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Neuroendocrine Carcinomas of theColon and RectumP. E. Bernick, M.D., 1 D. S. Klimstra, M.D.,2 J. Shia, M.D.,2 B. Minsky, M.D.,3

L. Saltz, M.D.,4 W. Shi, M.S.,5 H. Thaler, Ph.D., 5 J. Guillem, M.D.,1 P. Paty, M.D., 1

A. M. Cohen, M.D.,1 W. D. Wong, M.D. 1

1 Colorectal Service, Memorial Sloan-Kettering Cancer Center, New York, New York 2 Pathology Service, Memorial Sloan-Kettering Cancer Center, New York, New York 3 Radiation Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York 4 Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York 5 Epidemiology and Biostatistics Service, Memorial Sloan-Kettering Cancer Center, New York, New York

PURPOSE: This study was designed to review experience with neuroendocrine carcinomas of the colon and rectumat a single institution, with emphasis on the pathology andclinical characteristics of this uncommon malignancy.METHODS: A study group of patients was identified from aprospective colorectal service database. Pathology was reviewed and neuroendocrine tumors were classified by asingle pathologist. Medical records were retrospectively reviewed. RESULTS: From March 1975 to September 1998, 38patients with neuroendocrine carcinomas were identifiedfrom the colorectal service database comprising 6495 pa-tients (0.6 percent). These neuroendocrine carcinomas didnot include carcinoid tumors. Average patient age was 57 years (range, 29–86 years). There were 17 males (44.7 per-cent) and 21 females (55.3 percent). Tumors were locatedas follows: 17 colon, 14 rectum, 6 anal canal, and 1 appen-dix. The diagnosis of neuroendocrine carcinoma was sug-gested preoperatively from tissue biopsy in 59.3 percent(16/27) of patients evaluable. Pathology was reviewed andtumors were categorized as small cell carcinoma (n = 22) or large cell neuroendocrine carcinoma (n = 16). Most tumors(20/25 evaluable, 80 percent) stained positive by means of immunohistochemistry for neuroendocrine markers, in-cluding chromogranin (18/19), synaptophysin (10/15),and/or neuron-specific enolase (14/15). Metastatic disease was detected at the time of diagnosis in 69.4 percent of the

patients (25/36). Tumors were advanced at the time of di-agnosis, with American Joint Committee on Cancer (AJCC)Stage I (n = 6), Stage III (n = 7), and Stage IV (n = 25)tumors. As a group, these tumors had a poor prognosis, with a median survival of 10.4 months. One-year, two-year,and three-year survival was 46 percent, 26 percent, and 13percent, respectively. There was no significant difference insurvival based on pathologic subtypes. Median follow-uptime was 9.4 months (range, 0.6–263.7 months). CONCLU-SIONS: Neuroendocrine carcinomas of the colon and rec-tum are uncommon, comprising less than 1 percent of colon and rectal cancers. Pathologically, these tumors arepoorly differentiated carcinomas with distinctive cytoarchi-tectural features and are often immunoreactive for markersof neuroendocrine differentiation. The prognosis for high-grade neuroendocrine carcinomas is poor, as most patientshave metastatic disease at the time of diagnosis. [Key words:Neuroendocrine; Small cell; Carcinoma; Colon; Rectal]

N euroendocrine cells are distributed throughoutthe body and are found in the gastrointestinal

tract, pancreas, lung, thyroid, adrenal gland, andmany other organs. The gastrointestinal tract has thelargest population of neuroendocrine cells. Despite

this, neuroendocrine carcinomas of the colon and rec-tum are rare.

Colorectal neuroendocrine tumors are classified aseither low-grade carcinoid tumors or high-grade neu-roendocrine carcinomas. Carcinoid tumors are in gen-eral indolent and do not respond to cisplatin-basedchemotherapy, whereas high-grade neuroendocrinecarcinomas are aggressive but often do respond tran-siently to cisplatin-based chemotherapy.

Poster presentation at the meeting of the American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 24 to 29,2000.

