Secondary Neoplasia (Other than PTLPS)

  • André TichelliEmail author
Open Access


Secondary neoplasia (SN) after HSCT includes any malignant disorder occurring after HSCT, irrespectively, if related or not to transplantation.

47.1 Definitions

Secondary neoplasia (SN) after HSCT includes any malignant disorder occurring after HSCT, irrespectively, if related or not to transplantation. For an individual patient, a clear relationship between HSCT and SN often cannot be provided. In this chapter, post transplant lymphoproliferative disorders are not discussed (see Chap.  45).

47.2 Types of Secondary Neoplasia After HSCT


Therapy-related myeloid neoplasms (t-MN)a

Donor cell leukemia (DCL)b

Second solid neoplasms (SSN)c


t-MDS or t-AML after exposition chemo or radiation therapy

Hematologic neoplasms occurring in grafted donor cells

Solid cancers of any site and histology occurring after HSCT


Mainly after auto-HSCT

Not excluded after allo-HSCTd

After allo-HSCT only

After allo-HSCT and auto-HSCT


Within the first 10 years mainly


Increasing incidental rate with longer follow-up




Depends mainly on the cancer type

aPedersen-Bjergaard et al. (2000); Engel et al. (2018)

bSala-Torra et al. (2006); Wiseman (2011)

cKolb et al. (1999); Rizzo et al. (2009)

dYamasaki et al. (2017)

47.3 Pathophysiology

47.3.1 Therapy-Related Myeloid Neoplasms

t-MN are mainly associated with cytotoxic chemotherapy and radiation therapy that the patient has received either before HSCT or as conditioning. The causal role of ionizing radiation in the development of myeloid neoplasms has been demonstrated in atomic bomb survivors of Hiroshima/Nagasaki and in medical radiation workers employed before 1950.

Responsible cytotoxic drugs:
  • Alkylating agents, anthracyclines, and topoisomerase II inhibitors.

  • To a lesser extent antimetabolites and purines analogs.

  • Controversy exists on the role of azathioprine, methotrexate, hydroxyurea, and 6-mercaptopurines used for the treatment of malignant and nonmalignant diseases.

t-MN occur mainly after auto-HSCT, where the healthy HSC has been exposed to cytotoxic effect. Rarely t-MN can be observed after allo-HSCT, despite the donor cells have not been exposed to cytotoxic agents. Persistent microchimerism with few exposed residual recipient cells may explain the development of t-MN after allo-HSCT. The incidence of t-MN after allo-HSCT might increase, since chimeric states are observed more frequently after RIC-HSCT.

Today, increasingly cytotoxic drugs are applied after the allo-HSCT, either as GVHD prophylaxis (post transplant CY) or to prevent disease recurrence (post transplant maintenance). We do not yet know whether these procedures are at risk for t-MN after allo-HSCT.

47.3.2 Donor Cell Leukemia

The cause of donor-derived hematological malignancies remains speculative. Two different mechanisms may be involved (Sala-Torra et al. 2006; Wiseman 2011):
  • Malignant clone transmitted from the donor to the recipient

  • Malignant transformation in the recipient

Malignant clones transferred to the recipient are mainly of lymphoid origin, observed in older donors, and may evolve into a lymphoid neoplasm in the immunosuppressed host. Myeloid clone transfer has not been reported. However, systematic NGS analysis might allow to detect myeloid clones transmitted to the recipient.

Malignant transformation in the donor cells is probably of multifactorial causes:
  • Premature aging of the donor hematopoiesis in the recipient, more inclined to develop a leukemia

  • Abnormal microenvironment

  • Genetic predisposition

  • Acquired environmental factors

47.3.3 Second Solid Neoplasms (SSN)

Little is known about pathogenesis of SSN after HSCT. An interaction between cytotoxic treatment, genetic predisposition, environmental factors, viral infections, GVHD, and its immunosuppression may play a role.

