Full text of DOI:10.1177/021849230000800111

MO oR gI Gh eI NAL CONTRIBUT IAO T NY PICAL CARCINOID TUMORS OF LUNG: CLINICOPATHOLOGIC STUDY OF SIX CASES
ATYPICAL CARCINOID TUMORS
OF LUNG: CLINICOPATHOLOGIC
STUDY OF SIX CASES
Girish Moghe, MD, Nirmala A Jambhekar, MD,
Ramakant K Deshpande, MS, Rahul Hejmadi, MD,
Jitendra Vyas, MS1
Department of Pathology
1
Department of Surgery
Tata Memorial Hospital
Mumbai, India
ABSTRACT
This retrospective study of 6 cases of atypical carcinoid tumor was carried out to
highlight their clinicopathological features and behavior. All patients were over
4
0 years of age and were treated by surgical excision of the tumor. Four tumors
were central and 2 were peripherally located in the lung. Grossly, the tumors were
large with spotted areas of necrosis. Microscopically, all tumors had a typical
carcinoid pattern with spotted areas of necrosis and mitotic activity in the range
of 2 to 5 per 10 high-power fields. On immunohistochemistry, the tumors were
positive for neuron-specific enolase and cytokeratin. Follow-up ranging from 1 to
5
years was available in 4 patients; 2 are currently alive, 1 with local recurrence
and distant metastasis one year postoperatively, the other with no disease after 5
years. Two patients died; one had a local recurrence at 2 years and the other had
liver metastasis at 3 years.
(Asian Cardiovasc Thorac Ann 2000;8:41–5)
INTRODUCTION
histologic criteria: increased mitotic activity in the
The classification of pulmonary neuroendocrine tumors presence of a recognizable carcinoid pattern; pleomor-
of the lung has evolved substantially over the past two phism and irregularity of nuclei with prominent nucleoli,
decades. Previously, only two major categories of pul- hyperchromatism, and an abnormal nucleocytoplasmic
monary neuroendocrine tumors were recognized; the ratio; areas of increased cellularity with disorganization
relatively benign typical carcinoid and the highly aggres- of architecture; and areas of necrosis.
sive small-cell carcinoma. However, some tumors cannot
The clinicopathological features of 6 atypical carcinoid
tumors recorded at a cancer hospital over a 10-year period
are described with the aim of highlighting this little known
and underdiagnosed entity.
be satisfactorily placed in these polar groups because
they show focal necrosis and some mitotic activity, unlike
the typical carcinoid, while still retaining the overall
carcinoid pattern. The behavior of these tumors is inter-
mediate to that of the typical carcinoid and small-cell
1
carcinoma. In 1972, Arrigoni and colleagues coined PATIENTS AND METHODS
the term atypical carcinoids to describe such tumors. During analysis of all lung tumors accessioned from 1985
Essentially, atypical carcinoids can be distinguished within to 1995, 6 cases were found to fulfill the criteria for
the spectrum of neuroendocrine tumors by the following atypical carcinoids on histology. Five were primarily
For reprint information contact:
Nirmala A Jambhekar, MD Tel: 91 22 414 6750 Fax: 91 22 414 6937 email: medimail@tmc.ernet.in
Department of Pathology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai 400012, India.
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ATYPICAL CARCINOID TUMORS OF LUNG: CLINICOPATHOLOGIC STUDY OF SIX CASES
Moghe
examined from cases treated surgically in this hospital;
representative material was available for review in the
6
th case. Intraoperative frozen-section diagnosis of
carcinoid tumor was made in the first 5 cases prior to
receiving the fresh surgical specimens. Sections were
fixed in 10% formalin, embedded in paraffin wax, stained
with hematoxylin and eosin, and studied by light
microscopy. Immunohistochemical staining included a
panel of antibodies to cytokeratin (Dakopatt, Carpinteria,
CA, USA; dilution, 1:100), neuron-specific enolase
(
Dakopatt; dilution, 1:50), synaptophysin (Dakopatt;
dilution, 1:100), chromogranin (Dakopatt; dilution, 1:100),
and S-100 protein (Dakopatt; dilution, 1:300), using the
avidin-biotin-peroxidase complex and the peroxidase-
antiperoxidase technique with 3,3'-diaminobenzidine as
the chromogen. Samples of typical carcinoids were used
as controls for immunohistochemistry. Clinical and
operative details were obtained from the patients’ records.