Correspondence to: W. D. Wong, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, C-1067, New York,New York, 10021, USA, e-mail: [email protected] Colon Rectum 2004; 47: 163–169DOI: 10.1007/s10350-003-0038-1© The American Society of Colon and Rectal Surgeons

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Pathologically, high-grade neuroendocrine carcino-mas of the colon and rectum are poorly differentiatedcarcinomas with a high mitotic rate and foci of necro-sis. The growth patterns and cytologic features aretypical of neuroendocrine tumors. The presence of neurosecretory granules in the cytoplasm of tumorcells detected by electron microscopy is characteristic.Furthermore, neuroendocrine carcinomas typically stain for the immunohistochemical markers synapto-physin, chromogranin, or neuron-specific enolase(NSE).

The nomenclature and classification of neuroendo-crine tumors by pathologists have been controversial.Neuroendocrine carcinomas are a heterogeneousgroup of tumors that display aggressive clinical be-havior. Compared with adenocarcinomas, neuroen-docrine carcinomas of the colon and rectum report-edly have a significantly poorer prognosis. 1 – 3

Pathologic recognition of these tumors is importantbecause treatment options with alternative chemo-therapy have been proposed. 4,5

The aim of this study was to review experience with neuroendocrine carcinomas of the colon andrectum at a single institution, with emphasis on patho-logic and clinical characteristics.

PATIENTS AND METHODS

From March 1977 to September 1998, patients with

neuroendocrine carcinomas of the colon and rectum were identified from a prospective colorectal servicedatabase at the Memorial Sloan-Kettering Cancer Cen-ter (MSKCC) in New York, New York. Additional pa-tients treated nonoperatively at MSKCC were identi-fied from the pathology service database. A total of 38patients with neuroendocrine carcinomas were iden-tified. A single expert pathologist (DSK) reviewed thehistopathology for all cases. The tumors were classi-fied into 1) small cell carcinoma and 2) large cell neu-roendocrine carcinoma on the basis of histologic andimmunohistochemical findings.

Hematoxylin and eosin – stained slides were avail-able for review in each case. In addition, slidesstained by immunohistochemistry for neuroendocrinemarkers (chromogranin, synaptophysin, and/or NSE) were reviewed. Carcinoid tumors, atypical carcinoids,adenocarcinomas with carcinoid features (so-calledadenocarcinoid tumors), and adenocarcinomas withfocal scattered chromogranin-positive or synaptophy-sin-positive cells were not included in this study.

All cases contained a component with the his-tologic features typical of a high-grade neuro-endocrine carcinoma comprising at least 50 percentof the tumor. These features included a densely cellular, solid growth pattern, with cells arrangedin nests having minimal intercellular stroma. No glandformation was evident in these areas, althoughsome cases did show separate components of adeno-carcinoma (see below). The nuclear features alsosuggested neuroendocrine differentiation, witha stippled or “salt-and-pepper ” chromatin pattern.The high-grade nature of these foci was confirmed by the presence of necrosis and a mitotic rate of greaterthan ten mitoses per ten high power microscopicfields.

The tumors were then subdivided on the basis of cytologic features into small cell carcinomas and largecell neuroendocrine carcinomas. The small cell carci-

nomas resembled their pulmonary homonyms, hav-ing minimal cytoplasm, fusiform cell shape, finely granular chromatin, small or absent nucleoli, andnuclear moulding (Fig.1). The large cell neuroendo-crine carcinomas were characterized by cells withmore cytoplasm, a round or polygonal cell shape,prominent nucleoli, and a coarser chromatin pattern(Fig. 2). Thus, the criteria for separating small cellfrom large cell variants were similar to those pro-posed for the classification of pulmonary neuroendo-crine tumors. 6

