Diffuse intestinal angiomatosis as a possible paraneoplastic manifestation of small cell lung cancer: a case of small bowel angiomatosis

Abstract

Vascular malformations are rare, incompletely understood and heterogeneous in presentation and clinical course. They are known to be associated with a number of benign syndromes, commonly presenting in childhood. Angiomatosis is a form of vascular malformation, hardly documented in the English literature, and has only rarely been described in the small bowel. We present a case of a middle-aged female who developed small bowel obstruction secondary to diffuse small bowel angiomatosis and subsequently developed aggressive multifocal small cell lung cancer 2 months later. Her condition rapidly deteriorated with multiple metastases and she passed away 4 months later secondary to brain metastases and diffuse disease. Small cell lung cancer is well known for its association with paraneoplastic syndromes and has been reported to cause a rise in vascular endothelial growth factor. We postulate that in this case angiomatosis presented as a paraneoplastic syndrome associated with small cell lung cancer.

BACKGROUND

Vascular abnormalities of the small bowel are extremely rare. They are classified based on the predominant vascular channel present in the lesion: capillary, lymphatic or venous. Some may have components of more than one channel type. Angiomatosis is an uncommon and incompletely understood form of benign vascular malformation representing errors in normal vascular morphogenesis.¹ It is characterised by a diffuse excess of dilated, capillary-sized flat endothelial-lined blood vessels in normally vascular tissue. The majority of cases occur as part of a defined clinical syndrome—for example, Klippel-Trenaunay syndrome, which comprises a capillary-lymphatic-venous malformation, or Sturge Weber syndrome with cutaneous naevii associated with cerebral haemangioma.¹ Most angiomata are asymptomatic. Rarely do they occur in the gastrointestinal tract when they may present with gastrointestinal bleeding, obstructive symptoms or abdominal pain.¹ The angiogenesis of these lesions remains unknown. There are no previous reports of an association with malignancy.

We report a case of small bowel obstruction as a consequence of diffuse intestinal angiomatosis who was later diagnosed with aggressive metastatic small cell lung carcinoma. To our knowledge, this is the first case of diffuse intestinal angiomatosis presenting as a possible paraneoplastic syndrome in association with small cell lung cancer.

CASE PRESENTATION

A middle-aged Caucasian female presented to the emergency department with acute onset generalised abdominal pain and diarrhoea as well as weight loss of approximately 4 kg in the preceding 2 months. She had a history of arteriopathy, including peripheral vascular disease (bilateral external iliac artery angioplasty), myocardial infarction and multiple transient ischaemic attacks. Risk factors included hypercholesterolaemia, hypertension and 40 packs a year smoking history. There was a family history of cardiovascular disease, but no history of cancer.

On examination she was apyrexial and haemodynamically stable. Heart sounds one and two were clearly heard with no added sounds and the apex beat was undisplaced. Her lungs were clear in all zones with vesicular breath sounds. There was no focal neurological deficit. However, her abdomen was tender on palpation, with no evidence of a mass or peritonism. Digital rectal examination was normal.

INVESTIGATIONS

Initial blood results showed a white cell count of 23.1×10⁹/L (reference range: 4.0–11.0×10⁹/L), platelets 522×10⁹/L (150–450), c-reactive protein 207 mg/L (<3 mg/L). Renal and liver function tests were normal.

CT suggested an inflammatory process in the right iliac fossa, including a distended caecum, oedematous bowel and possibly a tiny pelvic perforation (fig 1A). CT angiography demonstrated patent mesenteric arteries. Flexible sigmoidoscopy and biopsies were normal to the splenic flexure.

Figure 1.

Axial image through pelvic brim demonstrating fluid-filled, dilated and mildly thickened small bowel (A), and a follow up scan 6 months later showing multiple new soft tissue lesions in the subcutaneous fat of the anterior abdominal wall (B).

Exploratory laparotomy revealed apparently necrotic small bowel. Two hundred centimetres was resected with the formation of a double-barrelled ileostomy. The remaining small bowel and colon appeared macroscopically normal.

DIFFERENTIAL DIAGNOSIS

Initial impression was of ischaemic bowel due to her past medical history. However CT angiography suggested this was unlikely.

Differential diagnoses then included inflammatory bowel disease and bowel perforation possibly secondary to colitis.

TREATMENT

Exploratory laparotomy revealed a short segment of apparently necrotic small bowel. Two hundred centimetres was resected with the formation of a double-barrelled ileostomy. The remaining small bowel and colon appeared macroscopically normal.

