—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 4 - Adenocarcinoma of Lung with Micropapillary Carcinoma Component

Jae Y. Ro
Ulsan University College of Medicine
Seoul, Korea


Click on each slide thumbnail image for an enlarged view
Clinical History:
A 70-year-old man who had a history of stroke took a CT scan of the chest demonstrating a 3.0 cm mass in the left lower lobe. A needle biopsy revealed an adenocarcinoma. He had a past history of hypertension, but there was no history of tuberculosis. He was a non-smoker. There was no remarkable family history. His general conditions were good and laboratory findings were within normal limits. Staging procedures including bone scan and MRI of the brain did not reveal metastasis. Left lower lobe lobectomy was performed 1 month after the histologic diagnosis of carcinoma.


Case 4 - Figure 1 - Gross photograph of left lower lobe of lung mass (3.5 cm in greatest dimension).
Case 4 - Figure 2 - Micropapillary formation from the surface of the large tumor glands.
Case 4 - Figure 3 - Micropapillary tufts are lying within retracted connective tissue spaces.


Case 4 - Figure 4 - High power of the micropapillary component.
Case 4 - Figure 5 - TTF-1 and CK7 immunostainings are positive in both the micropapillary and nonmicropapillary components of lung adenocarcinoma.

Pathologic Findings:
Left lower lobectomy specimen measured 17x10x5 cm and weighed 150 gm. There was a pleural puckering at the lateral basal segment. On sections, an ill-defined mass, measuring 3.5 x 2 x 2 cm was present in the lateral basal segment just beneath the pleural puckering. The mass was solid, grayish tan, granular and firm with areas of hemorrhage and necrosis. The tumor involved the pleura. There was no connection with bronchus and the bronchial margin was free of tumor. The remaining lung parenchyma was unremarkable. Multiple mediastinal, hilar and bronchial lymph nodes were submitted and two mediastinal nodes revealed tumor metastasis.

Microscopically, the tumor was composed of acinar, bronchioloalveolar and micropapillary adenocarcinoma components. The micropapillary component occupied approximately 40% of the tumor. The micropapillary component was characterized by small papillary tufts lying freely within alveolar spaces or encased within thin walls of connective tissue that represented retracted connective tissue spaces. These small, tight nests contained little or no fibrovascular connective tissue cores. Although the wall of the spaces containing micropapillae had a flattened endothelial lining in some, the wall in most did not have a lining. In some areas, the micropapillary tufts were floating within cystic spaces lined by tumor cells.

The cells of the micropapillary component showed small to moderate amounts of eosinophilic cytoplasm giving a high nucleus-to-cytoplasm ratio; in contrast in the nonmicropapillary areas, the tumor cells contained relatively abundant cytoplasm. The nuclei of the micropapillary carcinoma component had irregular outlines with irregular chromatin distribution and prominent nucleoli that generally shared the nuclear features of the adjacent nonmicropapillary areas.

The micropapillary components were more commonly seen at the periphery than in the center of the tumor. The remaining tumor components were of acinar and nonmucinous bronchioloalveolar carcinoma.. There were no psammoma bodies or calcifications. Two of 35 regional lymph nodes had metastases. The metastasis showed exclusively of micropapillary component.

The micropapillary as well as nonmicropapillary tumor cells were positive for CK7 and TTF-1 and negative for CK20. p53 and Ki-67 revealed about 1/3 of tumor cells being positively stained in both micropapillary as well as nonmicropapillary tumor cells. CD34 immunostaining demonstrated that some tumor cells being present in the vascular spaces, but most of tumor cells in the lacunar spaces.

Diagnosis: Adenocarcinoma of lung with micropapillary carcinoma component

A distinctive histologic feature with possible prognostic significance

Discussion:
Micropapillary carcinoma has been described from several different organs, including breast, urinary bladder, and ovary. However, this type of carcinoma has not been reported in the lung. The current World Health Organization (WHO) classification of lung tumors, which includes four major histologic types (squamous cell carcinoma, adenocarcinoma, large cell undifferentiated carcinoma and small cell carcinoma), and subtypes and variants of adenocarcinoma (Table 1) based on histologic growth patterns, does not make reference to micropapillary histology.1