Although the diagnosis of small cell carcinoma

did not necessitate documentation of neuroendo-crine differentiation immunohistochemically, thediagnosis of large cell neuroendocrine carcinomarequired positive immunohistochemical stainingfor one of the three neuroendocrine markers (chro-mogranin, synaptophysin, and NSE) in at least 10 per-cent of the tumor cells. Clinical information andfollow-up, where available, were obtained retrospec-tively from review of the hospital charts and elec-tronic hospital record. Clinical features studied in-cluded patient age, gender, tumor location, tumorstage, treatment, status, and length of follow-up. Tu-mors were staged according to the 1997 American Joint Committee on Cancer (AJCC) TNM staging sys-tem. 7 All survival data were calculated from the dateof diagnosis. Two patients were lost to follow-up. Sta-tistical analysis was performed by use of the Kaplan-Meier method for estimating survival curves and thelog-rank test for assessing differences in survival be-tween groups. A P value of <0.05 was consideredsignificant.

164 BERNICK ET AL Dis Colon Rectum, February 2004



RESULTS

Distribution of demographic and clinicopathologiccharacteristics is shown in Table 1. Tumors were lo-cated as follows: 17 colon (8 cecum, 2 right colon, 1hepatic flexure, 3 transverse colon, and 3 sigmoid co-lon), 14 rectum, 6 anal canal, and 1 appendix. Thediagnosis of neuroendocrine carcinoma was sug-gested preoperatively from tissue biopsy in 59.3 per-cent (16/27) of patients evaluable. Tumors were cat-egorized into the following two groups: 1) small cellcarcinoma (n = 22) and 2) large cell neuroendocrinecarcinoma (n = 16). Immunohistochemically, 80 per-cent of the tumors evaluable (20/25) stained positivefor neuroendocrine markers, including chromogranin

(18/19), synaptophysin (10/15), and/or NSE (14/15).Most of these tumors were advanced at the time of diagnosis, with Stage I (n = 6), Stage III (n = 7), andStage IV (n = 25) tumors. Most patients (25/36, or 69.4percent) had metastatic disease at the time of diagno-sis.

The distribution of treatments is shown in Table 2.Because the group of patients was quite heteroge-neous, individuals received different treatments for a variety of factors. Six were treated with surgery alone.Fifteen patients were treated with surgery and che-motherapy, and six patients were treated with surgery and combination chemotherapy/radiation therapy.Five patients were treated with chemotherapy alone(cisplatin, etoposide/VP-16, 5-FU/LV) and two with

Figure 1. A. Morphology of small cell carcinoma. The tu-mor cells have minimal cytoplasm, fusiform nuclei withgranular chromatin, and no nucleoli. Abundant necrosis isevidence of the high-grade nature of the tumor. B. Immu-nohistochemical staining of a small cell carcinoma for syn-aptophysin shows diffuse strong positivity. Not all cases of

small cell carcinoma stained positively for synaptophysinor chromogranin, but demonstration of neuroendocrinedifferentiation by immunohistochemistry is not required forthe diagnosis of small cell carcinoma.

Figure 2. A. Morphology of large cell neuroendocrinecarcinoma. The tumor cells are arranged in nests. Thereis more abundant cytoplasm, the nuclei are largeand round, and nucleoli are evident. A high mitoticrate reflects the high-grade nature of this tumor. B. Im-munohistochemical staining of a large cell neuro-

endocrine carcinoma for chromogranin shows diffusepositivity, confirming the neuroendocrine differentiation ofthe tumor.

165NEUROENDOCRINE COLORECTAL CARCINOMAS Vol. 47, No. 2



radiation therapy alone. One patient with a Stage IV large cell neuroendocrine carcinoma of the rectumreceived palliative radiation therapy alone for sacralbone metastases. Another patient received intraopera-tive radiation therapy (IORT) at the time of posteriorexenteration for a recurrent small cell carcinoma of the rectum, following a previous abdominoperinealresection. One patient who received no treatmentpresented to the hospital with metastatic small cellcarcinoma with liver metastases and ascites. This in-dividual had rapid progression of disease and expiredin the hospital three days after admission for pallia-tion.

