—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 1 - Gastric Micropapillary Carcinoma

Amitabh Srivastava
Dartmouth Hitchcock Medical Center
Lebanon, NH





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Clinical History
A 65 year old man presented with abdominal pain, anemia and an unintentional 15 lb weight loss over the past six months. Colonoscopy revealed two small polyps but no evidence of malignancy. Upper GI endoscopy showed an ulcer with heaped up margins in the distal stomach. Biopsies from the lesion showed high-grade dysplasia and intramucosal adenocarcinoma. However, endoscopic ultrasound examination was consistent with a T2 lesion and a distal gastrectomy was performed.


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D2-40 immunostain


Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The gastrectomy specimen showed an ulcerated mass with heaped up edges in the distal stomach. The gastric mucosa away from the tumor showed a chronic gastritis with atrophy and intestinal metaplasia. Sections from the mass lesion showed low and high grade dysplasia associated with an invasive adenocarcinoma. The mucosal component of the adenocarcinoma was composed of a conventional tubulo- papillary pattern. The deep invasive component was composed of small tumor cell clusters in lacunar spaces surrounded by a delicate fibrocollagenous stroma. The tumor cells in this latter component showed an inverse polarization with the apical cell surface facing out towards the stroma. An immunostain for D2-40 was performed and showed that the majority of lacunar spaces were not lined by endothelial cells. However, some foci of lymphatic invasion were also present. The tumor infiltrated through the muscularis propria and six lymph nodes were positive for metastatic adenocarcinoma.

Differential Diagnoses:
Conventional tubulo-papillary adenocarcinoma with extensive lymphatic invasion.

Final Diagnosis:
Gastric Micropapillary Carcinoma.

Case Discussion:

Introduction
Gastric cancer is the second most common cause of cancer related mortality worldwide. Several classifications of gastric cancer have been proposed over time but the Lauren and WHO classifications are the ones used most often in clinical practice. Lauren's classification of intestinal and diffuse type is relevant because of varying incidence trends for these two subtypes of gastric cancer, their distinct associations with environmental risk factors and with precursor lesions. The main histological types of gastric cancer recognized in the WHO classification include tubular, papillary, mucinous and signet ring cell carcinoma [1]. Other well recognized but rare subtypes include small cell carcinoma, hepatoid carcinoma, adenosquamous or squamous cell carcinoma, carcinoma with parietal cell, chief cell or Paneth cell differentiation, undifferentiated carcinoma, embryonal carcinoma, choriocarcinoma, and mixed exocrine-endocrine carcinoma. The prognostic value of histologic tumor type remains controversial and tumor stage continues to be the most significant prognostic factor in patients with gastric cancer. However, some histologic types such as hepatoid carcinoma and small cell carcinoma are widely accepted to be associated with a uniformly aggressive behavior and poor prognosis.

Micropapillary carcinoma (MPC) is a distinctive morphological variant that has been described in the breast, urinary bladder, lung, ovary, pancreas, salivary gland, and the colorectum [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. At some sites, such as the ovary and salivary glands, MPC has been reported to be associated with a high incidence of nodal metastases and poor prognosis, while at other sites the prognostic significance remains unclear. MPC involving the stomach has been reported in case reports [17] but two series of gastric MPC have been published recently that describe the features of this rare tumor type in greater detail [18, 19].

Clinical Features
The age and sex distribution of gastric MPC is not significantly different from that of conventional adenocarcinoma. Gastric MPC have so far been reported only from areas endemic for gastric cancer and show the same distal site predilection as conventional adenocarcinoma. Close to 90% of MPC have been reported to be located in the middle or distal third of the stomach. Gastric MPC are rare tumors and the reported prevalence in the two largest series so far has been less than 0.1%.

Morphologic & Immunophenotypic Features
The morphological features of MPC, regardless of tumor site, are quite distinctive. Small clusters of tumor cells without a fibrovascular core lie in clear lacunar spaces lined by a fibrocollagenous stroma. The pattern closely mimics lymphatic invasion but the lacunar spaces are devoid of an endothelial lining and this can be demonstrated easily by immunostains for endothelial markers D2-40 and CD31. Another distinctive feature of the epithelial component in MPC is the phenomenon of reverse polarization of tumor cells. The apical tumor cell surface is not oriented towards a central lumen, as in conventional adenocarcinoma, and is polarized towards the stromal surface instead. This can be demonstrated by PAS-D stain, and by immunostains for EMA/MUC1, which show membranous or cytoplasmic positivity polarized towards the retracted cleft-like space with no staining in the center of the tumor cell cluster [6, 20, 21]. Since MUC1 positivity is seen in only a minor subset of gastric carcinomas, the utility of MUC1 in diagnosis of gastric MPC may be limited. The "inside-out" polarization of tumor cells can also be seen on ultrastructural examination which shows the tumor cell microvilli oriented towards the lacunar space instead of a central lumen. This inverse polarity is thought to confer an ability to MPC tumor cells to detach from the stroma and invade easily into surrounding connective tissue. This may account for the high incidence of lymphatic and nodal invasion seen in this entity.