Histological analysis of the resected bowel unexpectedly revealed a diffuse excess of dilated capillary sized flat endothelial lined blood vessels within the mucosa (fig 2), submucosa and inner layer of muscularis propria. The lining endothelial cells showed no cytological atypia (fig 3), or evidence of dysplasia or malignancy. There were also focal areas of transmural inflammation with mucosal ulceration and peri-intestinal lymph nodes revealed only reactive changes. The overall histological picture was surprising and difficult to interpret. The appearance was not that of angioma, angiosarcoma, angiodysplasia or reactive changes due to bowel ischaemia. The diffuse vascular proliferation within the segment could best be described as angiomatosis.

Figure 2.

Diffuse excess of capillary sized blood vessels involving the small bowel mucosa and submucosa. H&E stain ×10.

Figure 3.

CD31 immunostain highlighting the endothelial cells of these blood vessels. H&E stain ×10.

The patient required total parenteral nutrition (TPN) for 2 months until the ileostomy was reversed with an ileo-colonic anastamosis.

OUTCOME AND FOLLOW-UP

At review 2 months later, she was noted to have multiple tender, mobile, subcutaneous masses over her abdominal wall and thorax reportedly growing rapidly in size. At this time, CT scan showed multiple new sub-cutaneous tissue nodules within abdominal and pelvic fat (fig 1B) thought to be subcutaneous angiomata; however, it also revealed a large left lung mass suspicious of a primary lung cancer. On initial presentation, the patient had had a reportedly normal chest x ray. However, given the size of the lung lesion now apparent on CT, it is likely that this tumour was present on initial presentation but may not have been radiologically evident.

Before urgent oncology and respiratory reviews had been arranged she was re-admitted complaining of abdominal pain, diarrhoea, dehydration and severe headache. The subcutaneous masses had increased in number and size over the abdomen and chest. A further CT now showed progressive enlargement of the lung mass encasing pulmonary vessels, with further soft tissue mass lesions in the chest wall, spleen, left kidney, tail of the pancreas and cerebral hemispheres. These findings were highly suggestive of disseminated malignancy.

Histological appearance of an excised subcutaneous nodule revealed high-grade neuro-endocrine carcinoma of the small cell type. Tumour cells were positive for chromogranin A, CD56 and TTf-1 immunostaining, in keeping with a lung primary.

Unfortunately the patient deteriorated rapidly with a reduced level of consciousness and right leg weakness. Further intervention was deemed futile and she was discharged home with community palliative care team support where she subsequently died a few days later.

DISCUSSION

Angiomatosis is a descriptive term for a form of vascular malformation with multiple abnormal capillary sized blood vessels in normally vascular tissue. Due to its rare nature there is no universal clinical definition. Vascular malformations are not tumours but rather vessel abnormalities due to errors of vascular morphogenesis. They tend to derive from embryonic capillary, venous, arterial or lymphatic channels or combinations thereof.² The majority are apparent in childhood resulting from an inborn error in vascular growth. Much of our understanding of vascular malformations is through study of affected children. A classification of vascular anomalies of infancy and childhood was first presented in 1982 by Mulliken and Glowaki.^2,3 In angiomatosis it is unclear whether similar factors are involved in promoting new vessel growth as in neovascularisation of the retina in conditions such as age related macular degeneration and diabetic retinopathy. In these conditions, a complex mix of factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium-derived growth factor, angiopoietins and extracellular matrix molecules are responsible for angiogenesis.⁴

Associations between vascular malformations and a variety of syndromes are well recognised and comprise a significant proportion of the published cases. Klippel-Trenaunay Syndrome comprises capillary malformations, soft tissue or bone hypertrophy and varicose veins.⁵ Blue rubber bleb syndrome is a rare syndrome comprised of venous malformations of the skin, gastrointestinal tract and other organs. It often presents with gastrointestinal haemorrhage usually in infancy.⁶ Other entities, such as Von Hippel Lindau and Sturge Weber syndromes, are partly characterised by vascular malformations.

