Cutaneous primary Neuroendocrine Tumors (NETs) are rare carcinomas: only 10 cases have been described in the literature to date. They equally affect men and women, on average aged 60-90 years and there is a predilection for presentation in the head and trunk. NET presents cytomorphological and immunohistochemical characteristics typical of high-grade tumors with Neuroendocrine (NE) differentiation. Here we describe a clinical case of a primary coetaneous NET with an atypical presentation and details its therapeutic management.
We present the case of a 60-year-old male with a primary cutaneous NET located in the sacro-coxigenic region without evidence of any distant disease at time of diagnosis. The diagnostic confirmation was based on immunohistochemical determination of Neuron-Specific Enolase (NSE) and Chromogranin A (Cg A). We surgically respected the tumor and because the resection margins were close, we also administered adjuvant radiotherapy.
NETs are rare, slow-growing tumors which usually have a good prognosis. Surgery with curative intent is the gold standard treatment, and this may or may be associated with adjuvant radiotherapy when adverse factors are presents or when the tumor is considered unrespectable.
Primary cutaneous Neuroendocrine Tumor (NETs) is a very rare [1,2] with an approximate global incidence of 5.25 in 100,000 cases [3]: only ten cases have previously been reported in the literature [4-13]. These neoformations can vary enormously, both in their biological and clinical behavior, in terms of their which location, degree of differentiation and secretory activity [14,15]. Despite this, most are low-grade neoplasms with an indolent course.
They are also called “carcinoid tumors” (well-differentiated neuroendocrine tumors) because they are characterized by the presence of neurosecretory granules which express specific markers, including Neuron-Specific Enolase (NSE), synaptophysin and Chromogranin A (Cg A) and CD56. In some cases, tumor cells secrete serotonin and other vasoactive substances which produce a carcinoid syndrome characterized by: abdominal pain, skin redness, diarrhea, sweating, palpitations etc [16].
NETs are derived from neural crest neuroendocrine cells called Kulchitsky cells and give rise to tumors with very different degrees of differentiation, varying from carcinoid tumors to the undifferentiated small cell (oat-cell) carcinomas. They are formed by epithelial cells which exhibit neuroendocrine differentiation and can present in any anatomical location, although they usually appear in the face and trunk. Their etiology is unknown and there is no known association with sun exposure, immunodepression or other predisposing factors.
The main diagnostic complexity in these cases lies in the distinction between primary cutaneous tumors and visceral neoplastic metastases because the latter may have a gastrointestinal or pulmonary origin but then cause cutaneous involvement. The mean age of presentation is between the sixth and ninth decade of life (mean 66.3 years) and studies have shown that the inicidence is similar between both sexes.
We recently treated a patient with a primary cutaneous neuroendocrine carcinoma, a different entity to Merkel-Cell Carcinoma (MCC) whose primary location was the sacro-coxygeal región. Metastases in the right lateral costal area and nasal pyramid also subsequently emerged. Given the infrequency of these tumor types and the atypical location and behavior of this instance, here we describe our clinical experience of the case.
Primary cutaneous NETs are rare with limited associated literature. Only 10 cases have been previously reported (Table 1 [19] and Table 2 [16]), many of which correspond to low-grade tumors (carcinoids), however, large cell carcinomas of this type are much rarer.
