3.1 Case report 1

leiomyosarcomas. Future genetic studies in this population could elucidate the predisposition for leiomyosarcomas in patients with retinoblastoma [35, 36].

option for trilateral retinoblastomas [38].

Retinoblastoma - Past, Present and Future

extraordinary secondary cancer risk [39].

nancies occur in the population at large [43].

cavities [44].

112

Children with the heritable form of retinoblastoma also have a very small risk to develop within a few years a tumor in the pineal gland; it is referred as a trilateral retinoblastoma. Tumors can start there, while the pineal gland can have cells similar to retina cells. That is why it is important to perform MRI of the head for several years after treatment of retinoblastoma to detect these tumors as early as possible. Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life [37]. Yamanaka, Hayno, and Takashima analyzed 211 cases of trilateral retinoblastomas. The average latency period between the onset of retinoblastomas and trilateral retinoblastomas was 1.5 1.8 years. Pineal tumors were found in almost 74% and sellar tumors in 22%. The overall median survival was 10.3 months, and the 5-year survival rate was 16%, while in patients receiving high-dose chemotherapy by stem cell transplantation, the survival time was significantly longer than with conventional chemotherapy. The authors conclude that trilateral retinoblastoma patients with an irradiation history had shorter survival than those without irradiation history for retinoblastoma, and high-dose chemotherapy should be considered as a potential treatment

Among patients with hereditary disease, treatment with radiotherapy in 95% was associated with a further increase in the risk of a subsequent cancer. After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma [18]. In the study of Wong et al., it was found that the incidence of secondary cancer after retinoblastoma treatment is higher due to the genetic predisposition. Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma survivors, and radiation treatment increases it. A radiation dose-response relationship is demonstrated in all types of soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life also in whole adulthood due to

The development of lung cancer is affected to a considerable extent by somatic mutations in the Rb1 gene in patients with an elevated risk for lung cancer. Higher risk of developing lung cancer is in patients undergoing chemotherapy and radiotherapy in retinoblastoma treatment [40, 41]. Some studies suggested there might

Bladder tumors are distinguished between malignant and nonmalignant. In this case, there is only a small difference between them that is difficult to determine microscopically. The most common bladder cancer is papilloma and papillomavirus, which together account for about 90% of all tumors. The borderline between malignant and nonmalignant bladder tumors is very thin [42]. Study of Marees et al. significantly elevated risk of bladder cancer among hereditary retinoblastoma patients after prolonged follow-up, whose prevalence is mostly 30 years after retinoblastoma treatment [18]. Alterations in an Rb1 pathway have been established as a major contributor to bladder tumorigenesis, and carriers of an Rb1 mutation have an elevated risk of bladder cancer, when they reach the ages at which these malig-

All available studies on the occurrence of secondary malignity after retinoblastoma treatment indicate that the most important risk factor remains the Rb1 gene mutation. Kleinerman describes in his study the risks of new cancers after radiotherapy in long-term survivors of retinoblastoma. Radiation increases the risk of another cancer in hereditary patients by 3.1-fold. Hereditary patients continue to have at significantly increased risk for sarcomas, melanoma, and cancers of the brain and nasal

also be an increased risk for lung cancer in non-irradiated patients [15].

Girl with bilateral retinoblastoma treated in 1989 in Bratislava by enucleation of the right eye and chemotherapy plus RT on the left side. Due to secondary complication, she underwent cataract surgery in 1993 and was aphakic and got glasses. In 2011 secondary tumor developed in the orbit region with infiltration to the brain. She underwent surgery three times by a neurosurgeon with adjuvant chemotherapy and high-dose RT due to verified leiomyosarcoma. In 2015 due to progression of the leiomyosarcoma, she underwent photon beam irradiation with gamma knife. Tumor masses infiltrating the orbit lead to exenteration of the orbit (Figures 1–3).

The risk of secondary malignancies after retinoblastoma treatment is high, but in contrast to bone cancers and leiomyosarcomas, chemotherapy was not associated with increased melanoma risk [10, 17]. The development of skin melanoma may be related to an underlying genetic predisposition associated with retinoblastoma rather than treatment modality. Major susceptibility genes for melanoma include CDKN2A and CDK4 which are both upstream from the Rb1 gene. In the future an additional investigation is necessary to understand the association between the development of melanoma and retinoblastoma treatment [45].

