Case of the Month: Gastrointestinal and Liver Pathology

 

History

A 35-year-old male, with a past medical history only significant for hypertension and a family history significant for inflammatory bowel disease (IBD) and colon cancer in a maternal grandmother, presented to the emergency
department with complaints of chest pain, shortness-of-breath and unintentional 30-pound weight loss for three months. The patient's blood carcinoembryonic antigen level was normal. A workup identified a 7.6 x 2.6 cm anterior mediastinal mass with associated lymphadenopathy, as can be seen on the patient's chest computerized tomography (CT) scan (Figure 1).

Figure 1: A CT scan showing a 7.6 x 2.6 cm anterior mediastinal mass

Flexible bronchoscopy did not reveal any endobronchial lesions. The patient underwent a robotically-assisted thymectomy, via a left thoracoscopic approach by cardiothoracic surgery. The mediastinal mass was noted to involve the thymus under thoracoscopy and was partially resected, due to extension into the right thorax and the need for a diagnosis prior to a more invasive approach. Histologically, the tumor was composed of malignant glands with marked pleomorphism. Some tumor cells form nests in a lacunar space (Figures 2a and b).

Figure 2a: Histologic features of the mediastinal mass (A. H&E stain, 100X) with arterial invasion (B. H&E stain, 400X)

Figure 2b: Arterial invasion is identified.

Additionally, more than five positive lymph nodes demonstrated extranodal extension with prominent lymphovascular invasion. No residual thymic tissue was identified. The adenocarcinoma of the anterior mediastinum was diffusely positive for CDX2, CK20, and ß-catenin (nuclear staining pattern) in addition to CK7 positivity. The tumor was negative for TTF-1, PAX8, cKIT, SALL4, markers for lung adenocarcinoma, thyroid carcinoma, thymic carcinoma and germ cell tumor. This might represent a rare primary thymic adenocarcinoma arising within a thymic cyst or a metastatic lesion, given this clinical presentation and the young age of the patient.

Next-generation sequencing was performed and revealed that the adenocarcinoma in the anterior mediastinum harbored mutations in KRAS (c.38G>A), SMAD4 (c.1081C>T), and MET (c.2962C>T).  However, a consensus was achieved that this was probably a metastatic lesion, likely colonic in origin, given the aberrant nuclear expression of ß-catenin frequently seen in colonic adenocarcinomas. 

A search for a potential occult primary malignancy was conducted with a positron emission tomography scan (PET/CT) along with an upper and lower endoscopy. The PET scan revealed a residual fluorodeoxyglucose (FDG) avid lesions in the anterior mediastinum (SUV max 1.56) and a lesion in the right colon near the hepatic flexure (SUV max 2.09). Endoscopy also identified a small, non-bleeding, ulcerated lesion in the duodenum, as well as a large, non-obstructing ascending colon mass. Biopsies confirmed the presence of lymphovascular carcinoma emboli in the colonic mucosa (Figure 3) and duodenal mucosa (Figure 4).

Figures 3a: Histologic features of the colonic biopsy (A. H&E stain, 100X; B. H&E stain, 200X

Figure 3b:

Figure 4a: Histologic features of the duodenal biopsy (A. H&E stain, 100X; B. H&E stain, 200X)

Figure 4b:

No precursor lesions were identified in the colonic or duodenal biopsies. The carcinoma has morphology similar to the poorly differentiated adenocarcinoma in the thymectomy specimen. 

This case was presented at a multidisciplinary tumor board. A consensus of colonic primary is favored because of the presence of a large, non-obstructing ascending colon mass. A resection of the primary colonic malignancy, followed by systemic chemotherapy, is recommended because of the young age of the patient. The patient underwent an uncomplicated laparoscopic right hemicolectomy. A granular, firm, beige-tan mucosal 2.8 cm x 2.5 cm mass is noted in the ascending colon (Figures 5a and b).

Figure 5a: Macroscopic examination of the right hemicolectomy

Figure 5b:

The mucosa adjacent to the mass is granular, roughened, and diffusely hyperemic. Histology of the right  hemicolectomy reveals a poorly differentiated carcinoma consisting of micropapillary (75 percent), mucinous (5 percent), signet ring cell (5 percent), and conventional colonic adenocarcinoma (15 percent) arising from tubular adenoma with high-grade dysplasia (Figures 6a - 6d).

Figures 6a - 6h: Histologic features and immunophenotype of colonic micropapillary carcinoma.

Figures 6a and 6b: Micropapillary carcinoma arising from tubulovillous adenoma (A, H&E stain, 20X) with high-grade dysplasia (B, H&E stain, 40X).

