Primary hepatic carcinoid tumours

Abstract

Background

Carcinoid tumours of the liver are predominantly metastases from the gastrointestinal tract. Primary hepatic carcinoids are extremely rare.

Discussion

In contrast to metastases, primary hepatic carcinoids are usually solitary and resectable. It is important that these tumours are differentiated from metastases. Complete surgical resection should be contemplated and is generally curative.

Introduction

Carcinoids are the most common gastrointestinal endocrine tumours ¹,² and metastases from these tumours frequently involve the liver ³. Primary hepatic carcinoids are extremely rare. A diagnosis of a hepatic carcinoid is far more likely to be a metastasis from the gastrointestinal tract than a true primary. Nonetheless, primary hepatic carcinoids need to be differentiated from metastatic lesions to institute appropriate treatment.

The article reviews the literature regarding these rare tumours, highlighting specific features that aid diagnosis, the management options and overall treatment outcomes.

Methods

An electronic search using Medline database was performed for available publications on primary hepatic tumours in English literature. Selected articles with ‘primary’, ‘liver’ and ‘carcinoid’ in the title, abstract or keyword list were identified and reviewed.

Incidence and aetiology

There are 65 cases of primary hepatic carcinoid tumours (including primary neuroendocrine carcinomas) reported in the English literature ¹,²,³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶,⁴⁷. Some of these are incompletely documented. Recently, Soga ⁴⁸ reported on 126 cases of primary hepatic neuroendocrine tumours identified in the Japanese Niigata Registry. However, the details of the individual cases in this series were not available in English for review and are only referred to herewith in part.

Carcinoid tumours comprise 1–2% of all gastrointestinal malignancies ⁴⁹,⁵⁰ and metastasise to the liver in approximately 5–10% of cases ⁵¹. Most hepatic carcinoids are metastases rather than primary tumours. Godwin and colleagues ⁵⁰ examined 2837 consecutive patients with carcinoid tumours without identifying a single liver primary. The most common sites of primary disease are the appendix (35%), small intestine (25%) and rectum (12%).

Carcinoid tumours originate from neuroendocrine cells (enterochromaffm or amine precursor uptake and decarboxylase [APUD] cells), which embryologically are of neural crest origin. Gastrointestinal carcinoids derive from cells that migrate from the neural crest to the foregut, midgut and hindgut. They are normally found throughout the gastrointestinal tract from mouth to anus, with the highest concentration of cells in the appendix and small intestine ⁴⁹. The pancreas contains a large number of these cells, the biliary tree only a few and the liver normally contains none. The histogenesis of hepatic neuroendocrine tumours is controversial. Yu-ping and Ji-Yao ⁴⁴ proposed three theories for the origin of primary hepatic carcinoids: from aberrant pancreatic tissue in the liver ⁵², from cells of neuroectodermal origin (including pluripotent primitive cells) ⁵,⁴⁵ or from neuroendocrine-programmed ecto-blasts ⁵³.

The term primary hepatic carcinoids is generally used to encompass three types of neuroendocrine tumours: typical carcinoids, atypical carcinoids and a variant type according to their histological growth patterns ⁵⁴,⁵⁵. The majority of reported tumours are true carcinoids (80%). The typical appearance histologically is of small uniform cells arranged in nests, cords and trabeculae, like their counterparts in other regions of the body, whereas the variant type often contains both neuroendocrine and carcinoma components, which may have different prognostic implications ⁴⁸.

Clinical features

Primary hepatic carcinoids occur more frequently in females than males (ratio 1.6:1), with a mean age of 49.8 years (range 8–83 years) at the time of diagnosis. In symptomatic patients, an abdominal mass with or without associated pain is the most common presenting feature, occurring in approximately 50% of cases ¹⁸,²⁷. Less than a third of cases are associated with clinically evident excess hormone production. True carcinoid syndrome is the most common manifestation of endocrine excess. It is reported in 8% (4 of 49) of cases. Other endocrine syndromes are even less common ¹⁷,²⁷,³⁷,⁴¹.

Primary hepatic carcinoid tumours are usually solitary. A single nodule was identified in 69% (42 of 61) of reported cases, with a mean tumour diameter of 11.1 cm. Extrahepatic metastases were detected in 16% of patients (10 of 64), either at the time of diagnosis or after the commencement of non-surgical treatment. They occurred more frequently in patients with neuroendocrine carcinoma than true carcinoids. Lymph node, bone and lung were the most common sites of spread ¹,⁴,⁷,¹¹,¹⁴,²³,²⁹,³¹,⁴³.