Gastric MPC occur almost always in association with conventional adenocarcinoma. In the stomach, tubular and papillary adenocarcinomas are the most common phenotype associated with MPC. The proportion of MPC is variable but is seldom more than 30%. Only a few gastric MPC in which the MPC component was greater than 50% have been reported. The MPC component is often present at the deep advancing edge of the tumor while the conventional tubular or papillary adenocarcinoma is preferentially localized to the more superficial aspect. In most cases of MPC, each lacunar space is occupied by a solitary, small tumor cell cluster. The presence of multiple tumor clusters within a single lacuna is more typical of lymphatic tumor emboli and can be confirmed with a D2-40 immunostain. The tumor cells in MPC show low grade cytological atypia and the presence of an undifferentiated tumor cell cluster with high grade nuclear atypia is often a sign of a lymphatic embolus in the setting of conventional adenocarcinoma. The intra-tumoral neutrophilic infiltration reported in ampullary MPC [6] has not been reported in gastric MPC thus far.

Similar to conventional adenocarcinoma, gastric MPC stain positively with MUC5AC and MUC6. However, MUC2 is negative in most MPCs, in contrast to the approximately 40% positivity in conventional gastric adenocarcinoma, suggesting a distinct pathogenetic pathway for gastric MPC. CK7 positivity has been reported in almost 75% of MPC which is similar to the reported prevalence in conventional adenocarcinoma. In contrast, roughly 25% of MPCs stain with CK20 which is significantly lower than 50-70% positivity reported in conventional adenocarcinoma. In the cases reported so far, p53 overexpression in gastric MPC is similar to that observed in conventional adenocarcinoma but the Ki-67 labeling index is significantly lower in MPC. HER2 and EGFR overexpression in gastric MPC is not significantly different from conventional adenocarcinoma [18]. Aberrant beta-catenin staining has been reported in 75% of gastric MPC and may have pathogenetic significance [19].

Prognostic Significance
Gastric MPC is associated with a high incidence of lymphatic invasion and nodal metastasis. In a recent study by Roh et al, 144 gastric carcinomas with foci suspicious for MPC were systematically screened with D2-40 and PAS-D stains to exclude conventional adenocarcinoma with lymphatic invasion and mucin pools, respectively [18]. Eleven of these 144 cases were finally accepted as examples of true MPC and the rest classified as conventional adenocarcinoma with lymphatic invasion. When MPC were compared to the conventional adenocarcinomas with lymphatic invasion, no clinicopathological differences were found and the overall survival for gastric MPC was not significantly different from that of conventional adenocarcinoma. The authors suggested that gastric MPC behave similar to conventional carcinomas and do not carry an adverse prognostic significance. A more recent large series of gastric MPC reported that the survival rate for Stage I-II gastric MPC is significantly worse when compared to Stage I-II conventional adenocarcinoma. This difference in survival was not observed for Stage III-IV tumors [19]. However, the control group in this latter study were 160 "randomly selected" cases of conventional adenocarcinoma and the diagnosis of MPC was made without use of D2-40 immunostains to exclude conventional carcinomas with lymphatic invasion. This may also explain why about 16% of MPC in this study were of the diffuse type according to the Lauren classification and over 30% poorly differentiated. The contradictory findings regarding prognostic relevance reported above clearly indicate the need for a systematic evaluation of the prognostic significance of gastric MPC in future studies.

Conclusion(s): Gastric MPC are rare
tumors that occur in association with conventional tubular and papillary adenocarcinomas. The morphologic hallmark of MPC is the presence of small tumor cell clusters surrounded by a cleft-like space simulating a retraction artifact. The tumor cells show inverse polarity where the apical surface is polarized towards the stromal surface instead of a central lumen. Gastric MPC are associated with a high incidence of lymphatic invasion, nodal metastasis and with high tumor stage. Whether this distinctive histological subtype carries independent prognostic significance remains to be established in future studies.

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