- Email: [email protected]
Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax
Accepted Manuscript Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax Niravkumar K. Sangani, MCh, Santosh Mathew Naliath, MCh PII:
S0003-4975(18)30546-0
DOI:
10.1016/j.athoracsur.2018.03.050
Reference:
ATS 31525
To appear in:
The Annals of Thoracic Surgery
Received Date: 19 December 2017 Revised Date:
5 March 2018
Accepted Date: 8 March 2018
Please cite this article as: Sangani NK, Naliath SM, Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax, The Annals of Thoracic Surgery (2018), doi: 10.1016/j.athoracsur.2018.03.050. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax
SC
Niravkumar K. Sangani, MCh, Santosh Mathew Naliath, MCh
RI PT
Running Head: Sarcomatoid lung cancer-pseudomesotheliomatous type with hemothorax
Address of Corresponding Author: Dr. Niravkumar Sangani
Cardiothoracic Surgery
Mussafah
AC C
Abu Dhabi, 2419
EP
P.O.Box 2419
TE D
Ahalia Hospital
UNITED ARAB EMIRATES
Email: [email protected]
Word count: 1519
M AN U
Department of Cardiothoracic Surgery, Ahalia Hospital-Mussafah, Abudhabi, United Arab Emirates
ACCEPTED MANUSCRIPT
Abstract A 44 year old male presented with spontaneous massive hemothorax. Computed tomography (CT) scan revealed thickened and nodular pleura with no evidence of lung tumour. Patient underwent right open
RI PT
total pleurectomy. Histopathology and Immunohistochemistry studies of the pleura confirmed poorly differentiated sarcomatoid squamous cell carcinoma of lung with metastasis to pleura. The carcinoma was psuedomesothelimatous type due to its presentation as diffuse pleural thickening. This presentation of
SC
sarcomatoid cancer as pseudomesotheliomatous type with massive hemothorax is rare and can be
considered as differential diagnosis in diffuse pleural thickening or hemothorax, especially in absence of
M AN U
clinically identifiable primary lung tumour.
AC C
EP
TE D
Key Words: Sarcomatoid, Lung cancer, Pseudomesotheliomatous, hemothorax, Hemothorax
ACCEPTED MANUSCRIPT
Sarcomatoid carcinoma of the lung (SARC) is a rare aggressive histologic subtype of non-small cell lung cancer .Pseudomesotheliomatous type of lung cancer implies presentation with diffuse involvement of the pleura in a manner simulating mesothelioma. Spontaneous hemothorax is an uncommon presenting sign
RI PT
of lung cancer. We report a case of poorly differentiated sarcomatoid squamous cell lung cancer with pseudomesotheliomatous growth pattern presenting as spontaneous massive hemothorax.
SC
A 44 year old male laborer presented with dry cough and right chest pain since two weeks. He was a chronic smoker (15 pack years). Chest x-ray demonstrated a right large pleural effusion. Computed
M AN U
tomography of the chest showed significant pleural effusion with associated passive collapse of lower lobe of right lung(Fig 1B). There was suggestion of right pleural thickening which appeared nodular at places (Fig 1A). No significant mediastinal lymphadenopathy was present. No lung or endobronchial tumour could be identified. On diagnostic thoracentesis, hemorrhagic fluid was aspirated. Intercostal
TE D
chest drain (No 32) was inserted which drained 2 litres of blood immediately with a total of 3.5 litres draining over the next 3 days. Pleural fluid cytology was negative for malignant cells. Bronchoscopy disclosed no endobronchial tumour.
EP
On examination of pleura by Video assisted thoracoscopic surgery (VATS), parietal pleura was thickened, irregular and nodular at places (Fig 2). The pleural surface showed diffuse bleeding. We
AC C
converted to right open posterolateral thoracotomy and performed a right total pleurectomy. We could not identify any right lung parenchymal lesion. Microscopy of the parietal pleura revealed hemorrhagic ulcerations infiltrated by neoplastic cells showing biphasic epitheloid and sarcomatoid growth pattern. Sheets of hemorrhagic epitheloid cells with pleomorphic vesicular nuclei, prominent nuclei with abundant focally vacuolated cytoplasm, many atypical mitoses and apoptotic bodies forming many slits were present. It was associated with wide necrosis, invading fat tissue and infiltrating adjacent skeletal muscle cells. It was accompanied by reactive lymphoid follicles, mixed inflammatory cells and hemosiderin
ACCEPTED MANUSCRIPT
laden macrophages in the stroma. On Immunohistochemical investigation, the neoplastic lesion was positive for immunomarkers Cytokeratin (AE1/AE3) and Vimentin. It was also diffusely positive for CK5/6 showing numerous spindled neoplastic cells (Fig 3). Immunomarkers CK7, TTF1, p63, CEA,
RI PT
HMB45, CD31, CD34 and Calretinin were negative. This was suggestive of poorly differentiated sarcomatoid squamous cell carcinoma of the right lung with metastasis of the parietal pleura. The patient was referred for palliative treatment due to the presentation as Stage IV lung cancer. The patient decided
SC
to go to his home country for further treatment and was lost to follow up.
