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Assessment of outcomes in typical and atypical carcinoids according to
latest WHO classification.Ann
Thorac Surg. 2003 Dec;76(6):1838-42.
BACKGROUND:
Pulmonary carcinoid tumors represent a group of malignant neoplasms
comprised of neuroendocrine cells. In 1999, the World Health
Organization (W.H.O.) proposed the definitive classification of
neuroendocrine tumors based on the criteria from Travis and
associates. The W.H.O. described two different groups of carcinoid
tumors: typical carcinoids (TC) and atypical carcinoids (AC). Few
reports have reviewed their data according to the current
classification, and therefore, prognosis and standard therapy for TC
and AC are still uncertain. METHODS: From 1980 to 2001, 98 pulmonary
resections have been performed for primary bronchial carcinoid tumors
in our Thoracic Department of the University of Milan. We reviewed
original histology using the current W.H.O. criteria and identified 88
patients with TC and 10 with AC. We reviewed the outcomes in each
group. RESULTS: The 5 year-overall survival rate was 91.9% for TC 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:
IA-B, 100%; IIA-B, 75%; and IIIA, 50%. At 10 years, they were: IA-B,
100%; IIA-B, 75%; and IIIA, 0%. The 5-year survival rates in the AC
group were: IA-B, 100%; IIA-B, 100%; and IIIA, 0%. At 10 years, they
were: IA-B, 100%; IIA-B, 66%; and IIIA, 0%. CONCLUSIONS: Prognosis is
favorable for both subtypes in the early stage. Advanced stages are
related to better prognosis in TC. Recurrences rate is worse in the AC
subtype. Our data suggest avoiding limited resections when feasible in
AC. Parenchyma-sparing resections should be encouraged in TC.
Typical and
atypical pulmonary carcinoids : outcome in patients presenting with
regional lymph node involvement.Chest.
2001 Apr;119(4):1143-50.
STUDY
OBJECTIVE: Typical pulmonary carcinoid tumors are well-differentiated
neuroendocrine tumors that are associated with good patient survival
rates, while atypical carcinoid tumors are more aggressive and have
worse patient survival rates. Because these tumors rarely involve the
thoracic lymph nodes at presentation, it is currently unknown to what
extent the presence of thoracic lymph node metastases at the time of
diagnosis influences patient survival. METHODS: A computerized search
of the medical records for pulmonary carcinoid tumor at the Mayo
Clinic from 1976 to 1997 revealed 517 patients, from which we
identified 36 patients with pulmonary carcinoid tumors involving
regional thoracic lymph nodes but without distant disease. For each
patient, we reviewed the tumor histology, stage, and outcome. In
addition, because the histologic criteria for the diagnosis of
carcinoid tumors had changed significantly during the time of the
study, we reexamined all of the histologic specimens using the current
World Health Organization (WHO) criteria for classifying pulmonary
neuroendocrine tumors. RESULTS: After reclassification with the WHO
criteria for neuroendocrine tumors, 23 patients had typical carcinoid
tumors with thoracic lymph node involvement. At the last follow-up, 19
patients had no evidence of disease (NED), 2 patients had developed
systemic metastases (SM) and are still alive, and 2 patients had died.
Eleven patients had atypical carcinoid tumors with thoracic lymph node
involvement. At the last follow-up, four patients had NED, seven
patients had developed SM within a median time of 17 months, and six
patients with SM died shortly thereafter (median survival time, 25.5
months), while one is still alive. Two patients had been reclassified
with large cell neuroendocrine carcinoma at the time of this review;
both of these patients had developed SM (at 4 months and 21 months
after diagnosis) and had died (at 15 months and 21 months after
diagnosis, respectively). CONCLUSIONS: These data suggest that
patients with atypical pulmonary carcinoid tumors with regional lymph
node metastases have a high likelihood of developing recurrent disease
if treated with surgical resection alone and have significantly worse
outcome (p < 0.001) compared to those patients with typical carcinoid
tumors with thoracic lymph node involvement.
Pulmonary atypical carcinoid: predictors of survival in 106 cases.Hum
Pathol. 2000 Oct;31(10):1255-65.
Pulmonary
neuroendocrine tumors (NE) include a spectrum of tumors from typical
carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine
carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known
about prognostic predictors for AC because of its rarity. Survival
analysis was performed on 106 ACs with clinical follow-up from the
AFIP and the Pathology Panel of the International Association for the
Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC
criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2
mm(2) of viable tumor or coagulative necrosis. Multiple clinical and
histologic features were analyzed by Kaplan-Meier and Cox regression
analysis. Of the clinical features, higher stage (P = .003) and a
tumor size of 3.5 cm or greater (P = .003) were associated with a
worse prognosis. Features that were histologically unfavorable by
univariate analysis were mitotic rate (P =.002), pleomorphism (P =
.018), and aerogenous spread (P =.007). Histologically favorable
features by univariate analysis were the presence of palisading (P =
.008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P
= .022) patterns. Female gender showed a trend toward a poorer
prognosis (P =.085) and was included in the multivariate model.