Soga ⁴⁸ reports a slightly lower mean tumour diameter of 9.5 cm in 88 cases, with extrahepatic metastases being significantly greater in tumours >5 cm. Lymph node, lung and bone metastases were identified in 22% (28 of 126), 9.5% (12 of 126) and 9.5% (12 of 126) patients respectively in this series.

Diagnosis

The diagnosis of primary carcinoid is rarely suspected preoperatively. Ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and angiography findings are sometimes useful in distinguishing carcinoid from other tumours. CT with intravenous contrast and MRI with gadolinium often show tumour enhancement, highlighting tumour hypervascularity ⁷,¹⁰,¹⁵,¹⁷,¹⁸,²⁰,²²,²⁷,³⁶. This may be further verified by angiographic findings of an intense rapid homogeneous vascular tumour blush ³,⁶,⁷,¹⁰,¹⁵,¹⁷,¹⁸,²⁴,²⁵,²⁷,³³,³⁶,³⁹,⁴¹,⁴³. Angiography may also define regions of neovascularisation ³⁶,³⁹. Octreotide receptor scintigraphy may be useful in identifying an extrahepatic site of disease in patients with suspected hepatic carcinoid tumours ⁵⁶. It may also be useful in the diagnosis of recurrent disease. Neuroendocrine markers such hydroxyindoleacetic acid (5-HIAA) and serum chromogranin A are far more likely to be elevated with extrahepatic primary carcinoid tumours than true primary hepatic carcinoids ¹⁸,⁵⁷.

Fine-needle aspiration cytology or biopsy in conjunction with imaging increases the diagnostic yield. In cases of primary hepatic carcinoid, preoperative cytology or biopsy resulted in a correct diagnosis in 12 of 14 cases ¹,³,¹²,¹⁸,²¹,²³,²⁴,²⁸,³¹,⁴⁷. Hepatocellular carcinoma was mistakenly diagnosed in three patients ¹,³,¹⁶.

Although clinically the majority of patients have no evidence of an endocrine syndrome, immunostaining for various hormones is positive in >70% of primary hepatic carcinoids ¹,²,³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶,⁴⁷,⁴⁸. Immunohistochemical techniques are critical in differentiating carcinoid from other tumours. Chromogranin A staining is detected in >80% of cases. Grimelius silver staining is slightly less common. When staining patterns are equivocal, characteristic dense-core neurosecretory granules on electron microscopy confirm the diagnosis of a neuroendocrine tumour ³³.

Treatment and outcomes

Surgical

Complete surgical resection was possible in the majority of reported cases. The resectability rate was 85% in 53 patients where adequate case details were available. Among this group, there was one operative death due to haemorrhage ³⁹. Iwo and colleagues ¹⁸ reviewed 39 patients with surgically resected primary hepatic carcinoids. The 5-year survival was 74%, with a mean of 44.7 months. Local recurrence occurred in 18% during follow-up. Isolated perihepatic lymph node involvement has been reported following surgical resection without remnant hepatic involvement, but this is very rare ¹⁶,¹⁸.

Soga reported a 5-year survival of 92.4% for 47 cases of primary neuroendocrine hepatic tumours with typical (n=40) and atypical (n=7) carcinoid features. In 15 patients with the variant subtype of carcinoids, the 5-year survival was 68% ⁴⁸. However, there was no significant difference between the various subgroups. The overall long-term survival of patients with primary hepatic carcinoids appears to be better than carcinoid tumours at other primary sites ⁴⁸.

Non-Surgical

There are a variety of non-surgical treatments available for carcinoid liver metastases. These include chemo-embolisation, local ablation and administration of somatostatin analogues ⁵⁸. In general, no single agent or combination chemotherapy trial to date has generated any significant beneficial survival effect in patients with metastatic carcinoid tumours, despite good short-term symptom relief in some patients. Experience with non-surgical treatment of primary hepatic carcinoids is far more limited. Transarterial chemo-embolisation (TACE) achieved good short-term response in two cases of primary hepatic carcinoid ⁷,¹⁸. In another case TACE was effective in significantly reducing tumour size prior to resection ¹⁶. Truly unresectable primary carcinoid tumours without evidence of extrahepatic spread appear ideally suited to liver transplantation ⁵⁹.

Conclusions

Primary hepatic carcinoids are uncommon and usually present as solitary large hepatic mass associated with abdominal pain. Preoperative diagnosis may be possible on examination of biopsy or aspirate specimens, aided by immunohistochemistry. More commonly they are diagnosed postoperatively. A diagnosis of hepatic carcinoid requires the exclusion of tumour at more common primary sites. Primary hepatic carcinoids are rarely associated with metastases and surgical resection is usually curative.