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Giant-cell carcinoma of the lung
Giant-cell carcinoma of the lung
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Giant cell carcinoma of the lung (GCCL) is a rare histological form of undifferentiated lung cancer traditionally classified within the non-small cell lung carcinomas. The characteristic feature of this highly lethal malignancy is the distinctive light microscopic appearance of its extremely large cells, which are bizarre and highly pleomorphic, and which often contain more than one huge, misshapen, pleomorphic [[cell nucleus|nucleus] ("syncytia"), which result from cell fusion.

Although it is common in the lung cancer literature to refer to histologically mixed tumors containing significant numbers of malignant giant cells as "giant cell carcinomas", technically a diagnosis of "giant cell carcinoma" should be limited strictly to neoplasms containing only malignant giant cells (i.e. "pure" giant cell carcinoma).^[1]

Aside from the great heterogeneity seen in lung cancers (especially those occurring among tobacco smokers), the considerable variability in diagnostic and sampling techniques used in medical practice, the high relative proportion of individuals with suspected GCCL who do not undergo complete surgical resection, and the near-universal lack of complete sectioning and pathological examination of resected tumor specimens prevent high levels of quantitative accuracy

Epidemiology

The true incidence, prevalence, and mortality of GCCL is generally unknown due to a lack of accurate cancer data on a national level. It is known to be a very rare tumor variant in all populations examined, however. In an American study of a database of over 60,000 lung cancers, GCCL comprised between 0.3% and 0.4% of primary pulmonary malignancies, with an age-adjusted incidence rate of about 3 new cases per million persons per year.^[2] Wit h approximately 220,000 total lung cancers diagnosed in the US each year,^[3] the proportion suggests that approximately 660 and 880 new cases are diagnosed in Americans annually.^[2]

^[4]

However, in a more recent series of 4,212 consecutive lung cancer cases, only one (0.024%) lesion was determined to be a "pure" giant cell carcinoma after complete sectioning of all available tumor tissue.^[5] While some evidence suggests GCCL may have been considerably more common several decades ago, with one series identifying 3.4% of all lung carcinomas as giant cell malignancies,^[6] it is possible that this number reflect

Most published case series and reports on giant cell-containing lung cancers show that they are diagnosed much more frequently in men than they are in women,^[7]^[8] with some studies showing extremely high male-to-female ratios (12:1 or more). In a study of over 150,000 lung cancer victims in the US, however, the gender ratio was just over 2:1, with women actually having a higher relative proportion of giant cell cancers (0.4%) than men (0.3%).^[2]

Giant cell carcinomas have been reported to be diagnosed in a significantly younger population than all non-small cell carcinomas considered as a group.^[7]^[9] Like nearly all lung carcinomas, however, GCC's are exceedingly rare in very young people: in the US SEER program, only 2 cases were recorded to occur in persons younger than 30 years of age between 1983 and 1987.^[2] The average age at diagnosis of these tumors has been estimated at 60 years.^[7]

The vast majority of individuals with GCCL are heavy smokers,^[7]

Although the definitions of "central" and "peripheral" can vary^[7] between studies, GCCL are consistently diagnosed much more frequently in the lung periphery.^[7] In a review of literature compiled by Kallenburg and co-workers, less than 30% of GCCL's arose in the hilum or other parts of the "central" pulmonary tree.^[9]

A significant predilection for genesis of GCCL in the upper lobes of victims has also been postulated.^[7]

Classification

For several decades, primary lung cancers were consistently dichotomously classified for treatment and research purposes into small cell lung carcinomas (SCLC's) and non-small cell lung carcinomas (NSCLC's), based on an oversimplified approach that is now clearly outmoded. The new paradigm recognizes that lung cancers are a large and extremely heterogeneous family of malignant neoplasms,^[10] with over 50 different histological variants included in the 4th (2004) revision of the World Health Organization typing system, the most widely used lung cancer classification scheme ("WHO-2004").^[1] These variants are increasingly appreciated as having different genetic, biological, and [[clinical medicine|clinical] properties, including prognoses and responses to treatment regimens, and therefore, that correct and consistent histological classification of lung cancers are necessary to validate and implement optimum management strategies.^[11]^[12]

About 1% of lung cancers are sarcomas, germ cell tumors, and hematopoietic tumors, while 99% of lung cancers are carcinoma. Carcinomas are tumors composed of transformed, abnormal cells with epithelial tissue architecture and/or molecular characteristics, and which derive from embryonic endoderm.^[2] 8 major taxa of lung carcinomas are recognized within the WHO-2004 classification:^[1]

The subclassification of GCCL among these major taxa has undergone significant changes in recent decades. Under the 2nd revision (1981) of the WHO classification, it was considered a subtype of large cell carcinoma.^[13] In the 3rd (1999) revision,^[14] it was placed within a taxon called "Carcinomas with Pleomorphic, Sarcomatoid, or Sarcomatous Elements", along with pleomorphic carcinoma, spindle cell carcinoma, carcinosarcoma, and pulmonary blastoma, which are (arguably) related variants. While the 4th revision ("WHO-2004") retained the same grouping of lesions as the 3rd revision, the name of the major taxon was shortened to "[[sarcomatoid carcinoma of the lung|sarcomatoid carcinomas]".^[1]

The current rules for classifying lung cancers under WHO-2004, while useful and improved, remain to some extent fairly complex, ambiguous, arbitrary, and incomplete.^[1] Although it is fairly common for mixed tumors that are seen to contain malignant giant cells to be called "giant cell carcinomas", accurate classification of a pulmonary tumor as a GCCL requires that the entire tumor consists only of malignant giant cells. Therefore, complete sampling of the entire tumor — obtained via a surgical resection — is absolutely necessary for a definitive diagnosis of GCCL to be made.^[1]

Microscopic Features and Cytology

The background contained numerous lymphocytes and neutrophils. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5-fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round.

In cytological preparations, giant cells typically appear as single cells or in flat loose clusters, and occasionally in fascicles.^[15]

GCCL are considered a member of the most common type of lung cancer, called "non-small cell carcinomas". This group of lethal neoplasms make up approximately 85% of all lung cancers.^[1] By the definition of "large-vs.-small cell carcinoma", the diameter of GCCL cells must be considerably greater than three times that of a resting (i.e. unstimulated) lymphocyte. Also by definition, GCCL do not contain any amount of these small, neurosecretory granule-containing, neuroendocrine cells that are characteristic of small cell carcinomas — when they do, the tumor should be classified as a combined small cell carcinoma.^[1]

Compared to most other lung cancer variants, cells comprising GCCL tend to be much larger (up to 150 micrometers diameter, or even larger),^[16] Both cells and nuclei show extreme variation in size distribution and shape. Carcinomatous giant cells carcinoma nuclei have been reported to average 5 times the size of lymphocyte nuclei. ^[15]

The cells from giant cell carcinomas are anaplastic, and show no evidence of cell maturation or differentiation, lacking the cytological and tissue architectural characteristics of squamous cell carcinoma, adenocarcinoma, neuroendocrine carcinomas, or other more differentiated lung cancer cell types. They tend to be highly pleomorphic (i.e. variable in characteristics), but are most often round and/or polygonal in shape, with a relatively low nuclear-to-cytoplasmic ratio. When associated with spindle cells, as they very frequently are in tumors with mixed histology, malignant giant cells tend to form loosely cohesive aggregate structures on cytological examination. However, when a biopsy sample consists purely of malignant giant cells, the cells tend to be single and disaggregated.^[1]

Case series suggest that the relative number of giant cells in a given tumor are generally directly proportional to the size of the tumor, and to the relative amount of necrosis.^[17]

Giant cells in a lung cancer are highly associated with the presence of spindle cells.^[18]

The chromatin of malignant giant cells tends to be hyperchromatic and coarsely clumped. Nucleoli are usually multiple and prominent.^[16]

Subcellular characteristics often noted in the malignant giant cells of GCCL cases include abundant mitochondria, concentric whorls of tonofilament-like fibrils, and aggregates of several pairs of centrioles.^[19]

Both "tumor cell-tumor cell" and "leukocyte-tumor cell" emperipolesis (i.e. active penetration of the latter by the former) is very commonly seen in cases of GCCL.^[19]

Tissue Architectural Features

In mixed tumors, giant cells are more likely to be found in higher proportions at the edge of a tumor.^[18] When extensive necrosis is present, it is possible for a giant cell tumor to have only a thin rim of viable cells remaining at the perimeter of the mass.

In one early case series, abundant production of loose malignant giant cells were noted to fill the alveoli of victims without destroying, infiltrating, or disturbing the normal underlying architecture, a pathologic behavior that bears some resemblance to the pneumonic variant of bronchioloalveolar carcinoma.^[20]

Extensive tumor necrosis and hemorrhage is extremely common in GCCL.^[20]

Although the issue has not been extensively studied in a controlled fashion, GCCL's have been noted to contain significantly elevated levels of VEGF.^[21] However, in one study where a giant cell carcinoma tumor that had been completely excised was sectioned and examined, no qualitative or quantitative abnormalities in tissue vascularization were noted.^[16]

GCCL have been noted to be encapsulated, and to be divided via septa into "pseudolobules", by a highly fibrous stroma, suggested to be produced commensurately with tumor growth. The capsule is typically infiltrated with malignant giant cells.^[22]

Macroscopic Features

Giant cell carcinomas of the lung frequently show extensive necrosis^[22] and myxoid degeneration.^[18]

A trend toward less vascularity and tissue density (with lower contrast enhancement on CT) has been noted toward the center of these lesions, especially in larger tumors, and even in tumors without a significant volume of gross necrosis.^[7]

Grossly, the cut surfaces of these malignancies are often gray-white or tan, and frequently show myxoid, necrotic, and/or hemorrhagic foci.^[7] These sorts of areas often show low levels of contrast enhancement on CT scanning.

Low encapsularity and high levels of tissue collagen tend to be observed, with high contrast enhancement in these areas.^[7]

GCCL have been seen to develop from/in emphysematous bullae.^[23]

Staining and Immunohistochemistry

A case of a brain metastasis from a giant cell lung carcinoma (both "pure") tested positive for cytokeratins AE1/AE3, and negative for CK-7, CK-20, TTF-1, and GFAP.^[24]

GCCL cells often stain intensely by Periodic acid-Schiff reagent, suggesting the presence of significant amounts of glycogen in the cell cytoplasm.^[22]

Differential Diagnosis

Under light microscopy, the giant malignant pleomorphic cells making up a GCCL resemble those found in choriocarcinoma,^[1] angiosarcoma,^[25] and some forms of true sarcoma,^[1] such as malignant fibrous histiocytoma^[1] and rhabdomyosarcoma.^[16] In some instances, they can also bear considerable resemblance to "activated" histiocytes seen in some inflammatory conditions.^[16]

A rare and potentially difficult differential diagnostic dilemma occurs when GCCL's must be separated from pulmonary or mediastinal choriocarcinomas, a critical distinction to me made because while there is a known standard of care for treating choriocarcinoma, as yet there is no generally accepted specific standard treatment for GCCL. Careful review of cell morphology is key to their delineation — while GCCL's show great variation in cell size distributions and morphologies in tumors, choriocarcinomas consistently contain only syncytiotrophoblasts and cytotrophoblasts.^[26]GCCL and primary pulmonary choriocarcinoma can also be differentiated on the basis of ultrastructural features by electron microscopy, although EM is not yet widely applicable. ^[27]

Occasionally, a bone metastasis of a GCCL could potentially be mistaken for a primary giant cell tumor of bone^[28] — interestingly, the latter entity can behave as a neoplasm of benign, frankly malignant,^[29] or borderline^[30] in its clinical behavior.^[31]

Sites of Metastasis

GCCL's are particularly notable among lung cancers for their extremely unusual tendency to metastasize to the [small intestine]], occasionally causing obstruction, severe bleeding, and/or intussusception. This clinical characteristic of GCCL has been seen in cases spanning over half a century in time.^[32]^[33]

Within the small bowel, the jejunum seems to be a preferred site for metastasis of GCCL.