The leukemogenicity of certain chemotherapeutic agents is well established, and there are connections between alkylating agents and a range of development of solid

#### Figure 1.

Case report 1: Patient after enucleation of her right eye in childhood; conjunctival sac clear; in her left eye, aphakia (clinical findings in 2015).

#### Figure 2.

Case report 1: Preoperative findings in 2017 by partial exenteration of the left orbit due to secondary tumor— Histopathologically confirmed leiomyosarcoma grade 2.

treatment received for retinoblastoma [54]. Due to results of Wong et al., although SMNs are more likely to be misclassified because histology is not specified, sensitivity analyses including 1-year versus 5-year survivors also yielded comparable results [22]. Skin malignancies are rare but usually are in the head region. Orbital malignancies are more frequent. In the study was presented a 22-year-old young man with history of bilateral retinoblastoma initially in childhood treated by enucleation of his left eye. The histopathology findings showed a moderately differentiated tumor with vitreous seeding. The patient received chemotherapy in addition to radiotherapy to his right eye. More than 20 years later, he got proptosis due to the right orbital tumor. The excisional biopsy of his orbital mass verified a spindle cell

Secondary Malignancies in Adulthood and after Retinoblastoma Treatment in Childhood

Boy with unilateral retinoblastoma treated in 1988 in Bratislava with enucleation

of the left eye globe and chemotherapy and RT. He got individual prosthesis

Case report 2: Secondary tumor in his upper right eye lid (histopathologically confirmed squamous cell

Case report 2: Patient 2 months after surgery due to secondary malignancy—Squamous cell carcinoma, in his

sarcoma with features of malignant fibrous histiocytoma [55].

DOI: http://dx.doi.org/10.5772/intechopen.86746

3.2 Case report 2

Figure 4.

Figure 5.

115

upper left eyelid.

carcinoma of the eyelid).

Figure 3. Case report 1: Clinical findings next month after surgery of the left orbit, healing without complications.

SMNs. Chemotherapy has also been associated with an increased risk for other types of malignancies, e.g., lung cancer after Hodgkin and non-Hodgkin lymphomas, stomach cancer after Hodgkin lymphoma in combination with high-dose abdominal RT, and colorectal cancer after childhood cancer [46, 47]. Increased sarcoma risk after childhood cancer is associated with anthracyclines therapy, especially after Hodgkin lymphoma or a primary sarcoma in childhood [48].

Hereditary retinoblastoma survivors who were treated with alkylating agents plus RT have a significantly higher risk of developing bone cancers and leiomyosarcomas than those treated with single RT. Excess risks of secondary cancers associated with alkylating agents plus RT persist for decades. Significantly higher incidence of leiomyosarcomas is diagnosed at a median age of 34 years. These risks are present during long-term follow-up of retinoblastoma survivors. Guide recommendations for future treatment protocols will define chemo-related SMN risk among retinoblastoma survivors, particularly in patients treated with chemotherapy without RT.

Current chemotherapy agents recommended for retinoblastoma include cyclophosphamide, ifosfamide, carboplatin, vincristine, etoposide, topotecan, and doxorubicin [49–51]. Most retinoblastoma survivors who received an alkylating agent received TEM, which is no longer used in clinical practice [52]. On the basis of the recently developed cyclophosphamide equivalent dose, TEM has substantially lower hematologic toxicity than agents used in current clinical practice. Generally there is the long latency period of SMN development and potentially different CT drugrelated adverse effect. In the future studies have to evaluate SMN risk with longterm follow-up of patients with retinoblastoma treated with current agents. The cyclophosphamide equivalent dose can be easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. The use of the cyclophosphamide equivalent dose is promising in future research, assessing cumulative alkylating agent exposure [53].

Several limitations of certain studies dealing with SMNs should be taken into account. On reports of family history of retinoblastoma and laterality to define hereditary status, some unilateral retinoblastoma survivors could have had a germline Rb1 mutation and should have been included into analysis [17, 34].

