Moderators: Dr. Elizabeth Brambilla, Dr. John English and Dr. Donald Guinee
Case 2 -
Atypical carcinoid tumour associated with adenocarcinoma
Dr. Philip Hasleton
Department of Histopathology
Manchester Royal Infirmary
Lung tumours with neuroendocrine (NE morphology) include typical carcinoid (TC), atypical carcinoid
(AC), large cell neuroendocrine carcinoma (LCNEC), small cell lung cancer lung cancer (SCLC) and
non-small cell lung cancer with NE morphology
68-year-old male, ex smoker, presented with hemoptysis. On CT scan, a mass was identified in the lingula and on bronchoscopy, there was a mass obliterating the left lingular bronchus. A left upper lobectomy was performed with a tumour protruding through the inferior bronchial resection margin, within 2 mm of the cut edge. The tumour was well demarcated, cream coloured and measures 6.0x3.5x3.5 cm. the uninvolved lung was unremarkable apart from emphysema at the apex.
Case 2 - Slide 1
Recently the incidence of pulmonary NE tumours has been described Denmark.
 This was a cancer registry-based analysis of patients, studied over
the period 1978-1997. The patients were followed up to 31 December 1999. There was no histological
verification of all of their cases. The recorded incidence of pulmonary NE tumours, other than SCLC,
increased two-fold amongst men (0.24-0.53 per 100,000 inhabitants per year) and three-fold in women
(0.14-0.41 per 100, 000 inhabitants per year) during the study period. The incidence of SCLC decreased
amongst men and leveled of amongst women. Reasons for this increase are not available but on the
twentieth anniversary of Chernobyl, it is fascinating to speculate if the fallout from this
disaster may have played a part. Studies from other countries in the Baltic and suffering from exposure
would be welcome to compare with rates from the rest of the world.
Carcinoid tumours are characterised by growth patterns (organoid, trabecular, insular, palisading,
ribbon, rosette-like arrangements) that suggest NE differentiation.
 Tumour cells have uniform cytologic features but moderate eosinophilic, finely
granular cytoplasm and nuclei with a finely granular chromatin. Typical carcinoids (TC) are carcinoid
tumours with fewer than 2 mitoses per 2mm2 and lacking necrosis. Atypical carcinoid (AC) is a
carcinoid tumour with 2-10 mitoses per 2mm2 and/or foci of necrosis.
TC and AC are both firm well-demarcated tan to yellow tumours. Typically TC are central tumours and
frequently endobronchial, the overlying mucosa may be intact or ulcerated and there maybe squamous
metaplasia. Association with airways may not be readily evident in peripheral tumours. 
Nuclear atypia and pleomorphism may be quite marked, even in TC. These are unreliable criteria for
distinguishing TC from AC.  At presentation, 10-15% of
TC have metastasised to regional lymph nodes and 5-10% of cases eventually spread to distant sites, such
as liver or bone. TC is classified by the WHO as a malignant tumour and it is frequent that surgeons
have to be appraised of this fact, since there is a belief this tumour behaves in a benign fashion. The
figures for lymph node spread are higher in AC, where 40-50% metastasised to regional nodes and beyond,
with 57% stage I disease, 21% stage II, 14% stage III and 8% stage IV at presentation. 
The histology has been referred to above but there are variations, oncocytic tumours have abundant
eosinophilic cytoplasm. Rarely the cytoplasm maybe be clear and can contain melanin. There may be a
spindle cell, papillary, pseudo-glandular, follicular or rosette-like patterns but true gland formation
is rare. The stroma is highly vascularized, due to TGF-a secretion by the tumour. In some cases
the stroma is hyalinized or may show cartilage or bone. Bone formation is seen in up to 33% of carcinoid
tumours, both typical and atypical. It is most probably related to secretion of IGF-1 and TGF-β.
 In central tumours, there is, if anything, a decrease
in NE cells in the bronchus in the region of the tumour.
 However, some cases may show NE hyperplasia, sometimes associated with airway fibrosis or
there may be diffuse idiopathic neuroendocrine hyperplasia.
 Such changes are most commonly seen in associated with peripheral carcinoids. Rare cases may
also show multiple tumourlets or multiple carcinoids tumours.
 Apart from focal necrosis and a mitotic rate, numbering between 2-10 mitoses per
2mm2, AC show the histological features referred to above.
Prognosis in AC was studied in 106 cases by Beasley et al.  Using clinico-histological
features, analysed by Kaplan-Meier and Cox regression analyses, they showed a worse prognosis was
associated with a higher stage (p =0.003) and a tumour size of 3.5 of greater (p = 0.003). The features
histologically unfavourable by univariate analysis were mitotic rate (p =0.002), pleomorphism (p
=0.018) and aerogenous spread (p =0.007). Histologically favourable features by univariate
analysis were palisading (p =0.008), papillary (p =0.039), pseudoglandular (p =0.026), and rosette (p
=0.022) patterns. The female gender showed a trend towards poorer prognosis (p =0.085).
