Colonic large cell neuroendocrine carcinoma obscured by an initial diagnosis of diverticulitis.
The largest population of neuroendocrine cells in the human body is in the gastrointestinal tract. However, neuroendocrine tumors of the colon and rectum are rare. (1) Neuroendocrine tumors in the gastrointestinal system are frequently carcinoid tumors; however, there is a subset of neuroendocrine tumors called large cell neuroendocrine carcinomas that have a different biological behavior from carcinoid tumors. These carcinomas are aggressive and have a poor prognosis. Large cell neuroendocrine tumors have been well described in the lung but are extremely rare in the colon and rectum. Most patients have metastatic disease at presentation. Treatment options are limited thus early diagnosis is critical. We present a single case at our institution and review the literature for a better understanding of this disease.
An 87-year-old-man presented to his primary care physician, with complaints of nausea, left lower quadrant pain and soft stools for three weeks. He was diagnosed with diverticulitis and treated with oral antibiotics, however, his symptoms persisted. Consequently, he presented to the emergency room (ER) at Tulane University Medical Center one week later with complaints of 12 hours of intermittent rigors and chills. Physical examination at this time revealed a soft, non-distended but tender abdomen in the lower quadrants bilaterally (left > right). No rebound or guarding was noted. His laboratory analysis showed leukopenia, with a white blood cell count of 2.2 K/mL, and anemia with a hemoglobin level of 10.8 gm/dL (MCV 91.5 FL). A computed tomography (CT) scan of the abdomen and pelvis was performed which showed inflammatory changes at the junction of the descending and sigmoid colon with bilateral inguinal and periaortic adenopathy (Figure 1). Intravenous antibiotics and hydration were administered with resolution of his abdominal tenderness. He was subsequently discharged five days after admission, on oral antibiotics, tolerating a regular diet. Approximately two weeks after hospital discharge, the patient returned to the clinic reporting recurrence of his abdominal pain, nausea and vomiting, with a 10-pound weight loss over the same period. His laboratory analysis at this time revealed a white blood cell count of 6.8 K/mL and a carcinoembryonic antigen (CEA) level of 156 ng/mL. After bowel preparation, he was taken to the operating room for exploration. Intraoperatively, there was a large mass in the sigmoid colon, attached to the pelvic wall with mesenteric lymphadenopathy. A left hemicolectomy was performed with primary anastomosis. The patient's postoperative course was uneventful and he was discharged home on postoperative day 10. After the pathologic diagnosis was confirmed, he was treated with oral capecitabine, however, the regimen was not completed due to intractable nausea and vomiting. Three months after resection a repeat CT scan of the abdomen and pelvis was performed which showed hypodense lesions in bilateral hepatic lobes, a right sacral lesion and retroperitoneal, mesenteric and inguinal lymphadenopathy, consistent with metastatic disease. The patient clinically deteriorated and subsequently died of his disease.
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Gross inspection showed an annular 5 cm tumor mass with an ulcerated surface infiltrating through the pericolonic adipose tissue to the serosal surface, Stage 3C (T3, N2, Mx). Microscopic examination demonstrated a poorly differentiated adenocarcinoma with a large cell neuroendocrine component and focal mucinous differentiation. The neuroendocrine areas had an organoid appearance and were composed of cells larger than small cell carcinoma with marked nuclear pleomorphism and frequent mitotic activity (Figures 2 and 3). The nuclei were large and hyperchromatic with prominent nucleoli. Extensive lymphovascular invasion was identified. Twenty-four lymph nodes were positive for metastatic carcinoma. Immunostaining was positive for synaptophysin and CK20 and focally positive for CD117 (Figure 4). Immunostaining was negative for chromogranin and CD57.