Although some survivors in studies are lost to follow-up due to different reasons, SMN risk estimates are unlikely to be affected, because response was not related to

Secondary Malignancies in Adulthood and after Retinoblastoma Treatment in Childhood DOI: http://dx.doi.org/10.5772/intechopen.86746

treatment received for retinoblastoma [54]. Due to results of Wong et al., although SMNs are more likely to be misclassified because histology is not specified, sensitivity analyses including 1-year versus 5-year survivors also yielded comparable results [22].

Skin malignancies are rare but usually are in the head region. Orbital malignancies are more frequent. In the study was presented a 22-year-old young man with history of bilateral retinoblastoma initially in childhood treated by enucleation of his left eye. The histopathology findings showed a moderately differentiated tumor with vitreous seeding. The patient received chemotherapy in addition to radiotherapy to his right eye. More than 20 years later, he got proptosis due to the right orbital tumor. The excisional biopsy of his orbital mass verified a spindle cell sarcoma with features of malignant fibrous histiocytoma [55].

#### 3.2 Case report 2

Boy with unilateral retinoblastoma treated in 1988 in Bratislava with enucleation of the left eye globe and chemotherapy and RT. He got individual prosthesis

#### Figure 4.

SMNs. Chemotherapy has also been associated with an increased risk for other types of malignancies, e.g., lung cancer after Hodgkin and non-Hodgkin lymphomas, stomach cancer after Hodgkin lymphoma in combination with high-dose abdominal RT, and colorectal cancer after childhood cancer [46, 47]. Increased sarcoma risk after childhood cancer is associated with anthracyclines therapy, especially after

Case report 1: Clinical findings next month after surgery of the left orbit, healing without complications.

Hereditary retinoblastoma survivors who were treated with alkylating agents

leiomyosarcomas than those treated with single RT. Excess risks of secondary cancers associated with alkylating agents plus RT persist for decades. Significantly higher incidence of leiomyosarcomas is diagnosed at a median age of 34 years. These risks are present during long-term follow-up of retinoblastoma survivors. Guide recommendations for future treatment protocols will define chemo-related SMN risk among retinoblastoma survivors, particularly in patients treated with

Current chemotherapy agents recommended for retinoblastoma include cyclophosphamide, ifosfamide, carboplatin, vincristine, etoposide, topotecan, and doxorubicin [49–51]. Most retinoblastoma survivors who received an alkylating agent received TEM, which is no longer used in clinical practice [52]. On the basis of the recently developed cyclophosphamide equivalent dose, TEM has substantially lower hematologic toxicity than agents used in current clinical practice. Generally there is the long latency period of SMN development and potentially different CT drugrelated adverse effect. In the future studies have to evaluate SMN risk with longterm follow-up of patients with retinoblastoma treated with current agents. The cyclophosphamide equivalent dose can be easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. The use of the cyclophosphamide equivalent dose is promising in future research, assessing cumulative alkylating agent exposure [53]. Several limitations of certain studies dealing with SMNs should be taken into account. On reports of family history of retinoblastoma and laterality to define hereditary status, some unilateral retinoblastoma survivors could have had a germline Rb1 mutation and should have been included into analysis [17, 34].

Although some survivors in studies are lost to follow-up due to different reasons, SMN risk estimates are unlikely to be affected, because response was not related to

Hodgkin lymphoma or a primary sarcoma in childhood [48].

chemotherapy without RT.

Retinoblastoma - Past, Present and Future

Figure 3.

114

plus RT have a significantly higher risk of developing bone cancers and

Case report 2: Secondary tumor in his upper right eye lid (histopathologically confirmed squamous cell carcinoma of the eyelid).

#### Figure 5.

Case report 2: Patient 2 months after surgery due to secondary malignancy—Squamous cell carcinoma, in his upper left eyelid.

without complications. In 2017 he developed "inflammation" of the right eye upper eye lid and was sent to an ophthalmologist for chalazion excochleation. By excisional biopsy was confirmed squamous cell carcinoma (Figures 4 and 5).

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