Multivariate analysis stratified for stage showed mitoses (P<.001), a
tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012)
to be the only negative independent predictors of prognosis and the
presence of rosettes (P = .016) to be the only independent positive
predictor. We further divided the AC into subgroups of low (2 to 5
mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and
compared the survival with TC and with LCNEC. Within the category of
AC, the patients with a higher mitotic rate had a significantly worse
survival than those with a lower mitotic rate (P<.001) stratified for
stage. Five- and 10-year survival rates for AC (61% and 35%,
respectively) stratified for stage were significantly worse than for
TC and better than that for LCNEC and SCLC. Chemotherapy or radiation
therapy was given in 12 of 52 and 14 of 52 cases, respectively, but
the data were insufficient to evaluate tumor response. We conclude
that AC is an aggressive neuroendocrine neoplasm with survival
intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor
size of 3.5 cm or greater, female gender, and presence of rosettes are
the only independent predictors of survival. Surgical resection
remains the treatment of choice, and the role of chemotherapy and
radiation therapy remains to be proven.
Survival analysis of
200 pulmonary neuroendocrine tumors with clarification of criteria for
atypical carcinoid and its separation from typical carcinoid.
Am J Surg Pathol. 1998 Aug;22(8):934-44.
Neuroendocrine
tumors of the lung embrace a spectrum from low-grade typical carcinoid
(TC), intermediate-grade atypical carcinoid (AC), and high-grade
categories of large cell neuroendocrine carcinoma (LCNEC) and small
cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to
critically evaluate the Arrigoni histologic criteria for AC using
statistical analysis to delimit more rigorously an intermediate
survival for AC between TC and the high-grade tumors of LCNEC and
SCLC. Histologic features that might predict prognosis were used for
Kaplan-Meier and Cox proportional hazards survival analysis, and an
optimal mitotic range for AC was calculated. The optimal mitotic range
for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power
fields). Based on this finding, we collapsed mitoses into three
categories (< 2; 2-10; > or = 11) and performed Cox multivariate
analysis for all 200 neuroendocrine tumors. Mitotic counts were the
only independent predictor of prognosis. Based on this analysis, we
propose that AC be defined as a tumor with neuroendocrine morphology,
mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power
fields), or coagulative necrosis. Using these criteria, the 200
neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and
50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and
35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC,
respectively. After stratification for stage, survival for AC was
significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was
significantly worse than for AC; but the survival for LCNEC was no
different than that for SCLC.
Typical and
atypical pulmonary carcinoids--pathologic and clinical analysis of 77
cases.Pneumonol
Alergol Pol. 1998;66(5-6):297-303.
Neuroendocrine
tumors of the lung represent a group of controversial pulmonary
neoplasms regarding their classification, criteria for diagnosis,
predictors of future behavior, and therapy. The histologic criteria
for their classification rest heavily on the proposed by Arrigoni et
al. in 1972, for atypical carcinoid (AC). According to these authors
AC has mitoses between 5 and 10 per 10 high power fields (HPF),
necrosis, hypercellularity and disorganized architecture. The survival
analysis performed by Flieder et al. (1997) for a variety of clinical
and histologic features revised the histologic criteria for separating
AC from typical carcinoid (TC) and proposed a range of mitotic counts
between 2 and 20 per HPF for AC. From 1978 until 1997, 77 resected
pulmonary carcinoids were reclassified for TCs and ACs according to
Flieder's et al. histologic criteria. The clinical and pathological
various features were studied for the group of 62 TCs and 15 ACs. 77
patients (pts) entered the study: 29(38%) males and 48(62%)females;
mean age 43 years, range 18-75 years, 46 pts underwent lobectomies, 16
bilobectomies, 12 pneumonectomies and 3 wedge resections. The patients
with TC were younger than those with AC (males: 40 vs 50 years and
females 42 vs 49 years). TCs were significantly smaller than ACs (mean
diameter respectively: 24 mm vs 33 mm). Fifty four (87%) of TCs and
all ACs had central localization. The time of patients observation
ranged from 2 months to 18 and half years; 2 patients with TC died due
to tumours progression; 3 due to other diseases. Regional lymph node
metastases occurred in 10% TCs and 33% ACs (p = 0.032). The
heterotopic bone formation appeared in 11(18%) TCs and 2(13%) ACs. The
mitotic counts for AC range between 2 and 6 per 10 HPF, accompanied by
small foci of necrosis in 2 cases. Peripheral carcinoids showed a
spindle-cell morphology. The performed study has highlighted the new
concept of the carcinoids classification and the importance of the
mitotic counts as histologic criteria for AC diagnosis. The data based
on the largest in Polish literature lung carcinoids collection.
Carcinoid tumors of the lung: do atypical features require aggressive
management?. Ann Thorac Surg 1995;59:78–83.