In 1991 Travis et al (2) identified a subset of pulmonary neuroendocrine tumors called, large cell neuroendocrine carcinomas (LCNECs). The pathologic features of this tumor have been described as large cells with abundant cytoplasm arranged in organoid, nested, trabecular, rosette-like or palisading patterns, low nuclear-cytoplasm ratio, a mitotic index greater than 10/10 per high power fields or a mitotic rate higher than 11 mitotic figures/2 [mm.sup.2] and the expression of a least one neuroendocrine marker. (2-4) In 2000, LCNEC was included in the World Health Organization classification of endocrine tumors in the colon and rectum, based on the work by Travis et al. (2,5) LCNECs of the colon are rare, representing <1% of all colorectal malignancies. (6) Prior to its identification as a separate disease entity, LCNEC was grouped with small cell neuroendocrine carcinoma. A review of the English language literature using the search term LCNEC revealed only 37 cases of LCNEC, most of which were single case reports with the largest case series of 16 patients reported by Bernick et al (7) (Table). Among the cases presented in the literature, the mean age of presentation was 55 years (range, 38-69 years), with an equal gender distribution. The most common presentation of this disease is abdominal pain. In our case, the patient was 87 years old, the oldest patient in the literature with signs and symptoms mimicking acute diverticulitis. Review of the literature also revealed the following anatomic distribution of LCNEC: ascending colon (30 %), rectum (30%), sigmoid (20%), transverse (10 %), and descending colon (10%). These carcinomas appear to be more aggressive than colorectal adenocarcinomas, with most patients presenting with metastatic disease. In the series published by Bernick et al, the median survival of patients diagnosed with LCNEC was only 10.7 months. (7)
Interestingly, pathologic examination of our tumor showed a large cell neuroendocrine carcinoma embedded in poorly differentiated adenocarcinoma. Rarely have large cell neuroendocrine carcinomas been found in association with colon adenocarcinoma. Kato and associates presented a case of CK-20 positive large cell neuroendocrine carcinoma suggesting a link between colonic adenocarcinoma and large cell neuroendocrine carcinomas as CK-20 is normally associated with colonic adenocarcinoma. (4) Park et al (6) presented a case report of a synchronous large cell neuroendocrine carcinoma in the transverse colon and a well-differentiated adenocarcinoma in the cecum.
The rarity of these tumors not only presents a diagnostic challenge but also therapeutic difficulties. There is no consensus on the treatment regimen for LCNEC. Adjuvant chemotherapy based on cisplatin, carboplatin, or cyclophosphamide has been shown to improve survival of patients with early stage LCNEC in the lung. (8) Currently, some authors recommend that extrapulmonary neuroendocrine carcinomas be treated similarly to their pulmonary counterparts; (7) however, our literature review details a variety of regimens which have been used without a clear benefit on survival (Table).
This case report adds to the sparse literature that exists about large cell neuroendocrine carcinoma in the colon and rectum. This article represents the first review in the English literature that has compiled data about patients' demographics, presenting symptoms and treatment exclusively on LCNEC. Early recognition and surgical resection of these tumors remains the mainstay of treatment. However, further research is needed as to the best adjuvant regimens for treating this disease and improving survival.
(1.) Ni SJ, Sheng WQ, Du X. Pathologic research update of colorectal neuroendocrine tumors. World J Gastroenterol 2010; 16:1713-1719.
(2.) Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. Am J Surg Pathol 1991;15:529-553.
(3.) Gravante G, Markiewicz D, Madeddu F, et al. Colonic large-cell neuroendocrine tumors. Can J Surg 2009;52:49-51.
(4.) Kato T, Terashima T, Tomida S, et al. Cytokeratin 20-positive large cell neuroendocrine carcinoma of the colon. Pathol Int 2005; 55:524-529.
(5.) Scolia E, Sobin LH, Arnold R. Endocrine tumors of the colon and rectum. In: Halmilton SR, Aaltonen LA, (editors). Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumors. Lyon: IARC Press; 2000:137-139.
(6.) Park JS, Kim L, Kim CH, et al. Synchronous large-cell neuroendocrine carcinoma and adenocarcinoma of the colon. Gut Liver 2010;4:122-125.
(7.) Bernick PE, Klimstra DS, Shia J, et al. Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum 2004;47:163-169.
(8.) Iyoda A, Hiroshima K, Toyozaki T, et al. Adjuvant chemotherapy for large cell carcinoma with neuroendocrine features. Cancer 2001;92:1108-1112.
(9.) Nojima H, Seike K, Kosugi C, et al. Advanced moderately differentiated neuroendocrine carcinoma of the rectum with favorable prognosis by postoperative chemoradiation. World J Surg Oncology 2010;8:29-32.
