bs_bs_banner

Pathology International 2015

doi:10.1111/pin.12284

Case Report

Clear cell carcinoid of the appendix: Report of two cases with literature review

Gu Hyum Kang,1 Byung Seok Lee1 and Dae Young Kang2 Departments of 1Internal Medicine and 2Pathology, Chungnam National University College of Medicine, Daejeon, Korea

The clear cell/lipid-rich change has been described in neuroendocine tumors in several organs, but rarely observed in the appendix. In this study, we describe the morphologic, immunohistochemical features of incidentally discovered appendiceal carcinoids entirely represented by clear cells in a 22-year-old man and a 52-year-old woman. Ultrastructual examination demonstrated abundant lipid droplets and dense core granules. The mechanism leading to lipid accumulation in the cytoplasm has not been discovered, but degenerative processes following recurrent inflammatory change might be considered. This uncommon variant of appendiceal classic carcinoid tumors may bear a superficial resemblance to goblet carcinoid and/or appendiceal metastases from clear cell carcinoma. Awareness of clear cell carcinoid of the appendix will prevent incorrect diagnosis and unnecessary aggressive management.

pathologic features of clear cell changes of the appendiceal WDETs have never been documented previously in Asian countries. We have identified two cases of appendiceal WDETs with clear cells at our institution over the past ten years; both patients were treated with appendectomy only without recurrence. The current report describes the clinico-pathologic, immunohistochemical, and ultrastuctural characteristics of two appendiceal carcinoids exclusively composed of clear cells with the literature review.

Key words: appendix, carcinoid, clear cell, neuroendocrine tumor

A 22-year-old man underwent simple appendectomy due to typical signs and symptoms of appendicitis. No evidence of tumor metastasis has been seen in the six month follow up.

Neoplasms of the appendix are rare. They are found in about 1% of appendectomy specimens.1 Well-differentiated neuroendocrine tumors (WDETs), traditionally referred to as carcinoids, are the commonest neoplasms of the appendix, comprising over 50% of appendiceal neoplasms.2 Typical morphologic features of carcinoids include small, uniform cells arranged in round solid nests with sometimes peripheral-cell palisading. Occasionally, there may also be glandular formations, forming a tubular or acinar pattern. The presence of appendiceal WDETs with clear cells have been sporadically reported,3,4 and in previous works by Chetty and Serra,5 La Rosa et al.6 and Rossi et al.7 However, clinicoCorrespondence: Dae Young Kang, MD, PhD, Department of Pathology, College of Medicine, Chungnam National University, 33 Munwha-ro, Jung-gu, Daejeon 301-721, Korea. Email: dykang@ cnu.ac.kr Received 12 September 2014. Accepted for publication 9 February 2015. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

CLINICAL SUMMARY Case 1

Case 2 A 52-year-old woman underwent hysterectomy with both salpingo-oophorectomy due to right ovarian mass observed during health checkup. Post-operation diagnosis was right ovarian mucinous cystadenoma with borderline malignancy and uterine myoma. Appendectomy was also performed during operation. The patient was alive and free of disease after mean follow-up period of 4 years. PATHOLOGICAL FINDINGS Case 1 Gross examination of the specimen showed a swollen appendix with an engorged serosa partly covered with purulent exudate. The size of the tumor was 0.5 cm × 0.4 cm

2

G. H. Kang et al.

a

b

c

Figure 1 Histologic findings of clear cell carcinoid of the appendix in Case 1. (a) Carcinoid tumor of the appendix composed of ‘clear’ or pale cytoplasm (H&E, 1:1). (b) The tumor cell show foamy microvesicular clear cytoplasm (H&E, ×400). (c) The tumor cell show Ki-67 index ≤1%.

measured under 1:1 power (Fig. 1). Microscopically the appendix showed neutrophilic infiltrate of the entire thickness of its wall with extension into the periappendiceal adipose tissue. The nodule corresponded to solid proliferation of monotonous neoplastic cells with abundant foamy microvesicular clear cytoplasm. The tumor infiltrated the whole layer of smooth muscle with vascular invasion, without lymphatic invasion, on the CD34 and D2-40 stains (Fig. 2). The clear cells showed no significant atypia. The mitotic count of the tumor was zero and Ki-67 proliferation index was ≤1 (Fig. 1). The tumor was classified as G1 according to the World Health Organization (WHO) 2010 classification.8 Immunohistochemical studies revealed positive staining of the tumor cells with antibodies against chromogranin A, synaptophysin and CD56. S-100 positive sustentacular cells have also been identified. There was negative reaction with antibodies against CK20 and CEA (Fig. 2). Electron microscopy examination on paraffin blocks demonstrated the presence of numerous small secretory granules of enterochromaffin type and prominent lipid droplets (Fig. 3). Case 2 Grossly, the appendix measured 4 cm in length and showed a thickened nodule of 1.2 cm of maximum diameter in the tip