Atypical
carcinoids are an intermediate form of tumor between low-grade
malignant typical carcinoid and high-grade malignant small cell
carcinoma, which represent the two ends of the spectrum of
neuroendocrine bronchopulmonary tumors. Between 1983 and 1993, 27
patients with atypical carcinoids underwent surgical treatment. The
histologic diagnosis of an atypical carcinoid was established if the
criteria proposed by Arrigoni and associates were fulfilled. Seven
pneumonectomies, 16 lobectomies, 2 segmentectomies, and 2 wedge
resections were performed. Thirteen patients (48.1%) had regional
nodal metastases and 6 patients (22%) had N2 disease at the time of
surgical therapy. Distant metastases developed in 5 patients (18.5%)
after initial treatment. The 10-year survival in patients with an
atypical carcinoid was 49%, versus the 84% 10-year survival rate
observed in patients with a typical carcinoid. We conclude that the
aggressive behavior of atypical carcinoids precludes the use of
limited surgical resection and requires a more aggressive approach,
with lobectomy and mediastinal lymph node dissection constituting a
minimal procedure. The same criteria used for well-differentiated lung
carcinoma should apply to this form of neuroendocrine lung tumor.
Adjuvant chemotherapy is recommended for patients with stage III or
distant metastases.
Atypical carcinoid
tumour of the lung: a study of 33 cases with prognostic features.
Histopathology 1994;24:363–369.
Atypical
carcinoids of the lung (well-differentiated neuroendocrine carcinomas)
are rare tumours of uncertain prognosis. We have studied 33
cases--male to female ratio 2:1, age range 22-75 years, mean 55 years,
80% smokers, 15 peripheral and 18 central, tumour size 1.2-9.5 cm.
Microscopically they had a nesting/insular, trabecular or lobular
pattern. Nuclear morphology was variable, round cells, large cells and
spindle cells being identified with small cell areas in five tumours.
Mitotic activity varied from 4 to 80 per 1.52 mm2. Areas of necrosis
were seen in all tumours. All 33 tumours were cytokeratin positive
(AE1/AE3 and CAM5.2), 32 were positive for neuron-specific enolase,
synaptophysin and chromogranin A. Electron microscopy showed dense core
granules in 29 available cases. Nineteen cases were stage I, nine
stage II, four stage III and one stage IV. Follow-up information was
available for 22 cases. Size, location, stage and large cell/small
cell morphology were important prognostic indicators. Large tumour
size, large cell or mixed large cell/small cell morphology, peripheral
localization and advanced stage were adverse prognostic indicators.
Mitotic activity and the presence of necrosis did not appear to
influence stage or behaviour.
Bronchopulmonary carcinoids: An analysis of 1,875 reported cases with
special reference to a comparison between typical carcinoids and
atypical varieties.Ann
Thorac Cardiovasc Surg. 1999
Aug;5(4):211-9.
This study was
undertaken to provide investigators working in this particular
research field with extensive and useful basic information based on an
analysis of a large reliable series of cases regarding tracheal and
bronchopulmonary carcinoids and their atypical varieties. A
statistical evaluation was carried out which included a total of 1,875
patients with tracheal and bronchopulmonary carcinoids; these were
divided into two series, one of 1,595 patients with typical carcinoids
and the other of 280 with atypical varieties. These two series were
compared regarding various aspects, which included the male to female
ratio, age distribution, clinical manifestations, successful
preoperative diagnosis, diagnostic accuracy of representative
procedures, sites of involvement, tumor size distribution, metastases,
carcinoid syndrome, serotonin activity in patients with or without the
syndrome, immunohistochemistry, electron microscopy, and postoperative
prognosis of the patients. The comparative analyses between the two
series disclosed statistically significant differences (p<0.01)
regarding various viewpoints; among others, such a difference was
proved in the average age, sites of involvement in the lung (central
or peripheral), rates and sites of metastases, adrenocorticotrophic
hormone (ACTH) production, the association rate of the carcinoid
syndrome, and postoperative 5-year and 10-year survival rates (93.3%
and 82.1% for the typical carcinoid series versus 68.8% and 58.6% for
the atypical variety series: p<0.0001). The postoperative 5-year and
10-year survival rates in the other two groups of patients with or
without metastases were likewise calculated and showed a statistically
significant difference (72.8% and 52.8% for the former versus 98.3%
and 95.4% for the latter: p<0.0001).
Atypical
carcinoid of the lung. A distinct clinicopathologic entity.Chest.
1988 Feb;93(2):370-5.
Eleven cases of
atypical carcinoid (AC) of the lung were identified during an
eight-year period. Their clinical features and treatment responses
were contrasted with our experience at Vanderbilt with small cell lung
cancer (SCLC) and a literature review of typical bronchial carcinoids
(TC). Clinically, there were no features to distinguish AC from TC
except for age at diagnosis (59 vs 49 years). Atypical carcinoid was
similar to SCLC with respect to many clinical features, although
female sex, absence of smoking history and localized disease at
presentation were more common in AC. Pathologically, these tumors were
distinguished by cellular atypia, necrosis, architectural disorder, or
increased mitotic rate in the presence of a recognizable carcinoid
pattern. Immunoperoxidase staining revealed no difference between AC
and TC or SCLC. Atypical carcinoid of the lung represents a distinct
clinicopathologic disease.
Atypical carcinoid tumors of the lung. J Thorac
Cardiovasc Surg 1972;64: 413–421.
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