GCCL also often metastasizes to bone,^[28] adrenal, brain,^[24] lung, liver, kidney,

Brain metastases from GCCL are particularly likely to cause significant cerebral hemorrhages as compared to other lung cancer variants, probably due to greatly increased rates of endothelial proliferation and neovascularization, tumor tissue growth, extensive necrosis, and aggressive local infiltrative character of GCCL cells.^[24]

Pathogenesis and Genetics

Several studies, both in giant cell tumor specimens and in cell lines, have identified rearrangement and amplification of the c-myc oncogene, sometimes in combination with mutations of the K-ras gene.^[34]^[35]

Overexpression of vascular endothelial growth factor (VEGF) has been shown to occur in GCCL and is thought to be related to the high metastatic potential of this lung cancer variant.^[21]

Malignant giant cells identical to those found in GCCL commonly occur in lung cancer cases with a prominent major or minor clear cell carcinoma pattern (for a discussion about this variant, see for example ^[36]). They have been hypothesized to derive from an undifferentiated multipotent malignant stem cell precursor that is generated in distal bronchioles via an as yet unknown oncogenetic pathway or oncogenetic driver.^[19]

Ultrastructurally, malignant giant cells often contain accumulations of microfilaments arranged in whorls near the cell nucleus. These entities appear similar in structure to microfilaments and bundles found in the D1 cell of the gastro-entero-pancreatic endocrine system, and it has been proposed that these D1 cells may be the cancer stem cell for at least some GCCL's. Identically appearing whorled filament structures have also been produced in certain airway cells of animals after treatment with carcinogenic nitrosamines.^[37]

Ultrastructural studies have suggested that the malignant giant cells in GCCL are of endodermal lineage.^[38]

Remarkably fast growing tumors.^[24]

Combined/Multiphasic Tumors Containing Giant Cells

Malignant giant cells are commonly found — and vary in relative proportion to a greater or lesser degree — in both primary tumors and metastatases of many different variants of lung carcinomas. A number of authors have noted that bizarre malignant giant cells occur more commonly in primary and secondary tumors — including any remaining tumor "deposits" — that have previously been treated with chemotherapy and/or radiation therapy in adjuvant or neoadjuvant protocols.^[38]

Imaging Characteristics

GCCL often presents as a large peripheral mass that is severely cavitated.^[39]

In a radiographic study of almost 2,000 lung cancer patients published 50 years ago, 3.4% of lung carcinomas proved to be cavitated masses,^[40] most of which were squamous cell carcinoma.

In a number of cases of severe cavitation, the resected tumor remnant consists of only a thin rim of proliferating cells.

Positron Emission Tomography Scanning

On Positron Emission Tomography scanning, GCCL has been found to have exceedingly high standardized uptake values (SUV) for radioactive glucose, values that are statistically significantly higher than in other histological variants of lung cancer.^[5]

Metabolic Pathways

PET scanning suggests that GCCL are tumors with particularly rapid metabolism, and that the metabolic pathways of GCCL may be unusually dependent on, or interlinked to, glycolysis.^[5]

Paraneoplastic Syndromes

GCCL have been long known^[41] for secretion of the beta subunit of human chorionic gonadotropin (beta-HCG), often in large amounts, which can lead to very high levels of estrogen and painful gynecomastia (breast enlargement) in males as paraneoplastic signs.^[42]

Giant cell lung cancers are well known for their paraneoplastic production and secretion of granulopoietic colony stimulating factor (G-CSF)^[35]^[43]

GCCL has also been reported to produce plasminogen activator as a paraneoplastic phenomenon.^[16]

Treatment

Because of its rarity, there have been no randomized clinical trials of treatment of GCCL, and all information available derives from small retrospective institutional series or multicenter metadata.^[44]

Prognosis

Giant cell lung cancers have long been considered to be exceptionally aggressive malignancies^[22]^[9]^[45] that grow very rapidly^[35] and have a very poor prognosis.^[8]

Many small series have suggested that the prognosis of lung tumors with giant cells is worse than that of most other forms of non-small cell lung cancer (NSCLC)^[18], including squamous cell carcinoma,^[8] and spindle cell carcinoma.^[8]

The overall five-year survival rate in GCCL varies between studies but is generally considered to be very low. The (US) Armed Forces Institute of Pathology has reported a figure of of 10%,^[46] and in a study examining over 150,000 lung cancer cases, a figure of 11.8% was given.^[2] However, in the latter report the 11.8% figure was based on data that included spindle cell carcinoma, a variant which is generally considered to have a less dismal prognosis that GCCL.^[18] Therefore, the likely survival of "pure" GCCL is probably lower than the stated figure.

In the large 1995 database review by Travis and colleagues, giant cell carcinoma was noted to have the third-worst prognosis among 18 histological forms of lung cancer (only small cell carcinoma and large cell carcinoma had shorter average survival).^[2]

Most GCCL have already grown and invaded locally and/or regionally, and/or have already metastasized distantly, and are inoperable, at the time of diagnosis.^[22]

History

Most sources credit Nash and Stout with publishing the first detailed report in the medical literature recognizing GCCL as a distinct clinicopathological entity in 1958.^[47] However, there is some evidence that suggests this tumor phenotype was described as early as 1951.^[20] In a report on 3 cases of giant cell lung carcinoma published in 1961 by Z.M. Naib, the author cites 2 previous studies related to GCCL — one published in 1951 by M.M. Patton and co-workers,^[48] and one published in 1955 by Walton and Pryce.^[49] In 1969, Dr. Alexander Kennedy, in a case series of 3 GCCL Kennedy published in 1969,^[22] credited Hadley and Bullock with the first usage of the term "giant cell carcinoma" 16 years prior.^[50]

GCCL was first confirmed as an epithelial tumor (and not a dedifferentiated pleomorphic sarcoma) in 1961.^[51] In 1964–65, theories were postulated that GCCL's were dediffentiated adenocarcinomas,^[52] and in some cases, were thought to derive from clear cell adenocarcinomas.^[36]

References

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^ Strang C, Simpson JA (1953). "Carcinomatous abscess of the lung". Thorax. 8 (1): 11–26. PMC 1019223. PMID 13038734. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Dailey JE, Marcuse PM (1969). "Gonadotropin secreting giant cell carcinoma of the lung". Cancer. 24 (2): 388–96. PMID 5796783. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Yaturu S, Harrara E, Nopajaroonsri C, Singal R, Gill S (2003). "Gynecomastia attributable to a human chorionic gonadotropin-secreting giant cell carcinoma of the lung". Endocr Pract. 9 (3): 231–5. PMID 12917067.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Kameda T; Kodama T; Shimosato Y (1982). Shimosato Y; Melamed MR; Nettesheim P (eds.). Morphogenesis of Lung Cancer. Vol. 2. Boca Raton, Florida: CRC Press. pp. 107–29.
^ Bae HM, Min HS, Lee SH, Kim DW, Chung DH, Lee JS, Kim YW, Heo DS (2007 Oct). "Palliative chemotherapy for pulmonary pleomorphic carcinoma". Lung Cancer. 58 (1): 112–5. doi:10.1016/j.lungcan.2007.05.006. PMID 17574296. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)
^ Razzuk MA, Urschel HC, Albers JE, Martin JA, Paulson DL (1976). "Pulmonary giant cell carcinoma". Ann. Thorac. Surg. 21 (6): 540–5. PMID 1275605. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Colby TV, Koss MN, Travis WD (1995). "Tumors of the lower respiratory tract". In Rosai J, Sobin LH (ed.). Atlas of Tumor Pathology. Washington DC: Armed Forces Institute of Pathology. pp. 259–75.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Nash AD, Stout AP (1958). "Giant cell carcinoma of the lung; report of 5 cases". Cancer. 11: 369–76.
^ Patton MM, McDonald JR, Moersch HJ (1951). "Bronchogenic large cell carcinoma". J Thor Surg. 22: 88.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Walter JB, Pryce DM (1955). "The histology of lung cancer". Thorax. 10 (2): 107–16. PMC 1019475. PMID 14396845. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Hadley GG, Bullock WK (1953). "Autopsy reports of pulmonary carcinoma; survey in Los Angeles County Hospital for 1951". Calif Med. 79 (6): 431–3. PMC 1521859. PMID 13106728. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Ozzello L, Stout AP (1961). "The epithelial origin of giant cell carcinoma of the lung confirmed by tissue culture. Report of a case". Cancer. 14: 1052–6. PMID 13731858.
^ Friedberg EC (1965). "Giant-Cell Carcinoma of the Lung: A dedifferentiated Adenocarcinoma". Cancer. 18: 259–64. PMID 14254083. {{cite journal}}: Unknown parameter |month= ignored (help)

External links

"Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart". World Health Organization Classification of Tumours. (Download Page).
"Lung cancer page". National Cancer Institute.

[who2004-1] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Travis, William D; Brambilla, Elisabeth; Muller-Hermelink, H Konrad; Harris, Curtis C, eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 92-832-2418-3. Retrieved 27 March 2010.

[TravisTravis-2] ^ ^a ^b ^c ^d ^e ^f ^g Travis WD, Travis LB, DeVesa SS (1995). "Lung Cancer". Cancer. 75: 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "TravisTravis" was defined multiple times with different content (see the help page).

[FactSheetLung-3] "Fact Sheet: Cancer of the Lung and Bronchus". National Cancer Institute, SEER Program. Retrieved February 24, 2012.

[MartinCorrea-4] Martin LW, Correa AM, Ordonez NG; et al. (2007). "Sarcomatoid carcinoma of the lung: a predictor of poor prognosis". Ann. Thorac. Surg. 84 (3): 973–80. doi:10.1016/j.athoracsur.2007.03.099. PMID 17720411. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) <!- Page given was 981? ->

[ParkLee-5] Park JS, Lee Y, Han J; et al. (2011). "Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung". Oncology. 81 (3–4): 206–13. doi:10.1159/000333095. PMID 22076573. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

[Hellstrom-6] Hellstrom HR, Fisher ER (1963). "Giant cell carcinoma of lung". Cancer. 16: 1080–8. PMID 14050012.

[KimKim-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Kim TH, Kim SJ, Ryu YH; et al. (2004). "Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings". Radiology. 232 (2): 554–9. doi:10.1148/radiol.2322031201. PMID 15215543. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[ZhaoSong-8] Zhao ZL, Song N, Huang QY, Liu YP, Zhao HR (February 2007). "[Clinicopathologic features of lung pleomorphic (spindle/giant cell) carcinoma—a report of 17 cases]". Ai Zheng (in Chinese). 26 (2): 183–8. PMID 17298750. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)CS1 maint: multiple names: authors list (link) (Chinese text)

[KallenbergJaque-9] Kallenberg F, Jaqué J (1979). "Giant cell carcinoma of the lung. Clinical and pathological assessment. Comparison with other large-cell anaplastic bronchogenic carcinomas". Scand J Thorac Cardiovasc Surg. 13 (3): 343–6. PMID 542838.