M AN U
Comment
The presenting feature of SARC as pseudomesotheliomatous type with hemothorax is unique. SARC is defined as a poorly differentiated non-small cell carcinoma that contains a component of sarcoma or sarcoma-like elements (at least 10% spindle and/or giant cells) [1] Sarcomatoid histology is rare and
TE D
present in 0.1% to 0.4% of all patients with non-small cell lung cancer [1] It has a locally aggressive nature partly due to the sarcomatoid elements which develop enhanced angiogenic activity and tumour cell motility.[2].Most present in heavy smokers as large masses at an advanced stage. SARC is a predictor
EP
of poor prognosis with significantly worse survival and higher recurrence rates [3]. Harwood et al [4] first reported a variant of peripheral lung cancer with diffuse pleurotropic growth pattern that closely
AC C
resembled malignant pleural mesothelioma on clinical, radiological and pathological examination. They therefore named it carcinoma of the pseudomesotheliomatous type. Their diagnostic criteria included pleural effusion, chest pain, dyspnea, absence of an intrapulmonary nodule and thickened pleura. In 4 out of 6 cases in their study, no primary site was identified. In our case too, the primary site was not ascertained by diagnostic imaging or intra operative examination. They proposed a possible origin of these cancers as a small subpleural tumour that became widely disseminated via the subpleural lymphatics. Koss et al in their study of lung cancer simulating mesothelioma were able to demonstrate a
ACCEPTED MANUSCRIPT
subpleural primary lung cancer in 3 of 14 lung specimens [5]. Small subpleural carcinomas which are subsumed within the thickened rind of pleural tumour might account for the occult character of the primary tumour in some cases of lung carcinomas mimicking mesothelioma [5].R.L.Attanos et al[6] has
RI PT
reported 5 cases of pleomorphic carcinoma (a subtype of sarcomatoid carcinoma) out of 47 with pseudomesotheliomatous growth. In 1 case, mixed squamous cell carcinoma with spindle cell areas (sarcomatoid cancer) was present; as seen in our report. Massive spontaneous hemothorax is a rare
SC
presenting sign of lung cancer. Snaebjornsson et al [8] reports a case of massive fatal hemothorax in a 74 year old male caused by pseudomesotheliomatous carcinoma of the lung due to diffuse bleeding from the
M AN U
pleural surface.
The possibilities after histological examination included lung or extrathoracic tumours metastatic to pleura, pleural mesothelioma, malignant melanoma and epithelioid angiosarcoma. Immunohistochemisty
TE D
was useful in confirmation of the diagnosis. Calretinin which is regarded as the most sensitive and specific mesothelial marker for malignant mesothelioma was negative. Because of its high vascularity, epitheliod angiosarcoma was considered, but markers for vascular differentiation (CD31 and CD34) were negative in the tumour cells. Melanoma marker HMB45 was negative. TTF-1 and CEA which are useful
EP
makers for primary pulmonary adenocarcinoma were negative. The epithelial lineage of the spindle cell components of sarcomatoid carcinoma were demonstrated by cytokeratin positive epithelial markers
AC C
(AE1/3). CK5/6 was diffusely positive due to the squamous differentiation. CK5/6 is also positive in malignant mesothelioma which was ruled out due to negative calretinin which is more sensitive. An awareness that some non-mesotheliomatous tumours may show CK5/6 positivity is important to prevent misdiagnosis. We converted to open thoracotomy with total pleurectomy since the pleural surface was diffusely bleeding. Also we could carefully inspect and palpate the entire lung for any lesions which were not seen on CT scan. The total pleurectomy would decrease the tumour load and help obtain a pleurodesis. A larger specimen for biopsy was obtained .In small biopsies, some tumour components (eg
ACCEPTED MANUSCRIPT
adenocarcinoma, SCC, large cell) may be under-/over represented or totally missing which may be
RI PT
misleading and hinder the definitive diagnosis of SARC from these small samples [8].