region. Microscopically the nodule corresponded to a solid proliferation of monotonous neoplastic cells with clear to foamy cytoplasm without appendicitis. The tumor infiltrated the smooth muscle with extension to the mesoappendix. The tumor was classified as NET G1 by Ki-67 proliferation index of the tumor. With immunochemistry, the tumor cells were stained with chromogranin A, synaptophysin and CD 56. S100 was negative in the tumor cells but highlighted the presence of several substentacular cells. CK20 and CK7 were negative in the tumor cells, while positive in the ovarian tumor. DISCUSSION The entity of the clear cell carcinoid, although rare, has been described in digestive endocrine tumors of different sites including the pancreas, stomach, gallbladder, and bile duct.9–13 In addition endocrine tumors of other sites including thyroid, thymus, adrenal medulla, and lung have been noted to contain clear cells.14–17 However, a small component of clear cells was found in conventional appendiceal carcinoids. Furthermore, the carcinoid entirely represented by clear cells describing in this study, which is exceedingly rare, figuring three and five cases, respectively, in the aforementioned papers.5,6

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

Clear cell carcinoid of the appendix

a

b

c

d

e

f

a

b

3

Figure 2 Immunohistochemically, tumor cells are positive for (a) CD34, (b) synaptophysin, (c) Chromogranin A, (d) CD56, and negative for (e) D2-40 and (f) CK20.

Figure 3 The electron microscopic image features a lipid-rich appendiceal endocrine tumor in Case 1. (a) At low magnification, tumor cell show fat droplets and dense neurosecretory granules (EM, ×8000). (b) At higher magnification, secretory granules show characteristics of enterochormaffin-type granule, and lipid droplets are well evident (EM, ×20000).

There are several neoplastic and non-neoplastic lesions entering the differential diagnosis with clear cell carcinoid of the appendix. Goblet cell carcinoid (GCC) and metastatic clear cell carcinoma of the kidney or ovary are the most important diagnostic contenders to be considered. Goblet cell carcinoid is more aggressive than conventional neuroendo-

crine tumors (NETs) of the appendix but less than adenocarcinoma, and right hemicolectomy is a consideration even for the low grade forms. The differential diagnosis of GCC is based on the recognition of the typical goblet cells identifiable in H&E- and AB-PAS-stained sections. Immunohistochemically, GCCs

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

4

G. H. Kang et al.

Table 1 Summary of reported cases of the carcinoid of the appendix exclusively composed of clear cells No. 1 2 3 4 5 6 7

Author 6

La Rosa et al. La Rosa et al.6 La Rosa et al.6 La Rosa et al.6 La Rosa et al.6 Present case Present case

Age(yr)/Sex

Site

Size (mm)

Associated pathology

Follow-up (yr)

25/M 46/M 27/M 36/M NK 22/M 52/F

Tip Body Tip Base Body Tip Tip

5 8 10 5 3 5 NE

Lymphoid hyperplasia NE Acute appendicitis Acute appendicitis Lymphoid hyperplasia Acute appendicitis Right ovarian mucinous cystadenoma

AFD (15) AFD (14) AFD (13) AFD (1) Lost to follow-up AFD (6 month) AFD (4)

AFD, alive, free of disease; NE, not evaluated; NK, not known.

show strong carcinoembryonic antigen (CEA) and cytokeratin (CK) positivity and are inconsistently positive for neuroendocrine markers such as chormogarnin A and synaptophysin.18 GCCs have been reported to show CK20 positivity in 100% of cases and CK7 positivity in 71% of cases, whereas conventional NETs showed CK20 positivity in 16% of cases and CK7 negativity in all cases.19 In addition, differential diagnosis with metastasis from clear cell renal or ovarian carcinoma is based on the more atypical nuclear features of the metastatic tumors. Both of our cases were chromogranin-, synaptophysin-, neural cell adhesion molecule (NCAM/CD56)-positive in this paper. The histological diagnosis of NETs is confirmed by immunohistochemical demonstration of neuroendocrine markers. Negative stains of CEA, CK20 and CK7 favor diagnosis of carcinoid rather than goblet cell carcinoid. Ultrastructual examination demonstrated intracytoplasmic lipid droplet and neurosecretory granules. Clear cell changes in tumor cells may have different explanations. Intracytoplasmic accumulation of glycogen, mucin, or lipid usually accounts for the clear cell appearance. However, not all cases of clear cell carcinoid tumors have demonstrated cytoplasmic lipid. Appendiceal tumors described by Edmonds et al.3 and Burke et al.4 closely correspond to clear cell carcinoid of the appendix from a morphologic view point. However, recent studies5–7 by ultrastructural examination have demonstrated that the lipid nature of the material accumulated in the cytoplasm is responsible for the foamy microvesicular feature. Our ultrastuctual study is in accordance with recent studies. The mechanism leading to lipid accumulation in the cytoplasm still needs to be identified. Considering our carcinoid cases are represented entirely by clear cells from tumors, we postulate that clear cell change could be a degenerative change altering fat metabolism in tumor cells. Although other factors altering fat metabolism need to be investigated, one of these factors could be inflammation. Inflammation might alter lipid metabolism, and lead to abnormal triglyceride accumulation within tumor cells. Although the prognosis of lipid-rich WDET is from limited data due to rare incidence, lipid-rich WDET seems to behave like other classic carcinoid without lipid containing cells and

has an indolent behavior (Table 1). Both of patients were alive and free of disease after a period of 6 months and 4 years, respectively, in this paper. The present study describes lipid accumulation imparting clear cell change to the cytoplasm of appendiceal WDET. Although prognostic features of this tumor appear not different from conventional appendiceal endocrine tumors, it must be differentiated form goblet cell carcinoid or metastases from clear cell adenocarcinoma. Recognition of this neoplasm in this site will prevent incorrect diagnosis and unnecessary aggressive management such as right hemicolectomy.

