Pulmonary heteroplasia_2
Short Summary

66-year-old female was diagnosed, following persistent cough, with non-operable tumor of her lung with satellite nodules, and chemotherapy was initiated (first Cisplatin and Gemcitabine, and then switched to Tarceva). Response evaluation following the fourth cycle of chemotherapy showed either stability or an initiation of tumor response, but bone scintigraphy that was performed 6 months later revealed an area of increased uptake in the left hemithorax which could be suggestive of a secondary bone lesion.

Patient's Questions
1)            How would you assess the progression of the disease?

2)            What is the prognosis?

3)            Do you suggest any possible diagnostic measures to complement those conducted so far?

4)            Any other treatments to use?
Medical Background

Sex: F, Age: 66 years
DiagnosisPulmonary heteroplasia
 
On 5/2007, following persistent cough for some months,the patient was diagnosed having a non-operable tumor of her lung with satellite nodules. Two separate needle biopsies revealed a composed/non uniform histology, although both histologic samples were related to a neuroendocrine tumor:
 
a. well differentiated neuroendocrine carcinoma (typical carcinoid)
b. adenocarcinoma with associated neuroendocrine differentiation.
 
On 7/2007chemotherapy (Cisplatin and Gemcitabine) was initiated.
 
On 9/2007 the first report about tumor markers revealed elevated levels:
ChromograninA (CgA) elevated to 380 and CEA elevated to 45. (It is unknown if these values were higher or lower than the pretreatment values which were not reported).
 
On 10/2007 a response evaluation following the fourth cycle of chemotherapy showed
either stability (by CAT scan) or an initiation of tumor response (by PET scan). (The level  of tumor markers was not reported at that time point). 
 
On 11/2007 the treatment was switched to Tarceva for 1 month (the reasons for
starting on Tarceva on that time and for stopping it just one month later were not reported).
On 12/2007 the level of CgA was found to have decreased to the normal level of 68 (!). (However, lacking the base line level of CgA [ previous to chemotherapy treatment] and the post chemotherapy level [previous to the treatment with Tarceva] it can't be
determined whether this serological response represents a late response to the first
administered chemotherapy, or a current response to the later administered Tarceva).
 
On 1/2008 a volumetric CAT scan demonstrated a moderate increase in size of a few satellite nodules at the edges of the main (and stable) nodular formation.
 
On 2/2008 following two months rest from treatment the value of CgA was still steady at the level of 58.
 
On 3/2008 a PET scan demonstrated persistence in the voluminous area of
pathological accumulation of the radiopharmaceutical in the upper lobe of the right lung which appeared largely unchanged both in size and in the fixation gradient of the radiopharmaceutical, as compared to 10/2007. In addition there was complete
normalization of the previously described fixation gradient of the radiopharmaceutical at the level of the II right and III left ribs.
 
On 4/2008 a whole body bone scintigraphy revealed a single area of increased uptake in the left hemithorax posterior arc of rib VII region which could be suggestive of a secondary bone lesion. (There is an intriguing discrepancy in the location of findings between the PET scan and the bone scintigraphy).
 
On 4/2008 the CgA value raised to 445 (!) representing a serological progression.
 
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The most recent significant clinical information is as follows:
-       on Nov 2007, admitted to DH to begin treatment with Tarceva 150 mg/day for 1 month;

-       blood test on Dec 2007 for dosage of Chromogranin A = 68.0 (normal values 19.4 - 98.1);

-       blood test on Jan 2008 for dosage of Somostatin = 20 (on empty stomach after 12 hours: < 26; 4 hours after meals </=80); NSE = 8.6 (less than 18.3); 5-OH- Urinary Indoleacetic acid = 9.6 (0.7 – 8.2).