Multivariate analysis in this study, stratified by stage, showed mitoses (p < than 0.001), tumour
size of 3.5cm or greater (p = 0.017) and female gender (p =0.012) were the only negative independent
factors of prognosis. The presence of rosettes (p = 0.016) was the only independent positive factor.
These authors also divided AC into subgroups with low (2-5 mitoses/2mm2) and high (6-10
mitoses/2mm2) mitotic counts and compared their survival with TC and LCNEC.
Patients with AC having a higher mitotic count had a significantly worse survival rate than those
with a lower mitotic count (p < than 0.001) when stratified for age. 5 - and 10 -year survival rates
for AC (61% and 35% respectively) stratified by stage was significantly worse than for AC but better than
those for LCNEC and SCLC. The data for response to chemo- or radio- therapy were insufficient to
evaluate tumour response.
A recent prognostic study,  using the 1999 WHO
criteria, of resected pulmonary carcinoid tumours had material from 121 TC and 42 AC. The TC were
predominantly N0 status (107/121) and 14 were N1. In the AC 15/42 were N0, 18 were N1 and 9 N2. All
patients were included in follow-up, with a median of 54 months and mean of 58 months, (range 4-150
months). This follow-up included yearly total body CT and bronchoscopy. The overall 5-year survival
rate was 90.3% with a mean survival time of 139 months (95% confidence interval, 133-145). In N0
patients with either TC or AC, no disease-related mortality was reported (100% 5-year survival). In N1
patients 5-year survival was 90.0% in TC and 78.8% in AC (p = 0.394). In AC with N2 disease, 5-year
survival was 22.2%. In this study prognosis was related more to nodal status than histological subtype.
No TC's had T2 disease, making true comparisons difficult. The authors found no statistical significance
between typical and atypical subtype in the N0 and the N1 patients.
Mezzetti et al.  collected 98 pulmonary
resections for primary bronchial carcinoid tumours, of which 88 had TC and 10 AC. The 5-year survival
rate for TC was 91.9% and 71% for AC. The 10-year overall survival rate was 89.7% for TC and 60% for
AC. The 5-year TNM-related survival rates in the TC group were 1A-B, 100%, 2A-B, 75% and 3A-50%. At 10
years they were 1A-B 100%, 2A-B 75% and 3A 0%.
The 5-year survival rate in the AC group was 1A-B 100%, 2A-B 100% and 3A 0%. At 10 years they were
1A-B 100%, 2A-B 66% and 3A-B 0%. Prognosis was favourable in both subtypes in early stage disease but in
advanced stage it was better in TC. The recurrence rate was worse in AC.
The prognosis of patients with TC in Denmark  ranged from 87% for patients
with TC to 44% in patients with AC but these authors did not have histological verification of their
The Beasley study  had immunohistochemistry available in 38 cases. Such studies are not
required for the diagnosis of AC using the WHO criteria. Cytokeratin "cocktail" stains were available in
31 cases, 26 (84%) showed at least some degree of positive staining, 11/13 (85%) cases stained with CAM
5.2 were positive, 31/33 cases (94%) chromogranin-positive, 30/33 (94%) cases were positive for
chromogranin, 30/33 (91%) cases were positive for synaptophysin and 21/28 (75%) cases were positive for
Leu-7. All the cases with immunohistochemical studies available showed some degree of staining with at
least one of the NE markers. When a percentage of cells staining with a particular marker was analysed,
a trend towards a better prognosis was identified with tumours 75% of cells or greater staining with
chromogranin, compared with tumours with less than 75% of cells staining (p = 0.082). No other
significant results were identified with regard to percentage of cells staining or the intensity of
Most carcinoid tumours stain for cytokeratin but 20% may be keratin negative.  NE markers,
such as chromogranin, synaptophysin and CD56 (NCAM) are typically strongly positive, especially in TC.
In AC staining for these markers may be patchy or focal. Results with TTF-1 have given varying results.
Some authors have shown both TC and AC are negative.
 Others have shown approximately a third of TC and most AC are positive.
The differences between the papers may be explained by the fact that Sturm et al.
 did not use the same antibody as the other authors.
The Du et al. paper 
showed all extra-pulmonary NE tumours were uniformly negative for TTF-1. In their TTF-1 positive cases
of TC and AC, 12/14 had a peripheral location and a spindle cell morphology. 11 tumourlets were positive
with this antibody. They concluded that TTF-1 expression was 100% specific, though not so sensitive, for
a lung primary in TC and AC.