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[KennedyA-22] ^ ^a ^b ^c ^d ^e ^f Kennedy A (1969). "Pathology and survival in operable cases of giant-cell carcinoma of the lung". J. Clin. Pathol. 22 (3): 354–60. PMC 474089. PMID 5784984. {{cite journal}}: Unknown parameter |month= ignored (help)

[ShirakusaSigematsu-23] Shirakusa T, Shigematsu N, Koga T, Yamagata Y (1980). "Giant cell carcinoma arising in a pulmonary bulla". Scand J Thorac Cardiovasc Surg. 14 (3): 307–9. PMID 7221506.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[HagiharaAbe-24] Hagihara N, Abe T, Wakamiya T, Sugita Y, Watanabe M, Tabuchi K (2010). "A case of brain metastasis from pulmonary giant cell carcinoma". Kurume Med J. 57 (1–2): 39–41. PMID 21727764.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[SpivachBorea-25] Spivach A, Borea B, Bertoli G, Daris G (1976). "[Primary lung neoplasm of rare incidence: giant cell carcinoma]". Minerva Med. (in Italian). 67 (34): 2233–49. PMID 986035. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Travis2010-26] Travis WD (2010). "Sarcomatoid neoplasms of the lung and pleura". Arch. Pathol. Lab. Med. 134 (11): 1645–58. doi:10.1043/2010-0086-RAR.1. PMID 21043818. {{cite journal}}: Unknown parameter |month= ignored (help)

[Hayakawa1977-27] Hayakawa K, Takahashi M, Sasaki K, Kawaoi A, Okano T (1977). "Primary choriocarcinoma of the lung: case report of two male subjects". Acta Pathol. Jpn. 27 (1): 123–35. PMID 557868. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[WillebrandWernitsch-28] Willebrand H, Wernitsch W, Elmohamed A (1970). "[Pulmonary metastases of a giant-cell carcinoma in the bone—benign or malignant?]". Chirurg (in German). 41 (9): 419–23. PMID 5471024. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[HuangXu-29] Huang L, Xu J, Wood DJ, Zheng MH (2000). "Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation". Am. J. Pathol. 156 (3): 761–7. PMC 1876848. PMID 10702390. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[WernerM-30] Werner M (2006). "Giant cell tumour of bone: morphological, biological and histogenetical aspects". Int Orthop. 30 (6): 484–9. doi:10.1007/s00264-006-0215-7. PMC 3172738. PMID 17013643. {{cite journal}}: Unknown parameter |month= ignored (help)

[PaiLalitha-31] Pai SB, Lalitha RM, Prasad K, Rao SG, Harish K (2005). "Giant cell tumor of the temporal bone—a case report". BMC Ear Nose Throat Disord. 5: 8. doi:10.1186/1472-6815-5-8. PMC 1253509. PMID 16162299. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

[Thomas1962-32] Thomas C (1962). "[Giant cell carcinoma of the lungs]". Frankf Z Pathol (in German). 72: 302–8. PMID 13981042.

[WellmanChafiian-33] Wellmann KF, Chafiian Y, Edelman E (1969). "Small bowel perforation from solitary metastasis of clinically undetected pulmonary giant cell carcinoma". Am. J. Gastroenterol. 51 (2): 145–50. PMID 5776147. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[IizukaShiraishi-34] Le Doussal JM, Gruaz-Guyon A, Martin M, Gautherot E, Delaage M, Barbet J (1990). "Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice". Cancer Res. 50 (11): 3445–52. PMID 2334941. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[TayaHosogai-35] Taya Y, Hosogai K, Hirohashi S; et al. (1984). "A novel combination of K-ras and myc amplification accompanied by point mutational activation of K-ras in a human lung cancer". EMBO J. 3 (12): 2943–6. PMC 557793. PMID 6098458. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[MorganMacKenzie-36] Morgan AD, Mackenzie DH (1964). "Clear-cell Carcinoma of the Lung". J Pathol Bacteriol. 87: 25–7. PMID 14106350. {{cite journal}}: Unknown parameter |month= ignored (help)

[Carstens1978-37] Carstens PH, Broghamer WL (1978). "Duodenal carcinoid with cytoplasmic whorls of microfilaments". J. Pathol. 124 (4): 235–8. doi:10.1002/path.1711240408. PMID 569192. {{cite journal}}: Unknown parameter |month= ignored (help)

[Sidhu1979-38] Sidhu GS (1979). "The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature". Am. J. Pathol. 96 (1): 5–20. PMC 2042351. PMID 37740. {{cite journal}}: Unknown parameter |month= ignored (help)

[39] Culiner MM, Abouav J, Reich SB (1958). "Cavitary carcinoma of the lung". Calif Med. 89 (5): 355–8. PMC 1512515. PMID 13585165. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Strang-40] Strang C, Simpson JA (1953). "Carcinomatous abscess of the lung". Thorax. 8 (1): 11–26. PMC 1019223. PMID 13038734. {{cite journal}}: Unknown parameter |month= ignored (help)

[DaileyMarcuse-41] Dailey JE, Marcuse PM (1969). "Gonadotropin secreting giant cell carcinoma of the lung". Cancer. 24 (2): 388–96. PMID 5796783. {{cite journal}}: Unknown parameter |month= ignored (help)

[YaturuHarrara-42] Yaturu S, Harrara E, Nopajaroonsri C, Singal R, Gill S (2003). "Gynecomastia attributable to a human chorionic gonadotropin-secreting giant cell carcinoma of the lung". Endocr Pract. 9 (3): 231–5. PMID 12917067.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[KamedaKodama-43] Kameda T; Kodama T; Shimosato Y (1982). Shimosato Y; Melamed MR; Nettesheim P (eds.). Morphogenesis of Lung Cancer. Vol. 2. Boca Raton, Florida: CRC Press. pp. 107–29.

[BaeMin-44] Bae HM, Min HS, Lee SH, Kim DW, Chung DH, Lee JS, Kim YW, Heo DS (2007 Oct). "Palliative chemotherapy for pulmonary pleomorphic carcinoma". Lung Cancer. 58 (1): 112–5. doi:10.1016/j.lungcan.2007.05.006. PMID 17574296. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)

[RazzukUrschel-45] Razzuk MA, Urschel HC, Albers JE, Martin JA, Paulson DL (1976). "Pulmonary giant cell carcinoma". Ann. Thorac. Surg. 21 (6): 540–5. PMID 1275605. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[ColbyKoss-46] Colby TV, Koss MN, Travis WD (1995). "Tumors of the lower respiratory tract". In Rosai J, Sobin LH (ed.). Atlas of Tumor Pathology. Washington DC: Armed Forces Institute of Pathology. pp. 259–75.{{cite book}}: CS1 maint: multiple names: authors list (link)

[NashStout-47] Nash AD, Stout AP (1958). "Giant cell carcinoma of the lung; report of 5 cases". Cancer. 11: 369–76.

[PattonMcDonald-48] Patton MM, McDonald JR, Moersch HJ (1951). "Bronchogenic large cell carcinoma". J Thor Surg. 22: 88.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[WaltonPryce-49] Walter JB, Pryce DM (1955). "The histology of lung cancer". Thorax. 10 (2): 107–16. PMC 1019475. PMID 14396845. {{cite journal}}: Unknown parameter |month= ignored (help)

[HadleyBullock-50] Hadley GG, Bullock WK (1953). "Autopsy reports of pulmonary carcinoma; survey in Los Angeles County Hospital for 1951". Calif Med. 79 (6): 431–3. PMC 1521859. PMID 13106728. {{cite journal}}: Unknown parameter |month= ignored (help)

[OzzelloStout-51] Ozzello L, Stout AP (1961). "The epithelial origin of giant cell carcinoma of the lung confirmed by tissue culture. Report of a case". Cancer. 14: 1052–6. PMID 13731858.

[Friedberg-52] Friedberg EC (1965). "Giant-Cell Carcinoma of the Lung: A dedifferentiated Adenocarcinoma". Cancer. 18: 259–64. PMID 14254083. {{cite journal}}: Unknown parameter |month= ignored (help)

