Case 1 -
Gastric Micropapillary Carcinoma
Dartmouth Hitchcock Medical Center
Click on slide thumbnail images for an enlarged view.
If you have any difficulties viewing these slides, email the webmaster.
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.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
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.
Conventional tubulo-papillary adenocarcinoma with extensive lymphatic
Gastric Micropapillary Carcinoma.
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 . 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
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  but two series of
gastric MPC have been published recently that describe the features of this rare tumor type in greater
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
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  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 . Aberrant beta-catenin staining has been reported in 75% of gastric MPC
and may have pathogenetic 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 . 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 .
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
- Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System: WHO Classification of Tumours. Lyon: IARC Press; 2000:37–52.
- Amin MB, Ro JY, el-Sharkawy T, et al. Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol.1994;18:1224–1232.
- Amin MB, Tamboli P, Merchant SH, et al. Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol. 2002;26:358–364.
- Haupt B, Ro JY, Schwartz MR, et al. Colorectal adenocarcinoma with micropapillary pattern and its association with lymph node metastasis. Mod Pathol 2007;20:729–733.
- Johansson SL, Borghede G, Holmang S. Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol. 1999;161:1798–1802.
- Khayyata S, Basturk O, Adsay NV. Invasive micropapillary carcinomas of the ampullo-pancreatobiliary region and their association with tumor-infiltrating neutrophils. Mod Pathol. 2005; 18:1504–1511.
- Kim MJ, Hong SM, Jang SJ, et al. Invasive colorectal micropapillary carcinoma: an aggressive variant of adenocarcinoma. Hum Pathol. 2006;37:809–815.
- Kondo T. Bile duct adenocarcinoma with minor micropapillary component: a case report. Cases J. 2009;2:51.
- Kondo T, Kitazawa R, Kitazawa S. Gastric remnant adenocarcinoma with micropapillary component. Dig Dis Sci. 2008;53: 2287–2289.
- Michal M, Skalova A, Mukensnabl P. Micropapillary carcinoma of the parotid gland arising in mucinous cystadenoma. Virchows Arch. 2000;437:465–468.
- Moritani S, Ichihara S, Hasegawa M, et al. Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast. Are WT1, CA125, and GCDFP-15 useful in differential diagnosis? Hum Pathol. 2008;39:666–671.
- Nagao T, Gaffey TA, Visscher DW, et al. Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance. Am J Surg Pathol. 2004;28:319–326.
- Sakamoto K, Watanabe M, De La Cruz C, et al. Primary invasive micropapillary carcinoma of the colon. Histopathology. 2005;47: 479–484.
- Siriaunkgul S, Tavassoli FA. Invasive micropapillary carcinoma of the breast. Mod Pathol. 1993;6:660–662.
- Walsh MM, Bleiweiss IJ. Invasive micropapillary carcinoma of the breast: eighty cases of an underrecognized entity. Hum Pathol. 2001;32:583–589.
- Yamamoto H, Uryu H, Segawa Y, et al. Aggressive invasive micropapillary salivary duct carcinoma of the parotid gland. Pathol Int. 2008;58:322–326.
- Shimoda M, Okada Y, Hayashi Y, et al. Primary invasive micropapillary carcinoma of the stomach. Pathol Int. 2008;58:513–517.
- Roh JH, Srivastava A, Lauwers GY, An J et al. Micropapillary carcinoma of Stomach. A Clinicopathologic and immunohistochemical study of 11 cases. Am J Surg Pathol 2010, 34:1139-1146.
- Eom DW, Kang GH, Han SH et al. Gastric micropapillary carcinoma: A distinct subtype with a significantly worse prognosis in TNM stages I and II. Am J Surg Pathol 2011; 35:84-91.
- Nassar H. Carcinomas with micropapillary morphology: clinical significance and current concepts. Adv Anat Pathol. 2004;11: 297–303.
- Nassar H, Pansare V, Zhang H, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol. 2004;17:1045–1050.