Conclusion
Sarcomatoid squamous cell lung cancer of pseudomesotheliomatous type presenting as massive
SC
hemothorax is a rare presentation by an uncommon tumour. It can be a considered as a differential
diagnosis for patients presenting with diffuse pleural thickening or massive hemothorax, especially in the
AC C
EP
TE D
M AN U
absence of a clinically or grossly identifiable primary lung tumour.
ACCEPTED MANUSCRIPT
References 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th edn. IARC 2015;88-94
RI PT
2. Pelosi G, Fraggetta F, Nappi O, et al. Pleomorphic carcinomas of the lung show a selective
distribution of gene products involved in cell differentiation, cell cycle control, tumour growth, and tumour cell motility:a clinicopathologic and immunohistochemical study of 31 cases. Am J
SC
Surg Pathol 2003;27:1203-15
3. Linda W.Martin, Arlene M.Correa, Nelson G.Ordonez et al. Sarcomatoid Carcinoma of the Lung:
M AN U
A Predictor of Poor Prognosis. Ann Thorac Surg 2007;84:973-81
4. Harwood TR, Gracey DR, Yokoo H. Pseudomesotheliomatous carcinoma of the lung. A variant of peripheral lung cancer.Am J Clin Pathol. 1976 Feb;65(2):159-67 5. Michael N.Koss, Marian Fleming, Ronald M.Przygodzki et al. Adenocarcinoa simulating Mesothelioma: A Clinicopathologic and Immunohistochemical Study of 29 cases. Annals of
TE D
Diagnostic Pathology. 1998 Apr;2(2):93-102 6. R L Attanoos, A R Gibbs. Pseudomesotheliomatous carcinomas of the pleura: a 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff. Histopathology.
EP
2003;43:444-452
7. Peter Snaebjornsson, Cornelis G.Vos, Koen J. Hartemink et al. Fatal Hemothorax caused by
AC C
Pseudomesotheliomatous Carcinoma of the Lung. Pathology Research International 2011, Article ID 836054, 5 pages
8. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med 2010;134:49-54
ACCEPTED MANUSCRIPT
Figure Legends Figure 1. (A) CT – Thorax showing thickened pleura with pleural nodules (B) CT –Thorax showing large
Figure 2. Gross specimen - thickened parietal pleura.
RI PT
right effusion.
Figure 3. Histology and Immunohistochemistry panel showing numerous spindled neoplastic cells with
AC C
EP
TE D
M AN U
SC
positive labeling for Cytokeratin (AE1/3) and CK5/6.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0003-4975(18)30546-0
DOI:
10.1016/j.athoracsur.2018.03.050
Reference:
ATS 31525
To appear in:
The Annals of Thoracic Surgery
Received Date: 19 December 2017 Revised Date:
5 March 2018
Accepted Date: 8 March 2018
Please cite this article as: Sangani NK, Naliath SM, Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax, The Annals of Thoracic Surgery (2018), doi: 10.1016/j.athoracsur.2018.03.050. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax
SC
Niravkumar K. Sangani, MCh, Santosh Mathew Naliath, MCh
RI PT
Running Head: Sarcomatoid lung cancer-pseudomesotheliomatous type with hemothorax
Address of Corresponding Author: Dr. Niravkumar Sangani
Cardiothoracic Surgery
Mussafah
AC C
Abu Dhabi, 2419
EP
P.O.Box 2419
TE D
Ahalia Hospital
UNITED ARAB EMIRATES
Email: [email protected]
Word count: 1519
M AN U
Department of Cardiothoracic Surgery, Ahalia Hospital-Mussafah, Abudhabi, United Arab Emirates
ACCEPTED MANUSCRIPT
Abstract A 44 year old male presented with spontaneous massive hemothorax. Computed tomography (CT) scan revealed thickened and nodular pleura with no evidence of lung tumour. Patient underwent right open
RI PT
total pleurectomy. Histopathology and Immunohistochemistry studies of the pleura confirmed poorly differentiated sarcomatoid squamous cell carcinoma of lung with metastasis to pleura. The carcinoma was psuedomesothelimatous type due to its presentation as diffuse pleural thickening. This presentation of
SC
sarcomatoid cancer as pseudomesotheliomatous type with massive hemothorax is rare and can be
considered as differential diagnosis in diffuse pleural thickening or hemothorax, especially in absence of
M AN U
clinically identifiable primary lung tumour.
AC C
EP
TE D
Key Words: Sarcomatoid, Lung cancer, Pseudomesotheliomatous, hemothorax, Hemothorax
ACCEPTED MANUSCRIPT
Sarcomatoid carcinoma of the lung (SARC) is a rare aggressive histologic subtype of non-small cell lung cancer .Pseudomesotheliomatous type of lung cancer implies presentation with diffuse involvement of the pleura in a manner simulating mesothelioma. Spontaneous hemothorax is an uncommon presenting sign
RI PT
of lung cancer. We report a case of poorly differentiated sarcomatoid squamous cell lung cancer with pseudomesotheliomatous growth pattern presenting as spontaneous massive hemothorax.