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@@ Line 25: / Line 25: @@
 h approximately 220,000 total lung cancers diagnosed in the [[United States|US]] each year,<ref name='FactSheetLung'>{{cite web |publisher=National Cancer Institute, SEER Program |title=Fact Sheet: Cancer of the Lung and Bronchus |url=http://seer.cancer.gov/statfacts/html/lungb.html |accessdate=February 24, 2012}}</ref> the proportion suggests that approximately 660 and 880 new cases are diagnosed in Americans annually.<ref name='TravisTravis' />
-<ref name='MartinCorrea'>{{cite journal | author = Martin LW, Correa AM, Ordonez ND ''et al.'' | year = 2007 | title = Sarcomatoid carcinoma of the lung - a predictor of poor prognosis | url = | journal = Ann Thorac Surg | volume = 84 | issue = | page = 981 }}</ref>
+<ref name='MartinCorrea'>{{cite journal |author=Martin LW, Correa AM, Ordonez NG, ''et al.'' |title=Sarcomatoid carcinoma of the lung: a predictor of poor prognosis |journal=Ann. Thorac. Surg. |volume=84 |issue=3 |pages=973–80 |year=2007 |month=September |pmid=17720411 |doi=10.1016/j.athoracsur.2007.03.099 |url=http://linkinghub.elsevier.com/retrieve/pii/S0003-4975(07)00910-1}} <!- Page given was 981? -></ref>
-However, in a more recent series of 4,212 consecutive lung cancer cases, only one (0.024%) [[lesion]] was determined to be a "pure" giant cell carcinoma after complete sectioning of all available tumor [[tissue]].<ref name='ParkLee'>Park JS, Lee Y, Han J, Kim HK, Choi YS, Kim J, Shim YM, Kim K: Clinicopathologic Outcomes of Curative Resection for Sarcomatoid Carcinoma of the Lung. ''Oncology'' 2011;81:206-213. DOI: 10.1159/000333095</ref> While some evidence suggests GCCL may have been considerably more common several decades ago, with one series identifying 3.4% of all lung carcinomas as giant cell malignancies,<ref name='Hellstrom'>{{cite journal |author=Hellstrom HR, Fisher ER |title=Giant cell carcinoma of lung |journal=Cancer |year=1963 |volume=16 |pages=1080–8 |pmid=14050012}}</ref> it is possible that this number reflect
+However, in a more recent series of 4,212 consecutive lung cancer cases, only one (0.024%) [[lesion]] was determined to be a "pure" giant cell carcinoma after complete sectioning of all available tumor [[tissue]].<ref name='ParkLee'>{{cite journal |author=Park JS, Lee Y, Han J, ''et al.'' |title=Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung |journal=Oncology |volume=81 |issue=3-4 |pages=206–13 |year=2011 |pmid=22076573 |doi=10.1159/000333095 |url=http://content.karger.com/produktedb/produkte.asp?DOI=10.1159/000333095}}</ref> While some evidence suggests GCCL may have been considerably more common several decades ago, with one series identifying 3.4% of all lung carcinomas as giant cell malignancies,<ref name='Hellstrom'>{{cite journal |author=Hellstrom HR, Fisher ER |title=Giant cell carcinoma of lung |journal=Cancer |year=1963 |volume=16 |pages=1080–8 |pmid=14050012}}</ref> it is possible that this number reflect
-Most published case series and reports on giant cell-containing lung cancers show that they are diagnosed much more frequently in men than they are in women,<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref><ref name='ZhaoSong'>{{cite journal |author=Zhao ZL, Song N, Huang QY, Liu YP, Zhao HR |trans_title=Clinicopathologic features of lung pleomorphic (spindle/giant cell) carcinoma--a report of 17 cases |journal=Ai Zheng |date=2007 Feb |volume=26 |issue=2 |pages=183–8 |pmid=17298750 |language=Chinese |title=[Clinicopathologic features of lung pleomorphic (spindle/giant cell) carcinoma--a report of 17 cases]}} [http://www.cjcsysu.cn/fulltextnew.asp?y=2007&m=2&ym=183 (Chinese text)]</ref> with some studies showing extremely high male-to-female ratios (12:1 or more). In a study of over 150,000 lung cancer victims in the US, however, the gender ratio was just over 2:1, with women actually having a higher relative proportion of giant cell cancers (0.4%) than men (0.3%).<ref name='TravisTravis' />
+Most published case series and reports on giant cell-containing lung cancers show that they are diagnosed much more frequently in men than they are in women,<ref name='KimKim'>{{cite journal |author=Kim TH, Kim SJ, Ryu YH, ''et al.'' |title=Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings |journal=Radiology |volume=232 |issue=2 |pages=554–9 |year=2004 |month=August |pmid=15215543 |doi=10.1148/radiol.2322031201 |url=http://radiology.rsnajnls.org/cgi/pmidlookup?view=long&pmid=15215543}}</ref><ref name='ZhaoSong'>{{cite journal |author=Zhao ZL, Song N, Huang QY, Liu YP, Zhao HR |trans_title=Clinicopathologic features of lung pleomorphic (spindle/giant cell) carcinoma—a report of 17 cases |journal=Ai Zheng |date=February 2007 |volume=26 |issue=2 |pages=183–8 |pmid=17298750 |language=Chinese |title=[Clinicopathologic features of lung pleomorphic (spindle/giant cell) carcinoma—a report of 17 cases]}} [http://www.cjcsysu.cn/fulltextnew.asp?y=2007&m=2&ym=183 (Chinese text)]</ref> with some studies showing extremely high male-to-female ratios (12:1 or more). In a study of over 150,000 lung cancer victims in the US, however, the gender ratio was just over 2:1, with women actually having a higher relative proportion of giant cell cancers (0.4%) than men (0.3%).<ref name='TravisTravis' />
-Giant cell carcinomas have been reported to be diagnosed in a significantly younger population than all non-small cell carcinomas considered as a group.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref><ref name='KallenbergJaque'>{{cite journal |author=Kallenberg F, Jaqué J |title=Giant cell carcinoma of the lung. Clinical and pathological assessment. Comparison with other large-cell anaplastic [[bronchus|bronchogenic]] [[carcinoma|carcinomas]]. |journal=Scand J Thorac Cardiovasc Surg |year=1979 |volume=13 |issue=3 |pages=343–6 |pmid=542838 }}</ref> Like nearly all lung carcinomas, however, GCC's are exceedingly rare in very young people: in the US [[Surveillance Epidemiology and End Results|SEER]] program, only 2 cases were recorded to occur in persons younger than 30 years of age between 1983 and 1987.<ref name='TravisTravis'/> The average age at diagnosis of these tumors has been estimated at 60 years.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref>
+Giant cell carcinomas have been reported to be diagnosed in a significantly younger population than all non-small cell carcinomas considered as a group.<ref name='KimKim'/><ref name='KallenbergJaque'>{{cite journal |author=Kallenberg F, Jaqué J |title=Giant cell carcinoma of the lung. Clinical and pathological assessment. Comparison with other large-cell anaplastic [[bronchus|bronchogenic]] [[carcinoma|carcinomas]]. |journal=Scand J Thorac Cardiovasc Surg |year=1979 |volume=13 |issue=3 |pages=343–6 |pmid=542838 }}</ref> Like nearly all lung carcinomas, however, GCC's are exceedingly rare in very young people: in the US [[Surveillance Epidemiology and End Results|SEER]] program, only 2 cases were recorded to occur in persons younger than 30 years of age between 1983 and 1987.<ref name='TravisTravis'/> The average age at diagnosis of these tumors has been estimated at 60 years.<ref name='KimKim'/>
-The vast majority of individuals with GCCL are heavy smokers,<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref>
+The vast majority of individuals with GCCL are heavy smokers,<ref name='KimKim'/>
-Although the definitions of "[[Hilum_of_lung|central]]" and "[[bronchiole|peripheral]]" can vary<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref> between studies, GCCL are consistently diagnosed much more frequently in the [[lung]] periphery.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref><ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref> In a review of literature compiled by Kallenburg and co-workers, less than 30% of GCCL's arose in the hilum or other parts of the "central" pulmonary tree.<ref name='KallenbergJaque' />
+Although the definitions of "[[Hilum_of_lung|central]]" and "[[bronchiole|peripheral]]" can vary<ref name='KimKim'/> between studies, GCCL are consistently diagnosed much more frequently in the [[lung]] periphery.<ref name='KimKim'/> In a review of literature compiled by Kallenburg and co-workers, less than 30% of GCCL's arose in the hilum or other parts of the "central" pulmonary tree.<ref name='KallenbergJaque' />
-A significant predilection for genesis of GCCL in the upper lobes of victims has also been postulated.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref>
+A significant predilection for genesis of GCCL in the upper lobes of victims has also been postulated.<ref name='KimKim'/>
 ===Classification===
@@ Line 53: / Line 53: @@
 #[[Salivary gland–like carcinoma of the lung|Salivary gland-like carcinoma]]
-The subclassification of GCCL among these major taxa has undergone significant changes in recent decades. Under the 2nd revision (1981) of the WHO classification, it was considered a subtype of [[large-cell lung carcinoma|large cell carcinoma]].<ref name='WHO2'>World Health Organization. Histological typing of Lung Tumours. 2nd Edn. Geneva: World Health Organization, 1981.</ref> In the 3rd (1999) revision,<ref name='WHO1999'>{{cite journal | author = Brambilla E, Travis WD, Colby TV ''et al.'' | year = 2001 | title = The new World Health Organization classification of lung tumours | url = | journal = Eur Resp J | volume = 18 | issue = | pages = 1059–68 }}</ref> it was placed within a taxon called "Carcinomas with Pleomorphic, Sarcomatoid, or Sarcomatous Elements", along with  [[pleomorphic carcinoma]], [[spindle cell carcinoma]], [[carcinosarcoma]], and [[pulmonary blastoma]], which are (arguably) related variants. While the 4th revision ("WHO-2004") retained the same grouping of lesions as the 3rd revision, the name of the major taxon was shortened to "[[sarcomatoid carcinoma of the lung|sarcomatoid carcinomas]".<ref name='who2004' />
+The subclassification of GCCL among these major taxa has undergone significant changes in recent decades. Under the 2nd revision (1981) of the WHO classification, it was considered a subtype of [[large-cell lung carcinoma|large cell carcinoma]].<ref name='WHO2'>{{cite book |author=World Health Organization |title=Histological typing of Lung Tumours |publisher=World Health Organization |location=Geneva |year=1981 |edition=2nd}}</ref> In the 3rd (1999) revision,<ref name='WHO1999'>{{cite journal |author=Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y |title=The new World Health Organization classification of lung tumours |journal=Eur. Respir. J. |volume=18 |issue=6 |pages=1059–68 |year=2001 |month=December |pmid=11829087 |url=http://erj.ersjournals.com/cgi/pmidlookup?view=long&pmid=11829087}}</ref> it was placed within a taxon called "Carcinomas with Pleomorphic, Sarcomatoid, or Sarcomatous Elements", along with  [[pleomorphic carcinoma]], [[spindle cell carcinoma]], [[carcinosarcoma]], and [[pulmonary blastoma]], which are (arguably) related variants. While the 4th revision ("WHO-2004") retained the same grouping of lesions as the 3rd revision, the name of the major taxon was shortened to "[[sarcomatoid carcinoma of the lung|sarcomatoid carcinomas]".<ref name='who2004' />
-The current rules for classifying lung cancers under WHO-2004, while useful and improved, remain to some extent fairly complex, ambiguous, arbitrary, and incomplete.<ref name='who2004' /> Although it is fairly common for mixed tumors that are seen to contain malignant giant cells to be called "giant cell carcinomas", ''accurate'' classification of a pulmonary tumor as a GCCL requires that the ''entire tumor'' consists ''only'' of malignant giant cells. Therefore, complete sampling of the entire tumor - obtained via a [[surgery|surgical]] [[resection]] - is absolutely necessary for a definitive diagnosis of GCCL to be made.<ref name='who2004' />
+The current rules for classifying lung cancers under WHO-2004, while useful and improved, remain to some extent fairly complex, ambiguous, arbitrary, and incomplete.<ref name='who2004' /> Although it is fairly common for mixed tumors that are seen to contain malignant giant cells to be called "giant cell carcinomas", ''accurate'' classification of a pulmonary tumor as a GCCL requires that the ''entire tumor'' consists ''only'' of malignant giant cells. Therefore, complete sampling of the entire tumor — obtained via a [[surgery|surgical]] [[resection]] — is absolutely necessary for a definitive diagnosis of GCCL to be made.<ref name='who2004' />
 ===Microscopic Features and Cytology===