Reference | Age (Years) and Gender | Location | Tumor Size (cm) and Duration (Years) | Clinical Diagnosis | Treatment | Follow-Up (Years) | Recurrence |
Van Dijk et al. [4] | 72, female | Scalp | 3/10 | Pilar cyst | Excision | 3.5 | No |
Smith and Chappell [5] | 62, female | Anterior chest | 1.5/10 | NC | Excision | 0.9 | No |
Colllna et al. [6] | 80, male | Scalp | 4/1 | NC | Excision | 1.75 | No |
Bart et al. [7] | 40, male | Epigastrium | 1/4 | Neurofibroma | Excision | 1.9 | No |
Sakamoto et al. [8] | 87, female | Anterior chest | 9.5/60 | NC | Excision | NC | No |
Courvllle et al. [9] | 60, male | Anterior chest | NC/NC | NC | Excision | 4 | No |
MacKenzie et al. [10] | 70, female | Scalp | 3/NC | Sebaceous cyst | Excision | 6 | Yesa |
Cokonls et al. [11] | 64, male | Middle back | 2/2 | NC | Excision | 1 | No |
Eloy-Garcia Carrasco et al. [12] | 58, female | Scalp | 4/1 | NC | Excision | 1 | No |
Kropinak et al. [13] | 70, female | Eyelid | 1/3 | NC | Excision | 0.67 | No |
Reference | Age MfF | Clinical | Ultra structure | Treatment | Course |
Van Dijk C et al. [4] | 72 yr female | Cystic lesion on forehead with flushing | Argophyllic granules | Exertion | Rushrfig resolved. No recurrence * 1 yr |
Sakamoto F et al. [8] | 75 yr Female | Hyperpigmented nodule with periumbilical induration. Elevated 5HIAA. Associated hyperparathyroidism | Strongly positive argentaffin reaction | Exertion | Not given in report |
Hoefnagel CA [20] | 80 yr male | Nodule behind right ear * 12m | Argophy Ik granules.Chromgranin positive Negative argentaffin reaction | Wide exocosion | No recurrence 21 months later |
Bart RS et al. [7] | 40 yr male | Red-tan soft nodule on abdomen * 4 years | Argophylk large and varied granules. NSE. keratin +ve | Wide exocosion | Alive and well 2 years later |
Smith PA et al. [5] | 62 yr female | Firm Nue-rth nodule on chest | Argophjrfcc granules. Postwe argentaffin reaction | Wide exocosion | Alive at 4 years. Well apart from claudication |
Courville P et al. [9] | 60 yr male | Erythematous nodule on chest | Argophyfcc granules. Positive argentaffin reaction.Chromogranin A. NSE | Excision | Alive without recurrence 4 years after excision |
Mackenzie DN et al. [10] | 70 yr female | Hard node on scalp with metastasis to occipital lymph node | Syruptophysin. NSE. keratin.CEA +ve | Excision of lesion and ocopital lymph node | 4 years later further lymph node metastasis.Metastatic noderecurrence 2 years later |
Table 2: Primary cutaneous neuroendocrine tumours [16].
NETs present as single cutaneous nodules, which adhere to the skin and have a yellowish appearance due to their high lipid content. They are usually, dome-shaped or protrude above the skin surface and extending into the Subcutaneous Tissue (SCC), in most cases. They express one or more neuroendocrine markers which can include cytokeratins AE1/AE3, CK7, MNF and CD56. Carcinoid tumors develop and grow slowly: most lesions are asymptomatic, although some have episodes of self-limiting bleeding, tenderness or pruritus. They may be accompanied by clinical symptoms of carcinoid syndrome which is secondary to the release of 5-hydroxytryptamine (5HT). They have a favorable prognosis because the percentage of recurrences is low and they rarely metastasize to distant sites [19].
Large cell neuroendocrine carcinomas NETs are even rarer and are harder to recognize and so their incidence is probably underestimated. These tumor cells are large and polygonal and have a high nucleo-to-cytoplasmic ratio, nuclei containing fine chromatin threads and a prominent nucleolus, but lack the characteristic paranuclear CK20 staining of MCCs. They have an aggressive phenotype similar to analogous lung cancer but because they are rare their prognosis is not known. Likewise, their optimal specific therapy is also unknown, although some cases have treated with radiotherapy.
The diagnosis is confirmation via histopathological and IHC techniques, however, imaging techniques such as CT and MRI, are also required to rule out systemic involvement. This consideration is key, because the presence of distant disease is a crucial prognostic factor and is associated with at least a 20% rediction in the predicted 5-year survival time (from 70% to less than 50%) [2]. Diagnosis can be complex for small tumors, when usngconventional imaging techniques and so Metaiosobenzylguanidine (MIGB) scintigraphy scans using somatostatin-octreotide analogues are also used. MIGB scans have a sensitivity of around 72-87% but a lower specificity [21,22].
In addition to these aforementioned difficulties, the diagnosis of primary neuroendocrine cutaneous tumors is complicated by the rarity of this type of neoplasia and the histopathological complexities associated with it. Therefore they are diagnosed by exclusion, first discarding other possible tumoral origins. The primary differential diafnosis is made against MCCa highly malignanti small cell tumor which expresses CK20 in is t cytoplasm and which contains cutaneous neuroendocrine tumor metastases from other locations [19].
Coetaneous metastases produced by visceral neuroendocrine tumors are having a low incidence; however, they should be differentiated from primary cutaneous NETs. The formed rare multifocal lesions with a limited 1-2cm size and also present clinical symptoms derived from the primary visceral tumor (e.g., digestive or respiratory problems) [23-25]. Radiological test are required to rule out the presence of primary tumors originating in, another organ and Thyroid Transcription Factor 1 (TTF1) staining is used to rule out a pulmonary origin. In our case, TTF1 was negative and no visceral neuroendocrine neoplasia was clinically or radiologically evident.
