—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 1 - So-called "Sclerosing Hemangioma"

David Klimstra
Memorial Sloan Kettering Cancer Center
New York, New York


Click on each slide thumbnail image for an enlarged view
Clinical History:
The patient is a 67 year-old female who presented with pneumonia, with only partial resolution following antibiotic treatment. A chest CT scan disclosed a 1.2 cm right lower lobe nodule that was circumscribed and non-calcified. Review of old chest radiographs showed the nodule, which had been stable over at least 6 years. A fine needle aspiration was performed and interpreted as positive for carcinoid tumor. A right lower lobectomy and mediastinal lymph node dissection were performed. Grossly, there was a 1.5 cm red to tan, slightly indurated spherical mass situated 1.4 cm deep to the pleural surface.

Diagnosis: So-called "Sclerosing Hemangioma"



Case 1 - Figure 1 - Low power view showing areas of sclerosis separating nests of epithelioid cells. Irregular cavernous spaces contain blood.
Case 1 - Figure 2 - The epithelioid cells contain central, round to oval nuclei. Slit-like spaces are lined by a second cell population consisting of cuboidal, hobnailed cells.


Case 1 - Figure 3 - Higher power shows focal clear cell change in the oval epithelioid cells. The cuboidal cells lining the slit-like spaces resemble type II pneumocytes.
Case 1 - Figure 4 - Immunohistochemical staining for TTF-1 shows positivity in both the oval cells and the cuboidal cells.

Discussion and Differential Diagnosis:
Histologically, the tumor has a heterogenous appearance. Some areas display a solid pattern, with monotonous pale, oval cells having moderate amounts of eosinophilic to focally clear cytoplasm. Elsewhere there are areas of hyalinization with entrapped strands of tumor cells between broad collagenous bands. Some foci show irregular cavernous spaces filled with blood, and abundant hemosiderin deposition is present in the adjacent tissues. Finally, there are papillary areas composed of similar oval tumor cells covered by a layer of hobnailed type II pneumocyte-like cells with foamy cytoplasm. Other features include aggregates of foamy histiocytes and the inclusion of strips of ciliated epithelium within the tumor.

This tumor has the typical microscopic features of so-called "sclerosing hemangioma" of the lung. This lesion was first described by Liebow and Hubbell in 1956. The term "sclerosing hemangioma" was applied because of the cavernous spaces containing blood that resembled a cavernous hemangioma. Since its initially description, this tumor has become a well recognized and distinctive (if enigmatic) entity. The majority of patients are females, with an average age in the 5th decade. Many cases are detected incidentally on routine chest x-rays, although some patients have symptoms such as chest pain, pneumonitis, or hemoptysis. Radiographically and grossly, the tumors are generally well-circumscribed and measure 2-3 cms, although larger examples (up to 8 cms) have been reported. A few multicentric examples have also been reported. Sclerosing hemangiomas are regarded to be benign tumors, although there are a handfull of reports of regional lymph node metastases. Even in these cases, long term survival has been achieved by surgical excision, and death due to tumor has not been reported.

The histologic features of the current case are typical. Four different histologic patterns are described including solid, papillary, sclerotic, and hemorrhagic regions. It is common for multiple patterns to exist, although not every example shows all four. On closer examination, there are two fundamental cell types making up sclerosing hemangiomas. The first is the predominant cell type in the solid pattern, which consists of sheets of oval to polygonal cells with relatively uniform nuclei and eosinophilic cytoplasm. Superimposed clear cell change may also be found in these regions. The nuclei display occasional folds and grooves, and mitotic activity is not seen. These oval cells are also found within the cores of the papillae in the papillary areas, and they are entrapped between the bundles of hyalinized stroma in the sclerotic areas. The second cell type consists of hobnailed, cuboidal cells lining the surface of the papillae. These cells contain abundant vacuolated, foamy cytoplasm and round nuclei that may have intranuclear inclusions. Also contained within the tumor may be areas of hemosiderin deposition, foamy histocytes, lamellated calcifications, and even regions of necrosis. A granulomatous variant has also been described.