-       Total body multi-layer volumetric CAT scanà
o   Cranial: normal.

o   Chest: at the level of the upper lobe of right lung we have confirmation of the presence of a solid formation, unhomogeneous, containing some areas of aerial bronchogram. It is likely that this area is, in part, constituted by pathological tissue and, in part, by areas of atelectasic parenchyma. At the maximum extension point the lesion has a transverse diameter of 68 mm (previous 67 mm) and an anterior-posterior diameter of 100 mm (previous 97 mm) and is therefore stable. The central area appears more patchy. At the edges of the main nodular formation a few satellite nodules are observed, ranging from 11 mm to 21 mm in size (previous diameters 5 and 16 mm). These nodular formations therefore demonstrate a moderate increase in size. Small nodular irregularities, which could be of a fibrous nature, can be observed at the level of the left lung. No pleural effusion. Regular morphology of the cardiovascular structures of the mediastinum. The lymphadenopathy is insignificant at the mediastinic level with the exception of a lymph node of 10 mm at the carinal level.

o   Abdomen-Pelvis: in the abdomen small cystic formation of the hepatic parenchyma are noted, but no secondary lesions. In the pelvis an increase was noted in the size of the uterus. The rest is normal.

As already reported in a previous PET exam, changes of osteoschlerotic type are confirmed at the second right and third left ribs, possibly repetitive in nature.

-       blood test on Feb 2008 with Chromogranin A dosage 58.0 (19.4 - 98.1);

-       PET of Mar 2008à, this test, compared with previous images performed in other locations, of which the most recent in October 2007, demonstrated a persistence in the voluminous area of pathological accumulation of the radiopharmaceutical in the upper lobe of the right lung, which appears largely unchanged in size and in the fixation gradient of the radiopharmaceutical. Slight hypercaptation of the radiotracer in an area of pleural thickening at the anterior arch of the IV left rib. Finally, complete normalization of the fixation gradient of the radiopharmaceutical is observed at the level of the II right and III left ribs.

-       blood test on Apr 2008 with Chromogranin A dosage = 445 (19.4 - 98.1);

-       CAT scan on April 2008 à
o   Cranial: no significant elements

o   Chest: at the level of the upper lobe of right lung we have confirmation of the presence of a solid formation, unhomogeneous, containing some areas of aerial bronchogram. It is likely that this area is, in part, constituted by pathological tissue and, in part, by areas of thickened-inflammatory parenchyma. At the maximum extension point the lesion has a transverse diameter of 70 mm previous 68 mm) and an anterior-posterior diameter of 12 mm (previous 10 mm) and is slightly larger. The central area appears less patchy. At the edges of the main nodular formation a few satellite nodules are observed, ranging from 11 mm to 34 mm in size (previous diameters 11 and 21 mm). These nodular formations therefore demonstrate a moderate increase in size. Small nodular irregularities, which could be of a fibrous nature, can be observed at the level of the left lung, stable. No pleural effusion. Regular morphology of the cardiovascular structures of the mediastinum. The lymphadenopathy is insignificant at the mediastinic level with the exception of a lymph node of 10 mm at the carinal level.

o   Abdomen-Pelvis: in the abdomen small cystic formation in the hepatic parenchyma are noted, but no secondary lesions. In the pelvis an
increase was noted in the size of the uterus. The rest is normal.

As already reported in a previous PET exam, changes of osteoschlerotic type are confirmed at the second right and third left ribs, possibly repetitive in nature.

Expert's Opinion

How would you assess the progression of the disease?
Based on all tests performed since 1/2008 I would conclude that there is disease progression. However, this progression seems to be minimal. Therefore, I would hold any interventional decisions until there is definitive progression, while proceeding with further evaluations aimed at the best substantiated decision in due time:
 
(A) I would repeat the CAT scan at 3 months intervals, always comparing the new scan to the base line scan (which was conducted on 1/2008 following the treatment by Tarceva). A PET scan, on the other hand, could be reserved exclusively for situations of uncertainty with regards to practical decisions, such as whether to stop a certain treatment in the presence of non conclusive information.
 
