- Case report
- Open Access
Neuroendocrine carcinoma arising in soft tissue: three case reports and literature review
© Hyer et al; licensee BioMed Central Ltd. 2007
- Received: 04 April 2007
- Accepted: 09 July 2007
- Published: 09 July 2007
Neuroendocrine tumours (NET) are tumours arising from neuroendocrine cells of neural crest origin. They are characterised by the presence of neurosecretory granules which react positively to silver stains and to specific markers including neuron specific enolase, synaptophysin and chromogranin. Metastasis to the skin occurs infrequently but primary soft tissue NET is excessively rare.
We report our experience with 3 such cases. In the first case, the NET originated in muscle and was treated with wide surgical excision and adjuvant radiotherapy. The second case presented as a subcutaneous mass in the foot and the tumour was positive on 123I mIBG scan. She has had prolonged recurrence-free survival following primary hypo-fractionated radiotherapy. In the third case, a cutaneous nodule proved to be a NET and at surgery, lymph node disease was present. He has remained disease-free after surgical excision without the need for external beam radiotherapy.
These tumours appear to have a good prognosis. Complete excision offers potentially curative treatment. Adjuvant radiotherapy may be helpful when the tumour margin is narrow. For patients with unresectable disease or where surgery would not be appropriate, radiotherapy appears to be an effective therapeutic option.
- Neuroendocrine Tumour
- Neuroendocrine Carcinoma
- Merkel Cell Carcinoma
- Neuroendocrine Marker
Neuroendocrine tumours (NET) most commonly originate in the appendix, small intestine, rectum and bronchus [1, 2]. The majority are of low-grade malignant potential with an indolent course and can be termed "carcinoids". The release of 5-HT and other vasoactive substances into the systemic circulation gives rise to the "carcinoid syndrome", consisting of flushing, wheezing, diarrhoea and eventually right-sided valvular heart disease . This syndrome is usually associated with bulky liver metastases. Metastasis to skin has been reported but typically occurs in association with metastases elsewhere [4, 5]. NET arising de novo in the skin are very rare and there are no reports of these tumours originating in soft tissues. We describe our experience of three cases.
No tumour was demonstrated elsewhere: mIBG and octreotide scans were negative as were CT scans of thorax, abdomen and pelvis.
Following excision he was treated with adjuvant radical dose external beam radiotherapy to the thigh in view of the depth of invasion of the tumour and its poor histological features. Following treatment his 5HIAA concentrations normalised and he remains free of relapse, five years later.
A 79 year frail old lady presented with a lump on the sole of the right foot which had gradually increased in size over the previous nine months. The right leg had gradually become more swollen and painful. She had not experienced flushing attacks or diarrhoea. On examination there was a hard subcutaneous mass on the plantar surface of the right foot involving the metatarsal heads with associated erythema and thinning of the skin. The entire right leg was swollen with lymphoedema.
CT scans of the chest, abdomen and pelvis showed metastatic lymph node enlargement in the right groin and pelvic side wall but no pathology in the liver or lungs.
Radical surgery was not possible because of the extent of tumour and the patient's general condition. Uptake of mIBG was deemed inadequate to contemplate curative treatment with a therapeutic dose of 131I mIBG. Instead, the patient was treated with external beam radiotherapy to the right foot (using 20 MeV electron beam) and to the right side of the pelvis (with parallel pairs of photons). The tumour dose was 30 Gy in 5 fractions with treatment given over 4 weeks (6 Gy once weekly).
MR scanning 10 months later revealed significant reduction in tumour size (3 × 1.5 cm) and no residual pelvic side-wall or inguinal disease. When last reviewed she was well with no cancer-related symptoms. The nodule on the sole of the right foot had not changed over 55 months follow-up and the lymphoedema had completely resolved.
A 61 year old retired civil servant was noted to have a swelling over the left iliac crest. Fourteen months previously he had undergone wide local excision and local radiotherapy for a high grade spindle cell sarcoma affecting the lower left leg. The site was well-healed with no evidence of recurrence. At follow-up, a 2 cm cutaneous nodule was noted over the left iliac crest; it was fleshy and smooth in consistency, being darker than surrounding skin. There were no palpable lymph nodes. He had no systemic symptoms such as flushing or diarrhoea.
Fine needle aspiration cytology (FNAC) of the nodule suggested malignancy. A skin ellipse was resected and included tumour nodules in the deep dermis. Immunohistochemistry showed strong and diffuse positive staining for neuroendocrine markers (NSE, chromogranin, synaptophysin) and CAM 5.2 but was negative for EMA, S100 and HMB45.
Histology was compared with the previous sarcoma but was totally different. Appearances were interpreted as consistent with a neuroendocrine tumour. 24 h urinary 5HIAA concentration was normal. CT scans of thorax, abdomen and pelvis revealed a 1.5 cm inguinal lymph node. FNAC of the node revealed malignant cells. An octreotide scan showed no sign of visceral metastasis or occult primary tumour. A left inguinal dissection was performed; eleven nodes were removed with one showing neuroendocrine tumour differentiation. Surgery was thought to have been complete such that adjuvant radiotherapy was not required. He remains free of recurrence at 79 months follow-up.