Since its description, sclerosing hemangioma has been repeatedly studied in an effort to determine the nature of the neoplastic cells. Despite the initial descriptor suggesting a vascular tumor, there is no evidence of endothelial differentiation in sclerosing hemangiomas. Rather, the oval cells have been recognized to be epithelial based on ultrastructural findings and occasional positivity for keratin. There have been proposals that the oval cells were endocrine or mesothelial, but confirmation of these hypotheses was not forthcoming (occasional scattered endocrine cells may be seen, but most authors agree that sclerosing hemangioma is not fundamentally an endocrine neoplasm). The hobnailed cuboidal cells lining the papillae are more clearly epithelial and show consistent diffuse positive staining for keratin and surfactant apoprotein. However, the differences in cytological appearance and immunohistochemical staining between the oval cells and the hobnailed cuboidal cells, along with the resemblance of the latter cell type to type II pneumocytes, raised the possibility that the cuboidal cells represented entrapped, metaplastic airway epithelium and were not neoplastic. Indeed, the focal presence of ciliated epithelium in the current case would support that some epithelium within the tumor is non-neoplastic. However, several recent observations suggest that at least a portion of the cuboidal, hobnailed epithelium is part of the neoplasm. One reported case showed polypoid growth into a bronchial lumen but still contained this cell type, a difficult observation to explain on the basis of entrapped peripheral air spaces. More importantly, Niho et al. demonstrated monoclonality of both cell types bases on non-random X chromosome inactivation. The results of this study suggested that both components are neoplastic and furthermore that both are derived from the same cell type. More recently, antibodies against thyroid transcription factor-1 (TTF-1) have been used to demonstrate that both cell types are of pulmonary epithelial origin (stains for thyroglobulin are uniformly negative). Epithelial membrane antigen (EMA) is also expressed by both cell types, although somewhat less intensely by the oval cells. Interestingly, careful examination of the cuboidal cells reveals subtle variations in cytology in different regions of the tumor. Immunohistochemical stains for EMA, Cam5.2, and PE10 (surfactant apoprotein) reveal that some of the cuboidal cells display diffuse, intense positivity for these three markers, whereas others with cytologic features more similar to the oval cells show intense positivity only for EMA, with minimal staining for PE10 and Cam5.2. Thus, it is likely that some of the cuboidal cells are truly neoplastic and are related to the pale cells, whereas others represent entrapped, metaplastic alveolar epithelium. Based on the female predominance, studies have been preformed to look for estrogen and progesterone receptors. Although convincing progesterone receptor expression may be detected, estrogen receptors are generally only focally and faintly detected by immunohistochemistry.

In summary, sclerosing hemangioma of the lung is a neoplasm of pulmonary epithelial origin with a characteristic combination of cell types and architectural patterns that help distinguish it from other benign and malignant tumors of the lung. Proposals have repeatedly been made to change the name, since it falsely suggests a vascular tumor. However, the term "sclerosing hemangioma" has so pervaded the pathologic and clinical literature that is would be difficult at this point to replace it, despite the attractive features of "sclerosing pneumocytoma", one of the proposed alternatives.

The differential diagnosis includes a number of epithelial and mesenchymal tumors of the lung. If sclerosing hemangiomas are sampled by fine needle aspiration, the appearance of sheets of epithelioid cells as well as strips of mildly atypical type II pneumocyte-like cells may suggest a diagnosis of bronchioloalveolar carcinoma. The presence of abundant hemorrhage and hemosiderin deposition may provide clues to the correct diagnosis. The oval cell component also resembles a carcinoid tumor (and in the current case a mistaken diagnosis of carcinoid was made on the fine needle aspiration). In tissue sections, it is the heterogeneity of the architecture as well as the focally hemorrhagic appearance that are most helpful in separating sclerosing hemangioma from both carcinoid and bronchioloalveolar carcinoma. The possibility of a true vascular neoplasm is not generally considered, since cavernous hemangiomas are exceedingly rare in the lung. A more frequently encountered vascular tumor of the lung, epithelioid hemangioendothelioma, does not resemble sclerosing hemangioma at all. It is an interesting paradox that the original description of this tumor, also by Liebow, used the term "intravascular bronchioloalveolar tumor", implying an epithelial nature to this vascular neoplasm, the converse implication of the term chosen for sclerosing hemangioma. Another benign epithelial tumor to be distinguished from sclerosing hemangioma is alveolar adenoma. These sharply circumscribed peripheral lung tumors also arise in older females. Like sclerosing hemangiomas, alveolar adenomas contain solid areas and numerous small cystic spaces. In these tumor, however, the cysts may be much larger and generally do not contain blood or hemosiderin. The heterogeneous low power appearance of sclerosing hemangiomas is lacking in alveolar adenomas, as are papillary regions. Two other unusual tumors that may be confused with sclerosing hemangioma both consist predominantly of an epithelioid cell population (that may resemble the oval cells) with entrapped metaplastic airway epithelium. The first is clear cell "sugar" tumor, a lesion now known to be composed of perivascular epithelioid cells that express HMB45 and lack staining or epithelial markers or TTF-1. The second is primary pulmonary meningioma, a rare tumor possibly related to the common meningothelial cell rests ("minute chemodectoma-like bodies") detected in perivascular regions of the lung periphery. Like sclerosing hemangiomas, pulmonary meningiomas express EMA and lack keratin positivity. However, they stain intensely for vimentin and do not show the characteristic architectural patterns of sclerosing hemangiomas.