Figure 6a:

Figure 6b:

Figure 6c: Micropapillary features of the invasive carcinoma without central fibrovascular core (C, H&E stain, 200X)

Figure 6d: Extensive lymphovascular invasion (D, H&E stain, 40X)

The tumor cells are positive for CK20, CDX2, CK7, ß-catenin (nuclear and cytoplasmic staining) (Figures 6e - 6g).

Figures 6e - 6g: The tumor cells show strong immunoreactivity of CK20, CDX2, ß-catenin staining (with a nuclear and cytoplasmic pattern), and CD10 (with a periphery pattern) (Immunostain, 40X, 40X, 400X, and 400X, respectively).

Figure 6e:

Figure 6f:

Figure 6g:

Immunohistochemical staining revealed a strong CD10 immunoreactivity at the periphery of the tumor nests (Figure 6h).

Figure 6h: CD10 immunoreactivity at the periphery of the tumor nests

A final pathology of the colonic specimen revealed an invasive, poorly differentiated adenocarcinoma, arising from a tubular adenoma with high-grade dysplasia and 13 of 28 lymph nodes positive for metastatic adenocarcinoma with a final pathologic stage of pT4apN2bpM1. Genetic testing by next-generation sequencing showed mutation of KRAS (c.38G>A), SMAD4 (c.1081C>T), and MET (c.2962C>T), identical to the adenocarcinoma in the anterior mediastinum. The colonic adenocarcinoma was microsatellite stable (MSS) on microsatellite instability testing. The comparison of the adenocarcinoma of the colon and the tumor in the anterior mediastinum is summarized in Tables 1 and 2. Tables 1 and 2.  

Table 1: Morphology and immunophenotype of the |adenocarcinoma
of the colon and tumor in the anterior mediastinum
Features Colonic adenocarcinoma Anterior mediastinal adenocarcinoma
Morphology
Precursor lesion Yes No
Differentiation Poor Poor
Micropapillary feature Present Present
Lymphovascular invasion Extensive Extensive
Lymph node metastasis Present Present
Immunophenotype
CDX2 Diffuse and strong immunoreactivity Diffuse and strong immunoreactivity
CK20 Diffuse and strong immunoreactivity Diffuse and strong immunoreactivity
CK7 Positive Positive
β-catenin Cytoplasmic and nuclear staining Cytoplasmic and nuclear staining
TTF-1 N/A Negative
PAX 8 N/A Negative
cKIT N/A Negative
SALL4 N/A Negative
Microsatellite status
Microsatellite stable Yes Yes


Table 2: Genetic mutational analysis by next generation sequencing in the adenocarcinoma of the colon and the tumor in the anterior mediastinum 
Gene analyzed Colonic adenocarcinoma Anterior mediastinal adenocarcinoma
ABL1    
AKT1    
ALK    
BRAF    
CTNNB1    
EGFR    
ERBB2/HER2
EZH2    
FBXW7    
FGFR1    
FGFR2    
FLT3    
GNA11    
GNAQ
HRAS    
IDH1
IDH2    
JAK2    
KIT    
KRAS    
MET    
MPL    
NOTCH1
NPM1    
NRAS    
PDGFRA    
PIK3CA    
PTEN    
PTPN11    
RET    
SMAD4    
SMO    
TP53    
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
c.38G>A p.G13D
c.2962C>T p.R988C
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
c.1081C>T p.R361C
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
c.38G>A p.G13D
c.2962C>T p.R988C
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
NMD
c.1081C>T p.R361C
NMD
NMD

The patient was seen to be doing well at his four-month follow-up. Given the final pathologic and genetic test results, the patient is going to continue on palliative chemotherapy with FOLFOX-bevacizumab.



Diagnosis

(Hover the cursor over the link above to read the diagnosis for this case.)
 


 

Discussion

Extrahepatic colorectal metastasis most commonly involves the lungs, lymph nodes and peritoneum, and it represents a significant surgical and oncologic challenge. This case is unique in that it involves colonic cancer metastasis to the thymus gland--a rare site of metastasis for any malignancy although, cases of metastatic breast, thyroid, testicular and prostate cancer have been documented. Although the histologic architecture of the thymus has been theorized to play a large role in its immunity from metastatic disease, the blood vessels, lymphatics and nerves making up the capsule and interlobular septum of the thymus gland do, in theory, provide a potential route for seeding of tumor cells.1 In the context of all clinicopathological and molecular information, the final diagnosis of this case was colonic micropapillary carcinoma with extensive lymphatic permeation in the colon and metastases via thoracic duct to anterior mediastinum including the thymus.