Primary cutaneous neuroendocrine tumours
Van Dijk C et al, 1975 
72 yr Female
Cystic lesion on forehead with flushing
Flushing resolved. No recurrence × 1 yr
Brody HJ et al, 1979 
75 yr Female
Hyperpigmented nodule with periumbilical induration. Elevated 5HIAA. Associated hyperparathyroidism
Strongly positive argentaffin reaction
Not given in report
Collina et al, 1988 
80 yr Male
Nodule behind right ear × 12 m
Argophyllic granules. Chromgranin positive Negative argentaffin reaction
No recurrence 21 months later
Bart RS et al, 1990 
40 yr Male
Red-tan soft nodule on abdomen × 4 years
Argophyllic large and varied granules. NSE, keratin +ve
Alive and well 2 years later
Smith PA et al, 1995 
62 yr Female
Firm blue-ish nodule on chest
Argophyllic granules. Postive argentaffin reaction
Alive at 4 years. Well apart from claudication
Courville P et al, 2000 
60 yr Male
Erythematous nodule on chest
Argophyllic granules. Positive argentaffin reaction. Chromogranin A, NSE
Alive without recurrence 4 years after excision
MacKenzie DN et al, 2003 
70 yr Female
Hard node on scalp with metastasis to occipital lymph node
Synaptophysin, NSE, keratin, CEA +ve
Excision of lesion and occipital lymph node
4 years later further lymph node metastasis. Metastatic node recurrence 2 years later
The diagnosis of primary cutaneous or soft tissue NET depends on exclusion of metastases from an occult tumour elsewhere. Unlike in primary skin NET, skin metastases from an occult primary are usually multiple . Since these tumours are slow growing indolent tumours, metastasis tends to be a late manifestation of advanced disease. The primary occult tumour will usually have attained a diameter of at least 1 cm and not infrequently 2 cm particularly when arising in the appendix or rectum [13, 14]. Consequently, the primary tumour is usually large enough for detection by diagnostic imaging. Furthermore, skin metastases from pulmonary or laryngeal NET are usually preceded by symptoms from the primary tumour .
Identifying small primary tumours may be difficult with conventional imaging techniques such as ultrasound, CT and MRI . Imaging with 123I mIBG shows a sensitivity and specificity of approximately 60% in identifying neuroendocrine tumours . Since NET usually express somatostatin receptors, scanning with radiolabelled somatostatin analogue (octreotide) is often helpful. Compared with mIBG imaging, octreotide scanning is more sensitive (72–87%) although less specific .
The presence of metastases is important prognostically as survival is reduced from 70% at 5 years (without metastases) to less than 50% (with metastases) .
Macroscopically, a NET usually appears as a yellow solid tumour because of its high lipid content. Histologically, they are composed of rows of cuboidal eosinophilic cells arranged in trabecular, follicular or glandular patterns. Definitive diagnosis requires specific histochemical and immunohistochemical staining. Markers of neuroendocrine differentiation include neuron-specific enolase, synaptophysin and chromogranin. Keratin staining (including CAM 5.2) is generally concentrated at one edge of the nucleus to give an appearance of "dot-like" keratin positivity. Neurosecretory granules can be seen ultrastructurally.
The differential diagnosis includes primary cutaneous neoplasms arising from neurosecretory cells (Merkel cells) in the skin. These tumours, known as Merkel cell carcinomas (MCC), are composed of uniform cells with scanty neoplasm, round to ovoid nuclei with finely dispersed chromatin, inconspicuous nucleoli and frequent mitotic figures. Small membrane-bound dense granules are seen in MCC at electron microscopy in contrast to NET where granules are often large and irregular. Early reports of neuroendocrine differentiation in MCC utilised silver staining reactions and demonstrated argyrophilia but negative argentaffin reactions . These have largely been superseded by specific stains for neuroendocrine markers such as chromogranin which can be positive in either MCC or NET. Immunohistochemical stains in MCC tumours show variable positivity for cytokeratin and CK20 often in a perinuclear arrangement in contrast to the more diffuse staining seen in NET  and in the cases reported here. More recently, distinctive cytogenetic abnormalities have been described in MCC which may help differentiate MCC from NET .
Clinically, MCC tumours are characterised by aggressive behaviour with local recurrences, frequent metastases and relatively poor response to conventional therapies [21, 22]. In case 1 the tumour clearly arose from muscle. The tumour in case 2 could have originated in the skin and invaded deeply as the histology showed it to be in the subcutaneous tissue. However, it would have been MCC stage II as the lymph nodes were involved and these tumours have a median survival of only 5 months . Similarly, the long recurrence-free survival in case 3 (also with lymph node disease) makes this unlikely to have been a MCC.
As with previous reports of cutaneous NET, primary surgical excision was the preferred treatment in our cases, combined with nodal clearance in (case 3) or adjuvant radiotherapy (case 1). Excision of a skin NET and lymph node metastasis was successful in a previous case report . Disease control in our patients has been good at long term follow-up.
In case 2, primary hypofractionated radiotherapy was used as radical surgery was not possible. This approach has been used for several other tumours e.g bladder, prostate where patients are frail and cannot tolerate conventionally fractionated radical doses . Radiotherapy has been used successfully to control unresectable NET in the brain, spinal cord and bone . Disease regression and symptom palliation was achieved in the majority of patients.
We believe these cases represent primary NET because no evidence of tumour could be found elsewhere after follow-up of 5 years. In only one patient were urinary 5 H-T metabolites increased and this patient did not experience features of the carcinoid syndrome presumably because the quantity of peptides secreted was too low.
The soft tissue lesions in all our patients had advanced slowly over a period of between 4 to 9 months and had metastasized only to regional lymph nodes and not to distant organs.
In summary, these tumours appear to have a good prognosis. Complete excision offers potentially curative treatment. Staging is required to exclude lymph node or distant metastases. Adjuvant radiotherapy may be helpful when the tumour margin is narrow. Patients with recurrent disease or aggressive histopathological appearances require radical radiotherapy doses. Although potentially beneficial, uptake of mIBG and octreotide is probably insufficient in the majority of cases to deliver tumouricidal doses. For patients with unresectable disease or where surgery would not be appropriate, radiotherapy appears to be an effective therapeutic option.
Patients' consent was obtained for publication of these case reports
We thank Professor Cyril Fisher for his helpful comments and for providing histological material for this report
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