Micropapillary morphology is being increasingly recognized as prognostically important histologic subtypes in carcinomas of different organs. Siriaunkgul and Tavassoli2 were the first to describe a micropapillary carcinoma in the breast as a rare variant of invasive breast carcinoma in nine patients. They noted that the micropapillary pattern was retained in the metastatic foci as well as in areas of recurrence. Subsequent studies have shown that this histologic feature has a high degree of aggressiveness, manifested by an advanced stage at presentation, extensive lymphovascular invasion, massive axillary node metastasis, and expression of unfavorable prognostic markers.3 Recently we have studied on 38 cases of breast carcinoma with micropapillary carcinoma component for CK7, CK20, ER, PR, p53, c-erbB2 and CD34 and the results were compared with non-micropapillary carcinoma component. The metastatic component was mostly of micropapillary component, p53 was higher in micropapillary component and ER positivity was lower in micropapillary component, indicating micropapillary carcinoma component being an aggressive phenotype of breast cancers.4

Amin et al5 described a micropapillary variant of urothelial carcinoma of the urinary bladder and have concluded, as have others, that such a histologic variant imparts a poor prognosis by virtue of a high incidence of vascular invasion, a high clinical stage at presentation, and a poor clinical outcome. However, the prognostic significance of the micropapillary component of ovarian serous tumor is not clear.

Papillary carcinoma of the lung has been described by Silver and Askin.6 They concluded that papillary carcinoma is a distinct clinicopathologic entity with considerably worse morbidity and mortality rates that bronchioloalveolar carcinoma. They defined papillary adenocarcinoma by the formation of papillary structures supported by central fibrovascular cores with complicated secondary and tertially branches and tufts, adding that this architectural pattern must constitute at least 75% of the neoplasm. They mentioned that a micropapillary pattern occurred in 23 of the 31 cases (74%) they studied. This excellent study addressed the issue of a predominant papillary histology and its relation to prognosis but did not delve further into the implications of a micropapillary component.

Amin et al7 first described a detailed histology with 35 cases of micropapillary carcinoma of the lung. The size of the primary tumors ranged from 0.8 to 6.0 cm (mean, 3.0 cm; median, 2.9 cm). The tumors were generally described as well circumscribed with a gray-white to tan-yellow cut surface containing focal areas of hemorrhage and necrosis. The primary tumors were all adenocarcinomas showing a mixture of the various histologic subtypes including acinar, papillary, solid, and bronchioloalveolar carcinomas. There was no case in which the entire tumor was composed of a single histologic subtype. The amount of micropapillary carcinoma component in tumor varied. Among the 24 resected primary tumors, 5 (21%) cases showed focal (< 5% of the tumor) micropapillary component, 14 (58%) cases had a moderate (5-30%) micropapillary component, and 5 cases (21%) demonstrated an extensive (> 30%) micropapillary component. The micropapillary component did not occur preferentially with the papillary subtype of adenocarcinoma or with any of the other subtypes. The micropapillary components were more commonly seen at the periphery than in the center of the primary tumors. Psammoma bodies or calcifications were associated with the papillary component in six of 31 cases (19%), but with the micropapillary component in only one case (3%). One of the striking findings, Amin at al found was that the histology of metastases was composed predominantly of the micropapillary component, and this phenomenon appears to be independent of the quantity of the micropapillary component present in the primary tumor.

In addition to reporting the presence of micropapillary component in lung adenocarcinoma, Amin et al7 brought attention to the fact that lung carcinomas should be included in the differential diagnosis of primary tumor sites when examining metastasis with micropapillary histology. Immunohistochemical findings of micropapillary carcinoma component are the same with nonmicropapillary areas. Most of cases are CK 7 positive, TTF-1 positive and CK20 negative (Table 2). Therefore, a careful histologic evaluation of the metastases as well as immunohistochemical staining will be helpful in determining the primary site.

Twenty-six of 35 patients of Amin et al's series7 had metastatic disease at the time of initial presentation, and an additional six patients developed subsequent metastases. Lymph node metastases were present in 26 of 32 patients (81%) with metastatic disease, with two patients having metastases to extramediastinal lymph nodes. Intrapulmonary metastases were seen radiologically in 17 patients (53%), with nine patients having intrapulmonary metastases at the time of initial presentation. Other sites of metastases included the brain (n=9), bone,9  liver,3  and rarer sites such as the jejunum, adrenal gland, and skin (1 for each).