Micropapillary carcinoma is an aggressive variant of colonic adenocarcinoma.2 It may show extensive lymph node metastasis, even when the tumor only invades the submucosa.3 This tumor has been recognized as a subtype with a high incidence of lymphovascular invasion and nodal metastases and adverse clinical outcome.4,5 One study reported micropapillary component was present in 10 percent of all colonic carcinomas with a median age of 56 years, and all of them were of American Joint Committee on Cancer Stages III and IV. Sixty percent of those had more than four positive lymph nodes and had a worse three-year survival.4 The aggressiveness of this tumor is also supported by one juvenile case of pulmonary lymphangitic carcinomatosis, caused by sigmoid colon cancer with a component of micropapillary carcinoma.            6 Histologically, micropapillary carcinoma is characterized by micropapillae formation by the neoplastic cells with reversed polarity in the absence of central fibrovascular core.7 The tumor nests are usually detached from the desmoplastic stroma with a lacunar-like spaces, which were negative for CD31.7 The reversed polarity is best demonstrated by immunohistochemical stain for villin and CD10 with immunoreactivity of these two proteins facing the stroma or lacunar-like spaces.7

The tumorigenesis of micropapillary carcinoma is not yet complete. Our case was microsatellite stable and had ß-catenin-nuclear translocation, in line with the observation that micropapillary carcinoma develops through the classical chromosomal instability pathway, as it tends to have a higher frequency of p53 alterations and a low incidence of microsatellite instability.5 Our case showed KRAS mutation, which is consistent with one previous report that 45 percent of micropapillary carcinomas harbor KRAS mutation.5 Our case is also unique in that it harbors mutation of SMAD4, a gene that is involved in the tumorigenesis of pancreatic adenocarcinoma, in addition to KRAS mutation. Although one study reported the basal surface of the neoplastic cell clusters in micropapillary carcinoma was diffusely positive for MUC1, a protein that has been implicated in pancreatic adenocarcinoma and may be the underlying mechanism for reversed polarity in micropapillary carcinoma.8,9 The exact role of SMAD4 mutation and MUC1 expression in the tumorigenesis of colonic micropapillary carcinoma needs further exploration.   

References

  1. Mushtaque M, Naqash SH, Malik AA, Malik RA, Kanday SA, Khan PS. Papillary carcinoma thyroid with metastasis to ectopic cervical thymus. World Journal of Surgical Oncology 2011; 9:22.
  2. Takahashi S, Kuroiwa G, Hirayama M, Tobioka H. [Advanced poorly differentiated adenocarcinoma of the colon with micropapillary carcinoma components except specific cytokeratin expressions, report of a case]. Nihon Shokakibyo Gakkai Zasshi. 2011 Dec;108(12):2016-22.
  3. Mukai S, Takakura Y, Egi H, Hinoi T, Saito Y, Tanimine N, Miguchi M, Adachi T, Shimomura M, Ohdan H. Submucosal invasive micropapillary carcinoma of the colon with massive lymph node metastases: a case report. Case Rep Oncol. 2012 Sep;5(3):608-15.
  4. Lino-Silva LS, Salcedo-Hernández RA, Caro-Sánchez CH. Colonic micropapillary carcinoma, a recently recognized subtype associated withhistological adverse factors: clinicopathological analysis of 15 cases. Colorectal Dis. 2012 Sep;14(9):e567-72.
  5. Verdú M, Román R, Calvo M, Rodón N, García B, González M, Vidal A, Puig X. Clinicopathological and molecular characterization of colorectal micropapillary carcinoma. Mod Pathol. 2011 May;24(5):729-38.
  6. Otsubo K, Kubo N, Nakashima N, Izumi M, Nakamori M, Koto H. A juvenile case of pulmonary lymphangitic carcinomatosis caused by sigmoid colon cancer with a component of micropapillary carcinoma. Nihon Shokakibyo Gakkai Zasshi. 2011 Dec;108(12):2016-22.
  7. Wen P, Xu Y, Frankel WL, Shen R. Invasive micropapillary carcinoma of the sigmoid colon: distinct morphology and aggressive behavior. Int J Clin Exp Pathol. 2008 Jan 1;1(5):457-60.
  8. Doi H, Konishi K, Omori R, Yanagawa T, Katagiri A, Yamochi T, Date Y, Kubota Y, Muramoto T, Yano Y, Kobayashi Y, Tojo M, Konda K, Murakami M, Yoshikawa N, Imawari M. Primary micropapillary carcinoma of the colon: a case report and literature review. Int Surg. 2011 Jan-Mar;96(1):82-6.
  9. Sakamoto K, Watanabe M, De La Cruz C, Honda H, Ise H, Mitsui K, Namiki K, Mikami Y, Moriya T, Sasano H. Primary invasive micropapillary carcinoma of the colon. Histopathology. 2005 Nov;47(5):479-84.
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