 The background contained numerous lymphocytes and neutrophils. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5-fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round.
-In cytological preparations, giant cells typically appear as single cells or in flat loose clusters, and occasionally in fascicles.<ref name='HiroshimaDosaka'>Hiroshima K, Dosaka-Akita H, Usuda K, Ogura S, Kusunoki Y, Kodama T, Saito Y, Sato M, Tagawa Y, Baba M, Hirano T, Horai T, Matsuno Y. Cytological characteristics of pulmonary pleomorphic and giant cell carcinomas. ''Acta Cytol'' 2011;55:173-9.</ref>
+In cytological preparations, giant cells typically appear as single cells or in flat loose clusters, and occasionally in fascicles.<ref name='HiroshimaDosaka'>{{cite journal |author=Hiroshima K, Dosaka-Akita H, Usuda K, ''et al.'' |title=Cytological characteristics of pulmonary pleomorphic and giant cell carcinomas |journal=Acta Cytol. |volume=55 |issue=2 |pages=173–9 |year=2011 |pmid=21325803 |doi=10.1159/000320860 |url=http://content.karger.com/produktedb/produkte.asp??DOI=000320860&typ=pdf}}</ref>
-GCCL are considered a member of the most common type of [[lung cancer]], called "[[Non-small-cell lung carcinoma|non-small cell carcinomas]]". This group of lethal neoplasms make up approximately 85% of all lung cancers.<ref name='who2004' /> By the definition of "large-vs.-small cell carcinoma", the diameter of GCCL cells '''must''' be considerably greater than three times that of a resting (i.e. unstimulated) [[lymphocyte]]. Also by definition, GCCL do '''not''' contain '''any''' amount of these small, neurosecretory granule-containing, [[neuroendocrine]] cells that are characteristic of [[small cell carcinoma|small cell carcinomas]] - when they do, the tumor should be classified as a [[combined small-cell lung carcinoma|combined small cell carcinoma]].<ref name='who2004' />
+GCCL are considered a member of the most common type of [[lung cancer]], called "[[Non-small-cell lung carcinoma|non-small cell carcinomas]]". This group of lethal neoplasms make up approximately 85% of all lung cancers.<ref name='who2004' /> By the definition of "large-vs.-small cell carcinoma", the diameter of GCCL cells '''must''' be considerably greater than three times that of a resting (i.e. unstimulated) [[lymphocyte]]. Also by definition, GCCL do '''not''' contain '''any''' amount of these small, neurosecretory granule-containing, [[neuroendocrine]] cells that are characteristic of [[small cell carcinoma|small cell carcinomas]] — when they do, the tumor should be classified as a [[combined small-cell lung carcinoma|combined small cell carcinoma]].<ref name='who2004' />
-Compared to most other lung cancer variants, cells comprising GCCL tend to be much larger (up to 150 micrometers diameter, or even larger),<ref name='DavidsonMcNicol'>Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS. Plasminogen activator-producing tumour. ''Br Med J'' 1969;1:88-91</ref> Both cells and nuclei show extreme variation in size distribution and shape. Carcinomatous giant cells carcinoma nuclei have been reported to average 5 times the size of lymphocyte nuclei. <ref name='HiroshimaDosaka'>Hiroshima K, Dosaka-Akita H, Usuda K, Ogura S, Kusunoki Y, Kodama T, Saito Y, Sato M, Tagawa Y, Baba M, Hirano T, Horai T, Matsuno Y. Cytological characteristics of pulmonary pleomorphic and giant cell carcinomas. ''Acta Cytol'' 2011;55:173-9.</ref>
+Compared to most other lung cancer variants, cells comprising GCCL tend to be much larger (up to 150 micrometers diameter, or even larger),<ref name='DavidsonMcNicol'>{{cite journal |author=Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS |title=Plasminogen-activator-producing tumour |journal=Br Med J |volume=1 |issue=5636 |pages=88–91 |year=1969 |month=January |pmid=5761832 |pmc=1982019 }}</ref> Both cells and nuclei show extreme variation in size distribution and shape. Carcinomatous giant cells carcinoma nuclei have been reported to average 5 times the size of lymphocyte nuclei. <ref name='HiroshimaDosaka'/>
 The cells from giant cell carcinomas are [[anaplastic]], and show no evidence of cell maturation or differentiation, lacking the [[cytology|cytological]] and tissue architectural characteristics of [[squamous cell carcinoma]], [[adenocarcinoma]], [[neuroendocrine]] carcinomas, or other more differentiated lung cancer cell types. They tend to be highly pleomorphic (i.e. variable in characteristics), but are most often round and/or polygonal in shape, with a relatively low nuclear-to-[[cytoplasm|cytoplasmic]] ratio. When associated with spindle cells, as they very frequently are in tumors with mixed histology, malignant giant cells tend to form loosely cohesive aggregate structures on cytological examination. However, when a [[biopsy]] sample consists purely of malignant giant cells, the cells tend to be single and disaggregated.<ref name='who2004' />
-Case series suggest that the relative number of giant cells in a given tumor are generally directly proportional to the size of the tumor, and to the relative amount of necrosis.<ref name='CacicOberman'>Cacic M, Oberman B, Dvornik G. Investigation of the applicability of the histological classification of bronchial carcinoma according to the World Health Organization. ''Tumori'' 1989;75:580-2.</ref>+
+Case series suggest that the relative number of giant cells in a given tumor are generally directly proportional to the size of the tumor, and to the relative amount of necrosis.<ref name='CacicOberman'>{{cite journal |author=Caci&#x107; M, Oberman B, Dvornik G |title=Investigation of the applicability of histological classification of bronchial carcinoma according to the World Health Organization |journal=Tumori |volume=75 |issue=6 |pages=580–2 |year=1989 |month=December |pmid=2482566 }}</ref>
-Giant cells in a lung cancer are highly associated with the presence of spindle cells.<ref name='MatsuiKitagawa'>Matsui K, Kitagawa M. Spindle cell carcinoma of the lung: a clinicopathologic study of three cases. ''Cancer'' 1991;67:2361-7.</ref>
+Giant cells in a lung cancer are highly associated with the presence of spindle cells.<ref name='MatsuiKitagawa'>{{cite journal |author=Matsui K, Kitagawa M |title=Spindle cell carcinoma of the lung. A clinicopathologic study of three cases |journal=Cancer |volume=67 |issue=9 |pages=2361–7 |year=1991 |month=May |pmid=1707339 }}</ref>
-The [[chromatin]] of malignant giant cells tends to be hyperchromatic and coarsely clumped. Nucleoli are usually multiple and prominent.<ref name='DavidsonMcNicol'>Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS. Plasminogen activator-producing tumour. ''Br Med J'' 1969;1:88-91</ref>
+The [[chromatin]] of malignant giant cells tends to be hyperchromatic and coarsely clumped. Nucleoli are usually multiple and prominent.<ref name='DavidsonMcNicol'/>
-Subcellular characteristics often noted in the malignant giant cells of GCCL cases include abundant mitochondria, concentric whorls of tonofilament-like fibrils, and aggregates of several pairs of centrioles.<ref name='WangSeemayer'>Wang NS, Seemayer TA, Ahmed MN, Knaack J. Giant cell carcinoma of the lung. A light and electron microscopic study. ''Hum Pathol'' 1976;7:3-16</ref>
+Subcellular characteristics often noted in the malignant giant cells of GCCL cases include abundant mitochondria, concentric whorls of tonofilament-like fibrils, and aggregates of several pairs of centrioles.<ref name='WangSeemayer'>{{cite journal |author=Wang NS, Seemayer TA, Ahmed MN, Knaack J |title=Giant cell carcinoma of the lung. A light and electron microscopic study |journal=Hum. Pathol. |volume=7 |issue=1 |pages=3–16 |year=1976 |month=January |pmid=172430 }}</ref>
-Both "tumor cell-tumor cell" and "leukocyte-tumor cell" emperipolesis (i.e. active penetration of the latter by the former) is very commonly seen in cases of GCCL.<ref name='WangSeemayer'>Wang NS, Seemayer TA, Ahmed MN, Knaack J. Giant cell carcinoma of the lung. A light and electron microscopic study. ''Hum Pathol'' 1976;7:3-16</ref>
+Both "tumor cell-tumor cell" and "leukocyte-tumor cell" emperipolesis (i.e. active penetration of the latter by the former) is very commonly seen in cases of GCCL.<ref name='WangSeemayer'/>
 ===Tissue Architectural Features===
-In mixed tumors, giant cells are more likely to be found in higher proportions at the edge of a tumor.<ref name='MatsuiKitagawa'>Matsui K, Kitagawa M. Spindle cell carcinoma of the lung: a clinicopathologic study of three cases. ''Cancer'' 1991;67:2361-7.</ref> When extensive necrosis is present, it is possible for a giant cell tumor to have only a thin rim of viable cells remaining at the perimeter of the mass.
+In mixed tumors, giant cells are more likely to be found in higher proportions at the edge of a tumor.<ref name='MatsuiKitagawa'/> When extensive necrosis is present, it is possible for a giant cell tumor to have only a thin rim of viable cells remaining at the perimeter of the mass.
-In one early case series, abundant production of loose malignant giant cells were noted to fill the [[alveoli]] of victims without destroying, infiltrating, or disturbing the normal underlying architecture, a [[pathology|pathologic]] behavior that bears some resemblance to the pneumonic variant of [[bronchioloalveolar carcinoma]].<ref name='Zaib'>Naib ZM. Giant cell carcinoma of the lung: cytological study of the exfoliated cells in sputa and bronchial washings. ''Dis Chest'' 1961;40:69-73</ref>
+In one early case series, abundant production of loose malignant giant cells were noted to fill the [[alveoli]] of victims without destroying, infiltrating, or disturbing the normal underlying architecture, a [[pathology|pathologic]] behavior that bears some resemblance to the pneumonic variant of [[bronchioloalveolar carcinoma]].<ref name='Zaib'/>
-Extensive tumor necrosis and hemorrhage is extremely common in GCCL.<ref name='Zaib'>Zaib ZM. Giant cell carcinoma of the lung: cytological study of the exfoliated cells in sputa and bronchial washings. ''Dis Chest'' 1961;40:69-73.</ref>
+Extensive tumor necrosis and hemorrhage is extremely common in GCCL.<ref name='Zaib'/>
-Although the issue has not been extensively studied in a controlled fashion, GCCL's have been noted to contain significantly elevated levels of [[VEGF]].<ref name='JiangLu'>{{cite journal | author = Jiang DF, Lu YL, Qiu ZY ''et al.'' | year = 2003 | title = Study of differential expression of molecules affecting the metastatic potential between highly and poorly metastatic human lung giant cell carcinoma | url = | journal = Zhonghua Zhong Liu Za Zai | volume = 25 | issue = | pages = 131–4 }}</ref> However, in one study where a giant cell carcinoma tumor that had been completely excised was sectioned and examined, no qualitative or quantitative abnormalities in tissue vascularization were noted.<ref name='DavidsonMcNicol'>Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS. Plasminogen activator-producing tumour. ''Br Med J'' 1969;1:88-91</ref>
+Although the issue has not been extensively studied in a controlled fashion, GCCL's have been noted to contain significantly elevated levels of [[VEGF]].<ref name='JiangLu'>{{cite journal | author = Jiang DF, Lu YL, Qiu ZY ''et al.'' | year = 2003 | title = Study of differential expression of molecules affecting the metastatic potential between highly and poorly metastatic human lung giant cell carcinoma | journal = Zhonghua Zhong Liu Za Zai | volume = 25 | pages = 131–4 }}</ref> However, in one study where a giant cell carcinoma tumor that had been completely excised was sectioned and examined, no qualitative or quantitative abnormalities in tissue vascularization were noted.<ref name='DavidsonMcNicol'/>
-GCCL have been noted to be encapsulated, and to be divided via septa into "pseudolobules", by a highly fibrous stroma, suggested to be produced commensurately with tumor growth. The capsule is typically infiltrated with malignant giant cells.<ref name='KennedyA'>Kennedy A. Pathology and survival in operable cases of giant-cell carcinoma of the lung. ''J Clin Pathol'' 1969;22:354-60</ref>
+GCCL have been noted to be encapsulated, and to be divided via septa into "pseudolobules", by a highly fibrous stroma, suggested to be produced commensurately with tumor growth. The capsule is typically infiltrated with malignant giant cells.<ref name='KennedyA'>{{cite journal |author=Kennedy A |title=Pathology and survival in operable cases of giant-cell carcinoma of the lung |journal=J. Clin. Pathol. |volume=22 |issue=3 |pages=354–60 |year=1969 |month=May |pmid=5784984 |pmc=474089 |url=http://jcp.bmj.com/cgi/pmidlookup?view=long&pmid=5784984}}</ref>