Two main types of SSN (Rizzo et al. 2009):
  • Radiation-related SSN
    • Proven for thyroid, breast, and brain cancers

    • Occur after a long latency (≥10 years after radiation)

    • Is dose related

  • GVHD/immunosuppression-related SSN
    • Squamous cell carcinoma of the skin and oropharyngeal area

    • Short latency

    • Can occur at different localizations

Association with viral infection
  • HCV infection associated with hepatocellular cancer

  • HPV associated with cervix cancer

47.4 Frequency and Risk Factors (See Table 47.1)

47.4.1 Remarks on SSN

The CI of second solid cancer is 2.2% at 10 years and 6.7% at 15 years (Rizzo et al. 2009).
Table 47.1

Frequency and risk factors

Type of SN


Risk factors


Great variability on the CI of t-MN after auto-HSCT

• In lymphoma patients between 1% at 2 years up to 24% at 43 months

• Lower CI for patients treated for breast cancer, germ cell tumor, and multiple myeloma

• Rare n-MN after HSCT for AID

CI depends mainly on pretransplant cytotoxic therapy and the use of TBI

CI of t-MN after allo-HSCT: 0.06-0.67% at 3 yearsa

• Quantity of pretransplant chemotherapy (see pathogenesis) and local radiotherapy

• Conditioning with TBI

• Older age at HSCT

t-MN are mainly observed after HSCT for lymphoma (NHL, HL)


Rare complication, with a CI <1% at 15 years

Possibly underestimated (difficulty to prove donor type of malignant cells)

Could represent up to 5% of post transplant leukemia “relapses”

No clear risk factor defined (too few, heterogeneous DCL)

Possible risk factorsb

• Malignant donor clone in the transplant

• G-CSF therapy

• In vivo T cell depletion

• Multiple transplantations



Breast, thyroid, bone, melanoma, connective tissue, brain, BCC

Breast cancer: 11% at 25 yearsc

Thyroid cancer: SIR 3.2 compared to general populationd

BCC: 6.5% at 20 yearse

Radiation before HSCT or TBI

Younger age at radiation

Longer follow-up

Light-skinned patients (BCC)

SSC of skin, oral cavity, and esophagus

SCC of the skin: 3.4 at 20 yearsf

Chronic GVHD

Prolonged GvHD therapy

IS including azathioprine

Male sex

Unrelated with radiation

At any time after HSCT

Hepatocellular carcinoma

Patients with HCV infection: CI 16% at 20 yearsg

HCV infection


Lung cancer

SIR 2.59 after BuCyh

Conditioning with Bu-Cy

Smoking prior to HCT

Cervix cancer


HPV reactivation



T cell depletion

BCC basal cell carcinoma of the skin, SSC squamous cell carcinoma, CI cumulative incidence, AID autoimmune disorders, SIR standardized incidence ratio

aYamasaki et al. (2017)

bEngel et al. (2018)

cFriedman et al. (2008)

dCohen et al. (2007)

eLeisenring et al. (2006)

fCurtis et al. (2005)

gPeffault de Latour et al. (2004)

hMajhail et al. (2011)

Increased risk for SSN after HSCT has been demonstrated from breast, thyroid, skin, liver, lung, oral cavity and pharynx, bone and connective tissues cancers and malignant melanoma.

An individual patient can present several subsequent different SSN after HSCT. Up to five different solid cancers have been observed in a patient treated with allo-HSCT.

Colorectal cancers have not been proven to be increased after HSCT. In non-transplanted cancer patients, second colorectal cancers are increased when treated with abdominal radiation (Henderson et al. 2012; Rapiti et al. 2008; van Eggermond et al. 2017).

So far there are few long-term data on SSN after RIC. A single-center study shows an increased rate of SSC compared to MAC during the first 10 years post-HSCT (Shimoni et al. 2013). There are not yet data on CI of SSN >10 years after RIC. SSN associated with TBI conditioning (breast, thyroid) might be lower after RIC than MAC.

47.5 Screening (Majhail et al. 2012) (See Also Chap.  21)

47.5.1 Therapy-Related Myeloid Neoplasms

Annual monitoring of full peripheral blood counts during the first 10 years after auto-HSCT (most t-MN occur within 10 years after HSCT)

In case of unexpected abnormalities (increased MCV, cytopenia, dysplasia in peripheral blood, monocytosis), extended analysis of blood and bone marrow (including cytogenetics and NGS)

47.5.2 Donor Cell Leukemia

Chimerism monitoring of the malignant cells in case of “relapse” or new hematological malignancy after allo-HSCT.

Whether search of an abnormal clone in the donor should be performed in case of donor origin of the malignancy remains controversial.