Recently Pelosi et al  have shown that normal
and hyperplastic bronchial neuroendocrine cells expressed E-cadherin/beta-catenin along the cell
membrane. NE tumours retained beta-catenin expression in all tumours and E-cadherin in most tumours,
with the exception of 9% of AC, 2% of LCNEC and 3% of SCLC. E-cadherin showed membrane-associated,
linear immunoreactivity in TC, whereas "membrane-disarrayed" (defined as a wrinkled staining of the
membrane as well as variable cytoplasmic accumulation of staining) and cytoplasmic staining (prevalent
cytoplasmic staining with only minimal or absent membrane labelling) were seen in most AC, LCNEC and SCLC
(p <0.001). Beta-catenin exhibited similar immunoreactivity patterns according to tumour type and a
close association was seen with E-cadherin subcellular distribution (p < 0.001). In AC, disarrayed
immunoreactivity for E-cadherin and/or beta catenin was associated with a non-trabecular growth pattern,
altered expression of the cell-motility marker fascin and lymph node metastases. In addition, a
disarrayed E-cadherin distribution pattern was associated with the pathologic lymph node classification
and the number of involved lymph nodes. Multivariate analysis confirmed a disarrayed E-cadherin or
beta-catenin pattern was an independent predictor for lymph node metastases in patients with AC.
A further paper by Pelosi et al.  showed that
fascin immunoreactivity might identify subsets of pulmonary carcinoid patients with different metastatic
potential to regional lymph nodes. Fascin-immunoreactivity was detected in only 5% of the 38 TC but 35%
of the 23 AC. The figure increased in LCNEC (83% of 40 cases) and 100% of 27 SCLC). Normal NE cells or
hyperplastic NE tumourlets were non-reactive. In both TC and AC but not in high-grade NE malignancy,
fascin immunoreactivity closely correlated with the presence of lymph node metastases.
The differential diagnosis of carcinoid tumours is large, since many tumours may show an NE pattern.
Bronchoscopic and frozen section samples can give rise to false-positive diagnoses. This author has
wrongly diagnosed a SCLC on a superficial biopsy from an AC, which subsequently came to resection.
Similar results have been found by others.
Tumourlets may resemble TC but are distinguished by
size, being less than 5mm in diameter. The higher grade NE tumours (LCNEC and SCLC) have a mitotic rate
greater than 10 per 2mm 2. Spindle-cell lesions may be confused with spindle cell squamous
carcinomas, pleomorphic carcinomas or mesenchymal tumours. This includes mesotheliomas, especially as
there is a case report of two AC presenting clinically as mesotheliomas.
 Immunohistochemistry may resolve these issues. Occasional
carcinoids may have a prominent papillary pattern and these may be confused with sclerosing haemangioma
or secondary bladder cancer. The former tumour is TTF-1 positive but is negative with NE stains.
The commonest problem is differentiating pseudoglandular or gland-like patterns in carcinoid tumours.
These can give rise to misdiagnoses of adenocarcinomas, mucoepidermoid carcinomas, acinic cell tumours,
and adenoid cystic carcinomas. Usually adenocarcinomas show more cytological atypia and mucin
production, though both may be seen in carcinoids. Adenocarcinomas may show NE-positivity but it is less
diffuse than in carcinoids.
A very rare differential is paraganglioma. S100-positive, sustentacular cells may be identified in
carcinoids. However, paragangliomas do not stain with cytokeratin, which is frequently positive in
carcinoids.  Glomus tumours may also resemble
carcinoids but are positive for smooth muscle actin and negative for NE markers.
 Secondary carcinoid tumours from extra-pulmonary sites, as
mentioned above, are TTF-1 negative.
The epithelial pattern of a carcinoid tumour maybe mimicked by metastatic breast or prostate
carcinoma, the appropriate markers (PSA, TTF-1, ER and PR) may well help in this situation. Another
diagnostic problem may be posed by metastatic medullary carcinoma of thyroid. This is NE-positive and
though it shows amyloid, occasionally this material may be identified in carcinoid tumours. Usually
there are multiple nodules from the rare cases of metastatic medullary carcinoma of thyroid in the lung.
The present case is interesting in two respects. The NE has a mitotic count above that seen in AC but
on histology strongly resembles an AC. This author has seen this "problem" several times before.
However the work of Travis in establishing the numbers of mitoses to differentiate the NE subtypes is
statistically robust. This case indicates how important mitotic count is as prognostic factor in NE
tumours. The second unusual feature is the combination of the tumour with an adenocarcinoma. In this
instance TTF-1 may be of little in differentiating the two tumours and as always reliance should finally
be placed on routine H & E sections.
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