References

  1. Aihara T, Nakajima T: Sclerosing hemangioma of the lung: pathological study and enzyme immunoassay for estrogen and progesterone receptors. Acta Pathol Jpn 1993, 43:507-515
  2. Alvarez-Fernandez E, Carretero-Albinana L, Menarguez-Palanca J: Sclerosing hemangioma of the lung. An immunohistochemical study of intermediate filaments and endothelial markers. Arch Pathol Lab Med 1989, 113:121-124
  3. Batinica S, Gunek G, Raos M, Jelasic D, Bogovic M: Sclerosing haemangioma of the lung in a 4-year-old child. Eur J Pediatr Surg 2002, 12:192-194
  4. Chan AC, Chan JK: Pulmonary sclerosing hemangioma consistently expresses thyroid transcription factor-1 (TTF-1): a new clue to its histogenesis. Am J Surg Pathol 2000, 24:1531-1536
  5. Chow LT, Chow WH, Tsui WM, Chan SK: Fine needle aspiration cytodiagnosis of pulmonary sclerosing hemangioma. Acta Cytol 1995, 39:609-611
  6. Devouassoux-Shisheboran M, Hayashi T, Linnoila RI, Koss MN, Travis WD: A clinicopathologic study of 100 cases of pulmonary sclerosing hemangioma with immunohistochemical studies: TTF-1 is expressed in both round and surface cells, suggesting an origin from primitive respiratory epithelium. Am J Surg Pathol 2000, 24:906-916
  7. Eggleston JC: The intravascular bronchioloalveolar tumor and the sclerosing hemangioma of the lung: misnomers of pulmonary neoplasia. Semin Diagn Pathol 1985, 2:270-280
  8. Fukayama M, Koike M: So-called sclerosing hemangioma of the lung. An immunohistochemical, histochemical and ultrastructural study. Acta Pathol Jpn 1988, 38:627-642
  9. Gal AA, Nassar VH, Miller JI: Cytopathologic diagnosis of pulmonary sclerosing hemangioma. Diagn Cytopathol 2002, 26:163-166
  10. Haas JE, Yunis EJ, Totten RS: Ultrastructure of a sclerosing hemangioma of the lung. Cancer 1972, 30:512-518
  11. Hill GS, Eggleston JC: Electron microscopic study of so-called "pulmonary sclerosing hemangioma". Report of a case suggesting epithelial origin. Cancer 1972, 30:1092-1106
  12. Huszar M, Suster S, Herczeg E, Geiger B: Sclerosing hemangioma of the lung. Immunohistochemical demonstration of mesenchymal origin using antibodies to tissue-specific intermediate filaments. Cancer 1986, 58:2422-2427
  13. Illei PB, Rosai J, Klimstra DS: Expression of thyroid transcription factor-1 and other markers in sclerosing hemangioma of the lung. Arch Pathol Lab Med 2001, 125:1335-1339
  14. Iyoda A, Baba M, Saitoh H, Hoshino H, Shibuya K, Nomoto Y, Horiuchi F, Hiroshima K, Ohwada H, Fujisawa T: Imprint cytologic features of pulmonary sclerosing hemangioma: comparison with well-differentiated papillary adenocarcinoma. Cancer 2002, 96:146-149
  15. Joshi K, Shankar SK, Gopinath N, Kumar R, Chopra P: Multiple sclerosing haemangiomas of the lung. Postgrad Med J 1980, 56:50-53
  16. Katzenstein AL, Gmelich JT, Carrington CB: Sclerosing hemangioma of the lung: a clinicopathologic study of 51 cases. Am J Surg Pathol 1980, 4:343-356
  17. Katzenstein AL, Weise DL, Fulling K, Battifora H: So-called sclerosing hemangioma of the lung. Evidence for mesothelial origin. Am J Surg Pathol 1983, 7:3-14