Reported cases of vascular malformations occurring in the small bowel are extremely rare.^1,2,7,8 Brown et al described disturbances of normal vascular malformation in the jejunum associated with Klippel-Trenaunay syndrome.⁹ We found only one similar case of small bowel angiomatosis in a 30-year-old patient with Down syndrome presenting with small bowel obstruction.⁷ Most visceral vascular malformations are associated with cutaneous lesions and are asymptomatic, although bleeding has been described. Lauro et al report the case of small bowel angiomatosis presenting over a period of 14 months with intermittent lower gastrointestinal bleeding.⁸ Our case presented with symptoms indicative of an “acute abdomen”. There was no evidence to suggest our patient had a syndrome known to be associated with a vascular anomaly and there were no cutaneous manifestations to suggest underlying vascular malformations.

Visceral vascular anomalies are often under diagnosed. Visualisation of the small bowel is difficult but visceral angiography is the most useful modality in establishing the location and nature of vascular anomalies.¹ A study on children suggested angiography should be undertaken without delay in those with gastrointestinal bleeding without obvious cause, allowing accurate diagnosis and to ensure safe and limited resection of bowel involved.¹⁰ CT and MR imaging are widely available and can be helpful in highlighting thickening of the bowel wall, although this feature is non-specific.^3,5

There is little documentation on how to treat angiomatosis. Its multifocal nature makes surgical resection of an affected area unlikely to entirely eradicate the disease. Cases are too rare to formally trial different anti-angiogenic pharmacological treatments. Studies in children show oral corticosteroids produce a good response in one-third of patients, with one-third showing equivocal response and the remaining third gaining no benefit.¹ Interferon alpha is usually reserved for severely affected patients and it has a better response rate than steroid treatment.^1,3 Targeting VEGF using medications such as Pegaptanib, an anti-VEGF aptamer, ranibizumab, an antibody fragment, and bevacizumab, a full-length humanised monoclonal antibody against VEGF,¹⁰ which are showing promising early results in trials for novel treatments for treating age related macular degeneration, could also be trialled.

Fishman et al also review different interventional treatments such as banding, embolisation plus scleropathy.¹ Surgery is reserved for the life-threatening and transfusion dependent cases^1,5 and only limited resection of the bowel is recommended.¹¹ The authors conclude an individualised approach to treatment is recommended due to the heterogeneity of these conditions.

Paraneoplastic syndromes are most frequently associated with small cell lung cancer. These syndromes are typically caused by ectopic hormone production or immune-mediated tissue destruction caused by neural antigen expression from cancer cells.¹² However, the gastrointestinal tract is rarely involved other than isolated case reports of severe gastrointestinal dysmotility due to the anti-neuronal activity of anti-hu antibody associated with small cell lung cancer.^13,14 Whilst there is no direct evidence linking angiomatosis and small cell lung cancer in our case, the close temporal relationship between the presentations of the two conditions suggests a possible association. The small cell lung cancer may have been present at the time of her initial presentation despite not being radiologically apparent on initial chest x ray.

Small cell lung cancer is associated with an increased production of VEGF and IL-8.^15,16 This observation is not usually associated with clinically overt vascular malformations outside of tumour site, but these factors work locally to promote tumour growth. Although not measured, it is possible that high levels of vascular endothelial growth factors in the blood stream were responsible for angiomatous changes in the small bowel and the subsequent haemangiomatous sub-cutaneous nodules that manifested as the small cell lung cancer advanced. Immunohistochemistry for VEGF on the small bowel resection specimen from our patient was negative. It was not possible, however, to measure for VEGF receptor number in the tissue. It may be possible that there were high levels of VEGF in the bloodstream stimulating VEGF receptors resulting in the subsequent angiomatosis. A potential “second hit” may exist. We speculate that underlying mesenteric ischaemia in this patient may have acted synergistically with tumour-associated VEGF resulting in the unusual vasculogenesis, but unfortunately the patient died and we did not have any stored serum samples to investigate this hypothesis further.

Small cell lung cancer should be considered as an underlying diagnosis in patients who present with angiomatosis and rarer neuro-endocrine syndromes beyond the scope of our current understanding of small cell lung cancer and associated conditions; especially if they have identified risk factors. Earlier diagnosis of small cell lung cancer, as with many cancers, allows for prompt treatment and improved 5-year survival. One may even postulate that successfully treating small cell lung cancer could promote regression of the small bowel angiomatosis.

LEARNING POINTS

• Small cell lung cancer can present in unusual ways as part of a paraneoplastic syndrome, including vascular malformation.

• Patients with vascular malformations, especially angiomatosis, should be screened for small cell lung cancer early on.

• Research is needed into the association between small cell lung cancer and vascular endothelial growth factor and whether this can cause angiomatosis.