Pulmonary adenocarcinoma: the expanding spectrum of histologic variants.Arch Pathol Lab Med. 2006 Jul;130(7):958-62.

Pulmonary adenocarcinoma is one of the most common types of lung cancer. Traditionally, adenocarcinomas have been divided based on their degree of resemblance to their parent tissues into 3 histopathologic types: well, moderately, and poorly differentiated. In the majority of cases, this schema is sufficient to categorize these lung tumors. However, there is a considerable group of tumors in which the histology is not that of the classic gland-forming neoplasm. Thus, although the terminology of adenocarcinoma is applied in such cases, the histopathologic features are different from those of the more conventional variants. The current review addresses these unusual variants and the importance of recognizing and properly categorizing them to avoid unnecessary additional workup or possible misdiagnosis.

Papillary adenocarcinoma of the lung is a more advanced adenocarcinoma than bronchioloalveolar carcinoma that is composed of two distinct histological subtypes.Pathol Int. 2005 Oct;55(10):619-25.

To clarify the clinicopathological nature of papillary adenocarcinoma (PA) of the lung, 20 cases of PA were collected consecutively from resected adenocarcinoma of the lung, studied immunohistochemically and, using molecular techniques, compared with bronchioloalveolar carcinoma (BAC). Clinicopathologically, PA occurred in 7.4% and dominantly in female patients. Morphologically, PA was divided into two subtypes according to the presence of residual alveolar structures, detected by elastica van Gieson stain. One of these subtypes was closely related to the morphology of BAC and might be diagnosed as adenocarcinoma with mixed subtypes. The other PA subtype was composed of tall columnar cells and grew compressively, which was similar to type F adenocarcinoma previously reported by Noguchi et al. Immunohistochemical studies using lung tissue-specific antigens, progression markers and tumor suppressor products found that PA seemed a more advanced adenocarcinoma than BAC, but no differences were observed among PA subtypes. Molecular biological analysis using three microsatellite markers at chromosome 3p revealed more frequent loss of heterozygosity in PA than BAC, with no differences among PA subtypes. These findings suggest that PA is a more advanced adenocarcinoma subtype than BAC. Further investigations are needed to clarify true PA as clinicopathologically and biologically independent from other histological subtypes of adenocarcinoma of the lung.

Micropapillary pattern: a distinct pathological marker to subclassify tumours with a significantly poor prognosis within small peripheral lung adenocarcinoma (</=20 mm) with mixed bronchioloalveolar and invasive subtypes (Noguchi's type C tumours).Histopathology. 2005 Jun;46(6):677-84.

AIMS: A micropapillary pattern (MPP) in lung adenocarcinoma, characterized by papillary structures with epithelial tufts lacking a central fibrovascular core, has been reported to be a new pathological marker of poor prognosis. However, its clinicopathological and prognostic significance in small lung adenocarcinomas (</=20 mm) remains undetermined. A new histological classification of small lung adenocarcinoma proposed by Noguchi et al. has been found to be useful since it has defined surgically curable bronchioloalveolar carcinoma (BAC)-type tumours (Noguchi's type A and B) based on the absence of active fibroblastic proliferation. However, BAC-type tumours with active fibroblastic proliferation (Noguchi's type C), which is adenocarcinoma with mixed subtypes including BAC and invasive carcinoma in the new World Health Organization (WHO) classification, account for most of the small adenocarcinomas and represent a heterogeneous group ranging from minimal to overtly invasive cancer with variable prognoses. Therefore, in this study the aim was to investigate whether MPP can be an additional histological marker(s) to subclassify this heterogeneous group in small lung adenocarcinoma. METHODS AND RESULTS: One hundred and twenty-two cases of small lung adenocarcinomas (</=20 mm in maximum dimension) classified according to the new WHO classification and Noguchi's proposal were analysed with reference to the presence of MPP. Of the 122 cases, 67 (55%) were MPP-positive and 55 (45%) were MPP-negative. Lymph node metastasis and pleural invasion were significantly more frequent in the MPP-positive group: 74% and 66% in the positive group versus 26% and 34% in the negative group, respectively. The 5-year survival of the MPP-positive group was 54%, whereas that of the MPP-negative group was 81% (P=0.024). The 5-year survival rates of BAC (Noguchi's type A and B) (n=14), mixed BAC and invasive adenocarcinoma (Noguchi's type C) (n=85) and invasive adenocarcinoma (Noguchi's type D and F) (n=23) were 100%, 68% and 36%, respectively. In patients with mixed BAC and invasive adenocarcinoma (Noguchi's type C tumours), the 5-year survival of the MPP-positive group (n=51) was 54%, significantly lower than that of the MPP-negative group (n=23) of 100% (P=0.02). CONCLUSIONS: MPP is a simple and distinct pathological marker to subclassify tumours with a significantly poor prognosis within small (</=20 mm) mixed BAC and invasive adenocarcinoma (Noguchi's type C tumours).