(10.) Lai CC, Wang CW, Changchien CR, et al. Neuroendocrine carcinomas of the colon and rectum: result of a 15 year experience. J Soc Colon Rectal Surgeon (Taiwan) 2008;19:87-95.
Lya Crichlow, MD; Paul Ikemire, MD; Monica Goswami, MD; and Charles F. Bellows, III, MD, FACS
Dr. Crichlow is a minimally invasive surgery fellow in the Department of Surgery at Tulane University Medical Center, New Orleans. Dr. Ikemire is in the Department of Surgery at Tulane University Medical Center, New Orleans. Dr. Goswami is an assistant professor in the Department of Pathology and Laboratory Medicine at Tulane University Medical Center, New Orleans. Dr. Bellows is an associate professor of surgery and chief of general and minimally invasive surgery and director of surgical research at Tulane University Medical Center, New Orleans.
Table. Studies of large cell neuroendocrine carcinomas in the colon and rectum. Study N Age Sex Presenting symptoms Bernick 16 Unknown Unknown Unknown et al (7) Kato et al (4) 1 69 Female Abdominal discomfort Lai et al (10) 6 38 Female Unknown 41 Male Unknown 44 Female Unknown 55 Male Unknown 64 Male Unknown 65 Male Unknown Gravante 1 51 Female Abdominal et al (3) pain, weight loss, black stools Park et al (6) 1 61 Male Abdominal discomfort Nojima et 1 58 Female Rectal al (9) bleeding Current 1 87 Male Abdominal study 2011 pain, fever, weight loss Study Sex Preoperative Tumor location biopsy Bernick Unknown Unknown Unknown et al (7) Kato et al (4) Female None Right colon with invasion into the duodenum and pancreas Lai et al (10) Female Unknown Rectum Male Unknown Sigmoid Female Unknown Ascending colon Male Unknown Descending colon Male Unknown Sigmoid Male Unknown Rectum Gravante Female None Cecum et al (3) Park et al (6) Male Yes Transverse colon: Large cell neuroendocrine tumor Cecum: well differentiated adenocarcinoma Nojima et Female Yes Rectum al (9) Current Male None Sigmoid colon study 2011 Study Sex Procedure Metastatic disease at presentation Bernick Unknown Unknown Unknown et al (7) Kato et al (4) Female Right hemicolectomy Liver and gastrojejunostomy Lai et al (10) Female Colostomy, biopsy Carcinomatosis Male High anterior None resection Female Right hemicolectomy, Liver hepatectomy Male Left hemicolectomy None Male High anterior None resection Male High anterior Liver resection Gravante Female None Liver et al (3) Park et al (6) Male Right hemicolectomy Small bowel Nojima et Female Abdominoperineal None al (9) resection Current Male Left hemicolectomy None study 2011 Study Sex Positive Chemotherapy lymph nodes Bernick Unknown Unknown Unknown et al (7) Kato et al (4) Female Unknown Irinotecan, 5-FU, levofolinate Lai et al (10) Female Unknown None Male Unknown 5-FU, LV Female Unknown Folfox Male Unknown CDDP, VP-16 Male Unknown None Male Unknown Folfori Gravante Female Unknown Unknown et al (3) Park et al (6) Male 7/20 Folfox Nojima et Female 9/11 Doxifluridine al (9) Current Male 24/24 Capecitabine study 2011 Study Sex Radiation Survival Bernick Unknown Unknown 10.7 month median et al (7) survival Kato et al (4) Female None D; 7 months Lai et al (10) Female None D; 2 months Male None D; 7 months Female None D; 7 months Male None D; 26 months Male None A; 14 months, NED Male None D; 3 months Gravante Female Unknown D; 3 weeks et al (3) Park et al (6) Male None A at 6 months; NED Nojima et Female Yes A; 5 years NED al (9) Current Male None D; 3 months study 2011 Superscript numbers in the left most column refer to references listed at the end of the article. A= Alive; D = Deceased; NED = No evidence of disease.
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|Author:||Crichlow, Lya; Ikemire, Paul; Goswami, Monica; Bellows, Charles F., III|
|Publication:||The Journal of the Louisiana State Medical Society|
|Article Type:||Case study|
|Date:||Jul 1, 2011|
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