47.5.3 Second Solid Cancer (Socie and Rizzo 2012)

Lifelong screening for SSN is recommended after auto-HSCT and allo-HSCT.

General recommendations are:
  • During annual control, clinical screening, reviewing for possible symptoms of SSN.

  • Receive at least country-specific general population recommendations for cancer screening.

  • Be informed and counseled about the risk of SSN.

Specific recommendations are included in Table 47.2.
Table 47.2

Screening for secondary solid cancer after HSCT


All patients

Encouraged to

• Perform regularly genital/testicular and skin self-examination

• To avoid unprotected UV skin exposure

Skin examination by dermatologist every 1–2 years

Patients at risk

More frequent examination by dermatologist

• After first skin cancer

• Patients with chronic skin GvHD

Oral cavity and pharynx

All patients

Examination during annual control

Patients at risk

Annual control by specialist if severe oral and pharynx GvHD

Histology in case of suspicious lesion


All patients

Annual thyroid palpation to identify suspicious thyroid nodules

Patients at risk (patients at risk after TBI or local radiation)

Regular thyroid ultrasound

Fine needle aspiration in case of a suspicious nodule


All patients

Discuss breast self-examination with their physician

Patients at risk

Screening mammography every 1 to 2 years starts at the age of 25 or 8 years after radiation, whichever occurs later, but not later than age of 40 years


All patients

Screening with pap smears every 1–3 years in women older than 21 or within 3 years of initial sexual activity, whichever occurs earlier


All patients

Encouraged to avoid smoking and passive tobacco exposure

Patients at risk

Patients at risk (high-dose busulfan conditioning and smoking), chest CT


Patients at risk

Patients with known HCV infection should be assessed for fibrosis/cirrhosis of the liver 8–10 years after HSCT (biopsy; fibroscan)


All patients

Screening should start at age 50 in absence of a family history (first-degree relative diagnosed with colorectal cancer before age 60): annual fecal occult blood testing, sigmoidoscopy every 5 years, with fecal occult testing every 3 years, or colonoscopy every 10 years


All patients

No specific recommendations

47.6 Treatment




Same treatment than de novo myeloid neoplasms

Early donor search and rapid allo-HSCTa

Decision-making including consideration of cumulative toxicity due to previous HSCT


No standard treatment

Treatment depends on the nature of disease

Reported treatmentsb

• Retransplantation

• Conventional chemotherapy


• Palliation


Should be treated as de novo cancers of the same type

aFinke et al. (2016); Kroger et al. (2011); Metafuni et al. (2018)

bEngel et al. (2018)

47.7 Outcome




Generally very poor

Median survival of 6 m

Identical outcome than t-MN in general


Few data available

In most cases, mortality high and OS poor

In a small series of 47 DCL, median survival 32.8% months

Death mainly due to progression or relapse of DCL


Mainly dependent on the type of SSNa

Favorable outcome

• Thyroid, breast, prostate, melanoma, cervix

Intermediate outcome

• Oropharyngeal, colorectal, bladder, renal, ovarian, endometrial

Poor outcome

• Pancreas, lung, brain, hepatobiliary, esophageal

aEhrhardt et al. (2016); Tichelli et al. (2018)

Key Points

  • Three types of secondary neoplasia may occur after HSCT: therapy-related myeloid neoplasms (t-MN), mainly after autoHSCT; donor cell leukemia (DCL) after allo-HSCT; second solid neoplasia (SSN) after auto-HSCT and allo-HSCT.

  • Pretreatment or conditioning with radiation and/or chemotherapy including alkylating agents, anthracyclines, and topoisomerase II inhibitors is mainly responsible for t-MN.

  • DCL are extremely rare and are either transmitted from the donor or newly transformed in the host.

  • Non-squamous second solid cancers (breast, thyroid, brain, etc.) are strongly related to local radiation or TBI and occur with long delay after HSCT. Squamous cell carcinoma of the skin, the oral cavity, and the pharynx is related with chronic GVHD and can occur early after HSCT.

  • Outcome of t-MN is poor, and allogeneic HSCT represents the only curative treatment.

  • Outcome of SSN depends mainly on the type of second cancer; second solid cancer should be treated as a de novo cancer of the same type.


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Authors and Affiliations

  1. 1.Department of HematologyUniversity Hospital BaselBaselSwitzerland

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