Pulmonary adenocarcinoma with micropapillary component: an immunohistochemical study. Case report.APMIS. 2005 Jul-Aug;113(7-8): 550-4.

Micropapillary carcinoma has been described in various organs, including the breast, urinary bladder, ovary and lung. We here present a case of pulmonary micropapillary carcinoma in a 72-year-old Japanese man who died of respiratory failure and septic shock, following which autopsy was performed. A mass measuring 2.5 x 2.5 x 2.5 cm was observed in the left lower lobe of the lung. The tumor showed moderately differentiated papillary adenocarcinoma with a focal micropapillary component. Carcinomatous lymphangiosis was also observed in the left lung and metastatic lesions were observed in the bilateral lung, liver, vertebra, muscle layer of the urinary bladder, right adrenal gland, spleen and lymph nodes. The micropapillary component was predominant at some metastatic sites. Immunohistochemically, both the adenocarcinoma and micropapillary components were positive for cytokeratin (CK) 7, CK19, TTF (thyroid transcription factor)-1, carcinoembryonic antigen (CEA) and surfactant apoprotein A (SP-A), and negative for CK20, estrogen receptor, progesterone receptor, uroplakin III, and CA125. The invasive area of the conventional adenocarcinoma component contained a large number of myofibroblasts, whereas the stroma of the micropapillary component contained a small number of myofibroblasts. However, no myofibroblasts were observed in the stroma of the central core of the non-invasive micropapillary carcinoma. Several lymphatic invasions by neoplastic cells were identified in the peripheral area of the micropapillary component using D2-40 antibody. The immuno-histochemical profile may be helpful in determining the primary location of the neoplasm containing micropapillary features. Myofibroblasts are present in the stroma of the invasive neoplastic nests in the micropapillary component as well as the conventional adeno carcinoma component, and D2-40 monoclonal antibody may be useful for evaluating the lymphatic invasion of pulmonary micropapillary carcinoma.

Possible mechanism of metastasis in lung adenocarcinomas with a micropapillary pattern.Pathol Int. 2005 Jul;55(7):419-24.

Micropapillary differentiation in adenocarcinomas has recently been associated with poor prognosis because these tumors are more likely to metastasize. However, no clear explanation exists as to why the presence of a micropapillary pattern is associated with metastasis. A case of primary lung adenocarcinoma with a prominent micropapillary pattern is presented here, with special reference to the immuno-histochemical expression of the E-cadherin-mediated system and IQGAP1. Histologically, the tumor was diagnosed as a moderately differentiated papillary adenocarcinoma, showing an extensive micropapillary pattern, with intrapulmonary metastases, pulmonary disseminations, lymphovascular invasions, and lymph node metastases. Immunohistochemically, positive staining for the adhesion molecules E-cadherin, alpha-catenin, and beta-catenin was detected in both the micropapillary and non-micropapillary areas, whereas IQGAP1 was detected in the micropapillary, but not in the non-micropapillary, area. The adhesive function of E-cadherin depends on the integrity of the entire cadherin-catenin-actin network, and thus the expression of IQGAP1 may lead to adherens junction disassembly, and consequently, the release of carcinoma cells organizing in a micropapillary pattern. This is the first report to suggest correlation between adenocarcinoma with a micropapillary pattern and the presence of adhesion molecules, and offers an intriguing first glimpse on the role of the micropapillary pattern in the process of metastasis.

Prognostic analysis of pulmonary adenocarcinoma subclassification with special consideration of papillary and bronchioloalveolar types.
Histopathology. 2004 Nov;45(5):468-76.

AIMS: The third edition of the World Health Organization (WHO) classification of lung tumours has been published and is expected to become the standard nomenclature. The aim of this study was to assess the usability and prognostic significance of the WHO classification in comparison with other recent classifications. METHODS AND RESULTS: One hundred and forty-seven resected pulmonary adenocarcinoma cases were reviewed and histologically classified according to the WHO classification (1999) and the classification by Noguchi (1995). Papillary carcinomas as described by Silver and Askin (1997) were also identified. Since the papillary type in the WHO classification is not strictly defined, we compared the following two kinds of WHO classification: (i) WHO-N; WHO classification adopting Noguchi Type F as the definition of the papillary type, namely, pure papillary adenocarcinoma without a bronchioloalveolar component; (ii) WHO-SA; WHO classification adopting papillary carcinoma by Silver and Askin as the definition of the papillary type, namely, tumour with papillary structure constituting at least 75% of the lesion. The bronchioloalveolar carcinoma of the WHO classification showed a better prognosis than other subtypes in both overall and Stage I disease limited survival analysis. In analysis limited to Stage III disease, only the papillary type of WHO-SA showed a significantly worse prognosis. CONCLUSIONS: WHO-SA is recommended for prognostic correlation.

Papillary lung carcinoma with prominent “morular” component. Am J Clin Pathol 2004;122:106–109.

Three cases of primary pulmonary papillary carcinomas with a prominent "morular" component involved 2 women and 1 man (age range, 25-68 years). The patients had symptoms related to the pulmonary mass, including chest pain, cough, and dyspnea. Radiographic evaluation of the thorax revealed the presence of a pulmonary mass. Surgical biopsies were obtained and reported as non-small cell carcinoma. All patients underwent lobectomy. Two tumors were located in the right upper lobe and 1 in the left upper lobe. The tumors were soft, white to tan, without evidence of necrosis or hemorrhage, and 2.5 to 3.5 cm in greatest diameter. The tumors were characterized predominantly by papillary architecture containing numerous "morules" composed of spindle cells without nuclear atypia or mitotic activity. Some morules were floating freely within papillary spaces; others seemed to detach from the papillary structures. Immunohistochemical studies of 2 tumors showed positivity for thyroid transcription factor-1, keratin, and carcinoembryonic antigen and negativity for thyroglobulin. The morules showed positive thyroid transcription factor-1 staining, weak keratin staining, and negative staining for smooth muscle actin, desmin, and HMB-45. These cases highlight an unusual phenomenon, that of primary papillary carcinomas of the lung with a prominent morular component.

Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol 2002;26:358–364.

Micropapillary carcinoma or a micropapillary carcinoma component has been reported in the ovary, breast, and urinary bladder and is generally thought to have prognostic significance. However, little has been written on micropapillary differentiation in lung carcinoma. We studied 35 cases of primary lung adenocarcinoma with a micropapillary component seen at the M.D. Anderson Cancer Center. The micropapillary component in these tumors ranged from focal to prominent and was seen at both primary and metastatic sites. This component was not associated with any particular histologic subtype of lung adenocarcinoma. Of the 15 cases with available material, 14 (93%) stained positive for cytokeratin 7, whereas only two of the 15 cases (13%) stained positive for cytokeratin 20. Thyroid transcription factor-1 immunostaining of tumor nuclei was seen in 12 of the 15 cases (80%). Immunostaining was seen in areas both with and without micropapillary differentiation. Thirty-three of 35 patients (94%) developed metastases, which occurred most commonly in the lymph nodes (n = 26), and also in the lung (n = 17), brain (n = 9 cases), bone (n = 9 cases), and other sites. Most metastases had a prominent micropapillary component, irrespective of the extent of the micropapillary carcinoma component in the primary lung tumor. Adequate clinical follow-up information was available for 29 patients. The mean follow-up was 25 months. At their last follow-up, 16 of 29 patients (55%) were still alive with disease, 5 (17%) were dead of disease, and 8 (28%) were alive with no evidence of disease. We believe that a micropapillary component occurring in lung adenocarcinoma should be reported, as this component may be more likely to metastasize. The presence of this component should alert the clinician to search more carefully for metastases and have a closer follow-up on these patients. It is also important to recognize this component in evaluating a metastasis from an unknown primary site, as it should alert the pathologist to a possible primary in the lung in addition to breast, urinary bladder, and ovary.

True papillary carcinoma of the lung: a distinct clinicopathologic entity. Am J Surg Pathol 1997;21:43–51.