 (B) I would repeatedly measure the levels of all possible markers of this "non
uniform" tumor, including CgA and CEA (which represent the neuroendocrine
component) as well as CA125 (which if is found to be positive it would represent the
adenocarcinoma component). These measurements should be conducted both at every time point in which treatment is changed and periodically thereafter.
 
 At the present time a repeated measurement of CgA and CEA levels would
serve two purposes:
a. for confirming the single significant increment documented so far in 4/2008, as a first suggestion of tumor progression;
b. if that marker elevation is confirmed then the repeated measurements would enable the estimation of its doubling time and of the rate of tumor progression.
 
C) With regards to the confounding findings in the ribs, with discrepancies
between PET scan and Skeleton Scintigraphy, I would conduct the follow up of these
suspected findings according to clinical symptoms: if they are asymptomatic they bear
no practical implications since the systemic treatment can be chosen and evaluated on the basis of the findings in the lung parenchyma.
      
What is the prognosis?
At one year since diagnosis and following exposure to two different treatment modalities there is no significant change: neither response to treatment nor "natural" progression. Therefore, it can be concluded that the prognosis is most probably consistent with that of a well differentiated tumor which is expected to grow further, however, most probably over several years.
 
Although the tumor of the patient is non curable, it is still limited to one lung and with no new metastases, thus reflecting its slow growing and less ominous nature.The next measurements of CgA levels will reveal its rate of increment, thus contributing to the better estimation of the prognosis.
 
Do you suggest any possible diagnostic measures to complement those conducted so far?
A) As already explained in my answer to question number 1, I would measure also markers of Non Small Cell Lung Cancer aimed to establishing the corresponding component of the tumor (adenocarcinoma) in addition to the neuroendocrine component.
(B) In view of the original diagnosis and in view of the presently raising levels of CgA, I consider it mandatory to perform a Somatostatin receptor scintigraphy (SRS).
 
Any other treatments to use?
( A ) If the SRS test results to be positive then the preferred treatment at the present stage would be that of high-dose targeted irradiation with radiolabeled somatostatin analogue(s) (as practiced either by Mueller-Brand J., in the Institute of Nuclear Medicine, University Hospital, University of Basel, Basel, Switzerland. [email protected] , or by Paganelli G., in the Nuclear Medicine Division, European Institute of Oncology, Milan, Italy.
 
( B ) I have no information regarding the effect of Tarceva or about the reason for stopping that treatment following just one month (11/2007). Nevertheless, one single month would seem to be a too short and insufficient period for discarding its use. The level of CgA at the end of treatment with Tarceva (68) which further decreased two months later (to 58) suggests a "trend to response" to Tarceva and would support resuming treatment with this medicament.
 
( C ) Further chemotherapy should be reserved for palliation purposes and as a last option if and when options (A) and (B) are exhausted and the disease becomes symptomatic. If there was no serious toxicity from the previously administered chemotherapy I would include platinol or carboplatin in the treatment regimen especially because there was no clear progression under previous treatment with four cycles of Cisplatin and Gemcitabine. Additional drugs to be considered (possibly in combination) would be etoposide, navelbine, pemetrexed or docetaxel.
 
 ( D ) In case that bothering/exhausting cough represents a limiting factor for the patient's quality of life, there is place for palliative external irradiation. Optimally, and provided that it is found feasible through bronchoscopy, this should be combined with endobronchial High Dose Rate (HDR) brachitherapy by radioactive seeds.
   
NOTE: Towards every new treatment an updated base line evaluation should be conducted, including all the parameters of tumor activity. These should include clinical symptoms and signs; all the relevant tumor markers (CgA, CEA, CA125); CAT scan and PET scan. Thereafter, these tests should be repeated for treatment evaluation at regular intervals, although the repetition of expensive PET scan might be reserved and limited for assistance in situations of uncertainty. Please enclose the records of all performed tests in case of a future follow up consultation.
 
I very much hope that the patient is in good performance status and asymptomatic with her slow growing disease and possibly does not require any treatment interventions at the present. However, if and when treatment becomes necessary for significant disease progression I hope that my suggestions will contribute to her health.
 

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