DISCLOSURE The authors declare no competing interests.

REFERENCES 1 Connor SJ, Hanna GB, Frizelle FA. Appendiceal tumors: Retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies. Dis Colon Rectum 1998; 41: 75–80. 2 In’t Hof KH, van der Wal HC, Kazemier G, Lange JF. Carcinoid tumour of the appendix: An analysis of 1,485 consecutive emergency appendectomies. J Gastrointest Surg 2008; 12: 1436–8. 3 Edmonds P, Merino MJ, LiVolsi VA, Duray PH. Adenocarcinoid (mucinous carcinoid) of the appendix. Gastroenterology 1984; 86: 302–5. 4 Burke AP, Sobin LH, Federspiel BH, Shekitka KM. Appendiceal carcinoids: Correlation of histology and immunohistochemistry. Mod Pathol 1989; 2: 630–7. 5 Chetty R, Serra S. Lipid-rich and clear cell neuroendocrine tumors (‘carcinoids’) of the appendix: Potential confusion with goblet cell carcinoid. Am J Surg Pathol 2010; 34: 401– 4. 6 La Rosa S, Finzi G, Puppa G, Capella C. Lipid-rich variant of appendiceal well-differentiated endocrine tumor (carcinoid). Am J Clin Pathol 2010; 133: 809–14. 7 Rossi G, Nannini N, Bertolini F, Mengoli MC, Fano R, Cavazza A. Clear cell carcinoid of the appendix: An uncommon variant of lipid-rich neuroendocrine tumor with a broad differential diagnosis. Endocr Pathol 2010; 21: 258–62. 8 Bosman FT, Carneiro F, Hruban R, Theise ND. WHO Classification of Tumours of the Digestive System. Lyon:

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

Clear cell carcinoid of the appendix

9

10

11

12

13

International Agency for Research on Cancer, 2010; 126–8. Jiang Y, Liu H, Long H, Yang Y, Liao D, Zhang X. Goblet cell carcinoid of the appendix: A clinicopathological and immunohistochemical study of 26 cases from southwest China. Int J Surg Pathol 2010; 18: 488–92. Alsaad KO, Serra S, Schmitt A, Perren A, Chetty R. Cytokeratins 7 and 20 immunoexpression profile in goblet cell and classical carcinoids of appendix. Endocr Pathol 2007; 18: 16–22. Guarda LA, Silva EG, Ordonez NG, Mackay B, Ibanez ML. Clear cell islet cell tumor. Am J Clin Pathol 1983; 79: 512– 7. Singh R, Basturk O, Klimstra DS et al. Lipid-rich variant of pancreatic endocrine neoplasms. Am J Surg Pathol 2006; 30: 194–200. Ordóñez NG, Mackay B, el-Naggar A, Bannayan GA, Duncan J. Clear cell carcinoid tumour of the stomach. Histopathology 1993; 22: 190–3.

5

14 Konishi E, Nakashima Y, Smyrk TC, Masuda S. Clear cell carcinoid tumor of the gallbladder. A case without von HippelLindau disease. Arch Pathol Lab Med 2003; 127: 745–7. 15 Todoroki T, Sano T, Yamada S et al. Clear cell carcinoid tumor of the distal common bile duct. World J Surg Oncol 2007; 5:6. doi:10.1186/1477-7819-5-6. 16 Landon G, Ordóñez NG. Clear cell variant of medullary carcinoma of the thyroid. Hum Pathol 1985; 16: 844–7. 17 Smith NL, Finley JL. Lipid-rich carcinoid tumor of the thymus gland: Diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 2001; 25: 130–3. 18 Unger PD, Cohen JM, Thung SN, Gordon R, Pertsemlidis D, Dikman SH. Lipid degeneration in a pheochromocytoma histologically mimicking an adrenal cortical tumor. Arch Pathol Lab Med 1990; 114: 892–4. 19 Gaffey MJ, Mills SE, Frierson HF Jr, Askin FB, Maygarden SJ. Pulmonary clear cell carcinoid tumor: Another entity in the differential diagnosis of pulmonary clear cell neoplasia. Am J Surg Pathol 1998; 22: 1020–5.

© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

Clear cell carcinoid of the appendix: Report of two cases with literature review.

The clear cell/lipid-rich change has been described in neuroendocine tumors in several organs, but rarely observed in the appendix. In this study, we ...
1MB Sizes 1 Downloads 11 Views