SC
A 44 year old male laborer presented with dry cough and right chest pain since two weeks. He was a chronic smoker (15 pack years). Chest x-ray demonstrated a right large pleural effusion. Computed
M AN U
tomography of the chest showed significant pleural effusion with associated passive collapse of lower lobe of right lung(Fig 1B). There was suggestion of right pleural thickening which appeared nodular at places (Fig 1A). No significant mediastinal lymphadenopathy was present. No lung or endobronchial tumour could be identified. On diagnostic thoracentesis, hemorrhagic fluid was aspirated. Intercostal
TE D
chest drain (No 32) was inserted which drained 2 litres of blood immediately with a total of 3.5 litres draining over the next 3 days. Pleural fluid cytology was negative for malignant cells. Bronchoscopy disclosed no endobronchial tumour.
EP
On examination of pleura by Video assisted thoracoscopic surgery (VATS), parietal pleura was thickened, irregular and nodular at places (Fig 2). The pleural surface showed diffuse bleeding. We
AC C
converted to right open posterolateral thoracotomy and performed a right total pleurectomy. We could not identify any right lung parenchymal lesion. Microscopy of the parietal pleura revealed hemorrhagic ulcerations infiltrated by neoplastic cells showing biphasic epitheloid and sarcomatoid growth pattern. Sheets of hemorrhagic epitheloid cells with pleomorphic vesicular nuclei, prominent nuclei with abundant focally vacuolated cytoplasm, many atypical mitoses and apoptotic bodies forming many slits were present. It was associated with wide necrosis, invading fat tissue and infiltrating adjacent skeletal muscle cells. It was accompanied by reactive lymphoid follicles, mixed inflammatory cells and hemosiderin
ACCEPTED MANUSCRIPT
laden macrophages in the stroma. On Immunohistochemical investigation, the neoplastic lesion was positive for immunomarkers Cytokeratin (AE1/AE3) and Vimentin. It was also diffusely positive for CK5/6 showing numerous spindled neoplastic cells (Fig 3). Immunomarkers CK7, TTF1, p63, CEA,
RI PT
HMB45, CD31, CD34 and Calretinin were negative. This was suggestive of poorly differentiated sarcomatoid squamous cell carcinoma of the right lung with metastasis of the parietal pleura. The patient was referred for palliative treatment due to the presentation as Stage IV lung cancer. The patient decided
SC
to go to his home country for further treatment and was lost to follow up.
M AN U
Comment
The presenting feature of SARC as pseudomesotheliomatous type with hemothorax is unique. SARC is defined as a poorly differentiated non-small cell carcinoma that contains a component of sarcoma or sarcoma-like elements (at least 10% spindle and/or giant cells) [1] Sarcomatoid histology is rare and
TE D
present in 0.1% to 0.4% of all patients with non-small cell lung cancer [1] It has a locally aggressive nature partly due to the sarcomatoid elements which develop enhanced angiogenic activity and tumour cell motility.[2].Most present in heavy smokers as large masses at an advanced stage. SARC is a predictor
EP
of poor prognosis with significantly worse survival and higher recurrence rates [3]. Harwood et al [4] first reported a variant of peripheral lung cancer with diffuse pleurotropic growth pattern that closely
AC C
resembled malignant pleural mesothelioma on clinical, radiological and pathological examination. They therefore named it carcinoma of the pseudomesotheliomatous type. Their diagnostic criteria included pleural effusion, chest pain, dyspnea, absence of an intrapulmonary nodule and thickened pleura. In 4 out of 6 cases in their study, no primary site was identified. In our case too, the primary site was not ascertained by diagnostic imaging or intra operative examination. They proposed a possible origin of these cancers as a small subpleural tumour that became widely disseminated via the subpleural lymphatics. Koss et al in their study of lung cancer simulating mesothelioma were able to demonstrate a
ACCEPTED MANUSCRIPT
subpleural primary lung cancer in 3 of 14 lung specimens [5]. Small subpleural carcinomas which are subsumed within the thickened rind of pleural tumour might account for the occult character of the primary tumour in some cases of lung carcinomas mimicking mesothelioma [5].R.L.Attanos et al[6] has
RI PT
reported 5 cases of pleomorphic carcinoma (a subtype of sarcomatoid carcinoma) out of 47 with pseudomesotheliomatous growth. In 1 case, mixed squamous cell carcinoma with spindle cell areas (sarcomatoid cancer) was present; as seen in our report. Massive spontaneous hemothorax is a rare
SC
presenting sign of lung cancer. Snaebjornsson et al [8] reports a case of massive fatal hemothorax in a 74 year old male caused by pseudomesotheliomatous carcinoma of the lung due to diffuse bleeding from the
M AN U
pleural surface.