It is premature to conclude that patients with pulmonary adenocarcinoma with a micropapillary pattern have a worse prognosis than do those with other lung adenocarcinomas in general because a comparative stage-by-stage study with adenocarcinoma without micropapillary component has not been done. However, Amin at al7 believe that the micropapillary component may be a poor prognostic feature in lung adenocarcinoma because of the frequent and selective presence of this micropapillary component in the vascular emboli and in the metastases. TNM staging and clinical follow-up information of Amin at al's patients are in Table 3.7

At this point, we think that the presence of a micropapillary carcinoma component occurring in lung adenocarcinoma should be noted in the pathology report to alert the clinician to the possibility of metastasis. In addition, when evaluating a metastasis with a micropapillary pattern from an unknown primary tumor, the pathologist should consider the lung a possible site for the primary tumor in addition to other primary sites such as the breast, urinary bladder, and ovary. We think that the micropapillary component in lung adenocarcinomas may show poor prognosis similar to its counterparts found in the breast and urinary bladder, and recognition of this pattern may have both differential and prognostic significance.

Table 1: WHO classification of lung adenocarcinomas
  • Adenocarcinoma
    • Acinar
    • Papillary
    • Bronchioloalveolar carcinoma
      • Non-mucinous (Clara cell/type II pneumocyte type)
      • Mucinous (goblet cell type)
      • Mixed mucinous and nonmucinous (Clara cell/type II pneumocytes and goblet cell type) or indeterminate
    • Solid adenocarcinoma with mucin formation
    • Mixed
  • Variants
    • Well-differentiated fetal adenocarcinoma
    • Mucinous ("colloid")
    • Mucinous cystadenocarcinoma
    • Signet ring cell carcinoma
    • Clear cell carcinoma

Table 2: Immunohistochemical results of CK7 and CK20 stainings on micropapillary carcinoma cases
Immunostaining profileCK7+/CK20-CK7+/CK20+CK7-/CK20+CK7-/CK20-
No of cases122*01**
* Both cases showed concomitant TTF-1 positivity
** This case was also TTF-1 negative

Table 3: TNM staging and clinical follow-up information
TNM Stage No of patients Subsequent metastasis Alive, NED AWD DOD LOF
IA 4 2 2 1 1 0
IB 5 5 0 4 1 0
IIA 2 1 1 0 1 0
IIB 0 0 0 0 0 0
IIIA 6 4 1 4 0 2
IIIB 5 1 0 4 1 0
IV 11 1 4 6 1 0
Not known 2 1 0 1 0 2
NED - no evidence of disease
AWD - alive with disease
DOD - dead of disease
LOF - lost to follow-up

References

  1. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E: Histological typing of tumors of lung and pleura. In: World Health Organization International Classification of Tumors, 3rd ed. Berlin: Springer-Verlag, 1999.
  2. Siriaunkgul S, Tavassoli FA: Invasive micropapillary carcinoma of the breast. Mod Pathol 6:660-662, 1993.
  3. Middleton LP, Tressera F, Sobel ME, Bryant BR, Alburquerque A, Grases P, Merino MJ: Infiltrating micropapillary carcinoma of the breast. Mod Pathol 12:499-504, 1999.
  4. Kim MJ, Gong GY, Joo HJ, Park JM, Ahn SH, Ro JY: Analysis keratin subtypes and prognostic markers in invasive ductal carcinoma of breast with micropapillary carcinoma component. Mod Pathol, 2002 (abstract for USCAP).
  5. Amin MB, Ro JY, el-Sharkawy T, Lee KM, Troncoso P, Silva EG, Ordonez NG, Ayala AG: Micropapillary variant of transitional cell carcinoma of the urinary bladder: histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 18:1224-1232, 1994.
  6. Silver SA, Askin FB: True papillary carcinoma of the lung: a distinct clinicopathologic entity. Am J Surg Pathol 21:43-51, 1997.
  7. Amin MB, Tamboli P, Merchant SH, Ordonez NG, Ro JS, Ayala AG, Ro JY: Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol 26:358-364, 2002.