RESULTS
All 6 patients with atypical carcinoids were over 40 years
of age (range, 40 to 60 years; mean, 49.8 years) and there
was an equal number of men and women. Clinical history
and details of treatment are listed in Table 1. Four tumors
were central and 2 were peripherally located in the lung;
they ranged in size from 3 × 3 × 2 cm to 7 × 6 × 5 cm.
Grossly, they were firm, yellowish white, and homogenous
with spotted areas of necrosis and hemorrhage (Figure 1).
No nodes were dissected from the lung specimens and
none of the tumors involved the pleura.
Microscopically, each tumor revealed a readily identifiable
carcinoid growth pattern that comprised a variety of
architectural types. Three tumors had a lobular and
trabecular pattern, 2 showed a mixture of lobular and
insular patterns, and 1 was predominantly lobular.
Prominent palisading at the periphery of the tumor nests
was seen in 3 specimens. A striking feature visible in all
tumors was the presence of spotted areas of necrosis in
the center of the lobules (Figure 2), despite the overall
carcinoid-like growth pattern.Afocal micro-acinar pattern
was also seen (Figure 3). The individual tumor cells were
three times the size of a normal lymphocyte and contained
a moderate amount of eosinophilic cytoplasm. The nuclei
were round with fine stippled salt-and-pepper-like
chromatin. Nuclear pleomorphism and prominent nucleoli
were seen in 3 tumors (Figure 4). Mitotic figures were
infrequent. However, 3 tumors had 2 mitotic figures per
1
0 high-power fields (HPF), whereas the other 3 had 5
mitoses per 10 HPF.
Immunohistochemistry revealed a focal weak positivity
for cytokeratin and strong positivity for neuron-specific
enolase in all 6 tumors. On the other hand, S-100 protein,
chromogranin, and synaptophysin were uniformly negative
in all tumors. The samples of typical carcinoid used as
controls showed strong positivity for cytokeratin, neuron-
specific enolase, chromogranin, and synaptophysin.
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ATYPICAL CARCINOID TUMORS OF LUNG: CLINICOPATHOLOGIC STUDY OF SIX CASES
3
Follow-up of 1 to 5 years was available in 4 cases (2 Valli and colleagues in 1994. Smaller series comprising
1
,4,5
patients were lost to follow-up). Two of these 4 patients 23, 17, and 6 cases have been published.
It is most
died of the disease; one developed a local recurrence 2 likely that the 41 cases reported under the term bron-
years postoperatively and the other developed liver chopulmonary Kulchitzky-cell carcinoma type II by
2
metastasis 3 years after surgery. Both patients received Paladugu and colleagues in 1985 were also atypical
adjuvant therapy comprising chemotherapy as well as carcinoids.
radiotherapy after developing recurrence and metastasis.
However, they did not respond. The other 2 patients are The 6 patients with atypical carcinoids in this study had
currently alive; one had a local recurrence in the first a mean age of 49.8 years, whereas in the previous series,
1
,3–5
5
postoperative year, which was treated with radiotherapy. the mean ages were 55, 51, 58, and 33.2 years.
The
She was free of disease for 1 year but was found to have age range for typical carcinoids is 23 to 70 years. The
metastatic deposits in the perineum at a recent follow-up. average size of the atypical carcinoids was 5 × 5.5 × 3.5
The other patient received local radiotherapy and is free cm, whereas the average size of typical carcinoids recorded
of disease after 5 years.
in this hospital was 2.5 cmin diameter. Grossly, the large-
cell neuroendocrine carcinomas average 3.2 cm in
diameter, whereas the small-cell carcinomas are frequently
DISCUSSION
Atypical carcinoids are uncommon tumors and together large, destructive, and surgically unresectable lesions when
5
with the typical carcinoids constitute less than 5% of all first seen.
2
lung tumors. In this 10-year period (1985 to 1995), 40
cases of typical carcinoids were recorded but there were Microscopically, the atypical carcinoids maintained the
only 6 cases of atypical carcinoids. The largest series of carcinoid growth pattern yet revealed mitosis and spotty
atypical carcinoids, comprising 33 cases, was reported by necrosis. Mitotic activity was 2 to 10 per 10 HPF in the
Figure 3. Atypical carcinoid of the lung showing a nesting pattern. A
Figure 1. Pneumonectomy specimen showing a large central tumor
micro-acinar pattern is also noted (hematoxylin and eosin stain, original
magnification ×100).
with areas of necrosis (arrow).