The possibilities after histological examination included lung or extrathoracic tumours metastatic to pleura, pleural mesothelioma, malignant melanoma and epithelioid angiosarcoma. Immunohistochemisty
TE D
was useful in confirmation of the diagnosis. Calretinin which is regarded as the most sensitive and specific mesothelial marker for malignant mesothelioma was negative. Because of its high vascularity, epitheliod angiosarcoma was considered, but markers for vascular differentiation (CD31 and CD34) were negative in the tumour cells. Melanoma marker HMB45 was negative. TTF-1 and CEA which are useful
EP
makers for primary pulmonary adenocarcinoma were negative. The epithelial lineage of the spindle cell components of sarcomatoid carcinoma were demonstrated by cytokeratin positive epithelial markers
AC C
(AE1/3). CK5/6 was diffusely positive due to the squamous differentiation. CK5/6 is also positive in malignant mesothelioma which was ruled out due to negative calretinin which is more sensitive. An awareness that some non-mesotheliomatous tumours may show CK5/6 positivity is important to prevent misdiagnosis. We converted to open thoracotomy with total pleurectomy since the pleural surface was diffusely bleeding. Also we could carefully inspect and palpate the entire lung for any lesions which were not seen on CT scan. The total pleurectomy would decrease the tumour load and help obtain a pleurodesis. A larger specimen for biopsy was obtained .In small biopsies, some tumour components (eg
ACCEPTED MANUSCRIPT
adenocarcinoma, SCC, large cell) may be under-/over represented or totally missing which may be
RI PT
misleading and hinder the definitive diagnosis of SARC from these small samples [8].
Conclusion
Sarcomatoid squamous cell lung cancer of pseudomesotheliomatous type presenting as massive
SC
hemothorax is a rare presentation by an uncommon tumour. It can be a considered as a differential
diagnosis for patients presenting with diffuse pleural thickening or massive hemothorax, especially in the
AC C
EP
TE D
M AN U
absence of a clinically or grossly identifiable primary lung tumour.
ACCEPTED MANUSCRIPT
References 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th edn. IARC 2015;88-94
RI PT
2. Pelosi G, Fraggetta F, Nappi O, et al. Pleomorphic carcinomas of the lung show a selective
distribution of gene products involved in cell differentiation, cell cycle control, tumour growth, and tumour cell motility:a clinicopathologic and immunohistochemical study of 31 cases. Am J
SC
Surg Pathol 2003;27:1203-15
3. Linda W.Martin, Arlene M.Correa, Nelson G.Ordonez et al. Sarcomatoid Carcinoma of the Lung:
M AN U
A Predictor of Poor Prognosis. Ann Thorac Surg 2007;84:973-81
4. Harwood TR, Gracey DR, Yokoo H. Pseudomesotheliomatous carcinoma of the lung. A variant of peripheral lung cancer.Am J Clin Pathol. 1976 Feb;65(2):159-67 5. Michael N.Koss, Marian Fleming, Ronald M.Przygodzki et al. Adenocarcinoa simulating Mesothelioma: A Clinicopathologic and Immunohistochemical Study of 29 cases. Annals of
TE D
Diagnostic Pathology. 1998 Apr;2(2):93-102 6. R L Attanoos, A R Gibbs. Pseudomesotheliomatous carcinomas of the pleura: a 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff. Histopathology.
EP
2003;43:444-452
7. Peter Snaebjornsson, Cornelis G.Vos, Koen J. Hartemink et al. Fatal Hemothorax caused by
AC C
Pseudomesotheliomatous Carcinoma of the Lung. Pathology Research International 2011, Article ID 836054, 5 pages
8. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med 2010;134:49-54
ACCEPTED MANUSCRIPT
Figure Legends Figure 1. (A) CT – Thorax showing thickened pleura with pleural nodules (B) CT –Thorax showing large
Figure 2. Gross specimen - thickened parietal pleura.
RI PT
right effusion.
Figure 3. Histology and Immunohistochemistry panel showing numerous spindled neoplastic cells with
AC C
EP
TE D
M AN U
SC
positive labeling for Cytokeratin (AE1/3) and CK5/6.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT