologist. He was trained at the Medical Oncology Department of the Ioannina University Hospital. He is currently working as a specialist at the Department of Medicine, Sotiria Hospital, University of Athens.
