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Colonic large cell neuroendocrine carcinoma obscured by an initial diagnosis of diverticulitis.

INTRODUCTION

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.

CASE PRESENTATION

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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PATHOLOGY

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.

DISCUSSION

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.

REFERENCES

(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
Geographic Code:1USA
Date:Jul 1, 2011
Words:1996
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