Survival analyses were based on the 36 patients

with completed follow-up data. Median follow-uptime was 9.4 months (range, 0.6 – 263.7). As a groupthese tumors had a poor prognosis, with an overallmedian survival of 10.5 months (95 percent confi-dence interval (CI), 6.7 – 18.9). Overall survival is illus-trated in Figure 3. Overall disease-specific mediansurvival was 16 months (95 percent CI, 8.5 – 21.7).Overall survival by pathologic classification is illus-trated in Figure 4. There was no significant differencebetween the overall survival curve of small cell carci-noma and that of large cell neuroendocrine carci-noma ( P = 0.9 by log-rank test) (Fig. 4). Overall survival rates and 95 percent CI for one-year, two-year,and three-year survival was 46 percent (95 percent CI,29 percent – 63 percent), 26 percent (95 percent CI, 10percent – 41 percent), and 13 percent (95 percent CI, 0percent – 26 percent), respectively.

DISCUSSION

Neuroendocrine carcinomas of the colon and rec-tum are rare tumors. The reported incidence of thistumor represents between 0.1 percent and 3.9 percentof all colorectal malignancies. 1 – 4,8 – 11 In this study,neuroendocrine carcinomas comprise less than 1 per-cent of colorectal malignancies that have been treatedat MSKCC. In fact, these tumors may be less common,as our data represent a single tertiary hospital expe-rience and are subject to selection and referral bias.Despite the fact that they are extremely rare, it is im-

portant to recognize neuroendocrine carcinomas of the colon and rectum pathologically, because they have been shown to carry a particularly poor prog-nosis, and patients may benefit from treatment withalternative cytotoxic chemotherapeutic agents. 12,13

Many of the terms used to describe neuroendocrinecarcinomas of the colon parallel the classification of pulmonary neuroendocrine carcinomas, a schemethat has demonstrated reproducibility among patholo-gists. 14,15 Two major types of pulmonary neuroendo-crine carcinomas, small cell carcinoma and large cellneuroendocrine carcinoma, appear to be well recog-nized on the basis of cytologic appearance of the tu-mor and the pattern of immunohistochemical stainingfor neuroendocrine markers. Small cell carcinomasare defined strictly morphologically, without the ne-cessity of demonstrating neuroendocrine differentia-tion by other techniques. Large cell neuroendocrinecarcinomas are defined by both neuroendocrine mor-phology and immunohistochemical positivity for neu-roendocrine markers.

Table 1.Distribution of Demographic and Clinicopathologic

Characteristics

Factor Mean Range

Age (years) 57 29–86Male 61.6 29–86Female 53.8 39–73

N %

GenderMale 17 44.7Female 21 55.3

LocationColon 17 44.73Rectum 14 36.84Anal canal 6 15.8Appendix 1 2.63

PathologySmall cell carcinoma 22 57.9Large cell neuroendocrine

carcinoma16 42.1

Tumor stage

Stage I 6 15.8Stage II 0 0Stage III 7 18.4Stage IV 25 65.8

Table 2.Distribution of Treatment

Treatment N %

Surgery only 6 15.8Surgery + CT 15 39.5Surgery + RT 1 2.6Surgery + CT + RT 6 15.8Surgery + CT + IORT 1 2.6CT only 5 13.2RT only 2 5.3CT + RT 1 2.6No treatment 1 2.6

CT = chemotherapy; IORT = intraoperative radiationtherapy; RT = radiation therapy.




Tumors with similar morphology to both small celland large cell pulmonary neuroendocrine carcinomasare recognized in the gastrointestinal tract. Terms thathave been used in the literature for neuroendocrinecarcinomas of the large bowel include “small cell car-cinoma, ” “oat cell” or “intermediate cell ” variants, and“not otherwise specified, ”2,3,9,15 – 20 “ well-differen-tiated neuroendocrine cancer ”3 and “moderately dif-ferentiated neuroendocrine carcinoma. ”2 The lattertwo groups imply carcinomas that have organoid,nesting, trabecular, rosette-like, and palisading pat-terns suggesting endocrine differentiation, which canbe confirmed by immunohistochemical analysis. Incontrast to small cell carcinomas, however, these tu-

mor cells are characterized by more abundant cyto-plasm, more vesicular nuclei, and more prominentnucleoli. In this study, we used the term “large cellneuroendocrine carcinoma, ” as proposed by the World Health Organization (WHO) classification of pulmonary tumors, for those neuroendocrine carcino-mas that are not of small cell type.