 ===Macroscopic Features===
-Giant cell carcinomas of the lung frequently show extensive necrosis<ref name='KennedyA'>Kennedy A. Pathology and survival in operable cases of giant-cell carcinoma of the lung. ''J Clin Pathol'' 1969;22:354-60</ref> and myxoid degeneration.<ref name='MatsuiKitagawa'>Matsui K, Kitagawa M. Spindle cell carcinoma of the lung: a clinicopathologic study of three cases. ''Cancer'' 1991;67:2361-7</ref>
+Giant cell carcinomas of the lung frequently show extensive necrosis<ref name='KennedyA'/> and myxoid degeneration.<ref name='MatsuiKitagawa'/>
-A trend toward less vascularity and tissue density (with lower contrast enhancement on CT) has been noted toward the center of these lesions, especially in larger tumors, and even in tumors without a significant volume of gross necrosis.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref>
+A trend toward less vascularity and tissue density (with lower contrast enhancement on CT) has been noted toward the center of these lesions, especially in larger tumors, and even in tumors without a significant volume of gross necrosis.<ref name='KimKim'/>
-Grossly, the cut surfaces of these malignancies are often gray-white or tan, and frequently show myxoid, necrotic, and/or hemorrhagic foci.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref> These sorts of areas often show low levels of contrast enhancement on [[CT]] scanning.
+Grossly, the cut surfaces of these malignancies are often gray-white or tan, and frequently show myxoid, necrotic, and/or hemorrhagic foci.<ref name='KimKim'/> These sorts of areas often show low levels of contrast enhancement on [[CT]] scanning.
-Low encapsularity and high levels of tissue collagen tend to be observed, with high contrast enhancement in these areas.<ref name='KimKim'>Kim TH, Kim SJ, Ryu YH. ''et al''. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings. ''Radiology 2004;232:554-9.</ref>
+Low encapsularity and high levels of tissue collagen tend to be observed, with high contrast enhancement in these areas.<ref name='KimKim'/>
-GCCL have been seen to develop from/in [[emphysema|emphysematous]] [[bulla|bullae]].<ref name='ShirakusaSigematsu'>Shirakusa T, Shigematsu N, Koga T, Yamagata Y. Giant cell carcinoma arising in a pulmonary bulla. ''Scand J Thorac Cardiovasc Surg'' 1980;14:307-9.</ref>
+GCCL have been seen to develop from/in [[emphysema|emphysematous]] [[bulla|bullae]].<ref name='ShirakusaSigematsu'>{{cite journal |author=Shirakusa T, Shigematsu N, Koga T, Yamagata Y |title=Giant cell carcinoma arising in a pulmonary bulla |journal=Scand J Thorac Cardiovasc Surg |volume=14 |issue=3 |pages=307–9 |year=1980 |pmid=7221506 }}</ref>
 ===Staining and Immunohistochemistry===
-A case of a brain metastasis from a giant cell lung carcinoma (both "pure") tested positive for cytokeratins AE1/AE3, and negative for CK-7, CK-20, TTF-1, and GFAP.<ref name='HagiharaAbe'>Hagihara N, Abe T, Wakamiya T, Sugita Y, Watanabe M, Tabuchi K. A case of brain metastasis from pulmonary giant cell carcinoma. ''Kurume Med J'' 2010;57:39-41.</ref>
+A case of a brain metastasis from a giant cell lung carcinoma (both "pure") tested positive for cytokeratins AE1/AE3, and negative for CK-7, CK-20, TTF-1, and GFAP.<ref name='HagiharaAbe'>{{cite journal |author=Hagihara N, Abe T, Wakamiya T, Sugita Y, Watanabe M, Tabuchi K |title=A case of brain metastasis from pulmonary giant cell carcinoma |journal=Kurume Med J |volume=57 |issue=1-2 |pages=39–41 |year=2010 |pmid=21727764 |url=http://joi.jlc.jst.go.jp/JST.JSTAGE/kurumemedj/57.39?from=PubMed}}</ref>
-GCCL cells often stain intensely by Periodic acid-Schiff reagent, suggesting the presence of significant amounts of glycogen in the cell [[cytoplasm]].<ref name='KennedyA'>Kennedy A. Pathology and survival in operable cases of giant-cell carcinoma of the lung. ''J Clin Pathol'' 1969;22:354-60</ref>
+GCCL cells often stain intensely by Periodic acid-Schiff reagent, suggesting the presence of significant amounts of glycogen in the cell [[cytoplasm]].<ref name='KennedyA'/>
 ===Differential Diagnosis===
-Under light [[microscope|microscopy]], the giant malignant pleomorphic cells making up a GCCL resemble those found in [[choriocarcinoma]],<ref name='who2004' /> angiosarcoma,<ref name='SpivachBorea'>Spivach A, Borea B, Bertoli G, Daris G. Primary lung neoplasm of rare incidence: giant cell carcinoma. ''Minerva Med'' 1976;67:2233-49</ref> and some forms of true [[sarcoma]],<ref name='who2004' /> such as malignant fibrous histiocytoma<ref name='who2004' /> and rhabdomyosarcoma.<ref name='DavidsonMcNicol'>Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS. Plasminogen activator-producing tumour. ''Br Med J'' 1969;1:88-91</ref> In some instances, they can also bear considerable resemblance to "activated" [[histiocyte|histiocytes]] seen in some [[inflammation|inflammatory]] conditions.<ref name='DavidsonMcNicol'>Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS. Plasminogen activator-producing tumour. ''Br Med J'' 1969;1:88-91</ref>
+Under light [[microscope|microscopy]], the giant malignant pleomorphic cells making up a GCCL resemble those found in [[choriocarcinoma]],<ref name='who2004' /> angiosarcoma,<ref name='SpivachBorea'>{{cite journal |author=Spivach A, Borea B, Bertoli G, Daris G |title=[Primary lung neoplasm of rare incidence: giant cell carcinoma] |language=Italian |journal=Minerva Med. |volume=67 |issue=34 |pages=2233–49 |year=1976 |month=July |pmid=986035 }}</ref> and some forms of true [[sarcoma]],<ref name='who2004' /> such as malignant fibrous histiocytoma<ref name='who2004' /> and rhabdomyosarcoma.<ref name='DavidsonMcNicol'/> In some instances, they can also bear considerable resemblance to "activated" [[histiocyte|histiocytes]] seen in some [[inflammation|inflammatory]] conditions.<ref name='DavidsonMcNicol'/>
-A rare and potentially difficult differential diagnostic dilemma occurs when GCCL's must be separated from pulmonary or [[mediastinum|mediastinal]] [[choriocarcinomas]], a critical distinction to me made because while there is a known standard of care for treating choriocarcinoma, as yet there is no generally accepted specific standard treatment for GCCL. Careful review of cell morphology is key to their delineation - while GCCL's show great variation in cell size distributions and morphologies in tumors, choriocarcinomas consistently contain only [[syncytiotrophoblasts]] and [[cytotrophoblasts]].<ref name='Travis2010'>Travis WD. Sarcomatoid neoplasms of the lung and pleura. ''Arch Pathol Lab Med'' 2010;134:1645-58.</ref>GCCL and primary pulmonary choriocarcinoma can also be differentiated on the basis of ultrastructural features by [[electron microscope|electron microscopy]], although EM is not yet widely applicable. <ref name='Hayakawa1977'>Hayakawa K, Takahashi M, Sasaki K, Kawaoi A, Okano T. Primary choriocarcinoma of the lung: case report of two male subjects. ''Acta Pathol Jpn'' 1977;27:123-35.</ref>
+A rare and potentially difficult differential diagnostic dilemma occurs when GCCL's must be separated from pulmonary or [[mediastinum|mediastinal]] [[choriocarcinomas]], a critical distinction to me made because while there is a known standard of care for treating choriocarcinoma, as yet there is no generally accepted specific standard treatment for GCCL. Careful review of cell morphology is key to their delineation — while GCCL's show great variation in cell size distributions and morphologies in tumors, choriocarcinomas consistently contain only [[syncytiotrophoblasts]] and [[cytotrophoblasts]].<ref name='Travis2010'>{{cite journal |author=Travis WD |title=Sarcomatoid neoplasms of the lung and pleura |journal=Arch. Pathol. Lab. Med. |volume=134 |issue=11 |pages=1645–58 |year=2010 |month=November |pmid=21043818 |doi=10.1043/2010-0086-RAR.1 |url=http://www.archivesofpathology.org/doi/full/10.1043/2010-0086-RAR.1}}</ref>GCCL and primary pulmonary choriocarcinoma can also be differentiated on the basis of ultrastructural features by [[electron microscope|electron microscopy]], although EM is not yet widely applicable. <ref name='Hayakawa1977'>{{cite journal |author=Hayakawa K, Takahashi M, Sasaki K, Kawaoi A, Okano T |title=Primary choriocarcinoma of the lung: case report of two male subjects |journal=Acta Pathol. Jpn. |volume=27 |issue=1 |pages=123–35 |year=1977 |month=January |pmid=557868 }}</ref>
-Occasionally, a bone metastasis of a GCCL could potentially be mistaken for a primary [[giant-cell tumor of bone|giant cell tumor of bone]]<ref name='WillebrandWernitsch'>Willebrand H, Wernitsch W, Elmohamed A. Pulmonary metastases of a giant-cell carcinoma in the bone--benign or malignant? ''Chirurg'' 1970;41:419-23.</ref> - interestingly, the latter entity can behave as a [[neoplasm]] of [[benign]], frankly malignant,<ref name='HuangXu'>Huang L, Xu J, Wood DJ, Zheng MH. Gene Expression of Osteoprotegerin Ligand, Osteoprotegerin, and Receptor Activator of NF-kB in Giant Cell Tumor of Bone. ''Am J Pathol'' 2000;156:761-7.</ref> or borderline<ref name='WernerM'>Werner M. Giant cell tumour of bone: morphological, biological and histogenetical aspects ''Int Orthop'' 2006;30:484-9.</ref> in its clinical behavior.<ref name='PaiLalitha'>{{cite journal | author = Pai SB, Lalitha RM, Prasad K, Rao SG, Harish K | year = 2005 | title = Giant cell tumor of the temporal bone—a case report | url = | journal = BMC Ear Nose Throat Disord | volume = 2005 | issue = | page = 8 }}</ref>
+Occasionally, a bone metastasis of a GCCL could potentially be mistaken for a primary [[giant-cell tumor of bone|giant cell tumor of bone]]<ref name='WillebrandWernitsch'>{{cite journal |author=Willebrand H, Wernitsch W, Elmohamed A |title=[Pulmonary metastases of a giant-cell carcinoma in the bone—benign or malignant?] |language=German |journal=Chirurg |volume=41 |issue=9 |pages=419–23 |year=1970 |month=September |pmid=5471024 }}</ref> — interestingly, the latter entity can behave as a [[neoplasm]] of [[benign]], frankly malignant,<ref name='HuangXu'>{{cite journal |author=Huang L, Xu J, Wood DJ, Zheng MH |title=Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation |journal=Am. J. Pathol. |volume=156 |issue=3 |pages=761–7 |year=2000 |month=March |pmid=10702390 |pmc=1876848 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9440(10)64942-5}}</ref> or borderline<ref name='WernerM'>{{cite journal |author=Werner M |title=Giant cell tumour of bone: morphological, biological and histogenetical aspects |journal=Int Orthop |volume=30 |issue=6 |pages=484–9 |year=2006 |month=December |pmid=17013643 |pmc=3172738 |doi=10.1007/s00264-006-0215-7 }}</ref> in its clinical behavior.<ref name='PaiLalitha'>{{cite journal |author=Pai SB, Lalitha RM, Prasad K, Rao SG, Harish K |title=Giant cell tumor of the temporal bone—a case report |journal=BMC Ear Nose Throat Disord |volume=5 |pages=8 |year=2005 |month=September |pmid=16162299 |pmc=1253509 |doi=10.1186/1472-6815-5-8 |url=http://www.biomedcentral.com/1472-6815/5/8}}</ref>
 ===Sites of Metastasis===
-GCCL's are particularly notable among lung cancers for their extremely unusual tendency to metastasize to the [small intestine]], occasionally causing [[Bowel obstruction|obstruction]], severe [[bleeding]], and/or [[Intussusception (medical disorder)|intussusception]]. This clinical characteristic of GCCL has been seen in cases spanning over half a century in time.<ref name='Thomas1962'>Thomas, C. ''Frankfurt Z Path'' 1962;72:302 ''et seq''.</ref><ref name='WellmanChafiian'>Wellmann KF, Chafiian Y, Edelman E. Small bowel perforation from solitary metastasis of clinically undetected pulmonary giant cell carcinoma. ''Am J Gastroenterol'' 1969;51:145-50</ref>
+GCCL's are particularly notable among lung cancers for their extremely unusual tendency to metastasize to the [small intestine]], occasionally causing [[Bowel obstruction|obstruction]], severe [[bleeding]], and/or [[Intussusception (medical disorder)|intussusception]]. This clinical characteristic of GCCL has been seen in cases spanning over half a century in time.<ref name='Thomas1962'>{{cite journal |author=Thomas C |title=[Giant cell carcinoma of the lungs] |language=German |journal=Frankf Z Pathol |volume=72 |pages=302–8 |year=1962 |pmid=13981042 }}</ref><ref name='WellmanChafiian'>{{cite journal |author=Wellmann KF, Chafiian Y, Edelman E |title=Small bowel perforation from solitary metastasis of clinically undetected pulmonary giant cell carcinoma |journal=Am. J. Gastroenterol. |volume=51 |issue=2 |pages=145–50 |year=1969 |month=February |pmid=5776147 }}</ref>
