Clinicopathologic Characteristics Of Secondary Malignancies In Survivors Of Allogeneic Hematopoietic Stem Cell Transplantation In Patients With Hematologic Malignancies

Allogeneic hematopoietic stem cell transplantation (SCT) is known to cure hematologic malignancies (HM). However, the risk of secondary malignancies (SM) is increased in long-term survivors. We report a series of 10 patients (pt) who developed SM and pre-malignant lesions post-SCT with predominance of squamous cell carcinomas (SCC) of oral cavity and esophagus.

Ten pt with median age 40 yrs(range 21-60) at SCT were diagnosed with 13 SM in a median follow up (f/u) of 8 yrs(range 1.5-13). Five pt developed oral and esophageal SCC (4 tongue, 1 esophagus). Four of the 5 pt had chronic GVHD & squamous dysplasia (SD) at the primary site 1 to 5 yrs prior to the diagnosis of SCC. Surgical pathology in 4 pt with oral SCC showed multifocal invasive SCC, high grade SD, SCC-in-situ and positive margin for invasive SCC. Three pt developed recurrences & 2 died. The details on individual pt are presented below (Table 1).

Pt 1 was 46 y/o M at SCT, developed 2 SCC (tongue and floor of mouth, pT1N0) 3 yrs post-SCT. He received chemotherapy; radiotherapy withheld due to severe oral GVHD. He has developed 4 recurrences in 2 years of f/u.

Pt 2 was a 40 y/o M at SCT, developed 2 SCC (pT1N1) of tonsil & tongue 8 yrs post-SCT. He is 8 yrs out of SCC after chemoradiation (CRT).

Pt 3 was a 35 y/o F at SCT, developed SCC (pT2N0) of tongue 8 yrs post-SCT. She received CRT & died 4 yrs later after recurrences.

Pt 4 was a 54 y/o F at SCT, developed stage II ER+, PR+ and Her-2+ breast cancer 8 yrs post-SCT. She did not tolerate trastuzumab & anastrazole due to flare up of GVHD. She developed pT4aN2b SCC of tongue 12 yrs post-SCT & died after 4 months.

Pt 5 was 31 y/o M at SCT, developed stage IIIA SCC of esophagus after 13 yrs. He had esophageal GVHD & high grade SD with +CMV 5 yrs prior to the diagnosis of SCC. He is currently receiving CRT.

Pt 6 was 60 y/o M at SCT, developed stage IIIB non-small cell lung cancer (NSCLC) 1.5 yr post-SCT. He received radiation alone due to bronchiolitis obliterans syndrome (BOS). He has no evidence of recurrence at 2 yrs f/u.

Pt 7 was a 38 y/o F at SCT, developed papillary urothelial carcinoma (pT1) 10 yrs post-SCT. She was treated with TURBT and remains free of cancer at 4 yrs.

Pt 8 was a 35 y/o F at SCT, developed HPV- oral SD 6 yr post-SCT and died of BOS.

Pt 9 was a 21 y/o F at SCT, developed vaginal and cervical SD 7 yr post-SCT and transferred care out of country.

Pt 10 was 53 y/o F at SCT, developed skin cancers.

LBCL indicates large B cell lymphoma; RIC, reduced intensity conditioning; MSD, matched sibling donor; MUD, matched unrelated donor; SCC, squamous cell carcinoma; BCC, basal cell carcinoma; PUC, papillary urothelial carcinoma; LVI, lymphovascular invasion; PNI, perineural invasion; SD, squamous dysplasia; SP, squamous papilloma; NPB, no prior biopsy; PY, pack year; NP, not performed; C, cyclosporine; P, prednisone; M, mycophenolate.

Our observation shows that the SCC of oral cavity and esophagus is a common SM in post-SCT patients for HM. SCC was often multifocal, negative surgical margin was not obtainable and employing standard therapy was difficult due to severe GVHD and other comorbidities. Aggressive recurrence was common. One out of 2 tumor samples tested was positive for HPV. Traditional risk factors of SCC (e.g. tobacco, alcohol) were either absent or remotely present suggesting potential implications of SCT specific risk factors (e.g. conditioning regimen, GVHD, immunosuppressants, viral infections). Patients and physicians should be aware of this association and lifelong vigilance and appropriate referral for screening and early biopsy should be considered in survivors of SCT.

No relevant conflicts of interest to declare.