Primary neuroendocrine coetaneous tumors, which have an incidence accounting for around 1% of malignant skin tumors, (although this incidence has increased probably because of increased population aging and greater sun exposure) [20] should also the differentiated from MCCs. MCC is more common in men, in which the median age at diagnosis is 76 years. Histological, it is characterized by diffuse tumor growth with a trabecular pattern, the presence of small uniform cells, with little cytoplasm surrounding an ovoid nucleus with fine threads of dispersed chromatin, the absence of a nucleolus and a high mitotic duplication rate: it shows a characteristic pronuclear staining pattern when stained with CK20.
MCC is also characterized by its aggressive behavior with local recurrences, frequent distant metastases and a poor response to conventional therapies [26,27]. The 5-year survival rate is around 50% for patients with NETs with nodal or distant involvement. The mean survival rate decreased to only 5 months for patients with MCCs.
The initial therapeutic approach, for patients with NETs is surgical resection which represents a potentially curative treatment. According to the recommendations, adjuvant radiotherapy should also be administered where nearby marins are affected or in the case of unresectable tumors.
The case we describe here had been developing over 20 years, with an exponential increase in tumor size observed in the last 5 months, suggesting that this low-grade NET had undergone a transformation to a high-grade carcinoma. Histological, this hypothesis is supported by the presence of a well-delimited 2cm area of intense fibrosis, calcification and bone metaphase containing fewer tumor cells than would normally correspond to the primary tumor site. Another possibility is that this was a metastatic tumor, what was undetectable by the available diagnostic modalities, similar to the case described in Jedrych J et al. [19].
In order to reach a diagnosis of visceral neoplasia, it may be useful to perform a MIGB scan using a somatostatin-octreotide analogue, as described above. In our case, we could not perform this test because the patient presented intense abdominal pain that required admission to hospital. Therefore we instead performed a PET/CT study.
We treated the patient with block surgical resection of the macroscopic lesion and, completed the treatment with external radiotherapy, thus minimizing the possibility of residual disease remaining in the surgical bed. Our patient then received standard systemic treatment without presenting any significant acute toxicity. This treatment consisted of a regieme of etoposide-cisplatin chemotherapy, which is applied in patients with poorly-differentiated unresectable high-grade (G3) neuroendocrine carcinomas or in those with systemic disease. The response rate is 40-80% with median response duration of 8-11 months and a median survival of 9-15 months [28]. Other potential therapeutic agents were doxorubicin, sunitinib or everolimus [29]. Before progression of the systemic disease, we started weekly second- line, paclitaxel treatment, although thos showed no clinical benefit and produced sever grade 4 mucosal toxicity (oral mucositis).
Given the rapid progression of the disease and absence of any benefits derived from abovementioned second-line treatment, we proposed a new line of treatment with Avelumab. This anti-PD-L1 monoclonal antibody has a suggested application in stage-4 MCCs which have progressed following cytotoxic chemotherapy, as reflected in its recently published phase 2 clinical trials [30]. Its use is also valid for solid metastases or locally-advanced gastric tumors, non-small cell lung tumors, ovarian tumors [31]. However we started administering a second round of the standard chemotherapy regieme described above, until our local Health Authority approved the use of this immunological therapy for our case.
We consider this case to be of relevance, not only because of its histology but also beacuses of its atypical location and its torpid development over 20-year. The lesión had significantly grown in size in the months leading up to the patient´s presentation and it had transformed into a large cell NET with a proliferation rate of 80%.
One possible explanation for this evolution is that it was initially a low-grade atypical NET carcinoma that transformed into high-grade NETs. This hypothesis ties in well with the histology data showing the presence of a well-delimited area of intense fibrosis, calcification and bone metaphase with less temporal cellularity than would normally correspond to the area of the primary tumor.
When it was diagnosed as an aggressive tumor (because of its high proliferation index, close margins, coetaneous involvement and diffuse positivity for NE markers) we chose to treat the patient with surgery associated with adjuvant treatment and EBRT in order to gain better local control. But when systemic progression and grade-4 toxicity presents after application of these two treatment lines we decided to request immunological therapy with Avelumab.
Citation: Parreno GH, Macías VM, Santander RL, Ferrero JLE, Caballer JB et al. (2017) Primary Cutaneous Neuroendocrine Carcinoma: Case with an Atypical Location. J Cancer Biol Treat 4: 011.
Copyright: © 2017 Herrando Parreno G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.