 Within the small bowel, the jejunum seems to be a preferred site for metastasis of GCCL.
-GCCL also often metastasizes to bone,<ref name='WillebrandWernitsch>Willebrand H, Wernitsch W, Elmohamed A. Pulmonary metastases of a giant-cell carcinoma in the bone--benign or malignant? ''Chirurg'' 1970;41:419-23.</ref> adrenal, brain,<ref name='HagiharaAbe'>Hagihara N, Abe T, Wakamiya T, Sugita Y, Watanabe M, Tabuchi K. A case of brain metastasis from pulmonary giant cell carcinoma. ''Kurume Med J'' 2010;57:39-41.</ref>
+GCCL also often metastasizes to bone,<ref name='WillebrandWernitsch'/> adrenal, brain,<ref name='HagiharaAbe'/> lung, liver, kidney,
+Brain metastases from GCCL are particularly likely to cause significant cerebral hemorrhages as compared to other lung cancer variants, probably due to greatly increased rates of endothelial proliferation and neovascularization, tumor tissue growth, extensive necrosis, and aggressive local infiltrative character of GCCL cells.<ref name='HagiharaAbe'/>
- lung, liver, kidney,
-Brain metastases from GCCL are particularly likely to cause significant cerebral hemorrhages as compared to other lung cancer variants, probably due to greatly increased rates of endothelial proliferation and neovascularization, tumor tissue growth, extensive necrosis, and aggressive local infiltrative character of GCCL cells.<ref name='HagiharaAbe'>Hagihara N, Abe T, Wakamiya T, Sugita Y, Watanabe M, Tabuchi K. A case of brain metastasis from pulmonary giant cell carcinoma. ''Kurume Med J'' 2010;57:39-41.</ref>
 ===Pathogenesis and Genetics===
-Several studies, both in giant cell tumor specimens and in cell lines, have identified rearrangement and amplification of the ''c-myc'' [[oncogene]], sometimes in combination with mutations of the ''K-ras'' gene.<ref name='IizukaShiraishi'>Iizuka M, Shiraishi M, Yoshida MC ''et al''. Joining of the ''c-myc'' gene and a Line 1 family member on Chromosome 8 in a human primary giant cell carcinoma. 'Cancer Res' 1990;50:3445-50.</ref><ref name=''TayaHosogai''>{{cite journal | author = Taya Y, Hosogai K, Hirohashi S ''et al.'' | year = 1984 | title = A novel combination of ''K-ras'' and ''c-myc'' amplification accompanied by point mutation activating ''K-ras'' in a human lung cancer case | url = | journal = The EMBO J | volume = 3 | issue = | pages = 2943–6 }}</ref>
+Several studies, both in giant cell tumor specimens and in cell lines, have identified rearrangement and amplification of the ''c-myc'' [[oncogene]], sometimes in combination with mutations of the ''K-ras'' gene.<ref name='IizukaShiraishi'>{{cite journal |author=Le Doussal JM, Gruaz-Guyon A, Martin M, Gautherot E, Delaage M, Barbet J |title=Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice |journal=Cancer Res. |volume=50 |issue=11 |pages=3445–52 |year=1990 |month=June |pmid=2334941 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=2334941}}</ref><ref name='TayaHosogai'>{{cite journal |author=Taya Y, Hosogai K, Hirohashi S, ''et al.'' |title=A novel combination of K-ras and myc amplification accompanied by point mutational activation of K-ras in a human lung cancer |journal=EMBO J. |volume=3 |issue=12 |pages=2943–6 |year=1984 |month=December |pmid=6098458 |pmc=557793 }}</ref>
-Overexpression of vascular endothelial growth factor (VEGF) has been shown to occur in GCCL and is thought to be related to the high metastatic potential of this lung cancer variant.<ref name='JiangLu'>{{cite journal | author = Jiang DF, Lu YL, Qiu ZY ''et al.'' | year = 2003 | title = Study of differential expression of molecules affecting the metastatic potential between highly and poorly metastatic human lung giant cell carcinoma | url = | journal = Zhonghua Zhong Liu Za Zai | volume = 25 | issue = | pages = 131–4 }}</ref>
+Overexpression of vascular endothelial growth factor (VEGF) has been shown to occur in GCCL and is thought to be related to the high metastatic potential of this lung cancer variant.<ref name='JiangLu'/>
-Malignant giant cells identical to those found in GCCL commonly occur in lung cancer cases with a prominent major or minor clear cell carcinoma pattern (for a discussion about this variant, see for example <ref name='MorganMacKenzie'>Morgan, AD and DH MacKenzie. Clear cell carcinomas. ''J Path Bact'' 1964;87:25 ''et seq.''.</ref>). They have been hypothesized to derive from an undifferentiated [[multipotent]] malignant [[stem cell]] precursor that is generated in distal [[bronchiole|bronchioles]] via an as yet unknown [[oncogenesis|oncogenetic]] [[metabolic pathway|pathway]] or [[oncogene|oncogenetic driver]].<ref name='WangSeemayer'>Wang NS, Seemayer TA, Ahmed MN, Knaack J. Giant cell carcinoma of the lung. A light and electron microscopic study. ''Hum Pathol'' 1976;7:3-16</ref>
+Malignant giant cells identical to those found in GCCL commonly occur in lung cancer cases with a prominent major or minor clear cell carcinoma pattern (for a discussion about this variant, see for example <ref name='MorganMacKenzie'>{{cite journal |author=Morgan AD, Mackenzie DH |title=Clear-cell Carcinoma of the Lung |journal=J Pathol Bacteriol |volume=87 |pages=25–7 |year=1964 |month=January |pmid=14106350 }}</ref>). They have been hypothesized to derive from an undifferentiated [[multipotent]] malignant [[stem cell]] precursor that is generated in distal [[bronchiole|bronchioles]] via an as yet unknown [[oncogenesis|oncogenetic]] [[metabolic pathway|pathway]] or [[oncogene|oncogenetic driver]].<ref name='WangSeemayer'/>
-Ultrastructurally, malignant giant cells often contain accumulations of microfilaments arranged in whorls near the cell nucleus. These entities appear similar in structure to microfilaments and bundles found in the D1 cell of the gastro-entero-pancreatic [[endocrine]] system, and it has been proposed that these D1 cells may be the cancer stem cell for at least some GCCL's. Identically appearing whorled filament structures have also been produced in certain airway cells of animals after treatment with [[carcinogenic]] nitrosamines.<ref name='Carstens1978'>Carstens PH, Broghamer WL Jr. Duodenal carcinoid with cytoplasmic whorls of microfilaments. ''J Pathol'' 1978;124:235-8.</ref>
+Ultrastructurally, malignant giant cells often contain accumulations of microfilaments arranged in whorls near the cell nucleus. These entities appear similar in structure to microfilaments and bundles found in the D1 cell of the gastro-entero-pancreatic [[endocrine]] system, and it has been proposed that these D1 cells may be the cancer stem cell for at least some GCCL's. Identically appearing whorled filament structures have also been produced in certain airway cells of animals after treatment with [[carcinogenic]] nitrosamines.<ref name='Carstens1978'>{{cite journal |author=Carstens PH, Broghamer WL |title=Duodenal carcinoid with cytoplasmic whorls of microfilaments |journal=J. Pathol. |volume=124 |issue=4 |pages=235–8 |year=1978 |month=April |pmid=569192 |doi=10.1002/path.1711240408 }}</ref>
-Ultrastructural studies have suggested that the malignant giant cells in GCCL are of endodermal lineage.<ref name='Sidhu1979>Sidhu GS. The endodermal origin of digestive and respiratory tract APUD cell0s. Histopathologic evidence and a review of the literature. ''Am J Pathol'' 1979;96:5-20.</ref>
+Ultrastructural studies have suggested that the malignant giant cells in GCCL are of endodermal lineage.<ref name='Sidhu1979'>{{cite journal |author=Sidhu GS |title=The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature |journal=Am. J. Pathol. |volume=96 |issue=1 |pages=5–20 |year=1979 |month=July |pmid=37740 |pmc=2042351 }}</ref>
-Remarkably fast growing tumors.<ref name='HagiharaAbe'>Hagihara N, Abe T, Wakamiya T, Sugita Y, Watanabe M, Tabuchi K. A case of brain metastasis from pulmonary giant cell carcinoma. ''Kurume Med J'' 2010;57:39-41.</ref>
+Remarkably fast growing tumors.<ref name='HagiharaAbe'/>
 ===Combined/Multiphasic Tumors Containing Giant Cells===
-Malignant giant cells are commonly found - and vary in relative proportion to a greater or lesser degree - in both primary tumors and metastatases of many different variants of lung carcinomas. A number of authors have noted that bizarre malignant giant cells occur more commonly in primary and secondary tumors - including any remaining tumor "deposits" - that have previously been treated with [[chemotherapy]] and/or [[radiation]] therapy in [[adjuvant]] or [[neoadjuvant therapy|neoadjuvant]] protocols.<ref name='Sidhu1979'>Sidhu GS. The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature. ''Am J Pathol'' 1979;96:5-20.</ref>
+Malignant giant cells are commonly found — and vary in relative proportion to a greater or lesser degree — in both primary tumors and metastatases of many different variants of lung carcinomas. A number of authors have noted that bizarre malignant giant cells occur more commonly in primary and secondary tumors — including any remaining tumor "deposits" — that have previously been treated with [[chemotherapy]] and/or [[radiation]] therapy in [[adjuvant]] or [[neoadjuvant therapy|neoadjuvant]] protocols.<ref name='Sidhu1979'/>
 ===Imaging Characteristics===
-GCCL often presents as a large peripheral mass that is severely cavitated.<ref name'Culiner'>Culiner MM, Abouav J, Reich SB. Cavitary carcinoma of the lung. ''Calif Med'' 1958;89:355-8.</ref>
+GCCL often presents as a large peripheral mass that is severely cavitated.<ref name'Culiner'>{{cite journal |author=Culiner MM, Abouav J, Reich SB |title=Cavitary carcinoma of the lung |journal=Calif Med |volume=89 |issue=5 |pages=355–8 |year=1958 |month=November |pmid=13585165 |pmc=1512515 }}</ref>
-In a radiographic study of almost 2,000 lung cancer patients published 50 years ago, 3.4% of lung carcinomas proved to be cavitated masses,<ref name='Strang'>Strang C, Simpson JA. Carcinomatous abscess of the lung. ''Thorax'' 1953;8:11.</ref> most of which were [[squamous cell carcinoma]].
+In a radiographic study of almost 2,000 lung cancer patients published 50 years ago, 3.4% of lung carcinomas proved to be cavitated masses,<ref name='Strang'>{{cite journal |author=Strang C, Simpson JA |title=Carcinomatous abscess of the lung |journal=Thorax |volume=8 |issue=1 |pages=11–26 |year=1953 |month=March |pmid=13038734 |pmc=1019223 |url=http://thorax.bmj.com/cgi/pmidlookup?view=long&pmid=13038734}}</ref> most of which were [[squamous cell carcinoma]].
 In a number of cases of severe cavitation, the resected tumor remnant consists of only a thin rim of proliferating cells.
 ===Positron Emission Tomography Scanning===
-On [[Positron Emission Tomography]] scanning, GCCL has been found to have exceedingly high standardized uptake values (SUV) for radioactive glucose, values that are statistically significantly higher than in other histological variants of lung cancer.<ref name='ParkLee'>Park JS, Lee Y, Han J, Kim HK, Choi YS, Kim J, Shim YM, Kim K: Clinicopathologic Outcomes of Curative Resection for Sarcomatoid Carcinoma of the Lung. ''Oncology'' 2011;81:206-213. DOI: 10.1159/000333095</ref>
+On [[Positron Emission Tomography]] scanning, GCCL has been found to have exceedingly high standardized uptake values (SUV) for radioactive glucose, values that are statistically significantly higher than in other histological variants of lung cancer.<ref name='ParkLee'/>
 ===Metabolic Pathways===
@@ Line 155: / Line 153: @@
 ===Paraneoplastic Syndromes===
-GCCL have been long known<ref name='DaileyMarcuse'>Dailey JE, Marcuse PM. Gonadotropin secreting giant cell carcinoma of the lung.''Cancer'' 1969;24:388-96</ref> for secretion of the ''beta'' subunit of human chorionic gonadotropin (''beta''-HCG), often in large amounts, which can lead to very high levels of [[estrogen]] and painful [[gynecomastia]] (breast enlargement) in males as paraneoplastic signs.<ref name='YaturuHarrara'>{{cite journal |author=Yaturu S, Harrara E, Nopajaroonsri C, Singal R, Gill S |title=Gynecomastia attributable to a human chorionic gonadotropin-secreting giant cell carcinoma of the lung |journal=Endocr Pract |year=2003 |volume=9 |issue=3 |pages=231–5 |pmid=12917067 }}</ref>