  18. Kay S, Still WJ, Borochovitz D: Sclerosing hemangioma of the lung: an endothelial or epithelial neoplasm? Hum Pathol 1977, 8:468-474
  19. Lee ST, Lee YC, Hsu CY, Lin CC: Bilateral multiple sclerosing hemangiomas of the lung. Chest 1992, 101:572-573
  20. Leong AS, Chan KW, Seneviratne HS: A morphological and immunohistochemical study of 25 cases of so-called sclerosing haemangioma of the lung. Histopathology 1995, 27:121-128
  21. Liebow AA, Hubbell DS: Sclerosing hemangioma (histiocytoma, xanthoma) of the lung. Cancer 1956, 9:53-75
  22. Moran CA, Zeren H, Koss MN: Sclerosing hemangioma of the lung. Granulomatous variant. Arch Pathol Lab Med 1994, 118:1028-1030
  23. Nagata N, Dairaku M, Ishida T, Sueishi K, Tanaka K: Sclerosing hemangioma of the lung. Immunohistochemical characterization of its origin as related to surfactant apoprotein. Cancer 1985, 55:116-123
  24. Nagata N, Dairaku M, Sueishi K, Tanaka K: Sclerosing hemangioma of the lung. An epithelial tumor composed of immunohistochemically heterogenous cells. Am J Clin Pathol 1987, 88:552-559
  25. Nakatani Y, Inayama Y, Kamijo S, Ogawa N: Sclerosing lung hemangioma. Am J Surg Pathol 1999, 23:240-243
  26. Niho S, Suzuki K, Yokose T, Kodama T, Nishiwaki Y, Esumi H: Monoclonality of both pale cells and cuboidal cells of sclerosing hemangioma of the lung. Am J Pathol 1998, 152:1065-1069
  27. Noguchi M, Kodama T, Morinaga S, Shimosato Y, Saito T, Tsuboi E: Multiple sclerosing hemangiomas of the lung. Am J Surg Pathol 1986, 10:429-435
  28. Ohori NP, Yousem SA, Sonmez-Alpan E, Colby TV: Estrogen and progesterone receptors in lymphangioleiomyomatosis, epithelioid hemangioendothelioma, and sclerosing hemangioma of the lung. Am J Clin Pathol 1991, 96:529-535
  29. Rodriguez-Soto J, Colby TV, Rouse RV: A critical examination of the immunophenotype of pulmonary sclerosing hemangioma. Am J Surg Pathol 2000, 24:442-450
  30. Satoh Y, Tsuchiya E, Weng SY, Kitagawa T, Matsubara T, Nakagawa K, Kinoshita I, Sugano H: Pulmonary sclerosing hemangioma of the lung. A type II pneumocytoma by immunohistochemical and immunoelectron microscopic studies. Cancer 1989, 64:1310-1317
  31. Tanaka I, Inoue M, Matsui Y, Oritsu S, Akiyama O, Takemura T, Fujiwara M, Kodama T, Shimosato Y: A case of pneumocytoma (so-called sclerosing hemangioma) with lymph node metastasis. Jpn J Clin Oncol 1986, 16:77-86
  32. Xu HM, Li WH, Hou N, Zhang SG, Li HF, Wang SQ, Yu ZY, Li ZJ, Zeng MY, Zhu GM: Neuroendocrine differentiation in 32 cases of so-called sclerosing hemangioma of the lung: identified by immunohistochemical and ultrastructural study. Am J Surg Pathol 1997, 21:1013-1022
  33. Yano M, Yamakawa Y, Kiriyama M, Hara M, Murase T: Sclerosing hemangioma with metastases to multiple nodal stations. Ann Thorac Surg 2002, 73:981-983
  34. Yousem SA, Hochholzer L: Alveolar adenoma. Hum Pathol 1986, 17:1066-1071
  35. Yousem SA, Wick MR, Singh G, Katyal SL, Manivel JC, Mills SE, Legier J: So-called sclerosing hemangiomas of lung. An immunohistochemical study supporting a respiratory epithelial origin. Am J Surg Pathol 1988, 12:582-590