There continues to be confusion as to whether papillary adenocarcinoma (PA) of the lung is a specific histologic entity or simply a variant of bronchioloalveolar carcinoma (BAC). We reviewed our files from 1981 through 1993 for all cases (n = 155) of resected primary lung adenocarcinoma specifically diagnosed as having papillary or bronchioloalveolar features. In addition, a random 10% (n = 67) of all remaining lung adenocarcinomas were reviewed. True PA was diagnosed when > or = 75% of the neoplasm contained papillary structures supported by fibrovascular cores with complicated secondary and tertiary branches. Marked nuclear atypia was present in 100%, and psammoma bodies were seen in 42% of cases. In contrast to BAC, true PA filled and distorted or replaced air spaces in the lung. Thirty-one cases of true PA were found, including 19 men and 12 women (mean age, 64.5 years). The lesions were solitary (n = 27) or multifocal (n = 4) with a mean diameter of 4.1 cm. Forty-five percent of patients had bronchopulmonary lymph node involvement at diagnosis; another 10% had extensive intrapulmonary lymphatic permeation by tumor. Disease-free survival for stage I and II PA was 40% (n = 15) and 25% (n = 8), respectively, at a mean of 3.4 and 3.5 years. Papillary adenocarcinoma of the lung is a distinct clinicopathologic entity with considerably worse morbidity and mortality than BAC.

Psammoma bodies in fine-needle aspiration cytology of papillary adenocarcinoma of the lung.Diagn Cytopathol. 1990;6(4):271-4.

The fine-needle aspiration (FNA) cytology of two cases of papillary adenocarcinoma of the lung is reported. Both cases showed psammoma bodies and papillary clusters of tumor cells in FNA specimens. Both tumors were resected and confirmed as primary papillary carcinoma of the lung by histologic examination and by clinicopathologic exclusion of the possibility of metastasis from other organs.

Papillary adenocarcinoma of lung with psammoma bodies: report of a case derived from type II pneumocytes. Histopathology. 1986 Aug;10(8): 877-84.

A 52-year-old woman underwent thoracotomy for the removal of a mass in the middle lobe of the right lung. Light microscopy showed a tumour with the morphology of a papillary adenocarcinoma with numerous psammoma bodies. Electron microscopy revealed the tumour cells to possess the lamellated intracytoplasmic inclusions characteristic of normal and neoplastic type II pneumocytes. Psammoma bodies have not previously been reported in type II cell carcinoma of the lung. Alveolar cell carcinoma should be considered in the differential diagnosis of a papillary adenocarcinoma with psammoma bodies occurring in the lung.

Relation of fine structure to prognosis for papillary adenocarcinoma of the lung.Hum Pathol. 1984 Sep;15(9):870-9.

Eight cases of papillary adenocarcinoma of the lung were investigated by light and electron microscopy. Prognoses for all but one patient were favorable. Two patients (husband and wife) who underwent tumor resection during the same year experienced no disease-related problems for more than seven years afterward. Microscopic study of the papillary adenocarcinomas revealed columnar, peg-shaped, mucus-secreting tumor cells lining the alveoli. The tumor tissue contained alveolar macrophages, with some multinucleated giant cells, interstitial lymphoid infiltrates, mildly thickened alveolar walls, and a few pneumoconiotic foci. These inflammatory stromal reactions in the tumor tissue might have been associated with the favorable prognoses. Nuclear inclusions were detected in some tumor cells in all cases. Ultrastructurally, the inclusions contained tubular, granular, crystalline, and electron-dense homogeneous structures in addition to unclassifiable nuclear bodies. The tubular structures were in close proximity to inner leaflets of the nuclear membranes. The papillary adenocarcinoma cells had features of totipotential bronchioloalveolar cells, differentiating toward type II pneumocytes, Clara cells, and ciliated epithelial cells.

Light and electron microscopic analysis of intranuclear inclusions in papillary adenocarcinoma of the lung.Acta Cytol. 1981 Sep-Oct;25(5):523-32.

The incidence and nature of intranuclear inclusions found in tumor cells of preoperative and postoperative cytologic, histologic and electron microscopic (EM) specimens were studied in 38 cases of papillary adenocarcinoma of the lung in order to assess the cytodiagnostic significance of these inclusions. The overall incidence of the intranuclear inclusions was 34%; the incidence was higher in the well-differentiated type of adenocarcinoma (48%). Four smear and four EM types of inclusions were recognized. Cytoplasmic invaginations (pseudoinclusions), single-membrane-bound inclusions, aggregates of 50-nm tubules and any combination of the above could be distinguished by EM. There was some correlation between the smear and EM types of inclusions. EM analysis suggests that intranuclear inclusions, except for pseudoinclusions, may be derived from the inner nuclear membrane. In routine cytology, the intranuclear inclusion is a good diagnostic marker for papillary adenocarcinoma of the lung.