+GCCL have been long known<ref name='DaileyMarcuse'>{{cite journal |author=Dailey JE, Marcuse PM |title=Gonadotropin secreting giant cell carcinoma of the lung |journal=Cancer |volume=24 |issue=2 |pages=388–96 |year=1969 |month=August |pmid=5796783 }}</ref> for secretion of the ''beta'' subunit of human chorionic gonadotropin (''beta''-HCG), often in large amounts, which can lead to very high levels of [[estrogen]] and painful [[gynecomastia]] (breast enlargement) in males as paraneoplastic signs.<ref name='YaturuHarrara'>{{cite journal |author=Yaturu S, Harrara E, Nopajaroonsri C, Singal R, Gill S |title=Gynecomastia attributable to a human chorionic gonadotropin-secreting giant cell carcinoma of the lung |journal=Endocr Pract |year=2003 |volume=9 |issue=3 |pages=231–5 |pmid=12917067 }}</ref>
-Giant cell lung cancers are well known for their paraneoplastic production and secretion of granulopoietic colony stimulating factor (G-CSF)<ref name=''TayaHosogai''>{{cite journal |author=Taya Y, Hosogai K, Hirohashi S ''et al'' |title=A novel combination of ''K-ras'' and ''c-myc'' amplification accompanied by point mutation activating ''K-ras'' in a human lung cancer case. |journal=EMBO J |date=1984 Dec |volume=3 |issue=12 |pages=2943–6 |pmid=6098458 |pmc=557793 }}</ref><ref name='KamedaKodama'>{{cite book |author1=Kameda T |author2=Kodama T |author3=Shimosato Y |editor1=Shimosato Y |editor2=Melamed MR |editor3=Nettesheim P |title=Morphogenesis of Lung Cancer |volume=Vol. 2 |location=Boca Raton, Florida |publisher=CRC Press |pages=107–29 |year=1982 }}</ref>
+Giant cell lung cancers are well known for their paraneoplastic production and secretion of granulopoietic colony stimulating factor (G-CSF)<ref name='TayaHosogai'/><ref name='KamedaKodama'>{{cite book |author1=Kameda T |author2=Kodama T |author3=Shimosato Y |editor1=Shimosato Y |editor2=Melamed MR |editor3=Nettesheim P |title=Morphogenesis of Lung Cancer |volume=2 |location=Boca Raton, Florida |publisher=CRC Press |pages=107–29 |year=1982 }}</ref>
-GCCL has also been reported to produce plasminogen activator as a paraneoplastic phenomenon.<ref name='DavidsonMcNicol'>Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS. Plasminogen activator-producing tumour. ''Br Med J'' 1969;1:88-91</ref>
+GCCL has also been reported to produce plasminogen activator as a paraneoplastic phenomenon.<ref name='DavidsonMcNicol'/>
 ===Treatment===
@@ Line 165: / Line 163: @@
 ===Prognosis===
-Giant cell lung cancers have long been considered to be exceptionally aggressive malignancies<ref name='KennedyA'>Kennedy A. Pathology and survival in operable cases of giant-cell carcinoma of the lung. ''J Clin Pathol'' 1969;22:354-60</ref><ref name='KallenbergJaque' /><ref name='RazzukUrschel'>Razzuk MA, Urschel HC Jr, Albers JE, Martin JA, Paulson DL. Pulmonary giant cell carcinoma. ''Ann Thorac Surg'' 1976;21:540-5</ref> that grow very rapidly<ref name=''TayaHosogai''>{{cite journal | author = Taya Y, Hosogai K, Hirohashi S ''et al.'' | year = 1984 | title = A novel combination of ''K-ras'' and ''c-myc'' amplification accompanied by point mutation activating ''K-ras'' in a human lung cancer case | url = | journal = The EMBO J | volume = 3 | issue = | pages = 2943–6 }}</ref> and have a very poor prognosis.<ref name='ZhaoSong' />
+Giant cell lung cancers have long been considered to be exceptionally aggressive malignancies<ref name='KennedyA'/><ref name='KallenbergJaque' /><ref name='RazzukUrschel'>{{cite journal |author=Razzuk MA, Urschel HC, Albers JE, Martin JA, Paulson DL |title=Pulmonary giant cell carcinoma |journal=Ann. Thorac. Surg. |volume=21 |issue=6 |pages=540–5 |year=1976 |month=June |pmid=1275605 }}</ref> that grow very rapidly<ref name='TayaHosogai'/> and have a very poor prognosis.<ref name='ZhaoSong' />
-Many small series have suggested that the prognosis of lung tumors with giant cells is worse than that of most other forms of non-small cell lung cancer (NSCLC)<ref name='MatsuiKitagawa'>Matsui K, Kitagawa M. Spindle cell carcinoma of the lung: a clinicopathologic study of three cases. ''Cancer'' 1991;67:2361-7.</ref>, including squamous cell carcinoma,<ref name='ZhaoSong' /> and spindle cell carcinoma.<ref name='ZhaoSong' />
+Many small series have suggested that the prognosis of lung tumors with giant cells is worse than that of most other forms of non-small cell lung cancer (NSCLC)<ref name='MatsuiKitagawa'/>, including squamous cell carcinoma,<ref name='ZhaoSong' /> and spindle cell carcinoma.<ref name='ZhaoSong' />
-The overall five-year survival rate in GCCL varies between studies but is generally considered to be very low. The (US) Armed Forces Institute of Pathology has reported a figure of of 10%<ref name='ColbyKoss'>Colby TV, Koss MN, Travis WD. (1995) Tumors of the lower respiratory tract. In Rosai J, Sobin LH (eds); Atlas of Tumor Pathology. Washington, DC, US: Armed Forces Institute of Pathology, pp. 259-75.</ref>, and in a study examining over 150,000 lung cancer cases, a figure of 11.8% was given.<ref name='TravisTravis'/> However, in the latter report the 11.8% figure was based on data that included [[spindle cell carcinoma]], a variant which is generally considered to have a less dismal prognosis that GCCL.<ref name='MatsuiKitagawa'>Matsui K, Kitagawa M. Spindle cell carcinoma of the lung: a clinicopathologic study of three cases. ''Cancer'' 1991;67:2361-7.</ref> Therefore, the likely survival of "pure" GCCL is probably lower than the stated figure.
+The overall five-year survival rate in GCCL varies between studies but is generally considered to be very low. The (US) Armed Forces Institute of Pathology has reported a figure of of 10%,<ref name='ColbyKoss'>{{cite book |author=Colby TV, Koss MN, Travis WD |chapter=Tumors of the lower respiratory tract |editor=Rosai J, Sobin LH |title=Atlas of Tumor Pathology |publisher=Armed Forces Institute of Pathology |location=Washington DC |year=1995 |pages=259–75 }}</ref> and in a study examining over 150,000 lung cancer cases, a figure of 11.8% was given.<ref name='TravisTravis'/> However, in the latter report the 11.8% figure was based on data that included [[spindle cell carcinoma]], a variant which is generally considered to have a less dismal prognosis that GCCL.<ref name='MatsuiKitagawa'/> Therefore, the likely survival of "pure" GCCL is probably lower than the stated figure.
 In the large 1995 database review by Travis and colleagues, giant cell carcinoma was noted to have the third-worst prognosis among 18 histological forms of lung cancer (only small cell carcinoma and large cell carcinoma had shorter average survival).<ref name='TravisTravis'/>
-Most GCCL have already grown and invaded locally and/or regionally, and/or have already metastasized distantly, and are inoperable, at the time of diagnosis.<ref name='KennedyA'>Kennedy A. Pathology and survival in operable cases of giant-cell carcinoma of the lung. ''J Clin Pathol'' 1969;22:354-60</ref>
+Most GCCL have already grown and invaded locally and/or regionally, and/or have already metastasized distantly, and are inoperable, at the time of diagnosis.<ref name='KennedyA'/>
 ===History===
-Most sources credit Nash and Stout with publishing the first detailed report in the medical literature recognizing GCCL as a distinct clinicopathological entity in 1958.<ref name='NashStout'>{{cite journal |author=Nash AD, Stout AP |title=Giant cell carcinoma of the lung; report of 5 cases |journal=Cancer |year=1958 |volume=11 |pages=369–76}}</ref> However, there is some evidence that suggests this tumor [[phenotype]] was described as early as 1951.<ref name='Zaib'>{{cite journal |author=Naib ZM |title=Giant cell carcinoma of the lung: cytological study of the exfoliated cells in sputa and bronchial washings |journal=Dis Chest |year=1961 |volume=40 |pages=69–73}}</ref> In a report on 3 cases of giant cell lung carcinoma published in 1961 by Z.M. Naib, the author cites 2 previous studies related to GCCL - one published in 1951 by M.M. Patton and co-workers,<ref name='PattonMcDonald'>{{cite journal |author=Patton MM, McDonald JR, Moersch HJ |title=Bronchogenic large cell carcinoma |journal=J Thor Surg  |year=1951 |volume=22 |pages=88}}</ref> and one published in 1955 by Walton and Pryce.<ref name='WaltonPryce'>{{cite journal |author=Walton JB, Pryce DM |title=History of the lung cancer |journal=Thorax |year=1955;10 |pages=107}}</ref> In 1969, Dr. Alexander Kennedy, in a case series of 3 GCCL Kennedy published in 1969,<ref name='KennedyA'>Kennedy A. Pathology and survival in operable cases of giant-cell carcinoma of the lung. ''J Clin Pathol'' 1969;22:354-60</ref> credited Hadley and Bullock with the first usage of the term "giant cell carcinoma" 16 years prior.<ref name='HadleyBullock'>Hadley GG and Bullock, WK. ''Calif Med'' 1953; 79, 431 ''et seq''.</ref>
+Most sources credit Nash and Stout with publishing the first detailed report in the medical literature recognizing GCCL as a distinct clinicopathological entity in 1958.<ref name='NashStout'>{{cite journal |author=Nash AD, Stout AP |title=Giant cell carcinoma of the lung; report of 5 cases |journal=Cancer |year=1958 |volume=11 |pages=369–76}}</ref> However, there is some evidence that suggests this tumor [[phenotype]] was described as early as 1951.<ref name='Zaib'>{{cite journal |author=Naib ZM |title=Giant cell carcinoma of the lung: cytological study of the exfoliated cells in sputa and bronchial washings |journal=Dis Chest |year=1961 |volume=40 |pages=69–73}}</ref> In a report on 3 cases of giant cell lung carcinoma published in 1961 by Z.M. Naib, the author cites 2 previous studies related to GCCL — one published in 1951 by M.M. Patton and co-workers,<ref name='PattonMcDonald'>{{cite journal |author=Patton MM, McDonald JR, Moersch HJ |title=Bronchogenic large cell carcinoma |journal=J Thor Surg  |year=1951 |volume=22 |pages=88}}</ref> and one published in 1955 by Walton and Pryce.<ref name='WaltonPryce'>{{cite journal |author=Walter JB, Pryce DM |title=The histology of lung cancer |journal=Thorax |volume=10 |issue=2 |pages=107–16 |year=1955 |month=June |pmid=14396845 |pmc=1019475 |url=http://thorax.bmj.com/cgi/pmidlookup?view=long&pmid=14396845}}</ref> In 1969, Dr. Alexander Kennedy, in a case series of 3 GCCL Kennedy published in 1969,<ref name='KennedyA'/> credited Hadley and Bullock with the first usage of the term "giant cell carcinoma" 16 years prior.<ref name='HadleyBullock'>{{cite journal |author=Hadley GG, Bullock WK |title=Autopsy reports of pulmonary carcinoma; survey in Los Angeles County Hospital for 1951 |journal=Calif Med |volume=79 |issue=6 |pages=431–3 |year=1953 |month=December |pmid=13106728 |pmc=1521859 }}</ref>
-GCCL was first confirmed as an epithelial tumor (and not a dedifferentiated pleomorphic [[sarcoma]]) in 1961.<ref name='OzzelloStout'>Ozzello L, Stout AP. The epithelial origin of giant cell carcinoma of the lung confirmed by tissue culture. Report of a case. ''Cancer'' 1961;14:1052-6</ref> In 1964-65, theories were postulated that GCCL's were dediffentiated adenocarcinomas,<ref name='Friedberg'>Giant-cell carcinoma of the lung: a dedifferentiated adenocarcinoma. ''Cancer'' 1965;18:259-64</ref> and in some cases, were thought to derive from clear cell adenocarcinomas.<ref name='MorganMacKenzie'>Morgan, AD and DH MacKenzie. Clear cell carcinomas. ''J Path Bact'' 1964;87:25 ''et seq.''.</ref>
+GCCL was first confirmed as an epithelial tumor (and not a dedifferentiated pleomorphic [[sarcoma]]) in 1961.<ref name='OzzelloStout'>{{cite journal |author=Ozzello L, Stout AP |title=The epithelial origin of giant cell carcinoma of the lung confirmed by tissue culture. Report of a case |journal=Cancer |volume=14 |pages=1052–6 |year=1961 |pmid=13731858 }}</ref> In 1964–65, theories were postulated that GCCL's were dediffentiated adenocarcinomas,<ref name='Friedberg'>{{cite journal |author=Friedberg EC |title=Giant-Cell Carcinoma of the Lung: A dedifferentiated Adenocarcinoma |journal=Cancer |volume=18 |pages=259–64 |year=1965 |month=February |pmid=14254083 }}</ref> and in some cases, were thought to derive from clear cell adenocarcinomas.<ref name='MorganMacKenzie'/>
 === References ===
@@ Line 184: / Line 182: @@
 ===External links===
-* [http://www.iarc.fr/en/publications/pdfs-online/pat-gen/index.php] World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (Download Page).
+*{{cite web |title=Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart |work=World Health Organization Classification of Tumours |url=http://www.iarc.fr/en/publications/pdfs-online/pat-gen/index.php}} (Download Page).
-* [http://www.cancer.gov/cancertopics/types/lung] Lung cancer page at the National Cancer Institute.
+*{{cite web |title=Lung cancer page  |publisher=National Cancer Institute |url=http://www.cancer.gov/cancertopics/types/lung}}
 {{Respiratory neoplasia}}