Figure 2. Atypical carcinoid of the lung showing a prominent nesting
pattern, spotted areas of necrosis, and focal peripheral palisading (arrow).
Figure 4. Tumor cells showing round nuclei with moderate pleo-
morphism, fine stippled chromatin, and infrequent mitotic activity (arrow).
(Hematoxylin and eosin stain, original magnification ×200.)
(Hematoxylin and eosin stain, original magnification ×100.)
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8
6
atypical carcinoids. Necrosis has not been described in 25% of lung tumors. It is highly aggressive and usually
typical carcinoids and the mitotic activity is sporadic (0 located centrally. Clinically, it is characterized by rapid
5
to 1 per 10 HPF). In contrast to both typical and atypical growth and early metastatic dissemination. The small-
carcinoids, the small-cell carcinomas and large-cell neuro- cell carcinomas are highly chemosensitive with a response
endocrine carcinomas have large areas of infarct-like rate greater than 80% in both limited and extensive disease,
9
necrosis. The cells of small-cell carcinoma are less than yet the 5-year survival rate is only 4%. Before the advent
three times the size of a small lymphocyte, with finely of systemic therapy, local surgical or radiation therapy
granular chromatin, no nucleoli, and a mitotic rate higher alone resulted in a very poor median survival ranging
9
than 10 per 10 HPF (range, 28 to 124 per HPF). Nuclear from 8 to 17 weeks. The median survival with com-
moulding and hematoxylin staining of DNA encrustation bination chemotherapy is 14 to 16 months for patients
of the vessel walls (Azzopardi effect) are frequently seen. with limited disease and 8 to 11 months for those with
1
0
The tumor cells of large-cell neuroendocrine carcinoma extensive disease.
are larger with a low nuclear-cytoplasmic ratio, vesicular
or fine nuclear chromatin with frequent nucleoli, and a The distinction of atypical carcinoids from other neuro-
6
high mitotic activity of 11 to 70 per HPF. Thus, the endocrine tumors should be based on morphological
atypical carcinoids occupy an intermediate morphological parameters that include the amount and pattern of necrosis,
position in the spectrum of bronchopulmonary neuro- cell size and amount of cytoplasm, nuclear chromatin,
endocrine tumors.
nucleoli, and most importantly, the mitotic rate. Immuno-
histochemistry can be used as a supplementary tool to
The immunohistochemical results in our study revealed morphology.Apart from the other neuroendocrine tumors,
weak positivity for cytokeratin and strong positivity for atypical carcinoids may also be confused with Askin-
neuron-specific enolase, whereas S-100, chromogranin, Rosai tumor (primitive neuroectodermal tumor of the
and synaptophysin were uniformly negative. In contrast, chest wall) and with a monophasic synovial sarcoma.
the typical carcinoids that served as controls showed Both of these tumors lack the carcinoid pattern and often
strong positivity for cytokeratin, neuron-specific enolase, have their dominant components in the chest wall or
chromogranin, and synaptophysin. Neuron-specific pleura with a smaller contiguous pulmonary component,
enolase can often stain nonspecifically and chromogranin unlike the atypical carcinoid that is largely an intra-
and synaptophysin are superior antibodies for assessing parenchymal tumor. In addition, immunoreactivity for
the neuroendocrine origin of any tumor. However, these Mic-2 in primitive neuroectodermal tumor and lack of
markers sometimes do not stain atypical carcinoids well, immunoreactivity for neural markers in synovial sarcoma
5
as noted in this study. Travis and colleagues also found are additional differentiating features.
a slightly lower overall percentage, distribution, and
The atypical carcinoid is underdiagnosed and often
unrecognized. The distinguishing features described in
this report are important in view of the therapeutic and
prognostic implications.
intensity of immunohistochemical staining for neuro-
endocrine and hormonal markers in atypical carcinoids
compared to typical carcinoids. They attributed this to a
lower degree of differentiation of atypical carcinoids than
typical carcinoids.
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