With selection criteria thus defined, most of ourpatients were at an advanced stage with metastaticdisease. As a result, overall median survival in thisstudy was only 10.4 months (range, 0 – 263.7). Thesefindings are in keeping with other studies in the lit-erature, which demonstrate that neuroendocrine car-cinomas behave aggressively and are associated with

Figure 3. Overall survival ofneuroendocrine carcinomasof the colon and rectum.

Figure 4. Overall survival bypathologic classification.




a worse prognosis than that of conventional adeno-carcinomas of the same stage. 1 – 4,15 – 17 For patients with extrapulmonary small cell carcinomas, includingsmall cell carcinoma of the colon and rectum, it isestimated that 80 percent have distant metastases atthe time of diagnosis. 18 In a review by Hung, 19 80percent of patients had liver and lymph node involve-ment at the time of diagnosis. In our study, 65 percent(25/36) of patients had distant metastatic disease atthe time of diagnosis.

Most of the neuroendocrine carcinomas in ourstudy were distributed in the rectum and cecum. Thisis consistent with other reports in the literature de-scribing a predominance of rectal and cecal lesions 3,19

and is similar to the tumor distribution of primary colorectal adenocarcinomas.

Several chemotherapeutic regimens have beenused to treat small cell lung cancer and have demon-

strated objective responses in terms of tumor regres-sion and improved median survival. It has been rec-ommended that extrapulmonary neuroendocrinecarcinomas, and particularly small cell carcinomas of the colon and rectum, be treated with cytotoxic che-motherapeutic regimens similar to those used forsmall cell carcinoma of the lung. 5,20 Cisplatin and eto-poside are the chemotherapeutic agents of choice forsmall cell lung cancer. In a small series evaluating thetreatment of metastatic anaplastic neuroendocrinecarcinomas of the colon and rectum, the combinationof cisplatin and etoposide was associated with a 67

percent response rate and a median survival of 19months. 5 However, validation of this chemotherapy regimen for the treatment of colorectal neuroendo-crine carcinomas has yet to be achieved. Median survival for patients with neuroendocrine carcinomas of the colon and rectum in the literature is between 5and 11 months. 2 – 4 Reported one-year survival ratesare between 10 percent and 15 percent. 8,19

Because of the small sample size and inconsistency of treatment in our series, we were unable to makeany definitive conclusions about the results of com-bined modality treatment for this heterogeneousgroup of patients. However, 77 percent (28/36) weretreated with chemotherapeutic regimens that in-cluded cyclophosphamide, cisplatin, etoposide (VP-16), doxorubicin and vincristine. These chemothera-peutic agents have been used to treat small cellcarcinomas of the lung and have generally not beenused to treat colorectal carcinoma. Although we areunable to generate a strict recommendation regardingthe optimal choice of chemotherapeutic regimen from

our review, we continue to recommend cisplatin andetoposide for stage III and IV tumors on the basis of objective responses demonstrated in our patients. Tofully assess the efficacy of alternative chemotherapies,however, it is critical to establish reproducible criteriafor classification to allow comparison of patients fromdifferent centers.

SUMMARY

Neuroendocrine carcinomas of the colon and rec-tum are uncommon, comprising less than 1 percent of colon and rectal cancers. Pathologically, these tumorsare poorly differentiated carcinomas that show fea-tures of neuroendocrine differentiation by light mi-croscopy, and they may stain with immunohisto-chemical reagents. The prognosis for neuroendocrinetumors is poor, because most patients have metastaticdisease at the time of diagnosis. The role of adjuvantchemotherapy requires further evaluation so that wemight better understand the overall treatment effectfor patients with neuroendocrine carcinomas of thecolon and rectum.

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